1-methylcarbapenem derivatives

专利摘要:
The present invention provides a 1-methylcarbapenem compound having excellent antimicrobial activity, a pharmacologically acceptable ester derivative thereof, a pharmacologically acceptable salt thereof, a pharmaceutical composition (particularly an antimicrobial agent) containing them as an active ingredient, and a pharmaceutical composition thereof. For the use of these compounds, ester derivatives or salts, or for the prevention or treatment of diseases (especially bacterial infections) in which a pharmacologically effective amount of these compounds, ester derivatives or salts is administered to warm-blooded animals (especially humans). The 1-methylcarbapenem compound of the present invention is represented by the following general formula (I): [Formula I] [Wherein R 1 is a group represented by COOR 3 (R 3 is a hydrogen atom, a C1-C6 alkyl group, etc.), a group represented by the formula CONR 4 R 5 (R 4 and R 5 are hydrogen atoms, which may be substituted C 1 -C 6 alkyl group), cyano group, group represented by the formula CH 2 OR 6 (R 6 is hydrogen atom, C 1 -C 6 alkyl group, etc.) or group represented by the formula CH 2 NR 7 R 8 (R 7 is hydrogen atom , A C1-C6 alkyl group and the like, R 8 is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkanoyl group, a C1-C6 alkoxycarbonyl group or the like); R 2 is a hydrogen atom or a C1-C6 alkyl group; n is 1, 2 or 3; X represents a sulfur atom or an oxygen atom.
公开号:KR20030048151A
申请号:KR10-2003-7006664
申请日:2001-11-14
公开日:2003-06-18
发明作者:고바야시요시유끼；시노주까쯔요시；간노오사무
申请人:상꾜 가부시키가이샤；
IPC主号:

专利说明:

1-methylcarbapenem derivative {1-METHYLCARBAPENEM DERIVATIVES}
[2] There is a need for the development of carbapenem derivatives having strong and balanced antimicrobial activity against a wide range of pathogenic bacteria. Japanese Patent Laid-Open No. 8-53453 discloses a 1-methylcarbapenem compound having a structure similar to the present invention.
[3] The inventors of the present invention have conducted various studies on 1-methylcarbapenem compounds over a long period of time. As a result, the compound (I) of the present invention has stronger antibacterial activity than conventional 1-methylcarbapenem derivatives, and bacterial infections, especially respiration. The present invention has been found to be effective as an antimicrobial agent for treating or preventing (especially treating) infectious diseases on machines.
[1] The present invention provides a 1-methylcarbapenem compound having excellent antimicrobial activity, a pharmacologically acceptable ester derivative or salt thereof, a pharmaceutical composition (particularly an antimicrobial agent) containing them as an active ingredient, these compounds for preparing the pharmaceutical composition, an ester The use of derivatives or salts, or methods of preventing and treating diseases (particularly bacterial infections) in which pharmacologically effective amounts of these compounds, ester derivatives or salts are administered to warm-blooded animals (especially humans).
[4] The present invention relates to a 1-methylcarbapenem compound represented by formula (I) or a pharmacologically acceptable salt or ester derivative thereof:
[5]
[6] Wherein, R ¹ is
[7] (1) the group represented by the formula COOR ³
[8] [Wherein, R ³ represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group],
[9] (2) the group represented by the formula CONR ⁴ R ⁵
[10] [Wherein, R ⁴ and R ⁵ are the same or different, a hydrogen atom, a C1-C6 alkyl group (which may be substituted with the same or different 1 or 2 groups selected from Substituent Group A below), a C3-C6 cycloalkyl group, A 3-6 membered heterocyclic group or a C6-C10 aryl group (which may be substituted with the same or different 1 or 2 groups selected from Substituent Group B below), or integrally with the nitrogen atom to which they are bonded Group which forms a six-membered nitrogen-containing heterocycle (may be substituted with the same or different 1 or 2 groups selected from Substituent Group B below),
[11] (3) cyano groups,
[12] (4) groups represented by the formula CH ₂ OR ⁶
[13] [Wherein R ⁶ is a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group] or
[14] (5) group represented by the formula CH ₂ NR ⁷ R ⁸
[15] [In formula, R <^7> represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, R <^8> represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, C6- C10 arylcarbonyl group (which may be substituted with the same or different 1 or 2 groups selected from Substituent Group B), C1-C6 alkoxycarbonyl group, 5 or 6 membered aromatic heterocyclic carbonyl group, C1-C6 alkylsulfonyl group or C6- C10 arylsulfonyl group, or R ⁷ and R ⁸ are integral with the nitrogen atom to which they are bonded to represent a succinimide group (which may be condensed with a phenyl group);
[16] Indicates,
[17] R ² represents a hydrogen atom or a C1-C6 alkyl group,
[18] n represents 1, 2 or 3,
[19] X represents a sulfur atom or an oxygen atom.
[20] Substituent group A may be a hydroxyl group, an amino group (which may be substituted with one or two C1-C6 alkyl groups), a carbamoyl group (the amino portion may be substituted with one or two C1-C6 alkyl groups), a carboxyl group, a cyano group , And a group containing a C1-C6 alkoxy group,
[21] Substituent group B includes a hydroxy C1-C4 alkyl group, an amino C1-C4 alkyl group (the amino moiety may be substituted with 1 or 2 C1-C6 alkyl groups), a carbamoyl group (the amino moiety is 1 or 2 C1-C6) Group which may be substituted with an alkyl group), a carboxyl group, a hydroxyl group, an amino group (which may be substituted with one or two C1-C6 alkyl groups), a C1-C6 alkoxy group, and a C1-C6 alkyl group.
[22] In the above, "C1-C6 alkyl group" in the definition of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , substituent group A and substituent group B is a straight chain having 1 to 6 carbon atoms. Or a branched saturated hydrocarbon group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl group and the like. In R <^2> , R <^3> , R <^6> , R <^7> , R <^8> , substituent group A, and substituent group B, Preferably it is a C1-C3 alkyl group, Especially preferably, it is a methyl group. In R <^4> , Preferably, it is a C1-C3 alkyl group, Especially preferably, it is a methyl or isopropyl group. In R <^5> , it is preferably a C2-C6 alkyl group, Most preferably, it is a 1-methyl- 2-methylpropyl group.
[23] "C3-C6 cycloalkyl group" in the definition of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represents a C 3 to C 6 cyclic hydrocarbon group, for example, cyclopropyl, cyclobutyl, Cyclopentyl and cyclohexyl group are mentioned, Preferably it is a cyclopropyl group.
[24] The "3- to 6-membered heterocyclic group" in the definition of R ⁴ and R ⁵ is a saturated heterocyclic group containing one or two oxygen, nitrogen and sulfur atoms, for example, aziridinyl, azetidinyl, pyrroli Dinyne, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, morpholinyl, piperazinyl, thiomorpholinyl, and the like. It is a 6-membered nitrogen-containing heterocyclic group, More preferably, it is an azetidinyl, a pyrrolidinyl, or a piperidinyl group.
[25] Examples of the "C6-C10 aryl group" in the definition of R ⁴ and R ⁵ and the "C6-C10 aryl" portion of the "C6-C10 arylcarbonyl group" and the "arylsulfonyl group" in the definition of R ⁸ include For example, a phenyl, indenyl, naphthyl group is mentioned, Preferably it is a phenyl group.
[26] In the definition of R ⁴ and R ⁵ , the "nitrogen-containing heterocycle" of the group "integrating with the nitrogen atom to which they are bonded to form a 3- to 6-membered nitrogen-containing heterocyclic group" contains one or two nitrogen atoms. And saturated heterocyclic groups which may contain oxygen or sulfur atoms include, for example, aziridino, azetidino, pyrrolidino, piperidino, morpholino, piperazino, and thiomorpholino groups. Preferably it is a 4-6 membered nitrogen-containing heterocycle, More preferably, it is an azetidino, a piperazino, a morpholino, or a thiomorpholino group.
[27] "C1-C6 alkanoyl group" in the definition of R ^{8 represents} a linear or branched alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, Valeryl, isovaleryl, pivaloyl, and hexanoyl groups are mentioned, Preferably it is a C1-C3 alkanoyl group, Most preferably, it is an acetyl group.
[28] The "C1-C6 alkoxy" moiety of the "C1-C6 alkoxycarbonyl group" in the definition of "C1-C6 alkoxy group" in the definition of R ⁸ and a substituent group is a linear or branched alkoxy having 1 to 6 carbon atoms. Group, for example, there may be mentioned methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and hexyloxy groups, preferably a C1-C3 alkoxy group, most preferably a methoxy group .
[29] The "5- or 6-membered aromatic heterocycle" portion of the "5- or 6-membered aromatic heterocyclic carbonyl group" in the definition of R ⁸ is an aromatic heterocyclic group containing 1 to 3 oxygen, nitrogen and sulfur atoms, for example Pyrrole, imidazole, thiazole, oxazole, isoxazole, furan, thiophene, triazole, thiadiazole, pyridine, pyrimidine, pyridazine, triazine and the like. Preferably furan, thiophene or pyridine.
[30] Examples of the "hydroxy C1-C4 alkyl group" in the substituent group B include a hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, preferably a hydroxy C1-C2 alkyl group, Most preferably, it is a hydroxymethyl group.
[31] Examples of the "amino C1-C4 alkyl group" in the substituent group B include aminomethyl, aminoethyl, aminopropyl, and aminobutyl groups, preferably aminoC1-C2 alkyl groups, and most preferably aminomethyl groups. to be.
[32] Substituent group A is preferably a group containing a hydroxyl group, an amino group (which may be substituted with 1 or 2 C1-C3 alkyl groups), a carbamoyl group, and most preferably an amino group (1 or 2 methyl or ethyl groups May be substituted).
[33] Substituent group B is preferably a hydroxy C1-C4 alkyl group, an amino C1-C4 alkyl group (the amino moiety may be substituted with 1 or 2 C1-C3 alkyl groups), a carbamoyl group (the amino moiety is 1 or 2 C1-C3 alkyl group), hydroxyl group, amino group (may be substituted with one or two C1-C3 alkyl group), more preferably hydroxymethyl group, aminomethyl group (amino part is 1 Or may be substituted with two methyl or ethyl groups), carbamoyl group (amino portion may be substituted with one or two methyl or ethyl groups), hydroxyl group, amino group (may be substituted with one or two methyl or ethyl groups) ), And even more preferably, it is an aminomethyl group or an amino group.
[34] "Pharmaceutically acceptable ester derivative" of compound (I) is a compound which is cleaved by chemical or biological methods such as hydrolysis in a human or animal body to produce the original compound (I) or a salt thereof. The ester derivative in which the carboxyl group or hydroxyl group of (I) is protected, and whether it is such a derivative is administered orally or intravenously to experimental animals, such as a rat and a mouse, and the body fluid of the following animal is investigated, It can determine by the original compound (I) or its salt which can be detected.
[35] As a protecting group which forms an ester derivative in a carboxyl group, it is C1-C10 alkyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyl C1-C4 alkyl group, C2-C10 alkanoyloxy C1-C4 alkyl group, C1-C10, for example. Alkoxycarbonyloxy C1-C4 alkyl group, phenyl group (This phenyl group may be substituted with one or two groups selected from halogen atom, C1-C4 alkyl group, C1-C4 alkoxy group, methylenedioxy group, C1-C6 alkanoyloxy group. Yes), a C1-C10 alkanoyloxybenzyl group, a phthalidyl group, a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group, etc. are mentioned.
[36] As a protecting group which forms an ester derivative in a hydroxyl group, C1-C10 alkanoyl group, C6-C10 arylcarbonyl group, C1-C10 alkoxycarbonyl group, an aminoacyl group, etc. are mentioned.
[37] As said "C1-C10 alkyl group", methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, hexyl, 2-hexyl, 3-hexyl, isohexyl, heptyl, octyl, nonyl, decyl group, etc. are mentioned, Preferably it is a C1-C6 alkyl group, More preferably, it is a C2-C4 alkyl group, Most preferably, it is an ethyl group.
[38] Examples of the "C3-C6 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, and are preferably cyclopentyl or cyclohexyl groups.
[39] As a "C3-C6 cycloalkyl C1-C4 alkyl group", for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentyl Ethyl, cyclopentylpropyl, cyclohexylmethyl, a cyclohexylethyl group, etc. are mentioned, Preferably it is a cyclopropylmethyl group.
[40] As a "C2-C10 alkanoyloxy C1-C4 alkyl group", for example, acetoxymethyl, 1- (acetoxy) ethyl, 1- (acetoxy) propyl, 1- (acetoxy) butyl, propionyloxymethyl, 1- (propionyloxy) ethyl, isopropionyloxymethyl, 1- (isopropionyloxy) ethyl, butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobuty Ryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, valeryloxymethyl, 1- (valeryloxy) ethyl, isovaleryloxymethyl, 1- (isovaleryloxy) ethyl , Hexanoyloxymethyl, 1- (hexanoyloxy) ethyl, octanoyloxymethyl, 1- (octanoyloxy) ethyl, decanoyloxymethyl, cyclopentylcarbonyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl , Cyclohexylcarbonyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl group, and the like, and preferably C2-C6 alkanoyloxymethyl or 1- (C2-C6 alkano An oxy) group.
[41] As "C1-C10 alkoxycarbonyloxy C1-C4 alkyl group", for example, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyl Oxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) butyl, propoxycarbonyloxymethyl, 1- (propoxycarbonyloxy) ethyl, isopropoxycarbonyloxy Methyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy) ethyl, s-butoxycarbonyloxymethyl, 1- (s-butoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy) ethyl, pentyloxycarbonyloxymethyl , 1- (pentyloxycarbonyloxy) ethyl, (1-methylbutyloxycarbonyloxy) methyl, 1- (1-methylbutyloxycarbonyloxy) ethyl, (2-methylbutyloxycarbon Carbonyloxy) methyl, 1- (2-methylbutyloxycarbonyloxy) ethyl, (3-methylbutyloxycarbonyloxy) methyl, 1- (3-methylbutyloxycarbonyloxy) ethyl, (1-ethylpropyl Oxycarbonyloxy) methyl, 1- (1-ethylpropyloxycarbonyloxy) ethyl, hexyloxycarbonyloxymethyl, 1- (hexyloxycarbonyloxy) ethyl, (1-methylpentyloxycarbonyloxy ) Methyl, 1- (1-methylpentyloxycarbonyloxy) ethyl, octyloxycarbonyloxymethyl, 1- (octyloxycarbonyloxy) ethyl, decyloxycarbonyloxymethyl, 1- (decyloxycarbono And alkyloxy) ethyl, cyclopentylcarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexylcarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) ethyl group, and the like. Preferably a C1-C6 alkoxycarbonyloxymethyl or 1- (C1-C6 alkoxycarbonyloxy) ethyl group.
[42] As the "substitutable phenyl group", for example, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-meth Methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl group, etc. are mentioned, Preferably it is an unsubstituted phenyl group.
[43] As a "C2-C10 alkanoyloxybenzyl group", for example, 2-acetoxybenzyl, 3-acetoxybenzyl, 4-acetoxybenzyl, 3-propionyloxybenzyl, 4-propionyloxybenzyl, 4-buty Ryloxybenzyl, 4-valeryloxybenzyl, 4-hexanoyloxybenzyl, 4-octanoyloxybenzyl, 4-decanoyloxybenzyl group, and the like, and preferably 3- or 4- (C2-C4 Alkanoyloxy) benzyl group.
[44] Examples of the "C1-C10 alkanoyl group" include formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, and decanoyl groups, and preferably C2-C6 alkanoyl groups to be.
[45] As "C6-C10 arylcarbonyl group", a benzoyl, 1-naphthoyl, 2-naphthoyl group is mentioned, for example, Preferably it is a benzoyl group.
[46] As a "C1-C10 alkoxycarbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxy Carbonyl group is mentioned, Preferably it is a C2-C6 alkoxycarbonyl group.
[47] As an "aminoacyl group", amino acid groups, such as glycyl, alanyl, (beta) -alanyl, leuyl, isoleyl, phenylalanyl, histidyl, asparagyl, prolyl, lysyl, etc. are mentioned, for example. And preferably a glycyl group.
[48] The compound (I) and pharmacologically acceptable ester thereof of the present invention can form a "pharmacologically acceptable salt" as needed.
[49] The term &quot; pharmacologically acceptable salt thereof &quot; means that the compound (I) of the present invention can be used as a salt, and the salt thereof, and as such salts, alkali metal salts such as sodium salts, potassium salts, lithium salts, calcium Salts, metal salts such as alkaline earth metal salts such as magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; Inorganic salts such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, tri Ethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethyl Amine salts such as ammonium salts and organic salts such as tris (hydroxymethyl) aminomethane salt; Inorganic acid salts such as hydrofluoric acid salts such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and iodide salts, nitrate salts, perchlorate salts, sulfate salts and phosphate salts; Lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, arylsulfonates such as benzenesulfonate, p-toluenesulfonate, acetic acid, malic acid, fumaric acid, succinate, citrate, tartaric acid Organic acid salts such as salts, oxalates and maleates; And amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and asparagine salts.
[50] Compound (I) of the present invention, pharmacologically acceptable salts and ester derivatives thereof include hydrates or solvates thereof.
[51] In the compound represented by the said general formula (I), the following compound is preferable.
[52] (1) About R ¹
[53] (1-1) A compound in which R ¹ is a group represented by the group represented by the formula CONR ⁴ R ⁵ , a cyano group, or the formula CH ₂ NR ⁷ R ⁸ .
[54] (1-2) A compound in which R ¹ is a group represented by the formula CONR ⁴ R ⁵ or a group represented by the formula CH ₂ NR ⁷ R ⁸ .
[55] (1-3) A compound in which R ¹ is a group represented by the formula CONR ⁴ R ⁵ .
[56] (2) About R ²
[57] (2-1) A compound in which R ² is a hydrogen atom or a C1-C3 alkyl group.
[58] (2-2) A compound in which R ² is a hydrogen atom.
[59] (3) About R ³
[60] (3-1) a compound in which R ³ is a hydrogen atom or a C1-C3 alkyl group,
[61] (3-2) A compound in which R ³ is a hydrogen atom, a methyl group or an ethyl group.
[62] (4) About R ⁴
[63] (4-1) A compound in which R ⁴ is a hydrogen atom or a C1-C3 alkyl group.
[64] (4-2) A compound in which R ⁴ is a hydrogen atom, methyl or isopropyl group.
[65] (5) About R ⁵
[66] (5-1) A compound in which R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted by the same or different 1 or 2 groups selected from substituent group A), or a 4-6 membered nitrogen heterocyclic group.
[67] (5-2) A compound in which R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted with the same or different 1 or 2 groups selected from substituent group A), azetidinyl, pyrrolidinyl or piperidinyl group.
[68] (6) about R ⁴ and R ⁵
[69] (6-1) R ⁴ and R ⁵ are to be integrated with the nitrogen atom to which they are bonded to form a 4 to 6 membered nitrogen-containing heterocycle (substituted with the same or different 1 or 2 groups selected from substituent group B) May be) phosphorus compounds.
[70] (6-2) R ⁴ and R ⁵ are united with the nitrogen atom to which they are bonded to an azetidino, piperazino, morpholino or thiomorpholino group (these groups being the same or different selected from substituent group B) May be substituted with 1 or 2 groups).
[71] (7) About R ⁶
[72] (7-1) A compound in which R ⁶ is a hydrogen atom or a C1-C3 alkyl group.
[73] (7-2) A compound in which R ⁶ is a hydrogen atom.
[74] (8) About R ⁷
[75] (8-1) A compound in which R ⁷ is a hydrogen atom or a C1-C3 alkyl group.
[76] (8-2) A compound in which R ⁷ is a hydrogen atom or a methyl group.
[77] (8-3) A compound in which R ⁷ is a hydrogen atom.
[78] (9) About R ⁸
[79] (9-1) R ⁸ is a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkanoyl group, a benzoyl group (may be substituted with the same or different 1 or 2 groups selected from substituent group B), C1-C3 alkoxy A compound which is a carbonyl group, a thiophencarbonyl group, a furancarbonyl group, or a pyridine carbonyl group.
[80] (9-2) R ⁸ is a hydrogen atom, a benzoyl group (may be substituted with the same or different 1 or 2 groups selected from substituent group B), thiophene-2-carbonyl group, furan-2-carbonyl group or pyridine-3 A compound which is a carbonyl group.
[81] (10) n
[82] (10-1) A compound in which n is 1.
[83] (11) About X
[84] (11-1) A compound in which X is an oxygen atom.
[85] The compound obtained by arbitrarily combining two or more preferable substituents in the above is more preferable, For example, the following compound is mentioned.
[86] (12) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ is a hydrogen atom or a C1-C3 alkyl group, R ⁵ is a hydrogen atom, a C1-C6 alkyl group (the same as selected from substituent group A or Or a 4-6 membered nitrogen-containing heterocyclic group), wherein R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom.
[87] (13) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ is a hydrogen atom, a methyl or an isopropyl group, R ⁵ is a hydrogen atom, a C1-C6 alkyl group (the same selected from substituent group A) Or an azetidinyl, pyrrolidinyl or piperidinyl group), n is 1, and X is an oxygen atom or a sulfur atom.
[88] (14) a group in which R ¹ is represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are united with the nitrogen atom to which they are bonded to form a 4- to 6-membered nitrogen-containing heterocycle (substituent group B And R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom.
[89] (15) a group in which R ¹ is represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are united with the nitrogen atom to which they are bonded to an azetidino, piperazino, morpholino or thiomorpholino group) Wherein these groups may be substituted with the same or different 1 or 2 groups selected from substituent group B), R ² is a hydrogen atom, n is 1 and X is an oxygen atom or a sulfur atom.
[90] (16) A compound in which R ¹ is a cyano group, R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom.
[91] (17) a group in which R ¹ is represented by the formula CH ₂ NR ⁷ R ⁸ (wherein R ⁷ is a hydrogen atom or a C1-3 alkyl group, R ⁸ is a hydrogen atom, a C1-C3 alkyl group, a C1-3 alkanoyl group , A benzoyl group (which may be substituted with the same or different 1 or 2 groups selected from substituent group B), a C1-C3 alkoxycarbonyl group, a thiophencarbonyl group, a furancarbonyl group or a pyridinecarbonyl group, R ² is a hydrogen atom, n is 1 and X is an oxygen atom or a sulfur atom.
[92] (18) R ¹ is a group represented by the formula CH ₂ NR ⁷ R ⁸ (wherein R ⁷ is a hydrogen atom or a methyl group, and R ⁸ is a hydrogen atom, a benzoyl group (the same or different 1 or selected from substituent group B) Two groups), thiophene-2-carbonyl group, furan-2-carbonyl group or pyridine-3-carbonyl group, R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom compound.
[93] The compound (I) of this invention can be illustrated concretely in Tables 1-5. In addition, the compound (I) of this invention is not limited to these exemplary compounds.
[94] In Tables 1 to 5, Me is methyl group, Et is ethyl group, Pr is propyl group, iPr is isopropyl group, Bu is butyl group, Pen is pentyl group, Hex is hexyl group, cPr is cyclopropyl group, cBu is cyclo A butyl group, cPen is a cyclopentyl group, cHex is a cyclohexyl group, Azt is an azetidinyl group, Pyr is a pyrrolidinyl group, Pip is a piperidinyl group, Ph is a phenyl group. Position indicates the binding position of the sulfur atom.
[95]
[96]
[97]
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[105]
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[108]
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[124]
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[134]
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[152]
[153]
[154]
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[158]
[159]
[160]
[161]
[162] In the compounds exemplified in the table above, preferred is
[163]
[164]
[165]
[166]
[167] Most preferred are the following compounds:
[168] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[169] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hide Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[170] (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[171] (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[172] (1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[173] (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[174] (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[175] (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[176] (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[177] (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[178] (1R, 5S, 6S) -2- {1- [4- (4-aminoazetidino) carbonyl-1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[179] (1R, 5S, 6S) -2- {1- [4- (4-aminoazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [ (1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[180] (1R, 5S, 6S) -2- {1- [4- (4-hydroxyazetidino) carbonyl-1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[181] (1R, 5S, 6S) -2- {1- [4- (4-hydroxyazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [(1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[182] (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[183] (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[184] (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[185] (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[186] (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[187] (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[188] (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[189] (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[190] (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[191] (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[192] (1R, 5S, 6S) -2- {1- [4- (piperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[193] (1R, 5S, 6S) -2- {1- [4- (piperazin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[194] (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[195] (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[196] (1R, 5S, 6S) -2- {1- [4-((1S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[197] (1R, 5S, 6S) -2- {1- [4-((1S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-oxazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[198] (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[199] (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-oxazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[200] (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[201] (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-oxazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[202] (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[203] (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[204] (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[205] (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[206] (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[207] (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[208] (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[209] (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[210] (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[211] (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[212] Embodiment
[213] The 1-methylcarbapenem derivative represented by the general formula (I) of the present invention can be produced by the methods described in the following A and B methods.
[214] [A law]
[215] The method A is a method for producing compound (I) by reacting a carbapenem compound represented by formula (II) with a mercapto compound represented by formula (III), followed by deprotection reaction.
[216]
[217] Wherein R, R ^1, R ^2, X and n are as defined above, L ¹ represents an elimination, P ¹ represents a protecting group of a carboxyl group, R ¹ p represents an R ¹ which may have a protective group.
[218] As the "protecting group of carboxyl group" of P ¹ , for example, a benzyl group which may have a substituent such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl (the substituent may be nitro, methyl, chlorine or meth). Oxy); Benzhydryl group; An allyl group which may have a substituent on two such as allyl, 2-chloroallyl or 2-methylallyl (the substituent being chlorine or methyl); The group which forms the pharmacologically acceptable ester mentioned above is mentioned, Preferably it is the benzyl group (In particular, 4-nitrobenzyl group) which may have a substituent.
[219] The "leaving group" of L ¹ is, for example, a group having the formula -OR ¹¹ or -S (O) R ¹² .
[220] R ¹¹ is a C1-C4 alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl group; C6-C10 arylsulfonyl groups such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl; DiC1-C6 alkylphosphoryl groups such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl, dipentylphosphoryl or dihexylphosphoryl; Or a diC6-C10 arylphosphoryl group such as diphenylphosphoryl or ditolylphosphoryl, preferably a diphenylphosphoryl group.
[221] R ¹² is, for example, a C1-C4 alkyl group such as methyl, ethyl, propyl or isopropyl; Halogeno C1-C4 alkyl groups such as fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl; 2-acetylaminoethyl group; 2-acetylamino vinyl group; C6-C10 aryl group such as phenyl or naphthyl which may have a substituent (this aryl group may have the same or different 1 to 3 substituents, the substituent being a halogen atom such as fluorine, chlorine, bromine; methyl, ethyl, C1-C4 alkyl groups such as propyl, isopropyl; C1-C4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy; such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl ( C1-C4 alkoxy) carbonyl group; carbamoyl, mono or di (C1-C4 alkyl) carbamoyl group; nitro group; hydroxyl group or cyano group) or pyridyl or pyrimidinyl which may have a substituent Heteroaryl group which may have one or two nitrogen atoms (The heteroaryl group may have the same or different 1 to 3 substituents, and the substituents are halo such as fluorine, chlorine and bromine. Atoms; C1-C4 alkyl groups such as methyl, ethyl, propyl, isopropyl; C1-C4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy; methoxycarbonyl, ethoxycarbonyl, t-part (C1-C4 alkoxy) carbonyl groups such as oxycarbonyl; carbamoyl, mono or di (C1-C4 alkyl) carbamoyl groups; nitro groups; hydroxyl groups or cyano groups).
[222] As the "protecting group of a hydroxyl group" contained in R ¹ p, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, or 4-methoxybenzyloxycarbonyl may be substituted. Benzyloxycarbonyl group (the substituent being nitro, methyl, chlorine or methoxy); An allyloxycarbonyl group in which a second position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl may be substituted (the substituent is chlorine or methyl); Tri (C1-C4 alkyl) silyl groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl; The group which forms the pharmacologically acceptable ester mentioned above is mentioned, Preferably it is a tri (C1-C4 alkyl) silyl group (especially t-butyl dimethyl silyl group).
[223] As the "protecting group of an amino group" contained in R ¹ p, for example, an allyloxycarbonyl group in which a second position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl may be substituted (the The substituent is chlorine or methyl); Benzyloxycarbonyl groups which may be substituted, such as benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl (the substituents are Methyl, methoxy, chlorine or nitro), preferably an allyloxycarbonyl group or 4-nitrobenzyloxycarbonyl group, and more preferably 4-nitrobenzyloxycarbonyl group.
[224] Roneun "protecting group of a carboxyl group" included in R ¹ p, can be used the protective group used as the above-mentioned P ^1.
[225] In the present method, a compound having the formula (II) is reacted with a compound having the formula (III) in the presence of a base to produce a compound having the formula (IV) (Step A1), and then a protecting group is reacted to remove the compound ( (I) process (2) of manufacturing (I). When L ¹ is a group represented by the formula -OR ¹¹ , the compound having formula (II) as a starting material is prepared by the method described in DH Shih et al., Heterocycles 21, 29 (1984) or a method similar thereto. do. In the case where L ¹ is a group represented by the formula -S (O) R ¹² , the raw material compound (II) is produced by the method described in JP-A-62-30781 or a method equivalent thereto. Hereinafter, each process is demonstrated.
[226] (Step A1 process)
[227] The first A1 step is a step of producing a compound having the general formula (IV), and is accomplished by reacting a compound (II) and a mercaptan derivative having the general formula (III) in the presence of a base in an inert solvent.
[228] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Esters such as ethyl acetate and methyl acetate; Ethers such as diethyl ether, tetrahydrofuran, dioxane, and the like, preferably acetonitrile, N, N-dimethylformamide or tetrahydrofuran, and particularly preferably acetonitrile.
[229] The base to be used is preferably organic amines such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine or inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and preferably organic amines. (Especially diisopropylethylamine).
[230] Reaction temperature is normally performed at -20 degreeC-40 degreeC (preferably -10 degreeC-20 degreeC). The reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours).
[231] After completion of the reaction, the target compound (IV) of the present step is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary. It is also possible to move to the next step without isolating the target compound (IV) as desired.
[232] (Step A2 process)
[233] Step A2 is a step of converting compound (IV) to compound (I), which is accomplished by removing the protecting group contained in compound (IV).
[234] Removal of protecting groups depends on the type of protecting group, but is generally used in the field of organic synthetic chemistry (eg, TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc.). Method as described in 1991).
[235] (1) When the protecting group is a benzyl group, a benzhydryl group which may have a substituent, or a benzyloxycarbonyl group which may have a substituent, these protecting groups can be removed by reacting hydrogen in the presence of a catalytic reduction catalyst in a solvent.
[236] As a catalytic reduction catalyst used, a palladium-carbon catalyst, a platinum catalyst, a rhodium-carbon catalyst etc. are mentioned, for example, Preferably it is a palladium-carbon catalyst.
[237] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and preferably alcohols such as methanol and ethanol; Ethers, such as tetrahydrofuran and dioxane, and a mixed solvent of these organic solvents and water, Preferably it is a mixed solvent of tetrahydrofuran and water.
[238] The reaction temperature is usually 0 ° C. to 50 ° C. (preferably 10 ° C. to 40 ° C.), and the reaction time is usually 5 minutes to 12 hours (preferably 30 minutes to 4 hours) depending on the type of raw material compound and catalyst. .
[239] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent, after filtering insoluble materials, such as a catalyst, from a reaction mixture. The obtained compound can be purified by conventional methods, for example, by recrystallization, preparative thin layer chromatography, column chromatography and the like, if necessary.
[240] (2) When the protecting group is an allyl group which may be substituted or an allyloxycarbonyl group which may be substituted, these protecting groups may be substituted with tri C1-C6 alkyl tin hydrides and organic carboxylic acid alkali metal salts in the presence of palladium in the solvent. Can be removed by action. You may add the organic base or organic substance which captures an allyl group.
[241] As palladium, bis (triphenyl phosphine) palladium chloride or tetrakis (triphenyl phosphine) palladium is preferable. As trialkyl tin hydrides, tributyl tin hydride is preferable. As organic carboxylic acid alkali metal salts, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate is preferable. As an organic base which captures an allyl group, morpholine is preferable and as an organic substance which captures an allyl group, dimethone is preferable.
[242] Preferable combinations as a deprotecting agent are a combination consisting of bis (triphenylphosphine) palladium chloride and tributyltin hydride or a combination consisting of tetrakis (triphenylphosphine) palladium and potassium 2-ethylhexanoate.
[243] The solvent to be used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; Esters such as ethyl acetate; Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Nitriles such as acetonitrile; Alcohols such as methanol, ethanol or propanol; Water or a mixed solvent thereof, and is preferably methylene chloride, ethyl acetate or a mixed solvent thereof.
[244] Although reaction temperature does not have a restriction | limiting in particular, Usually, it carries out at -20 degreeC-100 degreeC (preferably 0 degreeC-60 degreeC), and reaction time is 30 minutes-48 hours (preferably 30 minutes-12 hours) normally.
[245] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent, after filtering insoluble matter precipitated from the reaction mixture. The obtained compound can be purified by conventional methods, for example, by recrystallization, preparative thin layer chromatography, column chromatography and the like, if necessary.
[246] (3) When the protecting group is a silyl protecting group, the protecting group is treated with a compound which produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, potassium fluoride in acetic acid, or acetic acid, It can be removed by treatment with an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid.
[247] Moreover, when removing with a fluorine anion, it may advance on the conditions by which reaction was alleviated by adding organic acids, such as formic acid, acetic acid, and propionic acid.
[248] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Preferably, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; Nitriles such as acetonitrile and isobutyronitrile; Water; Organic acids such as acetic acid and these mixed solvents.
[249] The reaction temperature is usually 0 ° C to 100 ° C (preferably 10 ° C to 30 ° C), and the reaction time is not particularly limited, but is usually 1 to 24 hours (preferably 1 to 4 hours).
[250] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[251] (4) When the protecting group is a group which forms a pharmacologically acceptable ester in the carboxyl group or the hydroxyl group, these protecting groups are removed by acting a hydrolase in water or a mixed solvent of water and an organic solvent.
[252] As an organic solvent mixed with water, ethers or alcohols mixed with water such as tetrahydrofuran, dioxane, methanol, ethanol and propanol are preferable.
[253] It is preferable to add alkali metal salts such as sodium phosphate, sodium acetate, and sodium hydrogen carbonate to water or a mixed solvent of water and an organic solvent, or to maintain a pH of 6 to 8 as a pH buffer such as phosphate buffer.
[254] The hydrolase is not particularly limited as long as it can hydrolyze the ester bond, and examples thereof include pork liver-derived esterases.
[255] The reaction temperature is usually 10 minutes to 8 hours (preferably 30 minutes to 2 hours), and the reaction temperature is 10 to 50 ° C (preferably 30 to 40 ° C).
[256] After completion of the reaction, the target compound can be isolated and purified by ion exchange chromatography, reverse phase column chromatography, reprecipitation, recrystallization or the like.
[257] When compound (IV) contains two or more types of protecting groups, target compound (I) can be obtained by combining said deprotection reaction in order. In addition, when a pharmacologically acceptable ester derivative of compound (I) is desired, it is not necessary to remove the group forming the pharmacologically acceptable ester as a protecting group.
[258] Compound (I) thus obtained can be converted into a pharmacologically acceptable salt or ester derivative according to methods or techniques known in the art of pharmaceutical chemistry, in particular β-lactam antibiotics.
[259] The pharmacologically acceptable ester derivative in the carboxyl group of compound (I) can be prepared by reacting compound (I) with a halide corresponding to the desired ester residue in the presence of a base in a solvent.
[260] The halides to be used include chlorides, bromide or iodide, preferably iodide. When chloride or bromide is used, the reaction can be promoted by adding a catalytic amount of sodium iodide to the reaction solution.
[261] Examples of the base used may include organic amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and pyridine; And alkali metal carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, and are preferably organic amines (particularly 4-dimethylaminopyridine).
[262] The solvent to be used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. For example, nitriles such as acetonitrile; Amides such as N, N-dimethylformamide; Halogenated hydrocarbons, such as methylene chloride, are mentioned, Preferably they are amides (especially dimethylacetamide) or nitriles (especially acetonitrile).
[263] The reaction temperature is usually -20 to 50 ° C (preferably -10 to 20 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[264] Moreover, what was previously isolated as a salt by making compound (I) react with a base can also be made to react with halides as mentioned above.
[265] On the other hand, it can also be produced by reacting an alcohol corresponding to a desired ester residue in the presence of a condensing agent and a base.
[266] As a condensing agent, Mitsunobu reagent like diethyl azodicarboxylate; Phosphoric acid ester-based condensing agents such as diphenylphosphoryl azide; Carbodiimide-based condensing agents such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; Onium-based condensing agents such as iodide-2-chloro-1-methylpyridinium; and the like.
[267] Examples of the base used may include organic amines such as triethylamine, tributylamine, diisopropylethylamine and 4-dimethylaminopyridine.
[268] Other additives include triphenylphosphine, phosphines such as tributylphosphine, and alcohols for forming active esters such as 1-hydroxybenztriazole.
[269] As a solvent, Halogenated hydrocarbons, such as methylene chloride and dichloroethane; Amides such as N, N-dimethylformamide; Nitriles such as acetonitrile; And ethers such as tetrahydrofuran.
[270] As a preferable combination of these, diethyl azodicarboxylate and triphenyl phosphine; Iodide-2-chloro-1-methylpyridinium and tributylamine or triethylamine; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine or 1-hydroxybenztriazole.
[271] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[272] [B Act]
[273] Method B is a method for producing compound (III) used as starting material in method A.
[274]
[275] In the above, R ¹ p, R ² , X and n are as defined above. P ² represents a protecting group of a carboxyl group and is, for example, a C1-C4 alkyl group such as methyl, ethyl, propyl or butyl group; The benzyl group which may be substituted, such as benzyl and 4-methoxybenzyl, is mentioned, Preferably it is a C1-C4 alkyl group (especially ethyl group). P ³ represents a protecting group of a hydroxyl group, and examples thereof include silyl-based protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, preferably t-butyldiphenylsilyl Qi. L ² represents a leaving group, for example, a halogen atom such as a chlorine atom, bromine atom or iodine atom; Benzene which may be substituted by C1-C4 alkylsulfonyloxy or alkyl which may be substituted with fluorine such as methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy group A sulfonyloxy group is mentioned, Preferably it is the C1-C4 alkylsulfonyloxy group which may be substituted by fluorine. P ⁴ represents a protecting group of a mercapto group, and for example, a C 1 -C 4 alkanoyl group such as formyl, acetyl, propionyl, butyryl; The benzoyl group which may be substituted, such as benzoyl, toluoyl, and anisoyl, is mentioned, Preferably it is a C1-C4 alkanoyl group (especially an acetyl group).
[276] (Step B1)
[277] Step B1 is a step of preparing compound (VI) by introducing an amide group represented by the formula C (= X) NH ₂ to the nitrogen atom of compound (V).
[278] (1) This step is achieved by reacting compound (V) with cyanate or thiocyanate in a solvent.
[279] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include ethers such as tetrahydrofuran and diethyl ether; Halogenated hydrocarbons such as methylene chloride and dichloroethane; And a mixed solvent of these solvents and water, and preferably a mixed solvent of ethers and water (particularly a mixed solvent of tetrahydrofuran and water).
[280] Examples of the salts of cyanic acid or thiocyanic acid include alkali metal salts such as sodium salts and potassium salts or organic ammonium salts such as ammonium salts and triethylammonium salts, but are preferably alkali metal salts (particularly potassium salts).
[281] Acids may also be used to convert cyanates or thiocyanates to the corresponding acids in situ. Such acids include organic acids such as acetic acid and inorganic acids such as hydrochloric acid, preferably acetic acid or hydrochloric acid.
[282] The reaction temperature is usually -20 to 150 ° C (preferably -10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[283] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[284] (2) This step can also be achieved by the following method. This method includes the step of producing the following compound (XIII) from the compound (V) and the step of producing the compound (VI) from the compound (XIII).
[285]
[286] Wherein X and n are as defined above, and R ⁹ represents a C1-C4 alkyl group (preferably an ethyl group).
[287] The step of preparing compound (XIII) from compound (V) is a compound represented by formula (V) with a compound represented by formula X = C = N-COOR ⁹ (wherein X and R ⁹ are as defined above) in a solvent. Is achieved.
[288] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as methylene chloride and dichloroethane and these solvents. And a mixed solvent of water and water, preferably ethers or a mixed solvent of ethers and water (especially tetrahydrofuran or a mixed solvent of tetrahydrofuran and water).
[289] The reaction temperature is usually -20 to 150 ° C (preferably -10 to 50 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[290] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[291] The step of producing compound (VI) from compound (XIII) is achieved by reacting a base in solvent with compound (XIII).
[292] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, and the solvent and water. A mixed solvent is mentioned, Preferably it is alcohol or the mixed solvent of alcohol and water (especially ethanol or the mixed solvent of ethanol and water).
[293] Examples of the base used may include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate, and organic bases such as sodium methoxide and sodium ethoxide, preferably sodium hydroxide. to be.
[294] The reaction temperature is usually -20 to 15 ° C (preferably -10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[295] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[296] (B2 process)
[297] The B2 step is a step of producing a compound (VII) by ring closing the amide group of the compound (VI).
[298] This process acts on compound (VI) with a compound represented by the formula R ² CHL ³ COCOOP ² (wherein R ² and P ² are as defined above and L ³ represents a leaving group) in the presence of a base in a solvent. Is achieved. The leaving group for L ³ is preferably a halogen atom, particularly preferably a bromine atom.
[299] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, methylene chloride and dichloro. Halogenated hydrocarbons, such as ethane, and amides, such as N, N- dimethylformamide, are mentioned, Preferably, they are alcohol (especially ethanol).
[300] Examples of the base used may include an organic base such as triethylamine and diisopropylamine, an inorganic base such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, and preferably an organic base (especially triethylamine). to be.
[301] The reaction temperature is usually -20 to 150 ° C (preferably -10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[302] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[303] (Step B3)
[304] The B3 step is a step of introducing the protecting group P ³ to the hydroxyl group of the compound (VII) to produce the compound (VII).
[305] This process is achieved by methods commonly used in the field of organic synthetic chemistry (e.g., methods described in TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991). can do.
[306] Introduction of the silyl-based protecting group is accomplished by reacting compound (iii) with silyl halides or silyl triplates having a desired substituent in the presence of a base in a solvent.
[307] Examples of the silyl halides include trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride and t-butyldiphenylsilyl chloride, preferably t-butyldiphenylsilyl It's chloride.
[308] Examples of the silyl triplates include trimethylsilyl triplate, triethylsilyl triplate, t-butyldimethylsilyl triplate, and t-butyldiphenylsilyl triplate, preferably t-butyldiphenyl Silyl tree plate.
[309] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include amides such as dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran and di And ethers such as ethyl ether, and are preferably amides (particularly dimethylformamide) or halogenated hydrocarbons (particularly methylene chloride).
[310] Examples of the base used may include organic bases such as imidazole, triethylamine, lutidine, pyridine, dimethylaminopyridine, and are preferably imidazole or 2,6-lutidine.
[311] The reaction temperature is usually -20 to 50 ° C (preferably -10 to 40 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[312] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[313] (B4 process)
[314] The fourth B4 step is a step of converting the group represented by the formula COOP ² of the compound (VII) to the desired R ¹ p to produce the compound (VII).
[315] This process can be achieved by applying a functional group conversion reaction commonly used in the field of organic synthetic chemistry. In detail, it describes in the following C method-H method.
[316] (B5 process)
[317] A 5th process B5 is a process of removing compound protecting group P <^3> of the hydroxyl group of compound ( ⁱⁱⁱ ), and manufacturing compound ( ⁱⁱⁱ ).
[318] This process can be accomplished by methods commonly used in the field of organic synthetic chemistry (e.g., methods described in TWGreene, PGMWuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, Inc. 1991). Can be.
[319] If the protective group for a hydroxyl group P ³ is a silyl-based protecting group, the removal is accomplished in the same manner as in the method described in the A2 step (3).
[320] (B6 step)
[321] The B6 step is a step of producing the compound (XI) by converting the hydroxyl group of the compound (VII) to the leaving group L ² .
[322] (1) when the leaving group L ² is various sulfonyloxy groups
[323] This process is accomplished by reacting compound (iii) with a sulfonylating agent in the presence of a base in a solvent.
[324] Examples of the sulfonylating agent to be used include methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like. Preferably methanesulfonyl chloride.
[325] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform, ethers such as tetrahydrofuran and diethyl ether. And halogenated hydrocarbons (particularly methylene chloride).
[326] Examples of the base to be used include organic bases such as triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine, and are preferably triethylamine.
[327] The reaction temperature is usually -20 to 80 ° C (preferably -10 to 40 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[328] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[329] (2) When the leaving group L ² is a halogen atom
[330] This step is accomplished by reacting the compound (iii) with a halogenating agent in a solvent.
[331] As the halogenating agent used, for example, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, iodine, carbon tetrabromide, carbon tetrachloride, N-chlorosuccinimide, N-bromosuccinimide, diethylaminosulfatriflo A lead is mentioned, Preferably it is carbon tetrabromide.
[332] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane, ethers such as tetrahydrofuran and diethyl ether. And halogenated hydrocarbons (particularly methylene chloride).
[333] As an additive used, phosphines, such as a triphenyl phosphine and a tributyl phosphine, are mentioned, for example, Preferably it is a triphenyl phosphine.
[334] The reaction temperature is usually -20 to 100 ° C (preferably -10 to 50 ° C), and the reaction time is usually 10 minutes to 10 hours (preferably 0.5 to 24 hours).
[335] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[336] (B7 process)
[337] Step B7 is a step of converting leaving group L ² of compound (XI) into a protected mercapto group to produce compound (XII).
[338] This process is accomplished by reacting compound (XI) with a mercaptoating agent in a solvent.
[339] Examples of the mercaptoating agent used include alkali metal salts of thiocarboxylic acids such as sodium thioacetate, potassium thioacetate, sodium thiopropionate and sodium thiobenzoate or alkali metal salts of 4-methoxybenzyl mercaptan. And potassium thioacetate.
[340] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include tetrahydrofuran and ethers such as dioxane, acetate esters such as ethyl acetate and methyl acetate, and acetonitrile. And amides such as nitriles, dimethylformamide, and dimethylacetamide, and are preferably amides (particularly dimethylformamide).
[341] The reaction temperature is usually -20 to 150 ° C (preferably 0 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[342] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[343] (B8 process)
[344] The B8th step is a step of removing the protective group P ⁴ of the mercapto group of the compound (XII) to produce the compound (III).
[345] (1) When protecting group P ⁴ is alkanoyl group or arylcarbonyl group
[346] This process is accomplished by reacting compound (XII) with a salt of a hydrazine compound in a solvent.
[347] As the salt of the hydrazine compound, hydrazine acetic acid, N, N-dimethyl hydrazine acetic acid can be used, for example, hydrazine acetic acid.
[348] As a solvent used, the solvent used at the 1st process mentioned above can be used.
[349] Although reaction temperature is not specifically limited, Usually, it is -10 degreeC-40 degreeC (preferably 10 degreeC-30 degreeC), and reaction time changes with a solvent, reaction temperature, and the kind of reaction reagent, but is usually 30 minutes-24 hours (Preferably 1 hour to 8 hours).
[350] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent in the reaction mixture, followed by washing with water, followed by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[351] In addition, when the salt of a hydrazine compound is used as a deprotection agent, compound (III) can be used as a raw material of the above-mentioned A1 process, without isolating from a reaction liquid.
[352] This step is also achieved by reacting compound (XIII) with a base in a solvent.
[353] Examples of the base used may include salts of alkali metals such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide and sodium ethoxide, but are preferably sodium methoxide.
[354] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran, diethyl ether, amides such as dimethylformamide, halogenated hydrocarbons such as methylene chloride, dichloroethane, and the like, and alcohols (particularly methanol).
[355] The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).
[356] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[357] (2) when P ⁴ is a 4-methoxybenzyl group
[358] This step is achieved by reacting compound (XIII) with an acid in a solvent.
[359] As the acid to be used, sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid can be used, and preferably trifluoromethanesulfonic acid. In addition, the reaction can be promoted by coexisting anisole or thioanisole.
[360] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane, ethers such as tetrahydrofuran and diethyl ether, and acetic acid. And acetic acid such as trifluoroacetic acid, and acetic acid (particularly trifluoroacetic acid) is preferable.
[361] The reaction temperature is usually -20 to 100 ° C (preferably -10 to 80 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).
[362] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[363] [C Law]
[364] The C method is a method for producing compound (VII-1) having a desired ester residue by converting the protected carboxyl group of compound (VII).
[365]
[366] In the above, R ² , X, n, P ² and P ³ are as defined above, and R ^3p represents R ³ , which may be protected.
[367] (Step C1)
[368] The first C1 step is a step of producing the compound (XIV) by reducing the carboxyl ester group of the compound (VII) with a hydroxymethyl group.
[369] This process is achieved by making a compound (i) react with a reducing agent in a solvent.
[370] The reducing agent to be used is not particularly limited as long as it can reduce the carboxyl ester group and convert it to a hydroxymethyl group, and for example, alkali metal aluminum hydride such as lithium aluminum hydride, lithium borohydride, sodium borohydride Alkali metal boron hydrides, such as a lide, are mentioned, Preferably it is lithium aluminum hydride.
[371] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include ethers such as tetrahydrofuran and diethyl ether, and preferably tetrahydrofuran.
[372] The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 24 hours (preferably 0.5 to 24 hours).
[373] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, after adding the organic solvent which is not mixed with water to the reaction liquid mixture, and neutralizing and washing with water, it can obtain by distilling a solvent off. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[374] (Step C2)
[375] The second C2 step is a step of oxidizing the hydroxymethyl group of the compound (XIV) to produce the compound (XV).
[376] This step is achieved by reacting compound (XIV) with an oxidizing agent in a solvent, and includes a step of oxidizing a hydroxymethyl group to an aldehyde group and a step of oxidizing an aldehyde group to a carboxyl group.
[377] (1) Step of oxidizing hydroxymethyl group to aldehyde group
[378] The oxidizing agent to be used is not particularly limited as long as it can be converted into an aldehyde group by oxidizing a hydroxymethyl group, and for example, pyridinium chloro chromate, oxalyl chloride-dimethyl sulfoxide, trifluoroacetic acid-dimethyl sulfoxide, activity Manganese dioxide and the Dess Martin reagent are mentioned, Preferably it is active manganese dioxide.
[379] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane, and methylene chloride is preferable.
[380] The reaction temperature is usually -100 to 100 ° C (preferably -100 to 50 ° C), and the reaction time is usually 30 minutes to 108 hours (preferably 1 to 24 hours).
[381] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[382] (2) Step of oxidizing aldehyde group to carboxyl group
[383] The oxidizing agent to be used is not particularly limited as long as it can be converted to a carboxyl group by oxidizing an aldehyde group. And sodium chlorite-sodium dihydrogen phosphate-2-methyl-2-butene.
[384] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane, ethers such as tetrahydrofuran and diethyl ether, and t. Alcohols, such as butanol, and a mixed solvent of them and water are mentioned, Preferably it is a mixed solvent of tetrahydrofuran-methylene chloride-water-t-butanol.
[385] The reaction temperature is usually -20 to 50 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).
[386] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[387] (Step C3)
[388] The C3 step is a step of separately preparing the carboxyl compound (XV), and is accomplished by removing the protecting group of the compound (VII).
[389] This process can be performed similarly to process A2 of method A.
[390] (Step C4)
[391] The fourth C4 step is a step of esterifying the carboxyl group of the compound (XV) to produce the compound (VII-1).
[392] (1) This step is achieved by reacting compound (XV) with an alcohol compound represented by the desired formula R ^3p OH in the presence of a condensing agent in a solvent.
[393] As a condensing agent used, the thing described by the term of ester formation as described in A method A2 process can be used. It is also achieved via acid chloride using oxalyl chloride.
[394] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, halogenated hydrocarbons such as methylene chloride and dichloroethane, ethers such as tetrahydrofuran and diethyl ether, and dimethylform Amides such as amides, nitriles such as acetonitrile, and the like, preferably halogenated hydrocarbons (particularly methylene chloride).
[395] The reaction temperature is usually -50 to 100 ° C (preferably -20 to 50 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[396] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[397] (2) This step is also achieved by reacting compound (XV) with a compound represented by the desired formula R ^3p L ³ in the presence of a base in a solvent. L ³ represents a leaving group and is preferably a halogen atom (especially an iodine or bromine atom).
[398] As the base used, an inorganic base or an organic base can be used. As an inorganic base, For example, Carbonate, such as sodium carbonate, potassium carbonate, cesium carbonate; Hydrogen carbonate, such as sodium hydrogencarbonate and potassium hydrogencarbonate, is mentioned, Preferably it is cesium carbonate. Examples of the organic base include tertiary amines such as triethylamine and diisopropylethylamine; Dicyclic organic bases, such as DBU and DBN, are mentioned, Preferably it is diisopropylethylamine.
[399] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane, ethers such as tetrahydrofuran and diethyl ether, and dimethyl. Amides, such as formamide, and nitriles, such as acetonitrile, are mentioned, Preferably they are amides (especially dimethylformamide).
[400] The reaction temperature is usually -50 to 100 ° C (preferably -20 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[401] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[402] [D law]
[403] The D method is a method for producing compound (X-2) having a desired amide residue by converting a carboxyl group of compound (XV).
[404]
[405] In the above, R ² , X, n and P ³ are as defined above, and R ^4p and R ^5p represent R ⁴ and R ⁵ , which may be protected.
[406] (Step D1)
[407] This process is accomplished by reacting compound (XV) with a compound having the desired formula HNR ^4p R ^5p in the presence of a condensing agent in a solvent.
[408] This step can be performed by using the amino compound HNR ^4p R ^5p in place of the alcohol compound R ^3p OH in the C4 step of the C method described above.
[409] As the condensing agent, a phosphate ester-based condensing agent such as diethylphosphoryl cyanide and a carbonate-based condensing agent such as carbonyldiimidazole can be used. Preferred are diethylphosphoryl cyanide and carbonyldiimidazole.
[410] [E law]
[411] The E method is a method for producing compound (X-2) having a desired amide residue by converting the carboxyl ester group of compound (XIII).
[412]
[413] In the above, R ² , X, n, P ³ , R ^4p and R ^5p are as defined above. P ^2a represents a C1-C4 alkyl group in protecting group P ² of the carboxyl group described above.
[414] (Step E1)
[415] This step is accomplished by reacting compound (iii) with an amino compound represented by the desired formula HNR ^4p R ^5p in the presence of a catalyst in a solvent.
[416] Examples of the catalyst to be used include tri C1-C4 aluminum such as trimethyl aluminum, preferably trimethyl aluminum.
[417] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aromatic solvents such as benzene, toluene and mesitylene, and halogenated hydrocarbons such as methylene chloride and dichloroethane. And aromatic solvents (particularly benzene or toluene).
[418] The reaction temperature is usually -20 to 150 ° C (preferably -10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[419] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can be obtained by adding the organic solvent which is not mixed with water to the residue obtained by distilling off the reaction liquid mixture or the solvent of the reaction liquid mixture, neutralizing and washing with water, and then distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[420] [F Act]
[421] The F method is a method for producing a cyano compound (X-3) by converting the carboxyl ester group of the compound (XIII).
[422]
[423] In the above, R ² , X, n, P ³ and P ^2a are as defined above.
[424] (Step F1)
[425] This process is achieved by acting at a higher reaction temperature using an ammonium salt in place of the amino compound in the above-mentioned E method E1 process.
[426] As an ammonium salt, ammonium chloride is preferable and reaction temperature is performed at -20-150 degreeC (preferably -10-100 degreeC).
[427] [G Law]
[428] G method is a method of preparing compound (X-4) by introducing the desired substituent R ⁶ into the hydroxyl group of compound (XIV).
[429]
[430] This step is accomplished by reacting compound (XIV) with an alkylating agent in the presence of a base in a solvent or by reacting a reducing carbonyl compound with a reducing agent in the presence of an acid catalyst in a solvent.
[431] (1) Alkylation Method Under Basic Conditions
[432] Examples of the solvent used may include amides such as N, N-dimethylformamide and ethers such as tetrahydrofuran and diethyl ether. Preferably amides (especially N, N-dimethylformamide).
[433] Examples of the base used may include alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium hydroxide and potassium hydroxide, organic bases such as triethylamine and diisopropylamine, and preferably alkali metals. Hydrides (especially sodium hydride).
[434] Examples of the alkylating agent to be used include dialkyl sulfuric acid such as methyl iodide, alkyl halides typified by ethyl iodide, dimethyl sulfuric acid and diethyl sulfuric acid. Preferably alkylhalides (particularly alkyl iodide).
[435] The reaction temperature is usually -50 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).
[436] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[437] (2) Alkylation Method Under Acidic Conditions
[438] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane and ethers such as tetrahydrofuran and diethyl ether. And halogenated hydrocarbons (particularly methylene chloride).
[439] Examples of the acid catalyst include trialkylsilyl triplates such as trimethylsilyl triplate, triethylsilyl triplate, and t-butyldimethylsilyl triplate, and trimethylsilyl triplate is preferable.
[440] As the desired carbonyl compound, ketones such as acetone, methyl ethyl ketone and cyclohexyl ketone, alkylaldehydes such as acetaldehyde and propylaldehyde are preferable, and ketones are preferable.
[441] Examples of the reducing agent include trialkylsilanes such as triethylsilane and diphenylmethylsilane, and preferably trialkylsilane (particularly triethylsilane).
[442] The reaction temperature is usually -50 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).
[443] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[444] [H Law]
[445] The H method is a method for producing compound (VII-5) by converting the hydroxyl group of compound (XIV) to a group represented by the desired formula NR ^7p R ^8p .
[446]
[447] (H1 process)
[448] The H1 step is a step of introducing the leaving group L ³ into the compound (XIV) to produce the compound (XV), which can be achieved in the same manner as the B method B6 process described above.
[449] (H2 process)
[450] The second H2 step is a step of producing the amine compound (X-5a) from the compound (XV) and introducing a substituent as necessary to produce the compound (X-5b).
[451] (A) Manufacturing process of amine compound (VII-5a)
[452] This step is achieved by reacting compound (XV) with an aminating agent in a solvent. Alternatively, it is also achieved by reacting compound (XV) with an azide agent in a solvent to produce an azide compound, followed by a reducing agent.
[453] (1) Method of using an amination agent
[454] The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include amides such as dimethylformamide, alcohols such as methanol and ethanol, tetrahydrofuran and diethyl ether. The same ethers are mentioned, Preferably they are amides (especially dimethylformamide).
[455] The amine agent used may be, for example, alkylamines which may be substituted by primary such as methylamine and ethylamine; Aromatic amines which may be substituted, such as aniline and aminothiazole; Secondary substituted alkylamines, such as methyl ethylamine and dimethylamine, and salts (for example, hydrochloride) of these amines are mentioned. Of these, preferred are primary or secondary substituted alkylamines and salts thereof (particularly methylamine hydrochloride or dimethylamine hydrochloride).
[456] The reaction temperature is usually 0 to 150 ° C (preferably 10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[457] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[458] (2) How to use azide and reducing agents
[459] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, amides such as dimethylformamide, alcohols such as methanol and ethanol, tetrahydrofuran and diethyl ether Ethers are mentioned, Preferably they are amides (especially dimethylformamide).
[460] Examples of the azide agent include alkali metal azide such as sodium azide and lithium azide, and preferably alkali metal azide azide (particularly sodium azide).
[461] The reaction temperature is usually 0 to 150 ° C (preferably 10 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[462] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[463] The obtained azide compound is guided to the amine compound (VII-5a) by a reduction reaction.
[464] Reducing agents used include alkali metal aluminum hydrides such as lithium aluminum hydride, phosphines such as triphenylphosphine, and catalytic hydrogen reducing agents by metal catalysts such as palladium-carbon and platinum catalysts. Preferably a catalytic hydrogen reducing agent (in particular when palladium-carbon is used as a catalyst).
[465] The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include ethers such as tetrahydrofuran and diethyl ether, and alcohols such as methanol and ethanol. Preferably ethers (especially tetrahydrofuran).
[466] In the case of catalytic hydrogen reduction, the solvent used includes alcohols such as methanol and ethanol, and preferably methanol.
[467] The reaction temperature is usually -10 to 150 ° C (preferably 0 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[468] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[469] (B) Process of Preparation of Compound (VII-5b)
[470] This process is a process performed as needed, and is a process of manufacturing a compound (X-5b) by introducing a substituent into an amine compound (X-5a).
[471] This step is achieved by reacting the amine compound (X-5a) with a desired acylating agent, sulfonylating agent, phosphorylating agent, and chloroformate ester in the presence of a base in a solvent.
[472] The acylating agents include acetic anhydride, acid anhydrides such as benzoic anhydride, acid chlorides such as chloride and benzoic acid chloride, and are preferably acid chlorides (especially chloride acetate).
[473] Examples of the sulfonylating agent include acid chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, acid anhydrides such as anhydrous methanesulfonyl and anhydrous p-toluenesulfonyl, and preferably acid chlorides. (In particular, methanesulfonyl chloride).
[474] Examples of the phosphorylating agent include acid chlorides such as diethylphosphoryl chloride and dimethylphosphoryl chloride, and preferably diethylphosphoryl chloride.
[475] As chloroformate ester, ester compounds, such as methyl chloroformate, ethyl chloroformate, and benzyl chloroformate, are mentioned, Preferably it is chloroformate ester (especially methyl chloroformate).
[476] Bases to be used include organic bases such as triethylamine, diisopropylethylamine, pyridine, inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, preferably organic bases (especially triethylamine) to be.
[477] The solvent used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction, and examples thereof include ethers such as tetrahydrofuran and diethyl ether, and halogenated hydrocarbons such as methylene chloride and dichloroethane. And ethers (particularly tetrahydrofuran).
[478] The reaction temperature is usually 0 to 100 ° C (preferably 10 to 50 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[479] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[480] (Step H3 process)
[481] The H3 step is a step of producing the amine compound (X-5a) from the compound (XV) via an azide compound and introducing a substituent as necessary to produce the compound (X-5b).
[482] (A) Production process of azide compound
[483] This step is carried out by reacting compound (XV) with an azide agent (particularly diphenylphosphoryl azide), diethylazodicarboxylate and triphenylphosphine in a solvent.
[484] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, amides such as dimethylformamide, alcohols such as methanol and ethanol, tetrahydrofuran and diethyl ether Ethers are mentioned, Preferably they are ethers (especially tetrahydrofuran).
[485] The reaction temperature is usually 0 to 50 ° C (preferably 10 to 30 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).
[486] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[487] (B) Manufacturing Process of Amine Compound
[488] This process is a process of reducing an azide compound and manufacturing an amine compound (VII-5a), and can be performed similarly to the reduction process of H2 process (A) (1) mentioned above.
[489] (C) step of preparing compound (VII-5b)
[490] This process is a process performed as needed, and is a process of manufacturing a compound (X-5b) by introducing a substituent into an amine compound (X-5a), and can be performed similarly to the above-mentioned H2 process (B). .
[491] Compounds (X-1) to (X-5) obtained in Processes C to H can be converted into Compound (III), which becomes the raw material of the second-order side chain of Compound (I), following the process after Process B5 of Process B. have.
[492] [I Law]
[493] Method I is a method for separately preparing compound (X-6) in which X is an oxygen atom from compound (X) which is a synthetic intermediate of method B.
[494]
[495]
[496] In the above, R ¹ p, R ² , P ³ , n are as defined above, Z represents a protecting group of an amino group, preferably benzyloxycarbonyl group. P <^5> is a protecting group of a hydroxyl group, Preferably it is acyl-type protecting groups, such as an acetyl, benzoyl, pivaloyl group, Most preferably, it is a benzoyl group.
[497] (Step I-1)
[498] Step I-1 is a step of producing a compound (XVI) by converting a carboxyl group of an amino group-protected amino acid compound (XVIa) into a desired R ¹ p.
[499] This process can be performed according to the method chosen from the C method or the H method mentioned above. Moreover, in the compound (XVIa) which is a starting material, the compound whose R <^2> is a hydrogen atom can be manufactured from serine, and the compound whose R <^2> is a methyl group can be manufactured from threonine. Compounds in which R ² is other than a hydrogen atom and a methyl group can also be produced by methods known to those skilled in the art.
[500] (Step I-2 process)
[501] Step I-2 is a step of introducing compound to the hydroxyl group of compound (XVI) to produce compound (X ').
[502] This process can be performed similarly to process B3 process B3. Moreover, as a silyl type protecting group of P <^3> , Preferably it is t-butyl dimethyl silyl group.
[503] (Step I-3 process)
[504] Step I-3 is a step of removing the protecting group of the amino group of compound (X ') to produce compound (X').
[505] This process can be performed according to the method of A method A2 process (1). Preferred solvent is methanol.
[506] (Step I-4)
[507] The step (I-3) is a step of producing the compound (X ') by converting the amino group of the compound (X') to an isothiocyanate group.
[508] This step is achieved by reacting compound (X ') with carbon disulfide and a desulfurization agent in the presence of a base in a solvent.
[509] As the solvent, halogenated hydrocarbons (particularly methylene chloride) are preferable.
[510] Examples of hydrogen sulfide agents include halogenated formic acid esters (especially ethyl chloroformate) or quaternary nitrogen-containing reagents (especially 2-chloro-1-methylpyridinium iodide or 2-chloro-1-ethylbenzoxazolium tetrafluoroborate). desirable.
[511] As the base, tertiary amines (particularly triethylamine) such as triethylamine, diisopropylethylamine and tributylamine are preferable.
[512] The reaction temperature is usually -20 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours).
[513] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[514] (Step I-5 process)
[515] The fifth step I-5 is a step of reacting the compound (X ') with the desired cyclic amine to produce the compound (XX).
[516] This process can be performed according to the B method B1 process.
[517] (Step I-6 process)
[518] Step I-6 is a step of introducing compound (XXI) by introducing acyl-based protecting group P ⁵ into the hydroxyl group of compound (XX) and then removing silyl-based protecting group P ³ .
[519] (1) Introduction process of acyl-based protecting group P ⁵
[520] This process can be performed according to the method of H method H2 process (B).
[521] (2) Removal process of silyl protecting group P ³
[522] This process can be performed according to A method A2 process.
[523] (Step I-7 process)
[524] Step I-7 is a step of producing compound (XXII) by ring closing reaction of compound (XXI).
[525] This step is achieved by reacting compound (XXI) with a cyclization reagent (desulfurization reagent) in the presence of a base in a solvent.
[526] As the solvent, amides such as dimethylformamide, dimethylacetamide, halogenated hydrocarbons such as methylene chloride, and nitriles such as acetonitrile are used, and preferably acetonitrile.
[527] As the base, tertiary amines (particularly triethylamine) such as triethylamine, diisopropylethylamine and tributylamine are preferable.
[528] As a cyclization (dehydrosulfide) reagent, mercury salts, such as mercury oxide and mercuric chloride, or a quaternary nitrogen-containing reagent (especially 2-chloro-1-methylpyridinium iodide or 2-chloro-1-ethylbenzoxazolium tetrafluoro) Borate) is preferred.
[529] The reaction temperature is usually -20 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours).
[530] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, it can obtain by distilling off a solvent after adding the organic solvent which is not mixed with water to the residue obtained by distilling off the solvent of a reaction liquid mixture or a reaction liquid mixture, and neutralizing and washing with water. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[531] (Step I-8)
[532] The step I-8 is a step of producing the compound (XXIII) by dehydrogenating the compound (XXII).
[533] This step is accomplished by reacting compound (XXII) with a dehydrogenation reagent in a solvent.
[534] As the solvent, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and dichloroethane are used.
[535] As the dehydrogenation reagent, an oxidizing agent such as manganese dioxide is used.
[536] The reaction temperature is usually 0 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours).
[537] After the reaction is completed, the target compound is taken from the reaction mixture according to a conventional method. For example, an organic solvent that is not mixed with water is added to the residue obtained by distilling off the reaction mixture or the solvent of the reaction mixture, the insolubles are filtered off, washed with water, and then obtained by distilling off the solvent. The desired compound obtained can be further purified by conventional methods, for example, recrystallization, reprecipitation or chromatography, if necessary.
[538] (Step I-9 process)
[539] The step I-9 is a step of removing the acyl-based protecting group P ⁵ of compound (XXIII) and then introducing the silyl protecting group P ³ to produce compound (VII-6).
[540] (1) Removal process of acyl-based protecting group P ⁵
[541] This process can be performed according to the method of manufacturing compound (VI) from method A B1 process (2) and compound (iii).
[542] (2) Introduction process of silyl-based protecting group P ³
[543] This process can be performed according to process B3 process B3.
[544] [J Law]
[545] The compound (I) can be prepared by the following J method separately from the A method, and in particular, the preparation of the compound (I-1) or (I-2) in which R ¹ is represented by the formula COOR ³ or the formula CONR ⁴ R ⁵ . Applicable to
[546]
[547]
[548] In the above, R ¹ , R ¹ p, R ² , P ¹ , P ³ , X, L ¹ and n are as defined above. P ³ is preferably a t-butyldimethylsilyl group.
[549] (J1 step)
[550] Step J1 is a step of producing compound (IV-1) by condensing compound (II-1) protected with silyl protecting group P ³ and compound (III-1) wherein R ¹ p is a carboxyl group protected with allyl group.
[551] This process can be performed similarly to the A method A1 process mentioned above. Moreover, compound (II-1) of a starting raw material can be manufactured by making a compound (II) react with a silylating agent, and it can carry out according to B method B3 process. Compound (III-1) can be manufactured by B method.
[552] (J2 process)
[553] Step J2 is a step of producing compound (IV-2) by removing the protecting group allyl group of compound (IV-1).
[554] This process can be performed according to A method A2 process (2) mentioned above.
[555] (J3 process)
[556] The third step J3 is a step of modifying the carboxyl group of compound (IV-2) to produce compound (IV-3).
[557] This step can be carried out in accordance with the above-described B method B4 process (particularly the C method and the D method).
[558] (J4 step)
[559] The fourth J4 step is a step of removing the protective groups P ³ and P ¹ of the compound (IV-3) to produce the compound (I).
[560] (1) Removal of protector P ³
[561] This process can be performed according to A method A2 process (3) mentioned above.
[562] (2) Removal of Protector P ¹
[563] This process can be performed similarly to the A method A2 process mentioned above.
[564] Compounds having the formula (I) of the present invention or pharmacologically acceptable salts thereof are, for example, Gram-positive bacteria such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pneumococcal bacillus, Shigella, Proteus vulgaris Pneumococcus, a bacterium that causes strong and balanced antimicrobial activity against a wide range of pathogens, including Gram-negative bacteria such as Serratia, Enterobacter and Pseudomonas aeruginosa and anaerobes such as Bacteroides prazilis. It has strong antibacterial activity against penicillin-resistant bacteria and Haemophilus-influenza (including β-lactamase producing bacteria). Compound (I) of the present invention has high stability to β-lactamase including metallo-β-lactamase. Since compound (I) of the present invention has excellent body dynamics such as giving high peak blood concentration and long blood concentration half-life when administered orally or parenterally to a recipient, it is less administered than conventional drugs. Recovery and low doses are expected to treat the infection. Compound (I) of the present invention is also weak in toxicity to the kidneys. Accordingly, the compounds having the formula (I) of the present invention, pharmacologically acceptable salts or ester derivatives thereof, are useful, for example, as medicaments, and especially for treating or preventing bacterial infections, in particular respiratory infections caused by various pathogens (preferably Is useful as an antimicrobial agent.
[565] When using compound (I), a pharmacologically acceptable salt or ester derivative thereof, as a medicament, in particular an antimicrobial agent, it may be mixed with itself or with a suitable pharmacologically acceptable excipient, diluent or the like to form a tablet, capsule, granule, powder or syrup. It can be administered orally or the like or parenterally by injection or the like.
[566] These formulations include excipients (e.g., sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol; corn starch, potato starch, α-starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose, low degree of substitution) Cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, crosslinked carboxymethyl cellulose sodium; gum arabic; dextran; pullulan; hard silicic anhydride, synthetic aluminum silicate , Silicate derivatives such as magnesium aluminate silicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate), binders (e.g., excipients; gelatin; polyvinylpyrrolidone Macrogol and the like), disintegrants (e.g., the excipients; croscarmellose sodium, carboxyl) Sodium tilstar, chemically modified starch such as cross-linked polyvinylpyrrolidone, cellulose derivatives, and the like, glidants (for example, talc; stearic acid; calcium stearate, magnesium stearate, magnesium stearate; colloidal silica; Waxes such as beeswax and mercury; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; sodium lauryl sulfate, lauryl Lauryl sulfate, such as magnesium sulfate; silicic acid, such as silicic anhydride, silicic acid hydrate; starch derivatives in the above excipients; stabilizers (e.g., paraoxybenzoic acid esters such as methylparaben, propylparaben; chlorobutanol, benzyl alcohol Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride Sorbic acid, etc.), copulating agents (e.g., commonly used sweeteners, acidulants, fragrances, and the like), suspending agents (e.g., polysorbate 80, sodium carboxymethylcellulose, etc.), diluents, solvents for preparations ( For example, it is manufactured by a well-known method using additives, such as water, ethanol, glycerin, etc.).
[567] The amount used varies depending on the symptoms and age, but in the case of oral administration, the lower limit 10 mg (preferably 50 mg) and the upper limit 2000 mg (preferably 1000 mg) are used per intravenous administration. It is preferable to administer mg (preferably 100 mg) and upper limit 3000 mg (preferably 2000 mg) according to symptoms 1 to 6 times per day for adults.
[568] Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto. In Examples and Reference Examples, the nuclear magnetic resonance spectra were measured using sodium trimethylsilylpropionate-d ₄ as an internal standard for measurement in heavy water, and tetramethylsilane as an internal standard for other solvents. In addition, when the internal standard substance was not used in the measurement in heavy water, the signal position of the proton (HOD) in heavy water was 4.65 ppm.
[569] Example 1
[570] (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[571]
[572] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[573] 486 mg (1.71 mmol) of 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 1 were dissolved in 15 ml of dimethylformamide, followed by nitrogen. At atmosphere, 171.0 mg (1.86 mmol) of hydrazine acetate was added at room temperature, and it stirred for 1.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 30 ml of acetonitrile solution of 1.02 g (1.72 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 1.5 ml (8.61 mmol) of diisopropylethylamine were added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazole-2 -Yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a pale yellow solid, 752 mg, yield Obtained at 75%.
[574]
[575] (2) (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[576] Compound p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine-3- obtained in Example 1 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 744 mg (1.26 mmol) of 46 ml of tetrahydrofuran, 23 ml of distilled water It was dissolved in, and contact hydrogen reduction was conducted for 1.5 hours in a 30 ° C water bath in the presence of 736 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and 106 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmosil (elution solvent: distilled water to 3% acetonitrile-distilled water to 5% acetonitrile-distilled water to 7% acetonitrile). (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl as the target compound by purification with distilled water) and freeze drying. ] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 376 mg and yield 63%.
[577]
[578] Example 2
[579] (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[580]
[581] (1) P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[582] 380 mg (1.0 mmol) of 3-acetylthio-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 was dissolved in 15 ml of dimethylformamide. 115 mg (1.25 mmol) of hydrazine acetate was added at room temperature in nitrogen atmosphere, and it stirred for 3 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A 30 ml solution of 695 mg (1.17 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 0.84 ml (4.82 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thia Zol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a brown foam As a solid), it obtained 336 mg and yield 50%.
[583]
[584] (2) (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[585] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidine- obtained in Example 2 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 330 mg (0.474 mmol) in 16 ml of tetrahydrofuran, distilled water It dissolved in 8 ml, and contact hydrogen reduction was performed for 1.5 hours in 30 degreeC water bath in presence of 325 mg of 20% palladium hydroxide. After the completion of reaction, the reaction mixture was filtered, and 45 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using a cosmomolecule (elution solvent: distilled water), and freeze-dried to be the target compound (1R, 5S, 6S) -2- [1 -(4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2- M-3-carboxylic acid disodium salt was obtained as a white solid at 86 mg, yield 41%.
[586]
[587] Example 3
[588] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[589]
[590] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[591] 1.13 g (4.39 mmol) of 3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 3 was dissolved in 57 ml of dimethylformamide, followed by nitrogen atmosphere. Then, 485 mg (5.27 mmol) of hydrazine acetate were added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 2.61 g (4.39 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 3.1 mL (17.6 mmol) of diisopropylethylamine was added thereto and gradually added to room temperature. It stirred for 3 hours, heating up. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M brine, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride-3% methanol-methylene chloride-6% methanol-methylene chloride-9% methanol-methylene chloride) to obtain p-nitrobenzyl (1R, 5S, 6S)-. 2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 2.61 g in yield 94%.
[592]
[593] (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[594] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] obtained in Example 3 (1)] Dissolve 2.2 g (3.93 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate in 110 ml of tetrahydrofuran and 110 ml of distilled water. In the presence of 2.2 g of 10% palladium carbon, catalytic hydrogen reduction was performed at room temperature for 2 hours. After the completion of reaction, the reaction mixture was filtered, and 330 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomos (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water). By freeze drying, the desired compound was (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as 1.12 g and a yield 64% as a white solid.
[595]
[596] Example 4
[597] (1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[598]
[599] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[600] 760 mg (3.18 mmol) of 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine obtained in Reference Example 4 were dissolved in 38 ml of dimethylformamide, and 351 mg (3.81 mmol) of hydrazine acetate were added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.89 g (3.18 mmol) of acetonitrile 95 ml solution of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by the addition of 2.21 ml (12.7 mmol) of diisopropylethylamine to the room temperature as it was. It stirred for 4 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M brine, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1/4 to ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1). , 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate As a pale yellow solid, it obtained 1.65g and yield 96%.
[601]
[602] (2) (1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[603] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio obtained in Example 4 (1) 600 mg (1.11 mol) of -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water. , 600% of 10% palladium carbon was present, and catalytic hydrogen reduction was performed at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and 93 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water-3% of acetonitrile-18% acetonitrile-distilled water), and lyophilized to obtain the target compound (1R, 5S, 6S). -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 285 mg, yield 60%.
[604]
[605] Example 5
[606] (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[607]
[608] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[609] 570 mg (2.10 mmol) of 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 5 were dissolved in 28 ml of dimethylformamide. 291 mg (3.16 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred as it is for 2 hours. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.25 g (2.10 mol) of acetonitrile 25 ml of -methyl-carbafen-2-m-3-carboxylate was added dropwise thereto, and then 1.83 ml (10.5 mmol) of diisopropylethylamine was added thereto and gradually added to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl- 1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate Was obtained as a pale yellow solid at 774 mg, yield 64%.
[610]
[611] (2) (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[612] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidine-3 obtained in Example 5 (1) -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbaphen-2-m-3-carboxylate 768 mg (1.34 mmol) of tetrahydrofuran, distilled water 19 The solution was dissolved in mL and subjected to catalytic hydrogen reduction for 1.5 hours in a 30 ° C water bath in the presence of 757 mg of 20% palladium hydroxide. After the completion of reaction, the reaction mixture was filtered, and 115 mg of sodium bicarbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% acetonitrile-distilled water-5% acetonitrile-distilled water), and then lyophilized. Compound (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 392 mg and yield 64%.
[613]
[614] Example 6
[615] (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[616]
[617] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[618] 563 mg (1.49 mmol) of 3-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 6 was added to 28 ml of dimethylformamide. It dissolved, 264 mg (2.87 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred for 3 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.15 g (1.94 mmol) of acetonitrile (23 mL) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.7 mL (9.76 mmol) of diisopropylethylamine, and then slowly to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarba Moyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-car The carboxylate was obtained as a pale yellow solid at 777 mg, yield 68%.
[619]
[620] (2) (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[621] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Example 6 (1) 38 ml of 772 mg (1.31 mmol) of -3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate, tetrahydrofuran, It dissolved in 19 ml of distilled water, and contact hydrogen reduction was performed in 30 degreeC water bath for 1.5 hours in presence of 768 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtrated, and 112 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomosil and lyophilized to be (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2- M-3- sodium carboxylate was obtained as a white solid at 375 mg, yield 60%.
[622]
[623] Example 7
[624] (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[625]
[626] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[627] 450 mg (1.58 mmol) of 3-acetylthio-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 7 were dissolved in 23 ml of dimethylformamide. Hydrazine acetate 174 mg (1.89 mmol) was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 47 ml of acetonitrile of 939 mg (1.58 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.10 ml (6.31 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate 10% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl- 1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate Was obtained as a pale yellow solid, 753 mg, yield 81%.
[628]
[629] (2) (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[630] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine-3 obtained in Example 7 (1) -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 750 mg (1.23 mmol) in tetrahydrofuran 38 ml, distilled water 38 It melt | dissolved in ml, and contact hydrogen reduction was performed for 1.7 hours at room temperature in presence of 750 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 103 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% of acetonitrile-21% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 384 mg, yield 66%.
[631]
[632] Example 8
[633] (1R, 5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[634]
[635] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[636] 460 mg (1.65 mmol) of 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 8 were dissolved in 23 ml of dimethylformamide. Then, 182 mg (1.98 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 49 ml solution of 981 mg (1.65 mmol) of -methyl-carbafen-2-m-3-carboxylate (1.65 mmol) was added dropwise, followed by addition of 1.15 mL (6.60 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate-5% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [ 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 790 mg, yield 80%.
[637]
[638] (2) (1R, 5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[639] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine- obtained in Example 7 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 790 mg (1.31 mmol) in tetrahydrofuran, 40 ml of distilled water It melt | dissolved in 40 ml, and contact hydrogen reduction was performed for 1.7 hours at room temperature in the presence of 790 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 110 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-4% at acetonitrile-20% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 389 mg, yield 61%.
[640]
[641] Example 9
[642] (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[643]
[644] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[645] 550 mg (1.67 mmol) of 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 9 was dissolved in 28 ml of dimethylformamide. Then, 187 mg (2.03 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 50 ml solution of 993 mg (1.67 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.16 ml (6.68 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) ase. Thidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 346 mg, yield 33%. .
[646]
[647] (2) (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[648] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine- obtained in Example 9 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 340 mg (0.542 mmol) in 17 ml of tetrahydrofuran, distilled water It melt | dissolved in 17 mL, and performed contact hydrogen reduction at room temperature for 2 hours in presence of 340 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 46 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomolecule (elution solvent: distilled water-4% acetonitrile-28% acetonitrile-distilled water), and lyophilized to obtain the target compound (1R, 5S, 6S). -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 159 mg, yield 57%.
[649]
[650] Example 10
[651] (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[652]
[653] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[654] Dissolve 121 mg (1.09 mmol) of 3-acetylthio-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 10 in 19 ml of dimethylformamide. Then, 121 mg (1.31 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 32 ml of acetonitrile (648 mg (1.09 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.759 ml (4.36 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 4-ethyl acetate-5% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [ 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 598 mg, yield 86%.
[655]
[656] (2) (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[657] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine- obtained in Example 10 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 590 mg (0.919 mmol) in 30 ml of tetrahydrofuran, distilled water It melt | dissolved in 30 ml, and contact hydrogen reduction was performed at room temperature for 3 hours in the presence of 590 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 77 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water-4% at acetonitrile-28% acetonitrile-distilled water), and freeze-dried. Target compound (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ Sodium salt of (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as 318 mg as a white solid and yield 66%.
[658]
[659] Example 11
[660] (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[661]
[662] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[663] 410 mg (1.50 mmol) of 3-acetylthio-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 11 was dissolved in 20 ml of dimethylformamide, Hydrazine acetate 138 mg (1.50 mmol) was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 37 ml of acetonitrile (743 mg (1.25 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.873 ml (5.01 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl- 1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate Was obtained as a pale yellow solid at 485 mg, yield 62%.
[664]
[665] (2) (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[666] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine-3- obtained in Example 11 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 480 mg (0.762 mmol) of 24 ml of tetrahydrofuran, 24 ml of distilled water It was dissolved in, and contact hydrogen reduction was carried out at room temperature for 1.3 hours in the presence of 480 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 64 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% of acetonitrile-15% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 236 mg and yield 60%.
[667]
[668] Example 12
[669] (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[670]
[671] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-3-thiazol-2-yl) piperidin-4-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[672] 400 mg (1.27 mmol) of 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 13 were dissolved in 12 ml of dimethylformamide, Hydrazine acetate 152 mg (1.65 mmol) was added at room temperature in nitrogen atmosphere, and it stirred for 2.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 21 ml solution of 755 mg (1.27 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.11 ml (6.37 mmol) of diisopropylethylamine, and then slowly to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated brine and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxy Carbonyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 The carboxylate was obtained as a pale yellow solid at 296 mg, yield 38%.
[673]
[674] (2) (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[675] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine-4- obtained in Example 12 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 291 mg (0.578 mmol) in 14 ml of tetrahydrofuran, 7 ml in distilled water It was dissolved in, and contact hydrogen reduction was conducted for 1.5 hours in a 30 ° C water bath in the presence of 291 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and 42 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomole (elution solvent: distilled water-5% acetonitrile-distilled water-7% acetonitrile-distilled water), and then lyophilized. Compound (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 69 mg, yield 29%.
[676]
[677] Example 13
[678] (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[679]
[680] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-3-thiazol-2-yl) piperidin-4-yl] thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[681] 150 mg (0.353 mmol) of 4-acetylthio-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 was dissolved in 7.5 ml of dimethylformamide. Then, 46 mg (0.49 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 3.0 ml solution of 200 mg (0.353 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.09 ml (0.517 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) pi. Ferridin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a pale yellow solid at 220 mg, yield 89% Got it.
[682]
[683] (2) (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[684] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine obtained in Example 13 (1) 570 mg (0.788 mmol) of 4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate is 38 ml of tetrahydrofuran, It dissolved in 19 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in 30 degreeC water bath in presence of 572 mg of 20% palladium hydroxides. After the reaction was completed, the reaction mixture was filtered, and 132 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using a cosmomolecule (elution solvent: distilled water to 3% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylic acid disodium salt was obtained as a white solid at 285 mg and yield 76%.
[685]
[686] Example 14
[687] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[688]
[689] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[690] 400 mg (1.40 mmol) of 4-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 15 was dissolved in 20 ml of dimethylformamide, followed by nitrogen. At room temperature, 142 mg (1.54 mmol) of hydrazine acetate were added, and it stirred for 2 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.25 g (2.10 mmol) of acetonitrile 37 ml solution of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.61 ml (3.50 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl- 1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as a light yellow solid at 348 mg and yield 42%.
[691]
[692] (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[693] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl obtained in Example 14 (1) ] 4-6 mg (0.839 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was added to 30 ml of tetrahydrofuran and 15 ml of distilled water. It melt | dissolved and contact hydrogen reduction was performed for 2 hours in 30 degreeC water bath in presence of 0.50 g of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction mixture was filtered, and 71 mg of sodium hydrogencarbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction solution to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% acetonitrile-distilled water-5% acetonitrile-distilled water), and then lyophilized. Compound (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 127 mg, yield 32%.
[694]
[695] Example 15
[696] (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[697]
[698] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[699] 1.21 g (4.04 mmol) of 4-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 16 was dissolved in 36 ml of dimethylformamide. Then, 408 mg (4.43 mmol) of hydrazine acetate were added at room temperature under nitrogen atmosphere, and it stirred for 1.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 3.12 g (5.25 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 1.76 mL (10.1 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 20: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl- 1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as a pale yellow solid at 1.336g and yield 55%.
[700]
[701] (2) (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[702] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine- obtained in Example 15 (1) 4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 857 mg (1.424 mol) in 40 ml of tetrahydrofuran, distilled water It melt | dissolved in 20 mL, and contact hydrogen reduction was performed for 2 hours in 30 degreeC water bath in presence of 853 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and 120 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using cosmosil (elution solvent: distilled water-3% acetonitrile-distilled water-2% each acetonitrile-9% acetonitrile-distilled water). (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine-4- as a target compound Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate was obtained as a white solid at 317 mg, yield 46%.
[703]
[704] Example 16
[705] (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[706]
[707] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl ] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[708] 620 mg (1.98 mmol) of 4-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 16 was added to 35 ml of dimethylformamide. It dissolved, and 201 mg (2.18 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 2.35 g (3.96 mmol) of acetonitrile 65 ml solution of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.40 ml (8.04 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N- Dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m 3-carboxylate was obtained as a pale yellow solid at 495 mg, yield 41%.
[709]
[710] (2) (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[711] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperi obtained in Example 16 (1) 22 ml of tetrahydrofuran in 487 mg (0.791 mmol) of din-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate The solution was dissolved in 11 ml of distilled water and subjected to catalytic hydrogen reduction for 1.5 hours in a 30 ° C water bath in the presence of 485 mg of 20% palladium hydroxide. After the completion of reaction, the reaction mixture was filtered, and 67 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using cosmomos (elution solvent: distilled water-5% acetonitrile-distilled water-7% acetonitrile-distilled water-9% acetonitrile-distilled water) And purified by lyophilization to give the desired compound (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidine-4 -Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as 183 mg and yield 46% as a white solid.
[712]
[713] Example 17
[714] (1R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[715]
[716] (1) p-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[717] 210 mg (0.721 mmol) of (3S) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 18 was added to 10 ml of dimethylformamide. It dissolved, and 80 mg (0.865 mmol) of hydrazine acetate were added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 429 mg (0.721 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 0.502 mL (2.88 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride-10% methanol-methylene chloride) to obtain p-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- (4-carba Moyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3- The carboxylate was obtained as a light yellow solid at 412 mg, yield 100%.
[718]
[719] (2) (1R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[720] P-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine obtained in Example 17 (1) 15 ml of tetrahydrofuran, 410 mg (0.715 mmol) of -3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate, It was dissolved in 15 ml of distilled water, and contact hydrogen reduction was carried out at room temperature for 1.7 hours in the presence of 410 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 60 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% of acetonitrile-12% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 150 mg, yield 46%.
[721]
[722] Example 18
[723] (1R, 5S, 6S) -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[724]
[725] (1) p-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[726] 137 mg (0.541 mmol) of (3S) -3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 19 was dissolved in 7 ml of dimethylformamide. Then, 60 mg (0.649 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 16 ml solution of 322 mg (0.541 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise thereto, and then 0.376 ml (2.16 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred for 2 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- ( 4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m 3-carboxylate was obtained as a pale yellow solid at 251 mg, yield 84%.
[727]
[728] (2) (1R, 5S, 6S) -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[729] P-nitrobenzyl (1R, 5S, 6S) -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidine- obtained in Example 18 (1) 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 250 mg (0.450 mmol) in 12 ml of tetrahydrofuran, distilled water It melt | dissolved in 12 ml, and contact hydrogen reduction was performed for 2 hours at room temperature in presence of 250 mg of 10% palladium carbon. After the completion of reaction, the reaction mixture was filtered to add 38 mg of sodium hydrogen carbonate to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% of acetonitrile-15% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 128 mg, yield 64%.
[730]
[731] Example 19
[732] (1R, 5S, 6S) -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[733]
[734] (1) p-nitrobenzyl (1R, 5S, 6S) -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[735] 500 mg (1.84 mmol) of (3R) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 20 was added to 25 ml of dimethylformamide. It melt | dissolved and hydrazine acetate 204 mg (2.21 mmol) was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 1.09 g (1.84 mmol) of acetonitrile 55 ml of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 1.28 mL (7.36 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to 9% methanol-methylene chloride) to obtain p-nitrobenzyl (1R, 5S, 6S) -2-[(3R) -1- (4-carba Moyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3- The carboxylate was obtained as a pale yellow solid at 917 mg, yield 87%.
[736]
[737] (2) (1R, 5S, 6S) -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[738] P-nitrobenzyl (1R, 5S, 6S) -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine obtained in Example 19 (1) 45 ml of 917 mg (1.60 mmol) of -3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate, It was dissolved in 45 ml of distilled water and subjected to catalytic hydrogen reduction at room temperature for 1.7 hours in the presence of 917 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 134 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-2% at acetonitrile-16% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as 338 mg and yield 46% as a white solid.
[739]
[740] Example 20
[741] (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate (4)
[742]
[743] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[744] 20.8 ml of dimethylformamide in 415 mg (1.16 mmol) of 3-acetylthio-1- (4-4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 12 It dissolved in, and 137.0 mg (1.39 mmol) of hydrazine acetate was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 34.4 mL of acetonitrile of 690 mg (1.16 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 1.34 mL (7.69 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-t-butyldimethylsilyloxymethyl-1,3-thia Zol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as yellow syrup 719 mg, the yield was obtained by 94%.
[745]
[746] (2) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[747] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine- obtained in Example 20 (1)- 719 mg (1.09 mmol) of 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was added to 36 ml of anhydrous tetrahydrofuran. It was dissolved, 0.19 mL (3.3 mmol) of acetic acid and 3.3 mL (3.3 mmol) of tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added under ice-cooling, and then stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was further separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-) as a target compound. 1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate Was obtained as a yellow syrup phase, 426.2 mg, yield 72%.
[748]
[749] (3) (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[750] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] obtained in Example 20 (2)] Dissolve 426.2 mg (0.78 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate in 20 ml of tetrahydrofuran and 10 ml of distilled water. In the presence of 530 mg of 20% palladium hydroxide, catalytic hydrogen reduction was carried out at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was filtered, and 65.5 mg of sodium bicarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to 3% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4 -Hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 3-Sodium carboxylate was obtained as a white solid at 156 mg, yield 46%.
[751]
[752] Example 21
[753] (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[754]
[755] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[756] 142 mg (0.56 mmol) of 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 21 were dissolved in 7 ml of dimethylformamide. 62 mg (0.67 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 333 mg (0.56 mmol) of acetonitrile in 333 mg (0.56 mmol) of methyl-carbafen-2-m-3-carboxylate was added dropwise thereto, and then 0.39 mL (2.24 mmol) of diisopropylethylamine was added thereto. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl- 1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate Was obtained as a light yellow solid at 274 mg, yield 88%.
[757]
[758] (2) (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[759] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine-3 obtained in Example 21 (1) -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 344 mg (0.62 mmol) in 17 ml of tetrahydrofuran, distilled water 9 Dissolved in mL, and contact hydrogen reduction was performed for 2 hours in a 30 degreeC water bath in the presence of 20% palladium hydroxide 344 mg. After confirming the completion of the reaction, the reaction mixture was filtered, and 52 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: 5% acetonitrile / distilled water), and lyophilized to be the target compound (1R, 5S, 6S). -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 166 mg, yield 60%.
[760]
[761] Example 22
[762] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[763]
[764] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[765] 275 mg (1.14 mmol) of 3-acetylthio-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 22 were dissolved in 14 ml of dimethylformamide, and were in a nitrogen atmosphere. Then, 126 mg (1.37 mmol) of hydrazine acetate was added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 14 ml solution of 677 mg (1.14 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.79 ml (4.56 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile: methanol = 10: 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl). -1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as a pale yellow solid at 313 mg and yield 51%.
[766]
[767] (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[768] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] obtained in Example 22 (1)] 313 mg (0.582 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was dissolved in 16 ml of tetrahydrofuran and 8 ml of distilled water. In the presence of 313 mg of 20% palladium hydroxide, catalytic hydrogen reduction was carried out in a 30 占 폚 water bath for 2 hours. After the reaction was completed, the reaction mixture was filtered, and 49 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: 5% acetonitrile / distilled water), and lyophilized to be the target compound (1R, 5S, 6S). -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 110 mg, yield 44%.
[769]
[770] Example 23
[771] (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[772]
[773] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[774] 156 mg (0.70 mmol) of 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl) azetidine obtained in Reference Example 23 was dissolved in 8 ml of dimethylformamide, and 77 mg (0.84 mmol) of hydrazine acetate was added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 416 mg (0.70 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 0.49 ml (2.80 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidine -3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 309 mg, yield 84%.
[775]
[776] (2) (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[777] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio obtained in Example 23 (1) -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (21) 309 mg (0.59 mmol) in 16 ml of tetrahydrofuran, 8 ml in distilled water It was dissolved in, and contact hydrogen reduction was performed for 2 hours in a 30 ° C water bath in the presence of 309 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and 50 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using a cosmomolecule (elution solvent: 5% acetonitrile / water), and lyophilized to be the target compound (1R, 5S, 6S). -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 150 mg, yield 60%.
[778]
[779] Example 24
[780] (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[781]
[782] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[783] 247 mg (0.83 mmol) of 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 24 were dissolved in 12 ml of dimethylformamide, 92 mg (1.0 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 25 mL solution of 493 mg (0.83 mmol) of -methyl-carbafen-2-em-3-carboxylate (0.83 mmol) was added dropwise, followed by addition of 0.58 mL (3.32 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 10% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3 -Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a pale yellow solid As a yield, 321 mg and a yield of 65% were obtained.
[784]
[785] (2) (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[786] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine-3- obtained in Example 24 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 321 mg (0.54 mmol) in 15 ml of tetrahydrofuran and 15 ml in distilled water It was dissolved in, and contact hydrogen reduction was performed at room temperature for 2 hours in the presence of 321 mg of 10% palladium carbon. After the completion of reaction, the reaction mixture was filtered, and 45 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water-5% each acetonitrile-15% acetonitrile-distilled water), and freeze-dried. Target compound (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 162 mg and yield 65%.
[787]
[788] Example 25
[789] (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[790]
[791] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[792] 207 mg (0.62 mmol) of 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 25 were dissolved in 8 ml of dimethylformamide. 68.4 mg (0.74 mmol) of hydrazine acetate was added at 0 degreeC under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 370.5 mg (0.62 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 0.43 ml (2.48 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (1,3-thiazole-4-thiomor Pale yellow to polynocarbonyl-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate It obtained 246 mg as a solid and yield 61%.
[793]
[794] (2) (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[795] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine-3 obtained in Example 25 (1) -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 543 mg (0.84 mmol) in tetrahydrofuran, distilled water 30 It melt | dissolved in mL and performed contact hydrogen reduction for 2 hours at room temperature in presence of 543 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 70.6 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water-5% acetonitrile-20% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S). -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 277 mg, yield 62%.
[796]
[797] Example 26
[798] Ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[799]
[800] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R obtained in Example 3 357 mg (0.80 mmol) of 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was dissolved in 5 ml of dimethylacetamide, and the mixture was heated at 0 ° C. under a nitrogen atmosphere. Ethyl iodide 374 mg (2.40 mmol) was added, it stirred as it is for 1 hour, and also it stirred for 2 hours, heating up gradually to room temperature. After the reaction was completed, ethyl acetate was added, and the organic layer was washed sequentially with 10% saline solution, 10% sodium thiosulfate aqueous solution, saturated sodium bicarbonate water and saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then the filtrate was dried under reduced pressure. Concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate). The obtained purified product was dissolved in methylene chloride, and then powdered by sequentially adding diethyl ether and hexane, and then ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3- Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as colorless powder It obtained 387 mg and the yield 95%.
[801]
[802] Example 27
[803] Phenyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[804]
[805] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R obtained in Example 3 162 mg (0.36 mmol) of 1-hydroxyethyl] -1-methyl-carbafen-2-em-3-carboxylic acid sodium salt was dissolved in 1 ml of water and 1 ml of tetrahydrofuran, and 0.33 mL (0.33 mmol) of 1 M hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of acetonitrile, and 102 mg (1.1 mmol) of phenol, 22 mg (0.18 mmol) of dimethylaminopyridine, and 139 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature After adding (0.73 mmol) and stirring for 30 minutes, 139 mg (0.73 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and also it stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, the organic layer was washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate) to obtain phenyl (1R, 5S, 6S)- 2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained as a colorless powder at 66 mg, yield 36%.
[806]
[807] Example 28
[808] Pivaloyloxymethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[809]
[810] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R obtained in Example 3 ) -Hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate 402 mg (0.90 mmol) was dissolved in 5 ml of dimethylacetamide, and the mixture was kept at 0 ° C under a nitrogen atmosphere. 261 mg (1.08 mmol) of methyl iodide iodide was added, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate was added, and the organic layer was washed sequentially with 10% saline solution, 10% sodium thiosulfate aqueous solution, saturated sodium bicarbonate water and saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then the filtrate was dried under reduced pressure. Concentrated. It powdered by adding diethyl ether to the obtained residue, and pivaloyloxymethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) ase Thidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a colorless powder at 450 mg, yield 93%. .
[811]
[812] Example 29
[813] 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[814]
[815] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R obtained in Example 3 245 mg (0.55 mmol) of 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt were dissolved in 5 ml of dimethylacetamide, and the mixture was heated at 0 ° C. under a nitrogen atmosphere. 1-iodine ethyl-isopropyl carbonate 317 mg (1.21 mmol) was added, it stirred for 1.5 hours as it was, and also it stirred for 1.5 hours, heating up gradually to room temperature. After the reaction was completed, ethyl acetate was added, and the organic layer was washed sequentially with 10% saline solution, 0.1M hydrochloric acid, 10% aqueous sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then filtered. The solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate). The obtained purified product was dissolved in methylene chloride, and then powdered by sequentially adding diethyl ether and hexane, thereby obtaining 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [1- ( 4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em 3-carboxylate was obtained as a colorless powder at 266 mg, yield 88%.
[816]
[817] Example 30
[818] 1- (3-pentyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[819]
[820] (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R obtained in Example 3 402 mg (0.90 mmol) of 1-hydroxyethyl] -1-methyl-carbafen-2-em-3-carboxylic acid sodium salt was dissolved in 8 ml of dimethylacetamide, and the mixture was heated at 0 ° C. under a nitrogen atmosphere. 568 mg (1.98 mmol) of 1-iodine ethyl-3-pentyl carbonate were added, and it stirred as it is for 1 hour, and also it stirred for 2 hours, heating up gradually to room temperature. After completion of the reaction, ethyl acetate was added, and the organic layer was washed sequentially with 10% saline solution, 0.1M hydrochloric acid, 10% aqueous sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then filtered. The solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate) to obtain 1- (3-pentyloxycarbonyl Oxy) ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as colorless amorphous, 506 mg, yield 96%.
[821]
[822] Example 31
[823] (1R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[824]
[825] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[826] 235 mg (0.84 mmol) of 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 26 was dissolved in 12 ml of dimethylformamide, 103 mg (110 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred for 3 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 25 ml solution of 499 mg (0.84 mmol) of -methyl-carbafen-2-m-3-carboxylate (0.84 mmol) was added dropwise, followed by addition of 0.56 ml (3.36 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-pyrrolidinocar Bonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car The carboxylate was obtained as a pale yellow solid at 240 mg, yield 46%.
[827]
[828] (2) (1R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[829] Compound p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine-3 obtained in Example 31 (1) -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 240 mg (0.39 mmol) in 12 ml of tetrahydrofuran, 12 in distilled water It melt | dissolved in mL, and contact hydrogen reduction was performed for 1.5 hours in 35 degreeC water bath in the presence of 240 mg of 7.5% palladium carbon. After the completion of reaction, the reaction mixture was filtered, and 33 mg of sodium hydrogencarbonate was added to the filtrate. Acetic acid and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water to 3% acetonitrile-distilled water to 6% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)-. 2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 113 mg, yield 60%.
[830]
[831] Example 32
[832] (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[833]
[834] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[835] 276 mg (0.85 mmol) of 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 27 was dissolved in 20 ml of dimethylformamide, Under nitrogen atmosphere, hydrazine acetate 94 mg (1.02 mmol) was added at room temperature, and it stirred for 2 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 505 mg (0.85 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 0.59 mL (3.40 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-piperidinocar Bonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car The carboxylate was obtained as a light yellow solid at 464 mg, yield 87%.
[836]
[837] (2) (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[838] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine-3- obtained in Example 32 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 464 mg (0.74 mmol) 20 ml of tetrahydrofuran, 20 ml of distilled water It was dissolved in, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 464 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtrated, and 62 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, and chromatographed with cosmos (elution solvent: distilled water-2% acetonitrile-distilled water-5% acetonitrile-distilled water-10% acetonitrile-distilled water-20% acetonitrile-distilled water-30% aceto). (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine-3 as the target compound by purification with nitryl-distilled water) and freeze-drying -Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 171 mg, yield 45%.
[839]
[840] Example 33
[841] (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[842]
[843] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[844] 342 mg (1.15 mmol) of 3-acetylthio-1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 28 were dissolved in 12 ml of dimethylformamide. Then, 127 mg (1.38 mmol) of hydrazine acetate were added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 25 ml of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate 684 mg (1.15 mmol), and then 0.80 ml (4.60 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M brine, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopropyl). Carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 The carboxylate was obtained as a pale yellow solid at 606 mg, yield 88%.
[845]
[846] (2) (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[847] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine- obtained in Example 33 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 606 mg (1.01 mmol) in tetrahydrofuran, distilled water It melt | dissolved in 30 mL, and contact hydrogen reduction was performed for 2.5 hours in 35 degreeC water bath in the presence of 606 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 85 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)-. 2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 275 mg, yield 56%.
[848]
[849] Example 34
[850] (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[851]
[852] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[853] Dissolve 398 mg (1.28 mmol) of 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 29 in 15 ml of dimethylformamide. Then, 141 mg (1.53 mmol) of hydrazine acetate were added at room temperature under nitrogen atmosphere, and it stirred for 2.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 30 ml solution of 761 mg (1.28 mmol) of -methyl-carbafen-2-m-3-carboxylate (1.28 mmol) was added dropwise, followed by addition of 0.88 ml (5.12 mmol) of diisopropylethylamine to the room temperature as it was. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M brine, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclobutyl Carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 The carboxylate was obtained as a pale yellow solid at 578 mg, yield 74%.
[854]
[855] (2) (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[856] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine- obtained in Example 34 (1)- 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 578 mg (0.94 mmol) in 30 ml of tetrahydrofuran, distilled water It melt | dissolved in 30 ml, and contact hydrogen reduction was performed for 2.5 hours in 35 degreeC water bath in presence of 578 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 79 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)-. 2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 322 mg, yield 68%.
[857]
[858] Example 35
[859] (1R, 5S, 6S) -2- {1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[860]
[861] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[862] 1.35 g (3.97 mmol) of 3-acetylthio-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 30 were subjected to dimethylform. It dissolved in 40 ml of amides, added 438 mg (4.76 mmol) of hydrazine acetate at room temperature under nitrogen atmosphere, and stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 2.36 g (3.97 mmol) of acetonitrile 40 ml of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by the addition of 2.77 ml (15.9 mmol) of diisopropylethylamine to the room temperature as it was. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 1: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (4-methyl Piperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3-carboxylate was obtained as a pale yellow solid at 828 mg, yield 60%.
[863]
[864] (2) (1R, 5S, 6S) -2- {1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[865] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazole-2- obtained in Example 35 (1) Il] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 500 mg (0.78 mmol) in tetrahydro It was dissolved in 25 ml of furan and 25 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours in a 35 ° C water bath in the presence of 500% of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered and acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using cosmomos (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-). Purify with 8% acetonitrile-distilled water to 10% acetonitrile-distilled water to 12% acetonitrile-distilled water and freeze-dry to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (4-methyl Piperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3- sodium carboxylate was obtained as a white solid at 192 mg, yield 49%.
[866]
[867] Example 36
[868] (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[869]
[870] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[871] 3-acetylthio-1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 31 was diluted with dimethyl (1.07 mmol). It was dissolved in 18 ml of formamide, 118 mg (1.28 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 32 ml of acetonitrile was added dropwise to 636 mg (1.07 mmol) of -methyl-carbafen-2-m-3-carboxylate, and then 746 µl (4.28 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred for 6 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3- Methoxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbox Bafen-2-m-3-carboxylate was obtained as a pale yellow solid at 636 mg, yield 94%.
[872]
[873] (2) (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[874] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazole-2 obtained in Example 36 (1) -Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate to 630 mg (1.00 mmol) It was dissolved in 32 ml of hydrofuran and 32 ml of distilled water and subjected to catalytic hydrogen reduction at room temperature for 2 hours in the presence of 630 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 84 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 92: 8), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] 1-Methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 239 mg and yield 46%.
[875]
[876]
[877] Example 37
[878] (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[879]
[880] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[881] 893 mg (2.68 mmol) of 3-acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 32 was dissolved in 40 ml of dimethylformamide, followed by nitrogen. Under atmosphere, 296 mg (3.21 mmol) of hydrazine acetate were added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.59 g (3.21 mmol) of acetonitrile 53 ml solution of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.87 ml (10.7 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl). -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as light yellow solid at 1.2g and yield 71%.
[882]
[883] (2) (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[884] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl obtained in Example 37 (1) ] 400 mg (0.63 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was added to 120 ml of tetrahydrofuran and 120 ml of distilled water. It melt | dissolved and contact hydrogen reduction was performed at room temperature for 2 hours in presence of 400 mg of 7.5% palladium carbons. After the reaction was completed, the reaction mixture was filtered, and 53 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, and purified by chromatography using cosmomos (elution solvent: distilled water-4% acetonitrile-distilled water-8% acetonitrile-distilled water-12% acetonitrile-distilled water-16% acetonitrile-distilled water). By lyophilization, the desired compound (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as 211 mg and yield 64% as a white solid.
[885]
[886] Example 38
[887] (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[888]
[889] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazole-2 -Yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[890] 398.2 mg of 3-acetylthio-1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine obtained in Reference Example 33 ( 0.96 mmol) was dissolved in 20 ml of dimethylformamide, and 110 mg (1.19 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 38 ml of acetonitrile was added dropwise to 561.4 mg (0.94 mmol) of -methyl-carbafen-2-m-3-carboxylate, and then 0.7 ml (4.02 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (t-butyl Diphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained as pale yellow syrup phase in 605.3 mg, yield 80%.
[891]
[892] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3 -Yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[893] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3 obtained in Example 38 (1) -Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 605.3 mg ( 0.84 mmol) was dissolved in 30 mL of tetrahydrofuran, 0.15 mL (2.6 mmol) of acetic acid and 2.5 mL (2.5 mmol) of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were added sequentially under ice-cooling, and then room temperature Stirred for 1 day. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethyl Carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 3-carboxylate was obtained as a pale yellow solid at 383.7 mg, yield 75%.
[894]
[895] (3) (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[896] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl obtained in Example 38 (2) ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-carboxylate 383.7 mg (0.64 mmol) in tetrahydrofuran 20 mL and 9.6 mL of distilled water were dissolved, and catalytic hydrogen reduction was performed for 1 hour in a 30 ° C water bath in the presence of 400% of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction mixture was filtered, and 53.4 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-3% acetonitrile-distilled water-5% acetonitrile-distilled water-10% acetonitrile-distilled water) and freeze-dried. 1R, 5S, 6S) -2- {1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 152.2 mg and yield 49%.
[897]
[898] Example 39
[899] (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[900]
[901] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3 -Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[902] 3-acetylthio-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} obtained in Reference Example 34} 610 mg (1.37 mmol) of azetidine were dissolved in 30 ml of dimethylformamide, 152 mg (1.65 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 40 ml of acetonitrile solution of 814 mg (1.37 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 955 µl (5.48 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[( 1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 928 mg, yield 89%.
[903]
[904] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[905] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl obtained in Example 39 (1) ] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car 920 mg (1.23 mmol) of carboxylate were dissolved in 46 mL of tetrahydrofuran, and 208 μL (3.63 mmol) of acetic acid and 3.63 mL (3.63 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were sequentially added under ice-cooling. Then, it stirred at room temperature for 2 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained as a light yellow solid at 437 mg, yield 56%.
[906]
[907] (3) (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[908] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thia obtained in Example 39 (2) Zol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 430 mg (0.681 mmol) ) Was dissolved in 22 ml of tetrahydrofuran and 22 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 4 hours in the presence of 430 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 57 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 94: 6) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as 212 mg and yield 60% as a white solid.
[909]
[910] Example 40
[911] (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[912]
[913] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl]- 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[914] 3-acetylthio-1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazole-2- obtained in Reference Example 35 645 mg (1.50 mmol) of Japanese azetidine was dissolved in 32 ml of dimethylformamide, 166 mg (1.80 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 45 mL solution of 892 mg (1.50 mmol) of -methyl-carbafen-2-em-3-carboxylate (1.50 mmol) was added dropwise, followed by addition of 1.05 mL (6.0 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[( 1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 949 mg and yield 86%.
[915]
[916] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazole- 2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[917] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethyl obtained in Example 40 (1) Carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 940 mg (1.28 mmol) of 3-carboxylate was dissolved in 47 ml of tetrahydrofuran, and 221 µl (3.85 mmol) of acetic acid and 3.85 ml (3.85 mmol) of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were dissolved under ice cooling. It was added sequentially, and then stirred at room temperature for 3 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 99: 1-9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S ) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 462 mg, yield 58%.
[918]
[919] (3) (1R, 5S, 6S) -2- {1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate
[920] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1 obtained in Example 40 (2), 3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 460 mg (0.745 mmol) was dissolved in 23 ml of tetrahydrofuran and 23 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 3 hours in the presence of 460 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 63 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 82: 12) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 179 mg, yield 48%.
[921]
[922] Example 41
[923] (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[924]
[925] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl Rate
[926] 3-acetylthio-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazole obtained in Reference Example 36 500 mg (1.09 mmol) of 2-yl} azetidine was dissolved in 25 ml of dimethylformamide, 121 mg (1.31 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 33 ml of acetonitrile (648 mg (1.09 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 759 µl (4.36 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-1: 4) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [ (1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 694 mg, yield 84%.
[927]
[928] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazole -2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[929] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl- obtained in Example 41 (1) Propylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m 690 mg (0.914 mmol) of 3-carboxylate were dissolved in 35 ml of tetrahydrofuran, and 157 µl (2.74 mmol) of acetic acid and 2.74 ml (2.74 mmol) of 1M-tetrabutylammonium fluoride-tetrahydrofuran were dissolved under ice cooling. Were added sequentially and then stirred at room temperature for 2 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 388 mg, yield 66%.
[930]
[931] (3) (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate
[932] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1 obtained in Example 41 (2) , 3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 380 Mg (0.588 mmol) was dissolved in 19 ml of tetrahydrofuran and 19 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 2 hours in the presence of 380 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 49 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 164 mg and yield 52%.
[933]
[934] Example 42
[935] (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[936]
[937] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl Rate
[938] 3-acetylthio-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole obtained in Reference Example 37 450 mg (0.954 mmol) of 2-yl} azetidine was dissolved in 23 ml of dimethylformamide, 105 mg (1.14 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A 28 ml solution of 567 mg (0.954 mmol) of -methyl-carbafen-2-m-3-carboxylate (acetonitrile) was added dropwise, followed by addition of 665 µl (3.82 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-1: 4) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [ (1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 645 mg, yield 87%.
[939]
[940] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazole -2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[941] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl- obtained in Example 42 (1) Butylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m 640 mg (0.827 mmol) of 3-carboxylate were dissolved in 32 ml of tetrahydrofuran, and 142 µl (2.48 mmol) of acetic acid and 2.48 ml (2.48 mmol) of 1M-tetrabutylammonium fluoride-tetrahydrofuran under ice-cooling Were added sequentially and then stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] 1-Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 302 mg, yield 55%.
[942]
[943] (3) (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate
[944] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1 obtained in Example 42 (2) , 3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 300 Mg (0.455 mmol) was dissolved in 15 ml of tetrahydrofuran and 15 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 2.5 hours in the presence of 300 mg of 10% palladium carbon. After the completion of reaction, the reaction mixture was filtered to add 38 mg of sodium hydrogen carbonate to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 131 mg and the yield 53%.
[945]
[946] Example 43
[947] (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate
[948]
[949] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarba Moyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3- Carboxylate
[950] 3-acetylthio-1- {4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thia obtained in Reference Example 38 Zol-2-yl} azetidine 910 mg (1.93 mmol) was dissolved in 46 ml of dimethylformamide, 213 mg (2.31 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 58 ml of acetonitrile was added dropwise to 1.15 g (1.93 mmol) of -methyl-carbafen-2-m-3-carboxylate, and then 1.34 ml (7.72 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 4) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [ (1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 765 mg, yield 51%.
[951]
[952] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3- Thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[953] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2- obtained in Example 43 (1) -2- Methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2 760 mg (0.982 mmol) of -M-3-carboxylate was dissolved in 38 mL of tetrahydrofuran, and 169 μL (2.95 mmol) of acetic acid and 2.95 mL (1.95 mL of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were dissolved in ice-cooling. mmol) were added sequentially and then stirred at room temperature for 3 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 390 mg, yield 60%.
[954]
[955] (3) (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazole-2 -Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[956] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) obtained in Example 43 (2) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate 390 mg (0.591 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 2 hours in the presence of 390 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered to add 50 mg of sodium hydrogen carbonate to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S, 2S) -1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 136 mg, yield 42%.
[957]
[958] Example 44
[959] (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3- Sodium} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[960]
[961] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethyl Carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 3-carboxylate
[962] 3-acetylthio-1- {4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3 obtained in Reference Example 39. 770 mg (1.45 mmol) of -thiazol-2-yl} azetidine was dissolved in 39 mL of dimethylformamide, and 160 mg (1.74 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 43 ml of acetonitrile was added dropwise to 862 mg (1.45 mmol) of -methyl-carbafen-2-m-3-carboxylate, and then 1.01 ml (5.79 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 2-1: 4) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [ (2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 951 mg, yield 76%.
[963]
[964] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazole-2- Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[965] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyl) obtained in Example 44 (1) Oxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen 950 mg (1.10 mmol) of 2-M-3-carboxylate was dissolved in 48 ml of tetrahydrofuran, and 378 µl (6.60 mmol) of acetic acid and 6.60 ml of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were dissolved under ice cooling. (6.60 mmol) was added sequentially and then stirred at room temperature for 3 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1 to 85: 15) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2- Hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 499 mg, yield 72%.
[966]
[967] (3) (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[968] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3- obtained in Example 44 (2) Thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 490 mg (0.773 mmol) was dissolved in 25 ml of tetrahydrofuran and 25 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 2 hours in the presence of 490 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 65 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 9: 1) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1- Sodium hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid salt was obtained as a white solid at 187 mg, yield 47%.
[969]
[970]
[971] Example 45
[972] (1R, 5S, 6S) -2- (1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[973]
[974] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl} -1,3- Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[975] 3-acetylthio-1- (4- {2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) ase obtained in Reference Example 40 384 mg (0.89 mmol) of thydine was dissolved in 11 ml of dimethylformamide, 99 mg (1.07 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A 22-mL solution of 5.29 mg (0.89 mmol) of acetonitrile-methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 0.62 mL (3.56 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {2- [ (t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 263 mg, yield 50%.
[976]
[977] (2) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[978] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl} obtained in Example 45 (1) -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl Dissolve rate 622 mg (0.85 mmol) in 30 mL of tetrahydrofuran, and sequentially add 0.15 mL (2.55 mmol) of acetic acid and 2.55 mL (2.55 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution under ice-cooling. Then, it stirred at room temperature overnight. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2- Hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 263 mg, yield 50%.
[979]
[980] (3) (1R, 5S, 6S) -2- (1- {4-[(2-hydroxyethyl) -methyl-carbamoyl) -1,3-thiazol-2-yl} azetidine-3 -Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[981] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazole obtained in Example 45 (2) -2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 401 mg (0.65 mmol) Was dissolved in 20 ml of tetrahydrofuran and 20 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 401 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 5 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmoyl (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)- 2- (1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 134 mg and yield 41%.
[982]
[983]
[984] Example 46
[985] (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[986]
[987] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazol-2-yl] ase Thidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[988] Reference Example 41 p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazole- obtained in (10) 2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 209.7 mg ( 0.24 mmol) was dissolved in 10 mL of tetrahydrofuran, and 0.042 mL (0.7 mmol) of acetic acid and 0.72 mL (0.72 mmol) of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were sequentially added under ice-cooling, followed by room temperature. Stirred for 4 days. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbine. Bonylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2 -M-3-carboxylate was obtained as a pale yellow solid at 94.5 mg, yield 53%.
[989]
[990] (2) (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[991] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazole- obtained in Example 46 (1)- 2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 330.4 mg (0.38 mmol) 16.5 mL of tetrahydrofuran and 8.3 mL of distilled water were dissolved, and catalytic hydrogen reduction was performed at room temperature for 2 hours in the presence of 350% of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction mixture was filtrated, and 63.9 mg of sodium bicarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomolecule (elution solvent: distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-carr). Barmoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 -Sodium carboxylic acid disodium salt was obtained as a white solid at 158.7 mg, yield 79%.
[992]
[993] Example 47
[994] (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[995]
[996] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[997] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (t-butyldiphenylsilyloxy) azetidine-1-carbonyl] -1 obtained in Reference Example 42 (2). , 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3- 850 mg (0.878 mmol) of carboxylate were dissolved in 43 ml of tetrahydrofuran, and 301 µl (5.27 mmol) of acetic acid and 5.27 ml (5.27 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were sequentially removed under ice cooling. It was then added and stirred at room temperature for 1 day. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to methylene chloride: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [ 4- (3-hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyl Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a light yellow solid at 355 mg, yield 66%.
[998]
[999] (2) (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1000] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-thiazole-2 obtained in Example 47 (1) -Yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 350 mg (0.568) mmol) was dissolved in 18 ml of tetrahydrofuran and 18 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 2 hours in the presence of 350 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 48 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 9: 1) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] The sodium -1-methyl-carbafen-2-m-3-carboxylic acid salt was obtained as a white solid at 118 mg, yield 42%.
[1001]
[1002]
[1003] Example 48
[1004] (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1005]
[1006] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methyl-p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1007] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methyl-p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thia obtained in Reference Example 43 (3) Zol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 997 Mg (1.15 mmol) was dissolved in 50 mL of tetrahydrofuran, and 0.2 mL (3.44 mmol) of acetic acid and 3.44 mL (3.44 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were sequentially added under ice-cooling. After stirring at room temperature for 2 days. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 19: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methyl-p -Nitrobenzylcarbonylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 413 mg, yield 47%.
[1008]
[1009] (2) (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1010] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methyl-p-nitrobenzylcarbonylmethyl-carbamoyl) -1,3-thiazole obtained in example 48 (1) -2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 413 mg (0.54 mmol) Was dissolved in 20 ml of tetrahydrofuran and 20 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 2 hours in the presence of 413 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 91 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water), and freeze-dried to obtain (1R, 5S, 6S) -2- {1- [4- (carboxymethylmethyl-methyl). -Carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m 3-sodium carboxylic acid sodium salt was obtained as a white solid at 126 mg, yield 43%.
[1011]
[1012]
[1013] Example 49
[1014] (1R, 5S, 6S) -2- [1- (4-N-carbamoylmethyl-N'-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1015]
[1016] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1017] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazole-2- obtained in Reference Example 44 (2) Il] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 932 mg (1.27 mmol) ) Was dissolved in 50 ml of tetrahydrofuran, and 0.22 ml (3.81 mmol) of acetic acid and 3.81 ml (3.81 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were added sequentially under ice-cooling, and then 2 at room temperature. Stirred for one day. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoyl Methyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3-carboxylate was obtained as a light yellow solid at 424 mg, yield 53%.
[1018]
[1019] (2) (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1020] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazole-2- obtained in Example 49 (1) Il] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 424mg (0.67mmol) in tetrahydro It was dissolved in 20 ml of furan and 20 ml of distilled water and subjected to catalytic hydrogen reduction at room temperature for 2 hours in the presence of 424 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 57 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomolecule (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)- 2- {1- [4- (Carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1- Sodium hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid salt was obtained as a white solid at 115 mg, yield 33%.
[1021]
[1022]
[1023] Example 50
[1024] (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1025]
[1026] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidine-3- Yl-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1027] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] obtained in Reference Example 45 (2). Azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 428.6 mg (0.6 mmol) It was dissolved in 21 ml of tetrahydrofuran and 0.11 ml (1.9 mmol) of acetic acid and 1.8 ml (1.8 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were added sequentially under ice-cooling, and then stirred at room temperature for 3 days. It was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 8: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carr) Barmoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 -Carboxylate was obtained as a pale yellow solid in 310.5 mg, yield 85%.
[1028]
[1029] (2) (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1030] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] obtained in Example 50 (1)] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 10.5 mg (0.5 mmol) of tetrahydrofuran 15.5 The solution was dissolved in 7.8 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours in a 35 ° C water bath in the presence of 360% of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction mixture was filtered to add 42.3 mg of sodium bicarbonate to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmosil (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)-. 2- {1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 157 mg, yield 62%.
[1031]
[1032] Example 51
[1033] (1R, 5S, 6S) -2- {1- [4-((1S) -1-carboxy-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1034]
[1035] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl) -propylcarbamoyl]- 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1036] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl) -propyl obtained in Reference Example 46 (3) Carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen- 1.15 g (1.29 mmol) of 2-m-3-carboxylate was dissolved in 58 ml of tetrahydrofuran, and 222 µl (3.87 mmol) of acetic acid and 3.87 ml of 1M-tetrabutylammonium fluoride-tetrahydrofuran solution were dissolved under ice cooling. 3.87 mmol) was added sequentially, followed by stirring at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[( 1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 377 mg and yield 37%.
[1037]
[1038] (2) (1R, 5S, 6S) -2- {1- [4-((1S) -1-carboxyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1039] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl) -propyl obtained in Example 51 (1) Carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 370 mg (0.465 mmol) of 3-carboxylate were dissolved in 19 ml of tetrahydrofuran and 19 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 3 hours in the presence of 370 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 80 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 96: 4) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-carboxyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt was obtained as a white solid at 165 mg, yield 63%.
[1040]
[1041]
[1042] Example 52
[1043] (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1044]
[1045] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazole -2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1046] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1 obtained in Reference Example 47 (3). , 3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3- 930 mg (1.20 mmol) of carboxylate were dissolved in 47 ml of tetrahydrofuran, and 206 µl (3.60 mmol) of acetic acid and 3.60 ml (3.60 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were sequentially removed under ice cooling. It was then added and stirred at room temperature for 2 days. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 383 mg, yield 48%.
[1047]
[1048] (2) (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-sodium carboxylate
[1049] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1 obtained in Example 52 (1) -1 , 3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 380 Mg (0.577 mmol) was dissolved in 19 ml of tetrahydrofuran and 19 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 3 hours in the presence of 380 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 48 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 81: 9) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-sodium carboxylate salt was obtained as a white solid at 170 mg, yield 54%.
[1050]
[1051]
[1052] Example 53
[1053] (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1054]
[1055] (1) 3-acetylthio-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} ase obtained in Reference Example 48 312 mg (0.63 mmol) of thydine was dissolved in 9 ml of dimethylformamide, 70 mg (0.76 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 20 ml of acetonitrile solution of 452 mg (0.76 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.44 ml (2.52 mmol) of diisopropylethylamine, followed by stirring for 4 hours. . After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 193 mg, yield 39%.
[1056]
[1057] (2) (1R, 5S, 6S) -2- {1- [4- (carboxymethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid disodium salt
[1058] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1 obtained in Example 53 (1) -1 , 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 193 Mg (0.24 mmol) was dissolved in 9 ml of tetrahydrofuran and 9 ml of distilled water, and catalytic hydrogen reduction was performed for 3 hours in a 35 ° C water bath in the presence of 193 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 40 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using a cosmomolecule (elution solvent: distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1 -[4- (carboxymethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylic acid disodium salt was obtained as a white solid at 63 mg, yield 45%.
[1059]
[1060] Example 54
[1061] (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1062]
[1063] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1064] 347 mg (0.97 mmol) of 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 49 It was dissolved in 10 ml of formamide, and 108 mg (1.17 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 20 ml of acetonitrile solution of 696 mg (1.17 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 0.68 ml (3.88 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-iso Propyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2- Em-3-carboxylate was obtained as a pale yellow solid at 359 mg, yield 56%.
[1065]
[1066] (2) (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1067] Compound p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazole- obtained in Example 54 (1)- 2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 359 mg (0.55 mmol) It was dissolved in 12 ml of tetrahydrofuran and 12 ml of distilled water, and contact hydrogen reduction was performed for 3 hours in a 35 ° C water bath in the presence of 359 mg of 7.5% palladium hydroxide. After confirming the completion of the reaction, the reaction mixture was filtered, and 46 mg of sodium hydrogencarbonate was added to the filtrate. Acetic acid and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to 2% acetonitrile-distilled water), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4 -(Carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 195 mg, yield 65%.
[1068]
[1069]
[1070] Example 55
[1071] (1R, 5S, 6S) -2- {1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1072]
[1073] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1074] 344 mg (1.01 mmol) of 3-acetylthio-1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 50 were subjected to dimethylform. It dissolved in 10 ml of amides, 112 mg (1.22 mmol) of hydrazine acetate was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 20 ml of acetonitrile solution of 725 mg (1.22 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.70 ml (4.04 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (cyanomethyl -Isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3-carboxylate was obtained as a pale yellow solid at 245 mg, yield 39%.
[1075]
[1076] (2) (1R, 5S, 6S) -2- {1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1077] Compound p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazole-2 obtained in Example 55 (1) -Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate to 245 mg (0.39 mmol) It was dissolved in 12 ml of hydrofuran and 12 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 245 mg of 7.5% palladium carbon. After the completion of reaction, the reaction mixture was filtered, and 33 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was washed with the above-described mixed solvent, concentrated under reduced pressure, and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water) (1R, 5S, 6S) -2- {1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] 87 mg of thidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt as a white solid, yield 42% Got it.
[1078]
[1079]
[1080] Example 56
[1081] (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1082]
[1083] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1, 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1084] 3-acetylthio-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 51. } Azetidine 260 mg (0.500 mmol) was dissolved in 13 ml of dimethylformamide, 55 mg (0.600 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 15 ml solution of 297 mg (0.500 mmol) of methyl-carbafen-2-m-3-carboxylate (0.500 mmol) was added dropwise, followed by addition of 348 µl (2.00 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- ( p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a light yellow solid at 348 mg, yield 85%.
[1085]
[1086] (2) (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1087] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarb obtained in Example 56 (1) Bamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3 340 mg (0.414 mmol) of carboxylates were dissolved in 17 ml of tetrahydrofuran and 17 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 4.5 hours in the presence of 340 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 8: 2), and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -l-hydroxyethyl]- 1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 70 mg, yield 33%.
[1088]
[1089]
[1090] Example 57
[1091] (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1092]
[1093] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl ] -1,3-thiazol-2-yl} azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-car Carboxylate
[1094] 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole obtained in Reference Example 52. 280 mg (0.554 mmol) of 2-yl} azetidine was dissolved in 14 ml of dimethylformamide, and 61 mg (0.665 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 2 hours. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 329 g (0.554 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 356 µl (2.22 mmol) of diisopropylethylamine was added thereto and the temperature was gradually raised to room temperature. Stir overnight while stirring. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 399 mg and yield 89%.
[1095]
[1096] (2) (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1097] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidine- obtained in Example 57 (1) 3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2 390 mg (0.483 mmol) of -M-3-carboxylate was dissolved in 20 mL of tetrahydrofuran and 20 mL of distilled water, and contact hydrogen reduction was performed at room temperature for 4.5 hours in the presence of 390 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out liquid separation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 90 mg, yield 38%.
[1098]
[1099]
[1100] Example 58
[1101] (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1102]
[1103] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl ] -1,3-thiazol-2-yl} azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-car Carboxylate
[1104] 3-acetylthio-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole obtained in Reference Example 53. 280 mg (0.554 mmol) of 2-yl} azetidine was dissolved in 14 ml of dimethylformamide, and 61 mg (0.665 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 329 mg (0.554 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 386 µl (2.22 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 4.6 mg, yield 93%.
[1105]
[1106] (2) (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1107] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidine- obtained in Example 58 (1) 3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2 410 mg (0.508 mmol) of -M-3-carboxylate was dissolved in 21 mL of tetrahydrofuran and 21 mL of distilled water, and contact hydrogen reduction was performed at room temperature for 4.5 hours in the presence of 410 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was washed with the above-described mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomolate (elution solvent: distilled water to distilled water: acetonitrile = 76: 24), and lyophilized to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 101 mg, yield 41%.
[1108]
[1109]
[1110] Example 59
[1111] (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1112]
[1113] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- (p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3 -Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1114] 3-acetylthio-1- {4- [1- (p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} obtained in Reference Example 54} Azetidine 400 mg (0.814 mmol) was dissolved in 20 ml of dimethylformamide, 90 mg (0.977 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 25 ml of acetonitrile (484 mg (0.814 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 568 µl (3.26 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- ( p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 496 mg, yield 77%.
[1115]
[1116] (2) (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1117] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [1- (p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarba obtained in Example 59 (1) Moyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3- Carboxylate 490 mg (0.617 mmol) was dissolved in 25 ml of tetrahydrofuran and 25 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 4.5 hours in the presence of 490 mg of 20% palladium hydroxide. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbafen-2-m-3-carboxylic acid was obtained as white solid at 143 mg, yield 49%.
[1118]
[1119]
[1120] Example 60
[1121] (1R, 5S, 6S) -2- {1- [4- (piperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1122]
[1123] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thia Zol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1124] 3-acetylthio-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine obtained in Reference Example 55 546 mg (1.07 mmol) was dissolved in 15 ml of dimethylformamide, 118 mg (1.29 mmol) of hydrazine acetate was added under ice-cooling under nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 30 ml of acetonitrile solution of 636 mg (1.07 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.22 ml (1.29 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred for 1 hour, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethyl acetate: methanol = 1: 20) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(4- p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl ] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 215 mg, yield 29%.
[1125]
[1126] (2) (1R, 5S, 6S) -2- {1- [4- (piperadino-1-ylcarbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1127] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] obtained in Example 60 (1) -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate 539 mg (0.79 mmol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 539 mg of 7.5% palladium carbon. After the completion of reaction, the reaction solution was filtered, and ethyl acetate and distilled water were added to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Nitrile-distilled water to 13% acetonitrile-distilled water to 16% acetonitrile-distilled water to 20% acetonitrile-distilled water) and purified by lyophilization to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (Piperadino-1-ylcarbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbafen-2-m-3-carboxylic acid was obtained as a white solid at 107 mg, yield 27%.
[1128]
[1129]
[1130] Example 61
[1131] (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1132]
[1133] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazole- 2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1134] 3-acetylthio-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine 330.6 mg obtained in Reference Example 56. (0.68 mmol) was dissolved in 17 ml of dimethylformamide, and 82 mg (0.89 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 21 ml of acetonitrile 426 mg (0.72 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise thereto, and then 0.5 ml (2.9 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (p-nitro Benzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained as light yellow solid at 348.1 mg, yield 66%.
[1135]
[1136] (2) (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1137] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1 obtained in Example 61 (1), 3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 328.4 mg (0.42 mmol) was dissolved in 16.4 ml of tetrahydrofuran and 8.2 ml of distilled water, and catalytic hydrogen reduction was carried out for 2 hours in a 30 ° C water bath in the presence of 328.4 mg of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction mixture was filtered, and an ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was washed with the above-described mixed solvent, concentrated under reduced pressure, and chromatographed using cosmomosil (elution solvent: distilled water-5% acetonitrile-distilled water-10% acetonitrile-distilled water-15% acetonitrile-distilled water) And purified by lyophilization to give the desired compound (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 96.4 mg, yield 49%.
[1138]
[1139] Example 62
[1140] (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1141]
[1142] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3- Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1143] 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} ase obtained in Reference Example 57 Tidine 390 mg (0.793 mmol) was dissolved in 20 ml of dimethylformamide, 88 mg (0.952 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 24 ml solution of 471 mg (0.793 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 552 µl (3.17 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (p-nitro). Benzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 587 mg, yield 93%.
[1144]
[1145] (2) (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidino-1-carbonyl) -1,3-thiazol-2-yl] azetidine-3- Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1146] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (p-nitrobenzyloxycarbonyl) -azetidine-1-carbonyl]-obtained in Example 62 (1)- 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 580 mg (0.731 mmol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 5 hours in the presence of 580 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomole (elution solvent: distilled water to distilled water: acetonitrile = 8: 2) and lyophilized to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 135 mg and yield 39%.
[1147]
[1148]
[1149] Example 63
[1150] (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1151]
[1152] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3 -Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1153] 3-acetylthio-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) obtained in Reference Example 58) Azetidine 348.9 mg (0.71 mmol) was dissolved in 17.5 ml of dimethylformamide, 85.2 mg (0.93 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A 21 ml solution of 420.3 mg (0.71 mmol) of acetonitrile-methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.49 ml (2.8 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {methyl- [2- ( p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 267.5 mg, yield 47%.
[1154]
[1155] (2) (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3 -Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1156] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl obtained in Example 63 (1) } -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car 267.5 mg (0.33 mmol) of carboxylate was dissolved in 14 mL of tetrahydrofuran and 6.7 mL of distilled water, and contact hydrogen reduction was performed for 1.5 hours in a 30 ° C water bath in the presence of 300 mg of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction mixture was filtered, and an ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using cosmomosil (elution solvent: distilled water-5% acetonitrile-distilled water-10% acetonitrile-distilled water-15% acetonitrile-distilled water) And purified by lyophilization to give the desired compound (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -methyl-carbamoyl] -1,3-thiazole-2- 8} mg of aazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-em-3-carboxylic acid as a white solid, yield 51 Obtained in%.
[1157]
[1158] Example 64
[1159] (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1160]
[1161] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3 -Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1162] 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) obtained in Reference Example 59) 618 mg (1.35 mmol) of azetidine were dissolved in 30 ml of dimethylformamide, 149 mg (1.62 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 60 ml solution of 963 mg (1.62 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise thereto, and then 0.94 ml (5.40 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred for 8 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 310 mg, yield 30%.
[1163]
[1164] (2) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazole-2- Ylazetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1165] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl obtained in Example 64 (1) } -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car 4.47 g (5.88 mmol) of the carboxylates were dissolved in 220 mL of tetrahydrofuran, and 0.40 mL (7.06 mmol) of acetic acid and 7.06 mL (7.06 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were added sequentially under ice cooling. Then, it stirred at room temperature for 1 day. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2- Hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 1.79 g and yield 47%.
[1166]
[1167] (3) (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine -3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1168] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3- obtained in Example 64 (2) Thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 1.79 g (2.77 mmol) was dissolved in 90 mL of tetrahydrofuran and 90 mL of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 1.79 g of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 23 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomolecule (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)- 2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as 897 mg and yield 61% as a white solid.
[1169]
[1170]
[1171] Example 65
[1172] (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1173]
[1174] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3 -Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1175] 3-acetylthio-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) obtained in Reference Example 60) Azatidine 746 mg (1.43 mmol) was dissolved in 22 ml of dimethylformamide, 158 mg (1.72 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 1.02 g (1.72 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 1.00 mL (5.72 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred for 3 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 610 mg, yield 52%.
[1176]
[1177] (2) (1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine- 3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1178] P-nitrobenzyl (1R, 5S, 6S) -2- [l- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl obtained in Example 65 (1) } -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car The carboxylate 610 mg (0.74 mmol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 degreeC water bath in the presence of 610 mg of 7.5% palladium carbon. After confirming the completion of the reaction, ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Nitrile-distilled water to 12% acetonitrile-distilled water to 14% acetonitrile-distilled water to 16% acetonitrile-distilled water to 18% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2. -(1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 104 mg, yield 28%.
[1179]
[1180]
[1181] Example 66
[1182] (1R, 5S, 6S) -2- {1- [4-((1S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1183]
[1184] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcart Barmoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -l-hydroxyethyl] -1-methyl-carbafen-2-m-3 Carboxylate
[1185] 3-acetylthio-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3- obtained in Reference Example 61 780 mg (1.50 mmol) of thiazol-2-yl) azetidine was dissolved in 40 mL of dimethylformamide, 166 mg (1.80 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 45 mL solution of 892 mg (1.50 mmol) of -methyl-carbafen-2-m-3-carboxylate (1.50 mmol) was added dropwise, and then 1.05 mL (6.00 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 950 mg, yield 77%.
[1186]
[1187] (2) (1R, 5S, 6S) -2- {1- [4-((1S) -1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1188] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-{(1S) -2-methyl- [l- (p-nitrobenzyloxycarbonylamino) obtained in Example 66 (1) Methyl] -propylcarbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 950 mg (1.15 mmol) of 2-m-3-carboxylate was dissolved in 48 ml of tetrahydrofuran and 48 ml of distilled water, followed by catalytic hydrogen reduction at room temperature for 3 hours in the presence of 950 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was washed with the above-described mixed solvent, concentrated under reduced pressure, purified by chromatography using cosmomolate (elution solvent: distilled water to distilled water: acetonitrile = 76: 24), and lyophilized to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((1S) -1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained in 103 mg, yield 18% as a white solid.
[1189]
[1190]
[1191] Example 67
[1192] (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1193]
[1194] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine-3 -Yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1195] 265.2 mg (0.63 mmol) of 3-acetylthio-1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 62 was diluted with dimethylformamide. It dissolved in 14 ml, and 76.4 mg (0.5 mmol) of hydrazine acetates were added at room temperature in nitrogen atmosphere, and it stirred for 0.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 19 ml solution of 390 mg (0.66 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 0.44 ml (2.5 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzylcarbonyl Amino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m- 3-carboxylate was obtained as a pale yellow solid at 268.4 mg, yield 59%.
[1196]
[1197] (2) (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1198] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazol-2-yl obtained in Example 67 (1) ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 660 mg (0.89 mmol) was added to tetrahydrofuran. 30 ml and 30 ml of distilled water were dissolved, and contact hydrogen reduction was performed for 2 hours in a 35 degreeC water bath in presence of 606 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Purified by nitrile-distilled water to 13% acetonitrile-distilled water to 15% acetonitrile-distilled water and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3- Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid as a white solid It obtained 123 mg and the yield 34%.
[1199]
[1200]
[1201] Example 68
[1202] (1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1203]
[1204] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1205] 13 ml of dimethylformamide, 441 mg (1.39 mmol) of 3-acetylthio-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 63 It dissolved in, and 154 mg (1.67 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion Acetonitrile 26 ml solution of 993 mg (1.67 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 0.97 ml (5.56 mmol) of diisopropylethylamine was added slowly to the room temperature. It stirred for 30 minutes, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3 -Thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a pale yellow solid As a result, 307 mg and yield 53% were obtained.
[1206]
[1207] (2) (1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1208] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] ase obtained in Example 68 (1) 15 ml of tetrahydrofuran of 307 mg (0.52 mmol) of thidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate The solution was dissolved in 15 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 307 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 44 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water) and freeze-dried to obtain the target compound ( 1R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 135 mg, yield 53%.
[1209]
[1210]
[1211] Example 69
[1212] (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1213]
[1214] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1215] 698 mg (2.01 mmol) of 3-acetylthio-1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 64 were dissolved in 20 ml of dimethylformamide. Hydrazine acetate 222 mg (2.41 mmol) was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 40 ml of acetonitrile solution of 1.43 g (2.41 mmol) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 1.40 ml (8.94 mmol) of diisopropylethylamine was added thereto as it was to room temperature. It stirred for 2.5 hours, heating up gradually. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzoylamino- Methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3- The carboxylate was obtained as a pale yellow solid, 851 mg, yield 65%.
[1216]
[1217] (2) (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1218] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine-3 obtained in example 69 (1) -Yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 851 mg (1.31 mmol) in 40 ml of tetrahydrofuran, 40 in distilled water It dissolved in ml, and contact hydrogen reduction was performed for 2 hours in 35 degreeC water bath in presence of 851 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 110 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Purified by nitrile-distilled water to 15% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazole- 2-yl] -azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt as white solid 144 mg, yield 20%.
[1219]
[1220] Example 70
[1221] (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1222]
[1223] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1224] 1.00 g (2.68 mmol) of 3-acetylthio-1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 65 was added to 30 ml of dimethylformamide. It dissolved, 296 mg (3.21 mmol) of hydrazine acetate was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 1.75 g (2.94 mmol) of acetonitrile 60 ml of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.87 ml (10.7 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred for 3 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl ) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car The carboxylate was obtained as a pale yellow solid at 1.13 g and 61% yield.
[1225]
[1226] (2) (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1227] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Example 70 (1) -3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate (1.13 g (1.65 mmol)) in 55 ml of tetrahydrofuran, It dissolved in 55 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in 35 degreeC water bath in the presence of 1.13g of 7.5% palladium carbons. After the reaction was completed, the reaction mixture was filtered, and 139 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-8% acetonitrile-distilled water-12% acetonitrile-distilled water-16% aceto). Purified by nitrile-distilled water to 20% acetonitrile-distilled water) and freeze-dried to obtain the desired compound (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thia Zol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt white solid As a yield, 627 mg and a yield of 66% were obtained.
[1228]
[1229]
[1230] Example 71
[1231] (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1232]
[1233] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} ase Thidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1234] 490 mg (1.52 mmol) of 3-acetylthio-1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidine obtained in Reference Example 66 It was dissolved in 15 ml of dimethylformamide, 169 mg (1.83 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 30 ml solution of 1.09 g (1.83 mmol) of acetonitrile was added dropwise to -methyl-carbafen-2-m-3-carboxylate, and then 1.06 ml (0.68 mmol) of diisopropylethylamine was added thereto, and the mixture was gradually cooled to room temperature. It stirred for 2 and a half hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(thiophene-2-carbonyl-amino) methyl ] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car The carboxylate was obtained as a pale yellow solid at 997 mg, yield 100%.
[1235]
[1236] (2) (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1237] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazole- obtained in Example 71 (1)- 2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 997 mg (1.52 mmol) It was dissolved in 35 ml of tetrahydrofuran and 35 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 997 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 128 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, and chromatographed using cosmomolecule (elution solvent: distilled water-4% acetonitrile-distilled water-8% acetonitrile-distilled water-12% acetonitrile-distilled water-15% acetonitrile-distilled water-20% aceto Purified by nitrile-distilled water) and freeze-dried to obtain (1R, 5S, 6S) -2- (1- {4-[(thiophene-2-carbonyl-amino) methyl] -1,3-thiazole as the target compound. 2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt as white solid It obtained 287 mg and the yield 35%.
[1238]
[1239]
[1240] Example 72
[1241] (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1242]
[1243] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidine -3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1244] 3-41 mg (1.12 mmol) of 3-acetylthio-1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidine obtained in Reference Example 67 It was dissolved in 100 ml of formamide, 123 mg (1.34 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 20 ml solution of 797 mg (1.34 mmol) of 7-methyl-carbafen-2-m-3-carboxylate (1.34 mmol) was added dropwise, followed by addition of 0.78 mL (4.48 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred for 3 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as pale yellow solid at 641 mg and yield 89%.
[1245]
[1246] (2) (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1247] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazole-2 obtained in example 72 (1) -Yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate to 640 mg (1.00 mmol) It was dissolved in 32 ml of hydrofuran and 32 ml of distilled water, and contact hydrogen reduction was performed for 2 hours in a 35 ° C water bath in the presence of 640 mg of 7.5% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 84 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Purified by nitrile-distilled water to 15% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl]- 1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid Sodium salt was obtained as white solid at 218 mg, yield 41%.
[1248]
[1249]
[1250] Example 73
[1251] (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1252]
[1253] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1254] 599 mg (1.60 mmol) of 3-acetylthio-1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 68 was dissolved in 18 ml of dimethylformamide, followed by nitrogen. At room temperature, 177 mg (1.92 mmol) of hydrazine acetate were added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 1.14 g (1.92 mmol) of acetonitrile 36 ml of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 1.11 mL (6.40 mmol) of diisopropylethylamine, and then gradually to room temperature. It stirred for 30 minutes, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1,3-thiazole-2 -Yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate as a pale yellow solid, 640 mg, yield Obtained at 59%.
[1255]
[1256] (2) (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1257] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl obtained in Example 73 (1) ] 640 mg (0.95 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was added to 32 ml of tetrahydrofurans and 32 ml of distilled water. It melt | dissolved and contact hydrogen reduction was performed for 2 hours in 35 degreeC water bath in presence of 640 mg of 7.5% palladium carbons. After the reaction was completed, the reaction mixture was filtered, and 80 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure and chromatographed using cosmomosil (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% aceto). Purified by nitrile-distilled water to 15% acetonitrile-distilled water to 20% acetonitrile-distilled water and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4-phthalimidemethyl-1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt Was obtained as a white solid at 202 mg, yield 38%.
[1258]
[1259]
[1260] Example 74
[1261] (1R, 5S, 6S) -2- [1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1- Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1262]
[1263] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1264] 238 mg (0.73 mmol) of 3-acetylthio-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 69 was dissolved in 7 ml of dimethylformamide, followed by nitrogen. At atmosphere, 81 mg (0.88 mmol) of hydrazine acetate was added at room temperature, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 14 ml solution of 523 mg (0.88 mmol) of -methyl-carbafen-2-m-3-carboxylate (acetone nitrile) was added dropwise, followed by addition of 0.51 ml (2.92 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred for 2 hours, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-succinimidemethyl -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl The rate was obtained as a pale yellow solid at 211 mg and the yield 46%.
[1265]
[1266] (2) (1R, 5S, 6S) -2- [1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1267] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl obtained in Example 74 (1) ] 2-6 mg (0.34 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was added to 10 ml of tetrahydrofuran and 10 ml of distilled water. It melt | dissolved and contact hydrogen reduction was performed for 2 hours in 35 degreeC water bath in presence of 211 mg of 7.5% palladium carbons. After the reaction was completed, the reaction mixture was filtered, and 29 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomolecule (elution solvent: distilled water-2% acetonitrile-distilled water-4% acetonitrile-distilled water) and lyophilized to obtain the target compound (1R, 5S, 6S)- 2- [1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylic acid sodium salt was obtained as a white solid at 115 mg, yield 66%.
[1268]
[1269]
[1270] Example 75
[1271] (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1272]
[1273] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1274] 330 mg (1.17 mmol) of 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 71 was dissolved in 17 ml of dimethylformamide. 130 mg (1.41 mmol) of hydrazine acetate were added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 35 ml of acetonitrile was added dropwise with -methyl-carbafen-2-m-3-carboxylate 696 mg (1.17 mmol), followed by the addition of 815 μl (4.68 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1 , 3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate It obtained as a pale yellow solid at 605 mg, yield 89%.
[1275]
[1276] (2) (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1277] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine-3- obtained in Example 75 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 600 mg (1.03 mmol) in tetrahydrofuran, 30 ml of distilled water It was dissolved in, and contact hydrogen reduction was performed at room temperature for 2 hours in the presence of 600 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and 86 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 9: 1) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3-carboxylic acid sodium salt was obtained as a white solid at 278 mg, yield 58%.
[1278]
[1279]
[1280] Example 76
[1281] (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1282]
[1283] (1) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1284] 260 mg (0.835 mmol) of 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 72 was dissolved in 13 ml of dimethylformamide, 92 mg (1.00 mmol) of hydrazine acetate was added at room temperature in nitrogen atmosphere, and it stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 25 ml solution of 496 mg (0.835 mmol) of -methyl-carbafen-2-em-3-carboxylate (0.835 mmol) was added dropwise, followed by addition of 582 µl (3.34 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1 , 3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate As a pale yellow solid, 552 mg and the yield 100% were obtained.
[1285]
[1286] (2) (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1287] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine-3- obtained in Example 76 (1) Il] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 550 mg (0.835 mmol) in 28 ml of tetrahydrofuran, 28 ml in distilled water It was dissolved in, and contact hydrogen reduction was performed at room temperature for 2.5 hours in the presence of 550 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered to add 70 mg of sodium hydrogen carbonate to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 9: 1) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen- 2-M-3- sodium carboxylate was obtained as a white solid at 193 mg, yield 46%.
[1288]
[1289]
[1290] Example 77
[1291] (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1292]
[1293] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1294] 3-acetylthio-1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine obtained in Reference Example 73 was diluted with dimethyl (1.06 mmol). It was dissolved in 17 ml of formamide, 117 mg (1.27 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it is for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 32 ml of acetonitrile (630 mg (1.06 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 739 µl (4.24 mmol) of diisopropylethylamine was added thereto and the temperature was gradually raised to room temperature. Stir overnight while stirring. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3- Methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbox Bafen-2-m-3-carboxylate was obtained as a pale yellow solid in 550 mg, yield 85%.
[1295]
[1296] (2) (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1297] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-oxazole-2 obtained in Example 77 (1) -Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate to 550 mg (0.896 mmol) It was dissolved in 28 ml of hydrofuran and 28 ml of distilled water and subjected to catalytic hydrogen reduction at room temperature for 2 hours in the presence of 550 mg of 10% palladium carbon. After the completion of the reaction, the reaction mixture was filtered, and 75 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 92: 8) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 276 mg, yield 62%.
[1298]
[1299]
[1300]
[1301] Example 78
[1302] (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1303]
[1304] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3- Oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1305] 3-acetylthio-1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} ase obtained in Reference Example 74. 860 mg (1.61 mmol) of thydine were dissolved in 43 mL of dimethylformamide, 178 mg (1.93 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 hour as it was. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion A solution of 48 ml of acetonitrile was added dropwise to 957 mg (1.61 mmol) of -methyl-carbafen-2-m-3-carboxylate, followed by addition of 1.12 ml (6.44 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- ( t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 1.20 g and yield 89%.
[1306]
[1307] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1308] P-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] obtained in Example 78 (1)] -1,3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxyl 1.20 g (1.43 mmol) of the rate was dissolved in 60 ml of tetrahydrofuran, and 240 µl (4.30 mmol) of acetic acid and 4.30 ml (4.30 mmol) of 1M-tetrabutylammonium chloride-tetrahydrofuran solution were sequentially added under ice-cooling. Then, the mixture was stirred at room temperature for 4 days. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3- Hydroxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbox Bafen-2-m-3-carboxylate was obtained as a pale yellow solid at 325 mg, yield 38%.
[1309]
[1310] (3) (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid sodium salt
[1311] P-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-oxazole-2 obtained in Example 78 (2) -Yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate to 320 mg (0.534 mmol) It was dissolved in 16 ml of hydrofuran and 16 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 5 hours in the presence of 320 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtrated and 45 mg of sodium hydrogencarbonate was added to the filtrate. Ethyl acetate and distilled water were added to this reaction liquid, and liquid separation operation was performed. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 9: 1) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-sodium carboxylate salt was obtained as a white solid at 144 mg and yield 56%.
[1312]
[1313]
[1314] Example 79
[1315] (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1316]
[1317] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-ylcarbonyl] -1,3 -Oxazol-2-yl} azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1318] 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} obtained in Reference Example 75. Azetidine 190 mg (0.383 mmol) was dissolved in 10 ml of dimethylformamide, and 42 mg (0.460 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 11 ml of acetonitrile (228 ml (0.383 mmol)) of -methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by addition of 268 µl (1.53 mmol) of diisopropylethylamine, and the mixture was gradually cooled to room temperature. It stirred overnight, heating up. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- {4- [3- (p-nitro Benzyloxycarbonylamino) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid in 257 mg, yield 86%.
[1319]
[1320] (2) (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1321] P-nitrobenzyl (1R, 5S, 6S) -2- {1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-ylcarbonyl obtained in Example 79 (1) ] -1,3-oxazol-2-yl} azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car 250 mg (0.321 mmol) of carboxylates were dissolved in 13 ml of tetrahydrofuran and 13 ml of distilled water, and catalytic hydrogen reduction was performed at room temperature for 3.5 hours in the presence of 250 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 82: 18) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4- (3-amino-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 68 mg, yield 46%.
[1322]
[1323]
[1324] Example 80
[1325] (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1326]
[1327] (1) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl ] -1,3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car Carboxylate
[1328] 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole obtained in Reference Example 76. 530 mg (1.08 mmol) of 2-yl} azetidine was dissolved in 27 mL of dimethylformamide, 120 mg (1.30 mmol) of hydrazine acetate was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 hour as it is. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 32 ml of acetonitrile was added dropwise with 642 g (1.08 mmol) of -methyl-carbafen-2-m-3-carboxylate, and then 753 µl (4.32 mmol) of diisopropylethylamine was added thereto and the temperature was gradually raised to room temperature. Stir overnight while stirring. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 652 mg, yield 76%.
[1329]
[1330] (2) (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1331] Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidine- obtained in Example 80 (1) 3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2 650 mg (0.821 mmol) of -M-3-carboxylate was dissolved in 33 ml of tetrahydrofuran and 33 ml of distilled water, and contact hydrogen reduction was performed at room temperature for 4.5 hours in the presence of 650 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 76:24) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 129 mg and yield 33%.
[1332]
[1333]
[1334] Example 81
[1335] (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1336]
[1337] (1) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl ] Azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[1338] 280 mg (0.572 mmol) of 3-acetylthio-1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidine obtained in Reference Example 77 ) Was dissolved in 14 ml of dimethylformamide, 63 mg (0.686 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. P-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 in the system under ice-cooling under nitrogen atmosphere after confirmation of reaction completion 340 g (0.572 mmol) of acetonitrile 17 ml solution of -methyl-carbafen-2-m-3-carboxylate was added dropwise, and then 399 µl (2.29 mmol) of diisopropylethylamine was added thereto and the temperature was gradually raised to room temperature. The mixture was stirred for 4.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 10% saline and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((3R) -Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained as a pale yellow solid at 323 mg, yield 73%.
[1339]
[1340] (2) (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid
[1341] Compound p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3- obtained in Example 81 (1) Oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 320 mg (0.404) mmol) was dissolved in 16 ml of tetrahydrofuran and 16 ml of distilled water, followed by catalytic hydrogen reduction at room temperature for 4 hours in the presence of 320 mg of 10% palladium carbon. After the reaction was completed, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer was concentrated under reduced pressure, purified by chromatography using cosmomosil (elution solvent: distilled water to distilled water: acetonitrile = 79:21) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydrate Roxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid was obtained as a white solid at 88 mg, yield 46%.
[1342]
[1343]
[1344] Reference Example 1
[1345] 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine
[1346]
[1347] (1) (3-hydroxyazetidine-1-carbothioyl) carbamic acid ethyl ester
[1348] 20 g (83.6 mmol) of N-benzhydryl-3-hydroxyazetidine was dissolved in 600 ml of methanol, and contact hydrogen reduction was carried out for 2 hours in a 1 atm, 50 ° C. water bath in the presence of 20 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered and the catalyst was removed, and the obtained filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the residue, liquid extraction was performed, and the organic layer was extracted again with distilled water. The obtained aqueous layer was concentrated under reduced pressure to give a reddish brown oily product. Subsequently, after drying under reduced pressure, the compound was dissolved in 180 ml of tetrahydrofuran and 60 ml of distilled water, 19.7 ml (167 mmol) of ethoxycarbonylisothiocyanate was added under ice-cooling, and after 10 minutes, the mixture was returned to room temperature and stirred overnight. It was. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction solution and the solution was extracted. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain (3-hydroxyazetidine-1-carbothioyl) carbamate in the form of a yellow oil. The ester was obtained in 7.4 g, yield 43%.
[1349]
[1350] (2) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1351] 14.4 g (70.5 mmol) of (3-hydroxyazetidine-1-carbothioyl) carbamic acid ethyl ester obtained in Reference Example 1 (1) were dissolved in 72 ml of ethanol and 72 ml of distilled water, and sodium hydroxide was dissolved in the solution. g (353 mmol) was added and the mixture was heated to reflux for 16 hours. After confirming completion of the reaction, the reaction solution was cooled to room temperature and then 88 ml of 4N-hydrochloric acid gas-dioxane solution was added under ice cooling. Subsequently, 17.7 ml (141 mmol) of ethyl-2-bromopyruvate and 19.8 ml (141 mmol) of triethylamine were added to the system, and the mixture was further heated to reflux for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1 to 1: 1) to give 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl as a pale brown solid. ) -3-hydroxyazetidine was obtained in 8.5 g and yield 53%.
[1352]
[1353] (3) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1354] 676 mg (2.96 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 1 (2) was dissolved in 20.5 ml of methylene chloride, 0.28 ml (3.63 mmol) of methanesulfonyl chloride and 0.495 ml (3.56 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After the reaction was completed, ethanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2) to give 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl)-as a pale brown solid. 3-methanesulfonyloxyazetidine was obtained in 748 mg, yield 82%.
[1355]
[1356] (4) 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine
[1357] 37 ml of 742 mg (2.42 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 1 (3) It dissolved in, and added potassium thioacetate 1.11g (9.72mmol) at room temperature, and stirred for 6 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazole- as a light brown solid. 2-yl) azetidine was obtained with 494 mg, yield 71%.
[1358]
[1359] Reference Example 2
[1360] 3-acetylthio-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine
[1361]
[1362] (1) 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine
[1363] 8.5 g (37.2 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 1 (2) were dissolved in 255 ml of dimethylformamide. 19.4 ml (74.5 mmol) of t-butyldiphenylsilyl chloride and 5.07 g (74.5 mmol) of imidazole were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours as it was. After the reaction was completed, 2.59 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Ethyl acetate and 10% brine were then added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-2: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarpoxy as a pale brown solid. Bonyl-1,3-thiazol-2-yl) azetidine was obtained in 14.85 g and the yield 86%.
[1364]
[1365] (2) 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine
[1366] 5.0 g (10.7 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It melt | dissolved in 100 ml of hydrofuran, it dripped at the suspension of 250 ml of anhydrous tetrahydrofuran of 1.22 g (32.1 mmol) of lithium aluminum hydride previously adjusted, it was dripped under ice-cooling in nitrogen atmosphere, and it stirred for 1.5 hours after completion | finish of dripping. After confirmation of reaction completion, magnesium sulfate decahydrate was gradually added to the system under the same conditions, and when foaming from the system subsided, the mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was slowly added into the system, followed by saturated brine. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl) as a white solid. 3.88 g of -1,3-thiazol-2-yl) azetidine was obtained in a yield of 86%.
[1367]
[1368] (3) 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-thiazol-2-yl) azetidine
[1369] 3.88 g (9.15 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (2) was dried with anhydrous methylene chloride. It was dissolved in 194 ml, 19.4 g of active manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 7 hours. After the completion of reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-formyl-) as a white solid. 3.54 g of 1,3-thiazol-2-yl) azetidine was obtained in 92% yield.
[1370]
[1371] (4) 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-2-yl) azetidine
[1372] 3.5 g (8.28 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (3) was dissolved in anhydrous methylene chloride 21. Dissolved in mL, 105 mL of t-butanol and 41.4 mL of 2M 2-methyl-2-butene tetrahydrofuran solution were added into the system. Subsequently, a 21 ml aqueous solution of 1.88 g (16.6 mmol) of sodium chlorite and 1.99 g (16.6 mmol) of sodium dihydrogen phosphate was added dropwise into the system under ice cooling, followed by stirring for 1 hour. After the reaction was completed, ethyl acetate and 1M hydrochloric acid (pH: 2-3) were added to the system. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 5% methanol-ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- (4-carboxy-1,3-thia) on brown syrup. Zol-2-yl) azetidine was obtained in 2.43 g and 67% yield.
[1373]
[1374] (5) 3-t-butyldiphenylsilyloxy-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine
[1375] 224.8 mg (0.51 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (4) was dissolved in anhydrous methylene chloride. It was dissolved in ml, and 0.067 ml (0.76 mmol) of oxalyl chloride and 0.022 ml of catalytic amount of dimethylformamide were added to the system under ice-cooling. After 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure for 1 hour. The residue was again dissolved in 11.2 mL of anhydrous methylene chloride, 157 mg (1.0 mmol) of p-nitrobenzyl alcohol and 0.14 mL (1.0 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-p-nitrobenzylcarbonyl-) as a pale yellow syrup. 1,3-thiazol-2-yl) azetidine was obtained at 93 mg, yield 32%.
[1376]
[1377] (6) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1378] 93 mg (0.16 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (5) It was dissolved in 4.7 mL of anhydrous tetrahydrofuran, 0.028 mL (0.49 mmol) of acetic acid and 0.48 mL (0.48 mmol) of 1M tetrabutylammonium chloride-tetrahydrofuran solution were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) as a pale yellow solid. 3-2.4-hydroxyazetidine was obtained, yield 81%.
[1379]
[1380] (7) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1381] 648 mg (1.93 mmol) of 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 2 (6) was dissolved in anhydrous methylene chloride 20 It dissolved in ml, 0.31 ml (3.95 mmol) of methanesulfonyl chloride and 0.55 ml (3.95 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 3 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized with a mixed solvent of n-hexane-ethyl acetate to give 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxy as a white solid. Azetidine was obtained in 789 mg, yield 99%.
[1382]
[1383] (8) 3-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidine
[1384] 776 mg (1.88 mmol) of 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 2 (7) was dimethylform. It dissolved in 35 ml of amide, added potassium thioacetate 860 mg (7.53 mmol) at room temperature, and stirred for 4 hours in 90 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3- as a light brown solid). Thiazol-2-yl) azetidine was obtained in 73.8 mg, yield 11%.
[1385]
[1386] Reference Example 3
[1387] 3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine
[1388]
[1389] (1) 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine
[1390] 5.85 g (12.5 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was replaced with benzene 290. It dissolved in ml, and 56.4 ml of 0.67M ammonium chloride-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it stirred for 17 hours in 40 degreeC water bath. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1: 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1 as light brown solid). , 3-thiazol-2-yl) azetidine was obtained in 4.97 g, 91% yield.
[1391]
[1392] (2) 1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1393] 6.7 g (15.3 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 3 (1) were subjected to anhydrous tetrahydro It was dissolved in 200 ml of furan, 18.4 ml of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred as it is for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol: ethyl acetate) to obtain 1- (4-carbamoyl-1,3-thia Zol-2-yl) -3-hydroxyazetidine was obtained as a white solid at 2.78 g, yield 91%.
[1394]
[1395] (3) 1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1396] 1.0 g (5.02 mmol) of 1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 3 (2), 30 ml of methylene chloride and 5 ml of pyridine Was dissolved in, and 0.967 ml (12.5 mmol) of methanesulfonyl chloride and 1.75 ml (12.5 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours as it was. After confirming the reaction was completed, 0.405 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue and filtered to obtain 1.30 g of 1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine as a pale yellow solid, yield 94 Obtained in%.
[1397]
[1398] (4) 3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine
[1399] 3.04 g (11.0 mmol) of 1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 3 (3) was added to 152 ml of dimethylformamide. It was dissolved, 7.5 g (65.8 mmol) of potassium thioacetate was added at room temperature, and stirred for 10 hours in an 80 degreeC oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 4% methanol-ethyl acetate) to give 3-acetylthio-1- (4-carbamoyl-1,3-thiazole-2- as a light brown solid. Il) Azetidine was obtained in 1.97 g and yield 70%.
[1400]
[1401] Reference Example 4
[1402] 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine
[1403]
[1404] (1) 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-thiazol-2-yl) azetidine
[1405] 7.73 g (16.6 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) The solution was dissolved in ml, and 75 ml of a 0.67 M ammonium chloride-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, followed by stirring for 17 hours in a 50 ° C water bath. After confirming the reaction was completed, 100 ml of 10% acetic acid water was added into the system under ice cooling, and then ethyl acetate was further added into the reaction system, followed by stirring at room temperature for 30 minutes. The liquid separation operation was performed, and the aqueous layer was liquid-separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-) as a pale yellow solid. 6.98 g of thiazol-2-yl) azetidine was obtained in a yield of 76%.
[1406]
[1407] (2) 1- (4-cyano-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1408] 2.36 g (5.62 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-thiazol-2-yl) azetidine obtained in Reference Example 4 (1) were anhydrous tetrahydrofuran. It melt | dissolved in 115 mL, 6.7 mL (6.7 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution were added under ice cooling, and it stirred as it is for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 2) to obtain 1- (4-cyano-1,3-thiazole- 2-yl) -3-hydroxyazetidine was obtained as a white solid at 0.78 g, yield 77%.
[1409]
[1410] (3) 1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1411] 0.78 g (4.3 mmol) of 1- (4-cyano-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 4 (2) was dissolved in 40 ml of methylene chloride and ice-cooled. 1.0 ml (12.9 mmol) of methanesulfonyl chloride and 1.8 ml (12.9 mmol) of triethylamine were added under 10 minutes, and after 10 minutes, the reaction system was returned to room temperature and stirred for 40 minutes as it was. After confirming completion of the reaction, methanol was added to the system under ice cooling and stirred for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 1) to give 1- (4-nitrile-1,3-thiazol-2-yl) -3-methanesulfonyl as a white solid. Oxyazetidine was obtained in 1.12 g and 100% yield.
[1412]
[1413] (4) 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) -azetidine
[1414] 1.12 g (4.32 mmol) of 1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 4 (3) was dissolved in 56 ml of dimethylformamide. Then, potassium thioacetate 3.89 g (27.0 mmol) was added at room temperature, and it stirred for 4 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 3-acetylthio-1- (4-cyano-1,3-thiazole-2- as a brown solid). Il) -azetidine was obtained in 0.767 g, yield 75%.
[1415]
[1416] Reference Example 5
[1417] 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -azetidine
[1418]
[1419] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1420] 500 mg (1.07 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -azetidine obtained in Reference Example 2 (1) It dissolved in 25 ml, 3.21 ml of 0.67 M methylamine hydrochloride-trimethyl aluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 1.5 hours. After confirming completion of the reaction, 25 ml of 10% acetic acid water and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-) as a light brown solid. 4,79 mg of 1,3-thiazol-2-yl) azetidine was obtained in 99% yield.
[1421]
[1422] (2) 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1423] 4.74 g (10.5 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 5 (1) It was dissolved in 240 ml of anhydrous tetrahydrofuran, 12.6 ml (12.6 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and it stirred for 30 minutes as it is. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-N-methylcarbamoyl-1,3 -Thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid at 2.10 g, yield 96%.
[1424]
[1425] (3) 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1426] 2.15 g (10.1 mmol) of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 5 (2) was added to 45 ml of methylene chloride. It melt | dissolved, 3.12 mL (40.3 mmol) of methanesulfonyl chlorides, and 7.04 mL (50.5 mmol) of triethylamines were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After confirming completion of the reaction, methanol was added to the system under ice cooling and stirred for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to yield 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) as a pale yellow foamy solid. 3-95 methanesulfonyloxyazetidine was obtained in yield 100%.
[1427]
[1428] (4) 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -azetidine
[1429] 3.0 g (10.3 mmol) of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 5 (3) was dimethylformamide. It dissolved in 150 mL, added 7.07 g (61.9 mmol) of potassium thioacetate at room temperature, and stirred for 3 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 4-1: 10) to give 3-acetylthio-1- (4-N-methylcarbamoyl-1) as a light brown solid. , 3-thiazol-2-yl) azetidine was obtained in 2.41 g, yield 86%.
[1430]
[1431] Reference Example 6
[1432] 3-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1433]
[1434] (1) 3-t-butyldiphenylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1435] 500 mg (1.07 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, and added 3.21 ml of 0.67M dimethylamine hydrochloride-trimethylaluminum-benzene solution at room temperature under nitrogen atmosphere, and it heated and refluxed for 2 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- (4-N, N as a light brown solid). 500 mg of -dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine was obtained in 100% yield.
[1436]
[1437] (2) 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1438] 5.13 g (10.7 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 6 (1) ) Was dissolved in 250 ml of anhydrous tetrahydrofuran, 12.0 ml (12.0 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 30 minutes as it was. After the completion of reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 1- (4-N, N-dimethylcarbamoyl-1,3- Thiazol-2-yl) -3-hydroxyazetidine was obtained as a colorless transparent syrup at 2.42 g in yield 100%.
[1439]
[1440] (3) 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1441] 2.56 g (10.7 mmol) of 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 6 (2) The solution was dissolved in ml, and 2.4 ml (31.0 mmol) of methanesulfonyl chloride and 7.4 ml (53.1 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours as it was. After confirming completion of the reaction, methanol was added to the system under ice cooling and stirred for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give 1- (4-N, N-dimethylcarbamoyl-1,3-thiazole in light brown oil form. 2-28) -3-methanesulfonyloxyazetidine was obtained in 3.28 g with a yield of 100%.
[1442]
[1443] (4) 3-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1444] 3.40 g (11.1 mmol) of 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 6 (3) It was dissolved in 170 ml of formamide, 7.62 g (66.7 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 3 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 4: 1: 5: 1: 7: 1) to give 3-acetylthio-1- (4-N, N- in brown syrup). 2.71 g of dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine were obtained in a yield of 85%.
[1445]
[1446] Reference Example 7
[1447] 3-acetylthio-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1448]
[1449] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1450] 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, and 6.42 ml of 0.67M ethylamine hydrochloride-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 2 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1-1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-ethyl as a light brown solid). Carbamoyl-1,3-thiazol-2-yl) azetidine was obtained in 997 mg, yield 100%.
[1451]
[1452] (2) 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1453] 990 mg (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 7 (1) It was dissolved in 30 ml of anhydrous tetrahydrofuran, 2.56 ml (2.56 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and it stirred for 1.3 hours as it is. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate-5% methanol-ethyl acetate) to obtain 1- (4-N-ethylcarbamoyl-1,3- Thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid at 461 mg, yield 95%.
[1454]
[1455] (3) 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1456] 460 mg (2.02 mmol) of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 7 (2) was added to 23 ml of methylene chloride. It melt | dissolved, 0.469 mL (6.06 mmol) of methanesulfonyl chlorides, and 0.849 mL (6.06 mmol) of triethylamines were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.3 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to give 1- (4-N-ethylcarbamoyl-1,3-thiazole- as a pale yellow solid. 598 mg, yield 97% of 2-yl) -3-methanesulfonyloxyazetidine were obtained.
[1457]
[1458] (4) 3-acetylthio-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1459] 590 mg (1.93 mmol) of 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 7 (3) was added to dimethylformamide. It dissolved in 30 ml, 1.32 g (11.6 mmol) of potassium thioacetate was added at room temperature, and it stirred overnight in an 80 degreeC oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 2) to give 3-acetylthio-1- (4-N-ethylcarbamoyl-1) as a light brown solid. 4,3-thiazol-2-yl) azetidine was obtained in 82% yield.
[1460]
[1461] Reference Example 8
[1462] 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1463]
[1464] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1465] 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, 6.42 ml of 0.67M isopropylamine hydrochloride-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 2.5 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid. 1.01 g, yield 99% was obtained.
[1466]
[1467] (2) 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1468] 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine 1.01 g (2.11 mmol) obtained in Reference Example 8 (1). The solution was dissolved in 30 ml of anhydrous tetrahydrofuran, and 2.53 ml (2.53 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, followed by stirring for 30 minutes. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to give 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl ) -3-hydroxyazetidine as a white solid, 681 mg, yield 100%.
[1469]
[1470] (3) 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1471] 15 ml of methylene chloride 490 mg (2.03 mmol) of 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 8 (2) Was dissolved in, and 0.471 ml (6.09 mmol) of methanesulfonyl chloride and 0.854 ml (6.09 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to give 1- (4-N-isopropylcarbamoyl-1,3-thiazole as a pale yellow solid. 281-yl) -3-methanesulfonyloxyazetidine was obtained with 681 mg and 100% yield.
[1472]
[1473] (4) 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1474] 680 mg (2.03 mmol) of 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 8 (3) was dimethylform. It dissolved in 35 ml of amide, added potassium thioacetate 1.39 g (12.2 mmol) at room temperature, and stirred overnight in an 80 degreeC oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 461 mg of 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine as a pale brown solid, yield 81%. Got it.
[1475]
[1476] Reference Example 9
[1477] 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1478]
[1479] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1480] 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, 6.42 ml of 0.67 M cyclopentylamine trimethyl aluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 5 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid. It obtained 1.07 g and yield 99%.
[1481]
[1482] (2) 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1483] 1.07 g (2.12 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 9 (1) The solution was dissolved in 32 ml of anhydrous tetrahydrofuran, 2.54 ml (2.54 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 40 minutes as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to give 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl ) -3-hydroxyazetidine was obtained as a white solid at 528 mg, yield 93%.
[1484]
[1485] (3) 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1486] 16 ml of methylene chloride 520 mg (1.95 mmol) of 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 9 (2) It dissolved in, and methanesulfonyl chloride 0.452 mL (5.84 mmol) and triethylamine 0.818 mL (5.84 mmol) was added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2 to ethyl acetate) to give 1- (4-N-cyclopentylcarbamoyl-1,3-thiazole as a pale yellow solid. 2-91) -3-methanesulfonyloxyazetidine was obtained with 691 mg of yield 100%.
[1487]
[1488] (4) 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1489] 670 mg (1.95 mmol) of 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 9 (3) was subjected to dimethylform. It dissolved in 34 ml of amide, added 1.34 g (11.7 mmol) of potassium thioacetate at room temperature, and stirred overnight in an 80 ° C oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to give 3-acetylthio-1- (4-N-cyclopentylcarbamoyl) as a light brown solid. 1,3-thiazol-2-yl) -3-azetidine was obtained in 550 mg, yield 87%.
[1490]
[1491] Reference Example 10
[1492] 3-acetylthio-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1493]
[1494] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1495] 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, 6.42 ml of 0.67 M cyclohexylamine trimethyl aluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 2 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1-1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclocyclone) as a light brown solid. Hexylcarbamoyl-1,3-thiazol-2-yl) azetidine was obtained in 1.09 g and 99% yield.
[1496]
[1497] (2) 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1498] 1.09 g (2.10 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 10 (1) Was dissolved in 55 mL of anhydrous tetrahydrofuran, 2.52 mL (2.52 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1.5 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain 1- (4-N-cyclohexylcarbamoyl-1,3-thiazole-2- Il) -3-hydroxyazetidine was obtained as a white solid at 570 mg, yield 97%.
[1499]
[1500] (3) 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1501] Methyl chloride 17 ml of 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 10 (2) It was dissolved in, and 0.471 mL (6.08 mmol) of methanesulfonyl chloride and 0.852 mL (6.08 mmol) of triethylamine were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 17 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, followed by filtration to obtain 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine as a pale yellow solid. Mg, yield 100%.
[1502]
[1503] (4) 3-acetylthio-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1504] 730 mg (2.03 mmol) of 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 10 (3) was dimethylform. It dissolved in 37 mL of amides, added potassium thioacetate 1.39 g (12.2 mmol) at room temperature, and stirred for 15 hours in an 80 degreeC oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to give 3-acetylthio-1- (4-N-cyclohexylcarbamoyl) as a pale brown solid. 1,3-thiazol-2-yl) azetidine was obtained with 372 mg and yield 54%.
[1505]
[1506] Reference Example 11
[1507] 3-acetylthio-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1508]
[1509] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1510] 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) It dissolved in ml, and 6.42 ml of 0.67M morpholine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 2 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- (4-morpholinoca) as a light brown solid. Obtained 1.05 g of the carbonyl-1,3-thiazol-2-yl) azetidine in 97% yield.
[1511]
[1512] (2) 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1513] 1.05 g (2.07 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 11 (1) was anhydrous. It was dissolved in 32 ml of tetrahydrofuran, and 2.48 ml (2.48 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate) to give 1- (4-morpholinocarbonyl-1,3 -Thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid at 542 mg, yield 97%.
[1514]
[1515] (3) 1- (4-N-morpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1516] 540 mg (2.01 mmol) of 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 11 (2) was dissolved in 27 ml of methylene chloride. Then, 0.467 mL (6.03 mmol) of methanesulfonyl chloride and 0.845 mL (6.03 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it is. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate) to give 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-methane as a pale yellow solid. Sulfonyloxyazetidine was obtained with 688 mg and 99% yield.
[1517]
[1518] (4) 3-acetylthio-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1519] 680 mg (1.96 mmol) of 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 11 (3) was added to dimethylformamide 20. It dissolved in mL, added 671 mg (5.87 mmol) of potassium thioacetate at room temperature, and stirred for 18 hours in 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to give 3-acetylthio-1- (4-morpholinocarbonyl-1,3 as a light brown solid). -Thiazol-2-yl) azetidine was obtained in 411 mg, yield 64%.
[1520]
[1521] Reference Example 12
[1522] 3-acetylthio-1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine
[1523]
[1524] (1) 1- (4-hydroxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1525] 548.9 mg (1.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (2) was substituted with anhydrous tetrahydro It dissolved in 28 mL of furan, 1.56 mL (1.56 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, and it stirred as it is for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- (4-hydroxymethyl-1,3-thiazole. 2-yl) -3-hydroxyazetidine was obtained as a white solid at 230 mg, yield 96%.
[1526]
[1527] (2) 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1528] 226.5 mg (1.22 mmol) of 1- (4-hydroxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 12 (1) was dissolved in 11.5 ml of dimethylformamide. Under ice-cooling, 220 mg (1.46 mmol) of t-butyldimethylsilyl chloride and 120 mg (1.76 mmol) of imidazole were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 5 hours as it was. After confirming the reaction was completed, 2 ml of methanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazole-2- as a white solid. I) -3-hydroxyazetidine was obtained in 300.4 mg, yield 82%.
[1529]
[1530] (3) 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1531] 15 ml of methylene chloride 300.4 mg (1.00 mmol) of 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 12 (2) Was dissolved in, and 0.2 ml (2.49 mmol) of methanesulfonyl chloride and 0.35 ml (2.51 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate = 1: 1) to give 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazole-2- on yellow syrup. Il) -3-methanesulfonyloxyazetidine was obtained at 326.5 mg, yield 86%.
[1532]
[1533] (4) 3-acetylthio-1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine
[1534] 326.5 mg (0.86 mmol) of 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 12 (3) was subjected to dimethylform. It was dissolved in 16 ml of amide, potassium thioacetate 780 mg (5.41 mmol) was added at room temperature, and it stirred for 2 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1) to give 3-acetylthio-1- (4-t-butyldimethylsilyloxymethyl-1,3- on brown syrup. Thiazol-2-yl) azetidine was obtained in 191 mg, yield 62%.
[1535]
[1536] Reference Example 13
[1537] 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine
[1538]
[1539] (1) (4-hydroxypiperidine-1-carbothioyl) carbamic acid ethyl ester
[1540] 1.0 g (9.89 mmol) of 3-hydroxypiperidine was dissolved in 50 mL of tetrahydrofuran, 1.4 mL (11.9 mmol) of ethoxycarbonylisothiocyanate was added under ice-cooling, and after 10 minutes, the temperature was returned to room temperature overnight. Stirred. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction solution and the solution was extracted. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 2) to give 2.3 g of (4-hydroxypiperidine-1-carbothioyl) carbamic acid ethyl ester in the form of a yellow oil. And yield 100%.
[1541]
[1542] (2) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine
[1543] 2.3 g (9.89 mmol) of (4-hydroxypiperidine-1-carbothioyl) carbamic acid ethyl ester obtained in Reference Example 13 (1) were dissolved in 23 ml of ethanol and 23 ml of distilled water, and sodium hydroxide was added to the solution. 1.98g (49.5mmol) was added and it heated and refluxed for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then 12.4 mL of 4N-hydrochloric acid gas-dioxane solution was added under ice cooling. Subsequently, 2.5 mL (19.8 mmol) of ethyl-2-bromopyruvate and 2.8 mL (20.1 mmol) of triethylamine were added to the system, and the mixture was further heated to reflux for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 2: 1) to give 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4- in pale yellow syrup. 0.99 g of hydroxypiperidine was obtained in a yield of 39%.
[1544]
[1545] (3) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine
[1546] 128 mg (0.50 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 13 (2) was dissolved in 6.5 ml of methylene chloride. Then, 0.043 mL (0.56 mmol) of methanesulfonyl chloride and 0.084 mL (0.60 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 30 minutes as it was. After confirming the reaction was completed, 1 ml of ethanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-n-hexane = 5: 1 to give 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperi as a white solid. Dean was obtained with 81.0 mg and yield 49%.
[1547]
[1548] (4) 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine
[1549] 76 mg (0.23 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine obtained in Reference Example 13 (3) was prepared using dimethylformamide 4.0. The solution was dissolved in mL, and potassium thioacetate 145 mg (1.3 mmol) was added at room temperature, followed by stirring in a 90 ° C oil bath for 8 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazole- as a light brown solid. 2-yl) piperidine was obtained in 67 mg, 94% yield.
[1550]
[1551] Reference Example 14
[1552] 4-acetylthio-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) piperidine
[1553]
[1554] (1) 4-t-butyldimethylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine
[1555] 1.00 g (3.90 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 13 (2) was added to 50 ml of dimethylformamide. The solution was dissolved, 1.2 g (7.96 mmol) of t-butyldimethylsilyl chloride and 0.6 g (8.8 mmol) of imidazole were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 18 hours as it was. After the reaction was completed, ethanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1) to give 4-t-butyldimethylsilyloxy-1- (4-ethoxycarbonyl-1, in the form of a pale yellow oil. 3-thiazol-2-yl) azetidine was obtained in 1.38 g and 95% yield.
[1556]
[1557] (2) 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine
[1558] 1.0 g (2.7 mmol) of 4-t-butyldimethylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (1) was replaced with ethanol 20 The solution was dissolved in mL, and 5.4 mL (5.4 mmol) of 1N-sodium hydroxide aqueous solution was added under ice-cooling, followed by stirring at room temperature for 3.5 hours. After confirming the completion of the reaction, 1.8 ml of 2N hydrochloric acid was added under ice-cooling. (In-situ pH: 6-5) After that, ethyl acetate was slowly added into the system, followed by saturated brine. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from methanol-ethyl acetate to obtain 471 mg of primary crystals as white crystals. The residue obtained by concentrating the mother liquor was then purified by silica gel column chromatography (elution solvent: ethyl acetate: 2-propanol: water = 10: 4: 1-5: 2: 1) to give 4-t-butyldimethyl as a white solid. 440 mg of silyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine was obtained, which was obtained in a total of 911 mg and a yield of 99%.
[1559]
[1560] (3) 4-t-butyldimethylsilyloxy-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine
[1561] 902 mg (2.63 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) was dissolved in anhydrous methylene chloride 40 710 mg (5.3 mmol) of hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC), dissolved in ml, and cooled on ice under nitrogen atmosphere, 1.254 g (6.6 mmol), 788 mg (5.2 mmol) of p-nitrobenzyl alcohol was added, and it stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-t-butyldimethylsilyloxy-1- (4-p-nitrobenzyloxycarbonyl-) as a yellow solid. 1,3-thiazol-2-yl) piperidine was obtained in 916 mg, yield 73%.
[1562]
[1563] (4) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine
[1564] 300 mg (0.628 mmol) of 4-t-butyldimethylsilyloxy-1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (3) It was dissolved in 15 ml of anhydrous tetrahydrofuran, 0.22 ml (3.84 mmol) of acetic acid and 3.76 ml (3.76 mmol) of 1M tetrabutylammonium fluoride-tetrahydrofuran solution were added under ice-cooling, followed by stirring at room temperature for 21 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) as a pale yellow solid. It obtained 123 mg of 4-hydroxypiperidine and the yield 54%.
[1565]
[1566] (5) 4-methanesulfonyloxy-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine
[1567] 0.75 g (2.06 mmol) of 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 14 (4) was dried with anhydrous methylene chloride. It dissolved in 38 ml, 0.18 ml (2.33 mmol) of methanesulfonyl chloride and 0.35 ml (2.51 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 4-methanesulfonyloxy-1- (4-p-nitrobenzyloxycarbonyl-1, a colorless solid). 3-thiazol-2-yl) piperidine was obtained in 0.87 g, yield 96%.
[1568]
[1569] (6) 4-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine
[1570] 4-methanesulfonyloxy-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine 1.2 g (2.72 mmol) obtained in Reference Example 14 (5) was dimethyl. It was dissolved in 60 ml of formamide, 625 mg (5.47 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 3.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3- as a light brown solid). Thiazol-2-yl) piperidine was obtained with 769 mg, yield 88%.
[1571]
[1572] Reference Example 15
[1573] 4-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine
[1574]
[1575] (1) 4-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine
[1576] 150 ml of methylene chloride in 4.99 g (14.6 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) It dissolved in, and added 2.80 g (17.3 mmol) of carbonyldiimidazole at room temperature under nitrogen atmosphere, and stirred for 1.5 hours on the same conditions. After confirming the raw material loss, 8.7 ml of 28% aqueous ammonia was then added to the system and stirred for 30 minutes at room temperature. Subsequently, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated brine were added to the residue to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) obtained as a pale yellow solid 4-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazole 2-yl) piperidine was obtained in 2.90 g and 59% yield.
[1577]
[1578] (2) 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine
[1579] 1.226 g (3.59 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 15 (1) was substituted with anhydrous tetrahydro It dissolved in 30 ml of furan, 1.85 ml (32.3 mmol) of acetic acid and 32.3 ml (32.3 mmol) of 1.0 M tetra-n-butylammonium chloride-tetrahydrofuran solution were added under ice cooling, and it stirred for 24 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine. Was obtained as a white solid at 0.82 g, yield 100%.
[1580]
[1581] (3) 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine
[1582] Reference Example 15 1.93 g (8.49 mmol) of 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in (2) was dissolved in 100 ml of methylene chloride, and Under ice-cooling, 10.0 ml (129 mmol) of methanesulfonyl chloride and 18.0 ml (129 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 24 hours as it was. After confirming the reaction was completed, methanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to yield 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-methane as a pale yellow solid. The sulfonyloxypiperidine (31a) was obtained in 1.59 g and 61% yield.
[1583]
[1584] (4) 4-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine
[1585] 1.59 g (5.21 mmol) of 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine (31a) obtained in Reference Example 15 (3) was dimethylform. It dissolved in 80 ml of amides, added 1.19 g (10.4 mmol) of potassium thioacetate at room temperature, and stirred for 2.5 hours in a 90 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 10: 1) to give 4-acetylthio-1- (4-carbamoyl-1,3-thiazole-2 as a brown solid. -Yl) piperidine was obtained in 1.01 g and yield 68%.
[1586]
[1587] Reference Example 16
[1588] 4-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1589]
[1590] (1) 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1591] 200 mg (0.584 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) 6.0 It dissolved in mL, and 114 mg (0.703 mmol) of carbonyldiimidazole were added at room temperature in nitrogen atmosphere, and it stirred for 3 hours in 50 degreeC oil bath. After confirming the disappearance of the raw materials, 0.23 ml of 40% aqueous methylamine solution was subsequently added to the system, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 4) to give 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1) as a light brown solid. , 3-thiazol-2-yl) piperidine was obtained in 202.5 mg, yield 97%.
[1592]
[1593] (2) 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxypiperidine
[1594] 1.69 g (4.75 mmol) of 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 16 (1). Dissolve in 85 ml of anhydrous tetrahydrofuran, add 1.36 ml (23.8 mmol) of acetic acid and 23.8 ml (23.8 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling, and Stirred for 14.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-N-methylcarbamoyl-1,3 -Thiazol-2-yl) -4-hydroxypiperidine was obtained as a white solid in 1.48 g, 97% yield.
[1595]
[1596] (3) 4-methanesulfonyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1597] 35 ml of methylene chloride 1.143 g (4.74 mmol) of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 16 (2) Was dissolved in, and 0.44 mL (5.68 mmol) of methanesulfonyl chloride and 0.86 mL (5.68 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 4 hours as it was. After confirming the reaction was completed, methanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the resultant was filtered to obtain 1.438 g of a pale yellow solid of 4-methanesulfonyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine. And yield 95%.
[1598]
[1599] (4) 4-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1600] Reference Example 16 1.438 g (4.50 mmol) of 4-methanesulfonyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine obtained in (3) was dimethylform. It dissolved in 72 ml of amides, added 1.03 g (9.00 mmol) of potassium thioacetate at room temperature, and stirred for 2.5 hours in a 90 ° C oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 10: 1 to ethyl acetate) to give 4-acetylthio-1- (4-N-methylcarbamoyl-1, a light brown solid). 3-thiazol-2-yl) piperidine was obtained in 1.22 g and 91% yield.
[1601]
[1602] Reference Example 17
[1603] 4-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1604]
[1605] (1) 4-t-butyldimethylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1606] 0.98 g (2.86 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) was diluted with dimethylformamide. It melt | dissolved in mL, 559 mg (3.45 mmol) of carbonyldiimidazole were added under nitrogen atmosphere at room temperature, and it stirred for 3 hours in 50 degreeC oil bath. After confirming the disappearance of the raw materials, 100 ml of 50% aqueous dimethylamine solution was subsequently added to the system, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 3) to give 4-t-butyldimethylsilyloxy-1- (4-N, N-dimethylcarba in the form of a pale yellow oil. Moyl-1,3-thiazol-2-yl) piperidine was obtained in 995 mg, yield 94%.
[1607]
[1608] (2) 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine
[1609] Reference Example 17 2-13 g (5.76 mmol) of 4-t-butyldimethylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidine obtained in (1). ) Was dissolved in 85 ml of anhydrous tetrahydrofuran, and 1.65 ml (28.8 mmol) of acetic acid and 28.8 ml (28.8 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution were added under ice-cooling, Stir for 1.5 hours in the bath. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- (4-N, N-dimethylcarbamoyl-1. , 3-thiazol-2-yl) -4-hydroxypiperidine was obtained as a white solid at 1.47 g in 100% yield.
[1610]
[1611] (3) 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine
[1612] Methylene chloride 1.47 g (5.76 mmol) of 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 17 (2) It was dissolved in 60 mL, 0.82 mL (10.6 mmol) of methanesulfonyl chloride and 1.48 mL (10.6 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After confirming the reaction was completed, methanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to yield 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl as a pale yellow solid. ) -4-methanesulfonyloxypiperidine was obtained in 1.38 g and yield 72%.
[1613]
[1614] (4) 4-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidine
[1615] 1.33 g (3.99 mmol) of 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine obtained in Reference Example 17 (3) It was dissolved in 66 ml of dimethylformamide, 940 mg (8.23 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 3.0 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 5: 1-7: 1) to give 4-acetylthio-1- (4-N, N-dimethylcarbamoyl) as a light brown solid. 629 mg of -1,3-thiazol-2-yl) piperidine was obtained with a yield of 50%.
[1616]
[1617] Reference Example 18
[1618] (3S) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1619]
[1620] (1) {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester
[1621] 15 g (121.4 mmol) of (3R) -3-hydroxypyrrolidine hydrochloride were dissolved in 450 ml of tetrahydrofuran, 15.7 ml of ethoxycarbonylisothiocyanate was added under ice-cooling, and after 10 minutes, the temperature was returned to room temperature overnight. Stirred. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction solution and the solution was extracted. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate-n-hexane, and then collected by filtration to obtain 24.62 g of {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester as yellow crystals. Yield was 93%.
[1622]
[1623] (2) (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine
[1624] Reference Example 18 24.6 g (113 mmol) of {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester obtained in (1) were dissolved in 125 ml of ethanol and 125 ml of distilled water, and the solution Sodium hydroxide 31.6g (789mmol) was added, and it heated and refluxed overnight. After confirming the reaction was completed, the reaction solution was cooled to room temperature, and then 4N-hydrochloric acid gas-dioxane solution was added until pH 7 under ice cooling. Subsequently, 28.4 ml (226 mmol) of ethyl-2-bromopyruvate and 31.7 ml (226 mmol) of triethylamine were added and refluxed for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1: 1: 2) to give (3R) -1- (4-ethoxycarbonyl-1,3-thiazole as a light brown solid. 2-yl) -3-hydroxypyrrolidine was obtained at 19.26 g with a yield of 70%.
[1625]
[1626] (3) (3R) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine
[1627] (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine 3.0 g (12.4 mmol) obtained in Reference Example 18 (2) was subjected to dimethylform. It was dissolved in 90 ml of amide, 6.45 ml (24.8 mmol) of t-butyldiphenylsilyl chloride and 1.69 g (24.8 mmol) of imidazole were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred overnight. After the reaction was completed, 0.86 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Ethyl acetate and 10% brine were then added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1-1: 1) to give a pale brown solid (3R) -3-t-butyldiphenylsilyloxy-1- (4 5.85 g of -ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine was obtained in a yield of 90%.
[1628]
[1629] (4) (3R) -3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) pyrrolidine
[1630] 300 mg (0.624) of (3R) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 18 (3) mmol) was dissolved in 12 ml of ethanol and 3 ml of distilled water, and 1.56 ml (1.56 mmol) of a 1N-sodium hydroxide aqueous solution was added at room temperature, followed by stirring at room temperature for 6 hours. After confirming the reaction was completed, 1N hydrochloric acid was added under ice-cooling. (In-situ pH: 4-5) Ethyl acetate was gradually added into the system, followed by saturated brine. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3R) -3-t-butyldiphenylsilyloxy-1- (4) as a white solid. 305 mg of -carboxy-1,3-thiazol-2-yl) pyrrolidine was obtained in a yield of 97%.
[1631]
[1632] (5) (3R) -3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1633] Reference Example 18 (3R) -3-t-butyldiphenylsilyloxy-1- (4-carboxy-1,3-thiazol-2-yl) pyrrolidine 910 mg (2.01 mmol) obtained in (4). Was dissolved in 30 ml of dimethylformamide, and 652 mg (4.02 mmol) of carbonyldiimidazole were added at room temperature under a nitrogen atmosphere, followed by stirring in a 50 ° C oil bath for 4 hours. After confirming that the raw materials disappeared, 2.7 ml of 28% aqueous ammonia was then added to the system and stirred for 30 minutes at room temperature. Subsequently, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give (3R) -3-t-butyldiphenylsilyloxy-1- (4-N-carbamoyl-1,3-thiazol-2-yl) blood as a light brown solid. Lolidine was obtained at 730 mg, yield 80%.
[1634]
[1635] (6) (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine
[1636] Reference Example 18 (3R) -3-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine 950 mg (2.10 mmol) obtained in (5). The solution was dissolved in 20 ml of anhydrous tetrahydrofuran, 2.52 ml (2.52 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was returned to room temperature and stirred for 1.3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate-10% methanol-ethyl acetate) to obtain (3R). -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine was obtained as a white solid at 428 mg, yield 96%.
[1637]
[1638] (7) (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine and (3R) -1- (4-cyano- 1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine
[1639] 290 mg (1.36 mmol) of (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 18 (6) was added to methylene chloride 9 It was suspended in mL, 0.684 mL (8.85 mmol) of methanesulfonyl chloride and 1.24 mL (8.85 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After the reaction was completed, 0.33 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate to 10% methanol-ethyl acetate) to give (3R) -1- (4-carba as a pale yellow solid. 130 mg of moyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine, yield 45%, (3R) -1- (4-cyano-1,3-thiazole 2-yl) -3-methanesulfonyloxypyrrolidine was obtained as a pale yellow solid at 148 mg, yield 40%.
[1640] (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine
[1641]
[1642] (3R) -1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine
[1643]
[1644] (8) (3S) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1645] 190 mg (0.652 mmol) of (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine obtained in Reference Example 18 (7) was treated with aceto. It dissolved in 6 ml of nitriles, and it heated and refluxed for 4 hours by adding 223 mg (1.96 mmol) of potassium thioacetate at room temperature. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate-2% methanol-ethyl acetate) to obtain (3S) -3-acetylthio-1- ( 4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine was obtained at 135 mg, yield 77%.
[1646]
[1647] Reference Example 19
[1648] (3S) -3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) pyrrolidine
[1649]
[1650] 300 mg (1.10 mmol) of (3R) -1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine obtained in Reference Example 18 (7) was treated with acetonitrile. It dissolved in 9 ml, and added 376 mg (3.30 mmol) of potassium thioacetate at room temperature, and it heated and refluxed for 5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1 to 1: 1) to give a pale brown solid (3S) -3-acetylthio-1- (4-cyano-1). , 3-thiazol-2-yl) pyrrolidine was obtained in 137 mg, yield 50%.
[1651]
[1652] Reference Example 20
[1653] (3R) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1654]
[1655] (1) (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine
[1656] 970 mg (4.00 mmol) of (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 18 (2) was methylene chloride It dissolved in 30 mL, 1.24 mL (16.0 mmol) of methanesulfonyl chlorides, and 2.24 mL (16.0 mmol) of triethylamine were added under ice-cooling, and it stirred as it is for 1 hour. After the reaction was completed, 0.81 ml of ethanol was added into the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1 to 1: 1) to obtain (3R) -1- (4-ethoxycarbonyl-1,3-thiazole as a pale yellow solid. Ylyl-3-methanesulfonyloxypyrrolidine was obtained in 1.00 g and yield 78%.
[1657]
[1658] (2) (3S) -3-acetyl-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine
[1659] 1.0 g (3.12 mmol) of (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine obtained in Reference Example 20 (1) It dissolved in 30 ml of dimethylformamide, 919 mg (9.36 mmol) of potassium thioacetate was added at room temperature, and it stirred for 5.5 hours in 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1: 1) to give (3S) -3-acetyl-1- (4-ethoxycarbonyl-1, 3-thiazol-2-yl) pyrrolidine was obtained in 877 mg, 99% yield.
[1660]
[1661] (3) (3S) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine
[1662] 150 ml of ethanol in 5.0 g (17.6 mmol) of (3S) -3-acetyl-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 20 (2) Was dissolved in, and 60 mg (0.879 mmol) of sodium ethoxide was added at room temperature and stirred overnight under the same conditions. After confirmation of the reaction, 0.22 ml of 4N-hydrochloric acid gas-1,4-dioxane was added to the system and neutralized. Ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1: 1: 2), followed by white solid (3S) -1- (4-ethoxycarbonyl-1,3-thia 4.16 g of zol-2-yl) -3-hydroxypyrrolidine was obtained in a yield of 98%.
[1663]
[1664] (4) (3S) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine
[1665] (3S) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine 4.1 g (16.9 mmol) obtained in Reference Example 20 (3) was subjected to dimethylform. It was dissolved in 120 ml of amide, 8.8 ml (33.8 mmol) of t-butyldiphenylsilyl chloride and 2.3 g (33.8 mmol) of imidazole were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred overnight. After the reaction was completed, 1.18 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Ethyl acetate and 10% brine were then added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate = 4: 1 to 1: 1) to give (3S) -3-t-butyldiphenylsilyloxy-1- (4) as a light brown solid. 7.60 g of ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine was obtained in a yield of 94%.
[1666]
[1667] (5) (3S) -3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) pyrrolidine
[1668] 5.0 g (10.4) of (3S) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 20 (4) mmol) was dissolved in 200 ml of ethanol and 50 ml of distilled water, 26.0 ml (26.0 mmol) of 1N-sodium hydroxide aqueous solution was added at room temperature, and the mixture was stirred for 7.5 hours as it was. After confirming the reaction was completed, 1N hydrochloric acid was added under ice-cooling. (In-situ pH: 4-5) Ethyl acetate was gradually added into the system, followed by saturated brine. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a white solid of (3S) -3-t-butyldiphenylsilyloxy-1- (4- 4.71 g of carboxyl-1,3-thiazol-2-yl) pyrrolidine were obtained in a yield of 100%.
[1669]
[1670] (6) (3S) -3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1671] 4.7 g (10.4 mmol) of (3S) -3-t-butyldiphenylsilyloxy-1- (4-carboxy-1,3-thiazol-2-yl) pyrrolidine obtained in Reference Example 20 (5) Was dissolved in 140 ml of dimethylformamide, 3.37 g (20.8 mmol) of carbonyldiimidazole were added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 3.5 hours in a 50 ° C oil bath. After confirming the disappearance of the raw materials, 14 ml of 28% aqueous ammonia was subsequently added into the system, and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1-2: 1) to obtain (3S) -3-t-butyldiphenylsilyloxy-1- (4-N as a pale brown solid. 3.14 g of -carbamoyl-1,3-thiazol-2-yl) pyrrolidine was obtained in a yield of 67%.
[1672]
[1673] (7) (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine
[1674] (3S) -3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine 3.1 g (6.86 mmol) obtained in Reference Example 20 (6). ) Was dissolved in 90 ml of anhydrous tetrahydrofuran, 8.24 ml (8.24 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1.5 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate) to give (3S) -1- (4-carbamoyl-1. , 3-thiazol-2-yl) -3-hydroxypyrrolidine was obtained as 1.42 g as a white solid, yield 98%.
[1675]
[1676] (8) (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine
[1677] 1.42 g (6.66 mmol) of (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 20 (7) was obtained from methylene chloride 40 The mixture was suspended in 9 ml of pyridine, 2.58 ml (33.3 mmol) of methanesulfonyl chloride and 4.67 ml (33.3 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred as it was for 1 hour. After confirming completion of the reaction, 1.2 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate to 10% methanol-ethyl acetate) to give (3S) -1- (4-carbamoyl-1,3-thiazole as a pale yellow solid. 2-yl) -3-methanesulfonyloxypyrrolidine was obtained in 1.15 g and yield 60%.
[1678]
[1679] (9) (3R) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine
[1680] 1.15 g of (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine obtained in Reference Example 20 (7) was added to 35 ml of acetonitrile. It dissolved, and it heated and refluxed for 6 hours by adding 1.35 g (11.8 mmol) of potassium thioacetate at room temperature. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-2% methanol-ethyl acetate) to give (3R) -3-acetylthio-1- (4-carbamoyl-1,3-thia) as a light brown solid. Zol-2-yl) pyrrolidine was obtained in 962 mg, yield 90%.
[1681]
[1682] Reference Example 21
[1683] 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine
[1684]
[1685] (1) 1-carbamoyl-3-hydroxyazetidine
[1686] 5.36 g (22.4 mmol) of N-benzhydryl-3-hydroxyazetidine was dissolved in 250 ml of methanol and subjected to catalytic hydrogen reduction for 1 hour in a 1 atm, 50 ° C. water bath in the presence of 5.36 g of 10% palladium hydroxide. . After confirming the completion of the reaction, the reaction mixture was filtered, and after removing the catalyst, the obtained filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the residue, liquid extraction was performed, and the organic layer was extracted again with distilled water. The resulting aqueous layer was concentrated under reduced pressure to give a reddish brown oily product. Subsequently, after drying under reduced pressure, the preceding compound was dissolved in 10 ml of acetic acid and 20 ml of distilled water, and 20 ml of an aqueous solution of 2.91 g of sodium cyanate was added at room temperature, followed by stirring for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 5: 1) to give 1-carbamoyl-3-hydroxyazetidine as a colorless oil. Got it.
[1687]
[1688] (2) 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine
[1689] Reference Example 21 1-carbamoyl-3-hydroxyazetidine obtained in (1) was dissolved in 100 ml of dimethylformamide, and 18.0 ml (66.9 mmol) of t-butyldiphenylsilyl chloride under ice-cooling, 4.55 imidazole g (66.9 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After confirming the reaction was completed, 1 ml of ethanol was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to yield 1.45 g of white solid 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine in 2 steps. Yield was 18%.
[1690]
[1691] (3) 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-oxazol-2-yl) azetidine
[1692] 3.47 g (9.79 mmol) of 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine obtained in Reference Example 21 (2) was dissolved in 170 ml of tetrahydrofuran, and 4.11 g (48.95) of sodium hydrogencarbonate in the solution. mmol) and 2.5 ml (19.58 mmol) of ethyl-2-bromopyruvate were added and refluxed for 8 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3- white solid). 2.96 g of oxazol-2-yl) azetidine was obtained in a yield of 45%.
[1693]
[1694] (4) 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine
[1695] 325 mg (0.72 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 21 (3) It dissolved in ml, and 2.7 ml of 0.67M methylamine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it heated and refluxed for 1 hour. After confirming completion of the reaction, 20 ml of 10% acetic acid water was added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1, white solid). 3-oxazol-2-yl) azetidine was obtained in 236 mg, yield 75%.
[1696]
[1697] (5) 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine
[1698] 662 mg (1.52 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 21 (4) It was dissolved in 33 ml of tetrahydrofuran, and 1.5 ml (1.5 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred for 1 hour as it was. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-N-methylcarbamoyl-1,3 -Oxazol-2-yl) azetidine was obtained as a white solid at 210 mg, yield 70%.
[1699]
[1700] (6) 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine
[1701] 209 mg (1.06 mmol) of 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 21 (5) was dissolved in 5 ml of methylene chloride and 15 ml of pyridine. Then, under ice-cooling, 0.41 ml (5.30 mmol) of methanesulfonyl chloride and 0.74 ml (5.30 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After confirming completion of the reaction, 1 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-N-methylcarbamoyl-1,3 -Oxazol-2-yl) -3-methanesulfonyloxyazetidine was obtained as a white solid at 253 mg, yield 86%.
[1702]
[1703] (7) 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine
[1704] 252 mg (0.92 mmol) of 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 21 (6) was added to dimethylformamide. It melt | dissolved in 12 ml, 0.63 g (5.52 mmol) of potassium thioacetate was added at room temperature, and it stirred for 7 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine as a white solid. As a yield, 136 mg and a yield of 58% were obtained.
[1705]
[1706] Reference Example 22
[1707] 3-acetylthio-1- (4-N-carbamoyl-1,3-oxazol-2-yl) azetidine
[1708]
[1709] (1) 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine
[1710] Reference Example 21 (3) 1.70 g (3.77 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in (3) was converted to benzene 38 It dissolved in ml, and added 13.7 ml of 0.67 M methylamine trimethyl aluminum-benzene solution at room temperature under nitrogen atmosphere, and stirred for 4 hours in 50 degreeC water bath. After confirming the reaction was completed, 100 ml of 10% acetic acid water was added into the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-oxazol-2-yl) as a white solid. Obtained azetidine 0.83 g, yield 52%.
[1711]
[1712] (2) 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-hydroxyazetidine
[1713] 1.30 g (3.08 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine is dissolved in 60 ml of tetrahydrofuran and under ice-cooling 3.1 ml of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added, and it stirred as it is for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- (4-carbamoyl-1,3-oxazole. 2-yl) -3-hydroxyazetidine was obtained as a white solid at 0.43 g, yield 75%.
[1714]
[1715] (3) 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine
[1716] 423 mg (2.31 mmol) of 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 22 (2) was diluted with 10 ml of methylene chloride and 30 ml of pyridine. Was dissolved in, and 0.90 mL (11.55 mmol) of methanesulfonyl chloride and 1.60 mL (11.55 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After confirming completion of the reaction, 1 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- (4-carbamoyl-1,3-oxazole. 2-yl) -3-methanesulfonyloxyazetidine was obtained as a white solid at 470 mg, yield 78%.
[1717]
[1718] (4) 3-acetylthio-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine
[1719] 469 mg (1.80 mmol) of 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 22 (3) was added to 23 ml of dimethylformamide. It dissolved, 1.23 g (10.80 mmol) of potassium thioacetate was added at room temperature, and it stirred for 8 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-acetylthio-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine Was obtained as a white solid at 275 mg, yield 63%.
[1720]
[1721] Reference Example 23
[1722] 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl) azetidine
[1723]
[1724] (1) 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-oxazol-2-yl) azetidine
[1725] 357 mg (0.79 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 21 (3) It melt | dissolved in mL, and 2.8 mL of 0.67M methylamine trimethyl aluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it stirred for 7 hours in 60 degreeC water bath. After confirming completion of the reaction, 10 ml of 10% acetic acid water was added into the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-oxa in the form of a colorless oil. Zol-2-yl) azetidine was obtained in 130 mg, yield 41%.
[1726]
[1727] (2) 1- (4-cyano-1,3-oxazol-2-yl) -3-hydroxyazetidine
[1728] Reference Example 23 0.61 g (1.51 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-oxazol-2-yl) azetidine obtained in (1) was converted to tetrahydrofuran 30. It dissolved in ml, and added 1.5 ml of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling, and stirred as it is for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-cyano-1,3-oxazol-2-yl) -3 -Hydroxyazetidine was obtained as white solid at 0.21 g, yield 86%.
[1729]
[1730] (3) 1- (4-cyano-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine
[1731] Reference Example 23 214 mg (1.30 mmol) of 1- (4-cyano-1,3-oxazol-2-yl) -3-hydroxyazetidine obtained in (2) was added to 10 ml of methylene chloride and 5 ml of pyridine. It was dissolved, 0.50 ml (6.50 mmol) of methanesulfonyl chloride and 0.90 ml (6.50 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After confirming completion of the reaction, 1 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-cyano-1,3-oxazole-2- in the form of a colorless oil. Il) -3-methanesulfonyloxyazetidine was obtained by 310 mg and yield 98%.
[1732]
[1733] (4) 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl) azetidine
[1734] Reference Example 23 309 mg (1.27 mmol) of 1- (4-cyano-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine obtained in (3) was dissolved in 15 ml of dimethylformamide. Then, potassium thioacetate 0.87 g (7.62 mmol) was added at room temperature, and it stirred for 5 hours in 80 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl in the form of a colorless oil. ) Azetidine was obtained in 157 mg, yield 55%.
[1735]
[1736] Reference Example 24
[1737] 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1738]
[1739] (1) 3-t-butyldiphenylsilyloxy-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1740] Reference Example 2 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in (1) was converted to benzene 50 It dissolved in ml, and 4.6 ml of 0.67M azetidine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it refluxed for 4 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-azetidinocarbonyl-1 as a light brown solid). 0.63-g of 3-thiazol-2-yl) azetidine was obtained with a yield of 55%.
[1741]
[1742] (2) 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1743] 0.60 g (1.18 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 24 (1) was anhydrous. It was dissolved in 25 ml of tetrahydrofuran, 1.42 ml (1.42 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred for 30 minutes as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate) to give 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine Was obtained as a white solid at 242 mg, yield 86%.
[1744]
[1745] (3) 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1746] 242 mg (1.01 mmol) of 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 24 (2) were dissolved in 10 ml of methylene chloride. Then, 0.43 ml (3.04 mmol) of methanesulfonyl chloride and 0.24 ml (3.04 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 30 minutes as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue and filtered to yield 302 mg of 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine as a pale yellow solid, yield. Obtained at 94%.
[1747]
[1748] (4) 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1749] 302 mg (0.95 mmol) of 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 24 (3) was added to dimethylformamide 10. The solution was dissolved in mL, 0.65 g (5.70 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for 6 hours in an 80 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazole as a light brown solid. 2-yl) azetidine was obtained in 247 mg, yield 87%.
[1750]
[1751] Reference Example 25
[1752] 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1753]
[1754] (1) 3-t-butyldiphenylsilyloxy-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1755] Reference Example 2 1.0 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in (1) was converted to benzene 50 It dissolved in ml, and 4.6 ml of 0.67M thiomorpholine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it refluxed for 4 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring for 30 minutes at room temperature. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-thiomorpholinocarbonyl-) as a light brown solid. 1,3-thiazol-2-yl) azetidine was obtained in 1.16 g with a yield of 98%.
[1756]
[1757] (2) 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1758] 1.16 g (2.10 mmol) of 3-t-butyldiphenylsilyloxy-1- (1,3-thiazole-4-thiomorpholinocarbonyl-2-yl) azetidine obtained in Reference Example 25 (1) It was dissolved in 35 ml of anhydrous tetrahydrofuran, 2.52 ml (2.52 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred for 30 minutes as it was. After the completion of reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-thiomorpholinocarbonyl-1,3-thiazole-2- Il) -3-hydroxyazetidine was obtained as a white solid at 599 mg, yield 100%.
[1759]
[1760] (3) 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1761] 599 mg (2.50 mmol) of 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 25 (2) was added to 30 ml of methylene chloride. The solution was dissolved, and 0.49 ml (6.30 mmol) of methanesulfonyl chloride and 0.88 ml (6.30 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 30 minutes as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate) to give 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3- as a pale yellow solid. Methanesulfonyloxyazetidine was obtained by 709 mg and the yield 93%.
[1762]
[1763] (4) 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine
[1764] 709 mg (1.95 mmol) of 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 25 (3) was used as dimethylformamide. It dissolved in 20 ml, 1.34 g (11.7 mmol) of potassium thioacetate was added at room temperature, and it stirred for 5 hours in 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane: methylene chloride = 1: 1: 1) to give 3-acetylthio-1- (4-thiomorpholinocarbonyl-) as a light brown solid. 1,3-thiazol-2-yl) azetidine was obtained in 413 mg, yield 64%.
[1765]
[1766] Reference Example 26
[1767] 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1768]
[1769] (1) 3-t-butyldiphenylsilyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1770] 1.00 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to benzene 50. It dissolved in ml, and 7.6 ml of 0.67M pyrrolidine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it refluxed for 6 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-pyrrolidinocarbonyl-1,3 as a light brown solid). -Thiazol-2-yl) azetidine was obtained in 775 mg, yield 78%.
[1771]
[1772] (2) 3-hydroxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1773] 775 mg (1.58 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 26 (1) was dried. It was dissolved in 30 ml of tetrahydrofuran, and 2.01 ml (2.01 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 3-hydroxy-1- (4-pyrroli). Dinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained as a white solid at 290 mg, yield 72%.
[1774]
[1775] (3) 3-methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1776] 290 mg (1.14 mmol) of 3-hydroxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 26 (2) were dissolved in 9 ml of methylene chloride. Then, 0.30 ml (5.12 mmol) of methanesulfonyl chloride and 0.70 ml (5.12 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 1: 1-ethyl acetate) to give 3-methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1, 1) as a pale yellow solid. 3-thiazol-2-yl) azetidine was obtained in 335 mg, yield 89%.
[1777]
[1778] (4) 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1779] 335 mg (1.01 mmol) of 3-methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 26 (3) was added to dimethylformamide. It dissolved in mL, added 1.10 g (8.80 mmol) of potassium thioacetate at room temperature, and stirred for 5 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine as a pale brown solid. It obtained in 235 mg, yield 75%.
[1780]
[1781] Reference Example 27
[1782] 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1783]
[1784] (1) 3-t-butyldiphenylsilyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1785] 1.00 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to benzene 50. It dissolved in ml, and 7.3 ml of 0.67M piperidino-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it refluxed for 5 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-piperidinocarbonyl-1,3 as a light brown solid). -Thiazol-2-yl) azetidine was obtained with 607 mg, yield 56%.
[1786]
[1787] (2) 3-hydroxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1788] 607 mg (1.20 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 27 (1) was anhydrous. It was dissolved in 25 ml of tetrahydrofuran, 1.40 ml (1.40 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- (4-piperi). Dinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained as a white solid at 310 mg, yield 97%.
[1789]
[1790] (3) 3-methanesulfonyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1791] Dissolve 310 mg (1.16 mmol) of 3-hydroxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 27 (2) in 10 ml of methylene chloride. Then, 0.27 mL (3.48 mmol) of methanesulfonyl chloride and 0.49 mL (3.48 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-methanesulfonyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) ase as a pale yellow solid. Tidin was obtained with 346 mg and the yield 86%.
[1792]
[1793] (4) 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine
[1794] 346 mg (1.00 mmol) of 3-methanesulfonyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 27 (3) It dissolved in mL, added 687 mg (6.01 mmol) of potassium thiosionate at room temperature, and stirred for 4 hours in a 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine as a pale brown solid. 276 mg, yield 85% was obtained.
[1795]
[1796] Reference Example 28
[1797] 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1798]
[1799] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1800] 1.00 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to benzene 50. It dissolved in ml, and added 7.20 ml of 0.67M cyclopropylamine-trimethylaluminum-benzene solution at room temperature under nitrogen atmosphere, and refluxed for 2 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl-1) as a light brown solid. , 3-thiazol-2-yl) azetidine was obtained in 979 mg, yield 90%.
[1801]
[1802] (2) 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1803] 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine 907 mg (1.94 mmol) obtained in Reference Example 28 (1). Was dissolved in 40 mL of anhydrous tetrahydrofuran, and 2.30 mL (2.30 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1 hour as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine white. It obtained 367 mg and yield 81% as a solid.
[1804]
[1805] (3) 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1806] 10 ml of methylene chloride, 376 mg (1.57 mmol) of 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 28 (2) It was dissolved in, and 0.36 ml (4.71 mmol) of methanesulfonyl chloride and 0.66 ml (4.71 mmol) of triethylamine were added under ice cooling, and the mixture was stirred for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) as a pale yellow solid. 343 mg of 3-methanesulfonyloxyazetidine was obtained with a yield of 88%.
[1807]
[1808] (4) 3-acetylthio-1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1809] 433 mg (1.31 mmol) of 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 28 (3) was subjected to dimethylform. It dissolved in 20 ml of amides, 895 mg (7.84 mmol) of potassium thioacetate was added at room temperature, and it stirred for 5 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-N-cyclopropylcarbamoyl-1,3-thiazole as a light brown solid. 2-yl) azetidine was obtained in 343 mg, yield 88%.
[1810]
[1811] Reference Example 29
[1812] 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1813]
[1814] (1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1815] 1.00 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to benzene 50. It dissolved in ml, and added 7.30 ml of 0.67 M cyclobutylamine-trimethylaluminum-benzene solution at room temperature under nitrogen atmosphere, and refluxed for 2 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate: 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl-1) as a light brown solid. , 3-thiazol-2-yl) azetidine was obtained in 965 mg, yield 87%.
[1816]
[1817] (2) 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[1818] 966 mg (1.86 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 29 (1) The solution was dissolved in 40 ml of anhydrous tetrahydrofuran, 2.20 ml (2.20 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1 hour as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate: 1: 1-ethyl acetate) to give 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl)- 3-hydroxyazetidine was obtained as white solid, 433 mg, yield 95%.
[1819]
[1820] (3) 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[1821] 10 ml of methylene chloride, 433 mg (1.71 mmol) of 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 29 (2) It dissolved in, and methanesulfonyl chloride 0.30 ml (5.12 mmol) and triethylamine 0.70 ml (5.12 mmol) were added under ice cooling, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyl as a pale yellow solid. Oxyazetidine was obtained by 567 mg and yield 100%.
[1822]
[1823] (4) 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1824] 567 mg (1.71 mmol) of 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 29 (3) were used as dimethylform. It dissolved in 10 ml of amides, added potassium thioacetate 1.17 g (10.3 mmol) at room temperature, and stirred overnight in a 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 3) to give 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazole as a light brown solid. 2-yl) azetidine was obtained in 318 mg, yield 75%.
[1825]
[1826] Reference Example 30
[1827] 3-acetylthio-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1828]
[1829] (1) 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1830] 1.00 g (2.14 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to toluene 50. It dissolved in mL, and added 7.40 mL of 0.67M 1-methylpiperazine-trimethylaluminum-toluene solution at room temperature under nitrogen atmosphere, and refluxed for 3 hours. After confirming the reaction was completed, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazin-1-) as a light brown solid. 941 mg of carbonyl) -1,3-thiazol-2-yl] azetidine was obtained in 85% yield.
[1831]
[1832] (2) 3-hydroxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1833] 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine 941 obtained in Reference Example 30 (1). MG (1.81 mmol) was dissolved in 47 mL of anhydrous tetrahydrofuran, 2.17 mL (2.17 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred for 1 hour as it was. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 3: 1) to give 3-hydroxy-1- [4- (4-methylpipepe). Razin-1-carbonyl) -1,3-thiazol-2-yl] azetidine was obtained as a white solid at 422 mg, yield 83%.
[1834]
[1835] (3) 3-methanesulfonyloxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1836] 3-hydroxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine 422 mg (1.49 mmol) obtained in Reference Example 30 (2). The solution was dissolved in 21 ml of methylene chloride, 0.14 ml (1.79 mmol) of methanesulfonyl chloride and 0.25 ml (1.79 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: methanol = 3: 1) to give 3-methanesulfonyloxy-1- [4- (4-methylpiperazin-1-carbonyl)-as a pale yellow solid. 537 mg of 1,3-thiazol-2-yl] azetidine was obtained in 100% yield.
[1837]
[1838] (4) 3-acetylthio-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1839] 3-methanesulfonyloxy-1- [4- (4-methylpiperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidine 537 mg (1.49) obtained in Reference Example 26 (3). mmol) was dissolved in 16 ml of dimethylformamide, 1.02 g (8.94 mmol) of potassium thioacetate was added at room temperature, followed by stirring in a 90 ° C oil bath for 4 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium hydrogencarbonate water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-acetylthio-1- [4- (4-methylpiperazin-1-carbonyl) -1 as a light brown solid. , 3-thiazol-2-yl] azetidine was obtained in 261 mg, yield 51%.
[1840]
[1841] Reference Example 31
[1842] 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1843]
[1844] (1) 1-t-butoxycarbonyl-3-methoxyazetidine
[1845] 10.0 g (41.8 mmol) of 1-benzhydryl-3-hydroxyazetidine was dissolved in 300 ml of methanol, and contact hydrogen reduction was performed at room temperature for 3 hours in the presence of 10.0 g of 10% palladium carbon. After the completion of reaction, the reaction solution was filtered, and 18.2 g (83.6 mmol) of di-t-butoxycarbonyl anhydride was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 2) to obtain 1-t-butoxycarbonyl-3- 7.05 g of hydroxyazetidine was obtained in 97% yield. Subsequently, 2.5 g (14.4 mmol) of 1-t-butoxycarbonyl-3-hydroxyazetidine was dissolved in 125 ml of dimethylformamide, and 1.27 g (28.8 mmol) of sodium hydride (55% oil dispersion) was dissolved under ice-cooling. 10 minutes later, it returned to room temperature and stirred for 0.5 hours as it was. Next, 1.79 mL (28.8 mmol) of methyl iodide was added to the reaction system under ice cooling, and after 10 minutes, it returned to room temperature and stirred for 1 hour as it is. After confirming completion of the reaction, 10% acetic acid aqueous solution was added under ice cooling, followed by stirring for 30 minutes. Subsequently, ethyl acetate and 10% saline solution were added to the system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 2.18 g of 1-t-butoxycarbonyl-3-methoxyazetidine in the form of a colorless oil, yield 81 Obtained in%.
[1846]
[1847] (2) 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1848] Reference Example 31 1.60 g (13.9 mmol) of 1-t-butoxycarbonyl-3-methoxyazetidine obtained in (1) was dissolved in 26 ml of 1,4-dioxane, and 4N-hydrochloric acid gas-1 under ice-cooling 26 mL of 4-4-dioxane was added and then stirred at room temperature overnight. After the completion of the reaction, the reaction solution was filtered, ethyl acetate and diisopropyl ether were added to the obtained residue, and the filtrate was washed with diisopropyl ether, and then dried under reduced pressure to obtain white crystals 3-. The methoxyazetidine hydrochloride was obtained in 1.84 g and yield 100%. Subsequently, 500 mg (1.07 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 25 ml of toluene, 3.21 ml of a 0.67M 3-methoxyazetidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour in an 80 ° C hot water bath. After confirming the reaction was completed, 20 ml of 10% acetic acid water and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl)-as a pale brown solid. 366 mg, yield 67% of 1,3-thiazol-2-yl] azetidine was obtained.
[1849]
[1850] (3) 3-hydroxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1851] 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] ase obtained in Reference Example 31 (2). Tidine 870 mg (1.71 mmol) was dissolved in 45 mL of anhydrous tetrahydrofuran, 2.06 mL (2.06 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 0.5 hour as it was. . After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- [4- (3-methoxy -Azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine as a white solid, 481 mg, yield 100%.
[1852]
[1853] (4) 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1854] 480 mg of 3-hydroxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 31 (3) mmol) was dissolved in 25 ml of methylene chloride, 397 µl (5.13 mmol) of methanesulfonyl chloride and 719 µl (5.13 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it was. . After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5) to give 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carpoxy as a pale yellow solid. Bonyl) -1,3-thiazol-2-yl] azetidine was obtained in 568 mg, yield 96%.
[1855]
[1856] (5) 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
[1857] 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine 560 mg obtained in Reference Example 31 (4). (1.61 mmol) was dissolved in 28 ml of dimethylformamide, 1.10 g (9.67 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for 4.5 hours in an 80 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 97: 3) to give 3-acetylthio-1- [4- (3-methoxy-azetidine-1-) as a light brown solid. Carbonyl) -1,3-thiazol-2-yl] azetidine was obtained in 356 mg, yield 68%.
[1858]
[1859] Reference Example 32
[1860] 3-acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1861]
[1862] (1) 3-t-butyldiphenylsilyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1863] Reference Example 2 (2) To 2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in (1) was added to toluene 100 It dissolved in ml, and 14.6 ml of 0.67M aniline-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere, and it refluxed for 3 hours. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 3 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-phenylcarbamoyl-1,3- pale brown solid. 2.20 g of thiazol-2-yl) azetidine was obtained in 100% yield.
[1864]
[1865] (2) 3-hydroxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1866] 2.20 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 32 (1) It melt | dissolved in 110 mL of hydrofuran, 5.15 mL (5.15 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution were added under ice-cooling, and it stirred as it is for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to 3-hydroxy-1- (4-phenylcarbamoyl-1,3-thiazole 2-yl) azetidine was obtained as a white solid at 1.18 g in 100% yield.
[1867]
[1868] (3) 3-methanesulfonyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1869] Reference Example 32 1.18 mg (4.29 mmol) of 3-hydroxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in (2) was dissolved in 60 ml of methylene chloride, Under ice-cooling, 0.50 ml (6.44 mmol) of methanesulfonyl chloride and 0.90 ml (6.44 mmol) of triethylamine were added, followed by stirring for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 9: 1) to give 3-methanesulfonyloxy-1- (4-phenylcarbamoyl-1,3-thiazole as a pale yellow solid. 2-yl) azetidine was obtained in 1.36 g and 89% yield.
[1870]
[1871] (4) 3-acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1872] 40 ml of dimethylformamide was added to 1.28 g (3.85 mmol) of 3-methanesulfonyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 32 (3). It dissolved in, and added 2.60 g (23.1 mmol) of potassium thioacetate at room temperature, and stirred for 3 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- (4-phenylcarbamoyl-1,3-thiazole-2- as a light brown solid. Il) azetidine was obtained at 893 mg, yield 70%.
[1873]
[1874] Reference Example 33
[1875] 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1876]
[1877] (1) [2- (t-butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester
[1878] 2.0 g (32.7 mmol) of aminoethanol was dissolved in 60 ml of methylene chloride, 5.6 ml (41.3 mmol) of benzyl chloroformate and 5.5 ml (39.5 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. . After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 2) to obtain 5.2-g of (2-hydroxyethyl) -carbamic acid benzyl ester as a white solid, yield 84%. Subsequently, 5.37 g (27.5 mmol) of (N-benzyloxycarbonyl) -2-aminoethanol obtained was dissolved in 160 ml of dimethylformamide, and 8.6 ml (33.0 mmol) of t-butyldiphenylsilane chloride were imidazole under ice-cooling. 2.3 g (33.8 mmol) was added and the mixture was then stirred at room temperature overnight. After confirming the reaction was completed, ethanol was added to the system and stirred for 2 hours. Next, ethyl acetate and saturated sodium bicarbonate water were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1) to give [2- (t-butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester of colorless transparent syrup 11.93. g, yield 100% was obtained.
[1879]
[1880] (2) 3-t-butyldiphenylsilyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1881] Reference Example 33 3.01 g (6.9 mmol) of [2- (t-butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester obtained in (1) was dissolved in 150 ml of methanol, and 20% palladium hydroxide 3.0 carbon was obtained. In the presence of g, catalytic hydrogen reduction was carried out at room temperature. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 10: 1) to give 2- (t-) a pale brown syrup. Butyldiphenylsilyloxy) -ethylamine was obtained in 1.49 g and 72% yield. Subsequently, 1.16 g (2.49 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was obtained. It was dissolved in 58 ml of benzene, and 8.5 ml of a 0.67 M 2- (t-butyldiphenylsilyloxy) -ethylamine-trimethylaluminum-benzene solution was added under nitrogen atmosphere at room temperature to reflux for 5 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- {4- [2- (t-butyldiphenyl) as a light brown solid. Silyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 1.68 g and 94% yield.
[1882]
[1883] (3) 3-hydroxy-1- (4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl) azetidine
[1884] Reference Example 33 3-t-butyldiphenylsilyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazole-2 obtained in (2). 1.68 g (2.33 mmol) of -yl} azetidine was dissolved in 75 mL of anhydrous tetrahydrofuran, and 5.6 mL (5.6 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling. Stir for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-hydroxy-1- (4-hydroxyethylcarba). Moyl-1,3-thiazol-2-yl) azetidine was obtained as a white solid at 481.2 mg, yield 85%.
[1885]
[1886] (4) 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine
[1887] Reference Example 33 484.0 mg (1.98 mmol) of 3-hydroxy-1- (4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in (3) was subjected to 24.0 ml of dimethylformamide. Was dissolved in, and 352 mg (2.3 mmol) of t-butyldimethylsilane chloride and 116.3 mg (2.4 mmol) of imidazole were added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated sodium bicarbonate water were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 3) to give 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl]-a colorless transparent syrup. 53, 1 mg of 1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained, yield 75%.
[1888]
[1889] (5) 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine
[1890] Reference Example 33 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine 531.1 obtained in (4). Mg (1.49 mmol) was dissolved in 26.6 ml of methylene chloride, 0.3 ml (3.9 mmol) of methanesulfonyl chloride and 0.52 ml (3.7 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature as it was. Stirred. After confirming completion of the reaction, methanol was added to the reaction system and stirred for 30 minutes. Thereafter, ethyl acetate and saturated sodium bicarbonate water were added, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 1) to yield a pale yellow solid, 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1. 647.1 mg of 3-3-azol-2-yl} -3-methanesulfonyloxyazetidine was obtained in 100% yield.
[1891]
[1892] (6) 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1893] Reference Example 33 1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyase obtained in (5). 647.1 mg (1.49 mmol) of thydine was dissolved in 32.0 mL of dimethylformamide, 1.28 mg (8.9 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% brine were added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 2) to give 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarb as a light brown solid. Barmoyl] -1,3-thiazol-2-yl} azetidine was obtained at 398.2 mg, yield 65%.
[1894]
[1895] Reference Example 34
[1896] 3-acetylthio-1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1897]
[1898] (1) [(1S) -1- (t-butyldiphenylsilyloxymethyl) -propyl] -carbamic acid benzyl ester
[1899] 2.00 g (22.4 mmol) of L-ethylglycinol was dissolved in 60 ml of methylene chloride, 3.84 ml (26.9 mmol) of benzyl chloroformate and 3.77 ml (26.9 mmol) of triethylamine were added under ice-cooling, and then at room temperature. Stir for 2 hours. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to give [(1S) -1- (hydroxymethyl) -propyl] -carrine in the form of a colorless oil. A benzyl benzyl ester was obtained at 4.27 g and a yield of 85%. Subsequently, 4.27 g (19.1 mmol) of [(1S) -1- (hydroxymethyl) -propyl] -carbamic acid benzyl ester was dissolved in 128 ml of dimethylformamide, and t-butyldiphenylsilane chloride 5.97 was cooled under ice-cooling. ML (22.9 mmol) and 1.56 g (22.9 mmol) of imidazole were added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (extraction solvent: n-hexane: ethyl acetate = 6: 1-4: 1) to obtain [(1S) -1- (t-butyldiphenylsilyloxymethyl)-of white crystals. Propyl] -carbamic acid benzyl ester was obtained at 9.48 g and yield 100%.
[1900]
[1901] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[1902] Reference Example 34 3.70 g (8.00 mmol) of [(1S) -1- (t-butyldiphenylsilyloxymethyl) -propyl] -carbamic acid benzyl ester obtained in (1) was dissolved in 185 ml of methanol, and 10% Contact hydrogen reduction was performed at room temperature for 4 hours in the presence of 3.70 g of palladium carbon. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 9: 1) to give a colorless oil (1S) -1. -(t-butyldiphenylsilyloxymethyl) -propylamine was obtained in 2.32 g and yield 88%. Subsequently, 2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 ml of benzene, and 12.9 ml of a 0.67M (1S) -1- (t-butyldiphenylsilyloxymethyl) -propylamine-trimethylaluminum-benzene solution was added under nitrogen atmosphere at room temperature to reflux overnight. After confirmation of reaction completion, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-2: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1S) as a light brown solid. ) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 2.52 g, yield 79%.
[1903]
[1904] (3) 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1905] Reference Example 34 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3 obtained in (2). 2.52 g (3.50 mmol) of -thiazol-2-yl} azetidine was dissolved in 126 mL of anhydrous tetrahydrofuran and 8.40 mL (8.40 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling. Was added and stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- {in the form of a pale yellow oil. 947 mg of 4-[(1S) -1- (hydroxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine were obtained in a yield of 100%.
[1906]
[1907] (4) 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine
[1908] Reference Example 34 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine obtained in (3). 940 mg (3.50 mmol) was dissolved in 47 ml of dimethylformamide, 633 mg (4.20 mmol) of t-butyldimethylsilane chloride and 286 mg (4.20 mmol) of imidazole were added under ice cooling, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (extraction solvent: n-hexane: ethyl acetate = 2: 1 to 1: 3) to give 1- {4- (1S) -1- (t-butyldimethylsilyl in the form of a pale yellow oil. Oxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained in 1.00 g, yield 74%.
[1909]
[1910] (5) 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyase Tidin
[1911] Reference Example 34 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3- obtained in (4). Dissolve 1.00 mg (2.59 mmol) of hydroxyazetidine in 50 ml of methylene chloride, add 602 µl (7.78 mmol) of methanesulfonyl chloride and 1.09 ml (7.78 mmol) of triethylamine under ice-cooling, and after 10 minutes It returned to room temperature and stirred for 3 hours as it is. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S) -1- (t-butyldimethyl in the form of light yellow oil. Silyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained at 1.02 g and yield 85%.
[1912]
[1913] (6) 3-acetylthio-1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1914] Reference Example 34 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} -3- obtained in (5). 1.02 g (2.20 mmol) of methanesulfonyloxyazetidine was dissolved in 50 mL of dimethylformamide, 1.51 mg (13.2 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight at 80 ° C in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1-2: 1) to obtain 3-acetylthio-1- {4-[(1S) -1- in the form of light brown oil. (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 618 mg, yield 63%.
[1915]
[1916] Reference Example 35
[1917] 3-acetylthio-1- {4-[(1S) -2 (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1918]
[1919] (1) [(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethyl] -carbamic acid benzyl ester
[1920] 2.00 g (26.6 mmol) of L-alanineol was dissolved in 60 ml of methylene chloride, 4.57 ml (32.0 mmol) of benzyl chloroformate and 4.48 ml (32.0 mmol) of triethylamine were added under ice-cooling, and then at room temperature overnight. Stirred. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1-1: 2) to obtain white crystals of [(1S) -2-hydroxy-1-methyl-ethyl] -carr A benzyl benzyl ester was obtained at 4.61 g and yield 83%. Subsequently, 4.61 g (22.0 mmol) of [(1S) -1- (hydroxymethyl) -ethyl] -carbamic acid benzyl ester was dissolved in 140 ml of dimethylformamide, and 6.87 g of t-butyldiphenylsilane was dissolved under ice-cooling. ML (26.4 mmol) and 1.80 g (26.4 mmol) of imidazole were added, followed by stirring at room temperature for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-6: 1) to give [(1S) -2- (t-butyldiphenylsilyloxy)-as a colorless oil. 1-methyl-ethyl] -carbamic acid benzyl ester was obtained at 10.7 g and yield 100%.
[1921]
[1922] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thia Zol-2-yl} azetidine
[1923] 6.71 g (15.0 mmol) of [(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethyl] -carbamic acid benzyl ester obtained in Reference Example 35 (1) were dissolved in 340 ml of methanol. And 6.71 g of 10% palladium carbon were subjected to 2.5 hours of catalytic hydrogen reduction at room temperature. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 85: 15) to obtain a pale yellow oil (1S). ) 3- (t-butyldiphenylsilyloxy) -1-methyl-ethylamine was obtained at 3.93 g and yield 84%. Then, 2.0 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 ml of benzene, and 12.9 ml of a 0.67 M (1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere to reflux overnight. I was. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-2: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1S) as a light brown solid. ) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 2.77 g and yield 88%.
[1924]
[1925] (3) 3-hydroxy-1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine
[1926] 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] obtained in Reference Example 35 (2)- 2.77 g (3.77 mmol) of 1,3-thiazol-2-yl} azetidine was dissolved in 140 mL of anhydrous tetrahydrofuran, and 9.06 mL of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution (under ice cooling) 9.06 mmol) was added and stirred for 3.5 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain 3-hydroxy-1- [4-(( 1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine was obtained as a white solid at 911 mg, yield 94%.
[1927]
[1928] (4) 1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxy Azetidine
[1929] Reference Example 35 3-hydroxy-1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] ase obtained in (3). Tidine 910 mg (3.54 mmol) was dissolved in 46 ml of dimethylformamide, 586 mg (3.89 mmol) of t-butyldimethylsilane chloride and 265 mg (3.89 mmol) of imidazole were added under ice cooling, followed by stirring at room temperature for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 4) to give 1- {4-[(1S) -1- (t-butyldimethyl in the form of a pale yellow oil. Silyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained in 935 mg, yield 71%.
[1930]
[1931] (5) 1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulphate Phenyloxyazetidine
[1932] Reference Example 35 1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} obtained in (4). 930 mg (2.50 mmol) of 3-hydroxyazetidine was dissolved in 47 ml of methylene chloride, and 480 µl (6.20 mmol) of methanesulfonyl chloride and 869 µl (6.20 mmol) of triethylamine were added under ice cooling, and 10 After minutes, the reaction system was returned to room temperature and stirred as it was for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S) -2- (t-butyldimethyl) as a pale yellow oil. Silyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained in 1.16 g and 100% yield.
[1933]
[1934] (6) 3-acetylthio-1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} Azetidine
[1935] 1- {4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} obtained in Reference Example 35 (5). 1.16 g (2.50 mmol) of 3-methanesulfonyloxyazetidine was dissolved in 60 ml of dimethylformamide, 1.71 mg (15.0 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight at 80 ° C in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1-2: 1) to give 3-acetylthio-1- {4-[(1S) -2- in the form of light brown oil. (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained at 709 mg and yield 60%.
[1936]
[1937] Reference Example 36
[1938] 3-acetylthio-1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1939]
[1940] (1) [(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester
[1941] 2.00 g (19.4 mmol) of L-valinol were dissolved in 60 ml of methylene chloride, 3.32 ml (23.3 mmol) of benzyl chloroformate and 3.27 ml (23.3 mmol) of triethylamine were added under ice-cooling, and then 4.5 hours at room temperature. Stirred. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain [(1S) -1- (hydroxymethyl) -2-methyl-propyl as white crystals. ] -Carbamic acid benzyl ester was obtained by 4.56 g and 99% of yield. Subsequently, 4.56 g (19.2 mmol) of [(1S) -1- (hydroxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester was dissolved in 140 ml of dimethylformamide, and t-butyl chloride under ice-cooling. 6.00 ml (23.1 mmol) of diphenylsilane and 1.57 g (23.1 mmol) of imidazole were added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-6: 1) to obtain [(1S) -1- (t-butyldiphenylsilyloxymethyl)-of white crystals. 2-methyl-propyl] -carbamic acid benzyl ester was obtained at 10.1 g and yield 100%.
[1942]
[1943] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3- Thiazol-2-yl} azetidine
[1944] Reference Example 36 7.14 g (15.0 mmol) of [(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester obtained in (1) was dissolved in 215 ml of methanol. Then, contact hydrogen reduction was carried out for 3 hours at room temperature in the presence of 7.14 g of 10% palladium carbon. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2-9: 1) to obtain a colorless oil ( 1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylamine was obtained in 3.73 g and yield 73%. Subsequently, 2.0 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 ml of benzene, and 12.9 ml of a 0.67 M (1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere overnight. It was refluxed. After confirmation of reaction completion, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-4: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1S) as a light brown solid. ) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 1.98 g and 61% yield.
[1945]
[1946] (3) 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1947] 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] obtained in Reference Example 36 (2)] Dissolve 1.98 g (2.60 mmol) of -1,3-thiazol-2-yl} azetidine in 100 mL of anhydrous tetrahydrofuran, and 6.23 mL of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling. (6.23 mmol) was added and the resultant was stirred overnight. After confirmation of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {in the form of a colorless oil. 755 mg of 4-[(1S) -1- (hydroxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidine were obtained in a yield of 100%.
[1948]
[1949] (4) 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} -3-hydrate Roxyazetidine
[1950] 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazole-2- obtained in Reference Example 36 (3). Dissolve 750 mg (2.60 mmol) of Japanese azetidine in 38 ml of dimethylformamide, add 470 mg (3.12 mmol) of t-butyldimethylsilane chloride and 212 mg (3.12 mmol) of imidazole under ice-cooling, It stirred under 2 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 3) to give 1- {4-[(1S) -1- (t-butyldimethyl in the form of light yellow oil. Silyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained in 700 mg, yield 67%.
[1951]
[1952] (5) 1- {4- (1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulphate Phenyloxyazetidine
[1953] 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 36 (4). 700 mg (1.75 mmol) of} -3-hydroxyazetidine was dissolved in 35 ml of methylene chloride, and 406 µl (5.25 mmol) of methanesulfonyl chloride and 736 µl (5.25 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S) -1- (t-butyldimethyl in the form of light yellow oil. Silyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained at 895 mg, yield 100%.
[1954]
[1955] (6) 3-acetylthio-1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl } Azetidine
[1956] 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 36 (5). 890 mg (1.75 mmol) of} -3-methanesulfonyloxyazetidine was dissolved in 45 mL of dimethylformamide, 1.20 g (10.5 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight at 80 ° C in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 1) to give 3-acetylthio-1- {4-[(1S) -1- in the form of light brown oil. (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 502 mg, yield 63%.
[1957]
[1958] Reference Example 37
[1959] 3-acetylthio-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} ase Tidin
[1960]
[1961] (1) [(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester
[1962] 1.00 g (8.53 mmol) of L-leucineol was dissolved in 30 ml of methylene chloride, 1.46 ml (10.2 mmol) of benzyl chloroformate and 1.43 ml (10.2 mmol) of triethylamine were added under ice-cooling, and then at room temperature for 3 days. Stirred. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 1) to give [(1S) -1- (hydroxymethyl) -3-methyl- as a colorless oil. Butyl] -carbamic acid benzyl ester was obtained at 2.31 g and yield 100%. Subsequently, 4.84 g (19.3 mmol) of [(1S) -1- (hydroxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester was dissolved in 145 ml of dimethylformamide, and t-butyl chloride was cooled under ice-cooling. 6.01 ml (23.1 mmol) of diphenylsilane and 1.57 g (23.1 mmol) of imidazole were added, followed by stirring at room temperature for 8 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1-7: 1) to give [(1S) -1- (t-butyldiphenylsilyloxymethyl) as a colorless oil. 3-methyl-butyl] -carbamic acid benzyl ester was obtained in 9.22 g and yield 98%.
[1963]
[1964] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3- Thiazol-2-yl} azetidine
[1965] 7.35 g (15.0 mmol) of [(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester obtained in Reference Example 37 (1) were dissolved in 220 ml of methanol. Then, catalytic hydrogen reduction was performed at room temperature for 4 hours in the presence of 7.35 g of 10% palladium carbon. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2-9: 1) to obtain a colorless oil ( 4.50 g of 1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylamine was obtained in yield 84%. Subsequently, 2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 ml of benzene, and 12.9 ml of a 0.67 M (1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere overnight. It was refluxed. After confirming completion of the reaction, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 0 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-4: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1S) as a light brown solid. ) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 2.14 g, yield 64%.
[1966]
[1967] (3) 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[1968] 3-t-butyldiphenylsilyloxy-1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] obtained in Reference Example 37 (2)] 2.14 g (3.72 mmol) of -1,3-thiazol-2-yl} azetidine was dissolved in 107 mL of anhydrous tetrahydrofuran and 8.94 mL of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling. (8.94 mmol) was added and it stirred for 4 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- {in the form of a pale yellow oil. 825 mg of 4-[(1S) -1- (hydroxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in a yield of 74%.
[1969]
[1970] (4) 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3-hydrate Roxyazetidine
[1971] 3-hydroxy-1- {4-[(1S) -1- (hydroxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole-2- obtained in Reference Example 37 (3). Dissolve 820 mg (2.74 mmol) of Japanese azetidine in 41 mL of dimethylformamide, and add 495 mL (3.29 mmol) of t-butyldimethylsilane chloride and 224 mg (3.29 mmol) of imidazole under ice-cooling. Stir overnight under. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S) -1- (t-butyldimethyl in the form of light yellow oil. 731 mg of silyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained in a yield of 65%.
[1972]
[1973] (5) 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3-methane Sulfonyloxyazetidine
[1974] 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 37 (4). 730 mg (1.76 mmol) of} -3-hydroxyazetidine was dissolved in 37 ml of methylene chloride, and 409 µl (5.29 mmol) of methanesulfonyl chloride and 741 µl (5.29 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S) -1- (t-butyldimethyl in the form of light yellow oil. Silyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained at 846 mg, yield 98%.
[1975]
[1976] (6) 3-acetylthio-1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl } Azetidine
[1977] 1- {4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 37 (5). 840 mg (1.71 mmol) of} -3-methanesulfonyloxyazetidine was dissolved in 42 ml of dimethylformamide, 1.17 mg (10.2 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight at an 80 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 1) to give 3-acetylthio-1- {4-[(1S) -1- in the form of light brown oil. 452 mg of (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine were obtained in a yield of 56%.
[1978]
[1979] Reference Example 38
[1980] 3-acetylthio-1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} Azetidine
[1981]
[1982] (1) [(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butyl] -carbamic acid benzyl ester
[1983] 2.20 g (18.8 mmol) of L-isoleucine was dissolved in 66 ml of methylene chloride, 3.22 ml (22.5 mmol) of benzyl chloroformate and 3.15 ml (22.5 mmol) of triethylamine were added under ice-cooling, and then at room temperature. Stir for 1.5 hours. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 1) to give [(1S, 2S) -1- (hydroxymethyl) -2- in the form of a colorless oil. Methyl-butyl] -carbamic acid benzyl ester was obtained at 4.17 g and yield 88%. Subsequently, 4.17 g (16.6 mmol) of (2S)-(N-benzyloxycarbonyl) -2-amino-3-methylbutanol was dissolved in 125 ml of dimethylformamide, and 5.18 g of t-butyldiphenylsilane was dissolved under ice-cooling. ML (19.9 mmol) and 1.35 g (19.9 mmol) of imidazole were added, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1-5: 1) to give colorless crystals of [(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl 6.72 g of) -2-methyl-butyl] -carbamic acid benzyl esters were obtained by yield 83%.
[1984]
[1985] (2) 3-t-butyldiphenylsilyloxy-1- {4-[([(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl]- 1,3-thiazol-2-yl} azetidine
[1986] 200 ml of methanol 6.72 g (13.7 mmol) of [(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butyl] -carbamic acid benzyl ester obtained in Reference Example 38 (1) Was dissolved in, and contact hydrogen reduction was carried out for 2 hours at room temperature in the presence of 6.72 g of 10% palladium carbon. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography ( Elution solvent: methylene chloride: methanol = 98: 2-9: 1) to purify (1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylamine in colorless oil form 4.04 g and the yield were obtained by 83%. Subsequently, 2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 ml of benzene, and 12.9 ml of a 0.67 M (1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere. It was refluxed overnight. After confirming completion of the reaction, 200 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1S) as a light brown solid. , 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 1.89 g, yield 57%.
[1987]
[1988] (3) 3-hydroxy-1- {4-[(1S, 2S) -1- (hydroxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} ase Tidin
[1989] 3-t-butyldiphenylsilyloxy-1- {4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarba obtained in Reference Example 38 (2) Moyl] -1,3-thiazol-2-yl} azetidine 1.89 g (2.45 mmol) was dissolved in 95 ml of anhydrous tetrahydrofuran, and 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling. 5.87 mL (5.87 mmol) was added and the mixture was stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- {in the form of a pale yellow oil. 811 mg of 4-[(1S, 2S) -1- (hydroxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine were obtained in a yield of 100%.
[1990]
[1991] (4) 3-hydroxy-1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[1992] 3-hydroxy-1- {4-[(1S, 2S) -1- (hydroxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole- obtained in Reference Example 38 (3)- Dissolve 1.34 g (4.48 mmol) of 2-yl} azetidine in 67 mL of dimethylformamide, and add 810 mg (5.37 mmol) of t-butyldimethylsilane chloride and 527 mg (5.37 mmol) of imidazole under ice-cooling. The mixture was stirred for 2.5 hours under ice-cooling. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 5: 1-3: 1) to give 3-hydroxy-1- {4-[(1S, 2S) -1- in the form of a pale yellow oil. (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 1.35 g and yield 97%.
[1993]
[1994] (5) 1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3 Methanesulfonyloxyazetidine
[1995] 3-hydroxy-1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3 obtained in Reference Example 38 (4). 1.35 g (3.26 mmol) of -thiazol-2-yl} azetidine was dissolved in 68 ml of methylene chloride, and 758 µl (9.79 mmol) of methanesulfonyl chloride and 1.37 ml (9.79 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain 1- {4-[(1S, 2S) -1- (t- in the form of pale yellow oil. Butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained at 1.55 g and yield 97%.
[1996]
[1997] (6) 3-acetylthio-1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[1998] 1- {4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2 obtained in Reference Example 38 (5). Dissolve 1.55 g (3.15 mmol) of -yl} -3-methanesulfonyloxyazetidine in 78 mL of dimethylformamide, add 2.16 g (18.9 mmol) of potassium thioacetate at room temperature, and stir overnight in an 80 ° C oil bath. It was. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1-2: 1) to obtain 3-acetylthio-1- {4-[(1S, 2S)-in the form of light brown oil. 910 mg of 1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine were obtained at a yield of 61%.
[1999]
[2000] Reference Example 39
[2001] 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl } Azetidine
[2002]
[2003] (1) t-butyldiphenylsilyloxy-N-carbenzyloxy-L-serine methyl ester
[2004] 4.0 g (16.7 mmol) of N-carbobenzyloxy-L-serine was dissolved in 200 ml of benzene and 50 ml of methanol, and 10.9 ml (21.7 mmol) of 2M-trimethylsilyldiazomethane hexane solution was added thereto under ice cooling. After stirring at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to obtain 4.40 g of a colorless oil form N-carbobenzyloxy-L-serine methyl ester in a yield. Obtained at 100%. Subsequently, 4.40 g (16.7 mmol) of N-carbobenzyloxy-L-serine methyl ester was dissolved in 210 ml of dimethylformamide, and 5.20 ml (20.0 mmol) of t-butyldiphenylsilane chloride and imidazole 1.36 under ice-cooling. g (20.0 mmol) was added, and it stirred at room temperature after that for 3 days. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-6: 1) to obtain t-butyldiphenylsilyloxy-N-carbenzyloxy-L-serine methyl ester. 8.18 g, yield 99% was obtained.
[2005]
[2006] (2) [2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethyl] -carbamic acid benzyl ester
[2007] Reference Example 39 11.5 g (24.8 mmol) of t-butyldiphenylsilyloxy-N-carbenzyloxy-L-serine methyl ester obtained in (1) was dissolved in 115 ml of tetrahydrofuran and 230 ml of ethanol, under ice-cooling. Sodium borohydride 1.88g (49.6mmol) and lithium chloride 2.10g (49.6mmol) were added, and it stirred at room temperature overnight after that. After confirming completion of the reaction, methylene chloride and 10% acetic acid water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with methylene chloride, and the obtained organic layer was washed with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 1) to give [2- (t-butyldiphenylsilyloxy) -1- (hydro) in the form of a colorless oil. Roxymethyl) -ethyl] -carbamic acid benzyl ester was obtained at 9.26 g and yield 81%. Subsequently, 9.26 g (20.0 mmol) of [2- (t-butyldiphenylsilyloxy) -1- (hydroxymethyl) -ethyl] -carbamic acid benzyl ester was dissolved in 280 ml of dimethylformamide, and then cooled on ice. 7.79 ml (30.0 mmol) of chloride t-butyldiphenylsilane and 2.04 g (30.0 mmol) of imidazole were added, and it stirred at room temperature after that for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline solution were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1-9: 1) to give [2- (t-butyldiphenylsilyloxy) -1- (t in the form of a colorless oil). -Butyldiphenylsilyloxymethyl) -ethyl] -carbamic acid benzyl ester was obtained at 13.6 g and yield 97%.
[2008]
[2009] (3) 3-t-butyldiphenyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1 , 3-thiazol-2-yl} azetidine
[2010] Reference Example 39 13.6 g (19.5 mmol) of [2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethyl] -carbamic acid benzyl ester obtained in (2) were obtained. It dissolved in 410 ml, and catalytic hydrogen reduction was performed at room temperature for 3.5 hours in the presence of 13.6 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2-9: 1) to give a colorless oil. 9.34g of-(t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylamine was obtained by yield 84%. Subsequently, 2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). Was dissolved in 100 mL of benzene, and 12.9 mL of 0.67M 2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylamine-trimethylaluminum-benzene solution was added to a room temperature under a nitrogen atmosphere. At reflux overnight. After confirming completion of the reaction, 200 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 3 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1-4: 1) to give 3-t-butyldiphenyloxy-1- {4- [2- ( t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 3.19 g, yield 75%. .
[2011]
[2012] (4) 3-hydroxy-1- {4- [2-hydroxy-1- (hydroxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2013] Reference Example 39 3-t-butyldiphenyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylcart obtained in (2) 3.19 g (3.23 mmol) of barmoyl] -1,3-thiazol-2-yl} azetidine are dissolved in 160 mL of anhydrous tetrahydrofuran and 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran under ice cooling 11.6 mL (11.6 mmol) of solution was added, and the mixture was stirred for 2 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1-8: 2) to give 3-hydroxy-1- {4- [ 2-hydroxy-1- (hydroxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as 1.21 g as a white solid, yield 100%.
[2014]
[2015] (5) 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl}- 3-hydroxyazetidine
[2016] Reference Example 39 3-hydroxy-1- {4- [2-hydroxy-1- (hydroxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} ase obtained in (4). Tidin 750 mg (2.74 mmol) was dissolved in 38 ml of dimethylformamide, 951 mg (6.31 mmol) of t-butyldimethylsilane and imidazole 430 mg (6.31 mmol) were added under ice-cooling, and the mixture was stirred overnight under ice-cooling. It was. After confirming the completion of the reaction, ethyl acetate and 10% ethyl acetate were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to give 1- {4- [2- (t-butyldimethylsilyloxy) -1 as pale yellow crystals. -(t-Butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-hydroxyazetidine was obtained in 970 mg, yield 71%.
[2017]
[2018] (6) 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl}- 3-methanesulfonyloxyazetidine
[2019] 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole obtained in Reference Example 39 (5)- 1.27 g (2.53 mmol) of 2-yl} -3-hydroxyazetidine was dissolved in 64 ml of methylene chloride, and 587 µl (7.59 mmol) of methanesulfonyl chloride and 1.06 ml (7.59 mmol) of triethylamine were dissolved under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 2) to give 1- {4- [2- (t-butyldimethylsilyloxy) -1 as pale yellow crystals. -(t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained in 1.56 g and 100% yield.
[2020]
[2021] (7) 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole- 2-yl} azetidine
[2022] 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole- obtained in Reference Example 39 (6)- 1.56 g (2.53 mmol) of 2-yl} -3-methanesulfonyloxyazetidine was dissolved in 78 ml of dimethylformamide, 1.73 g (15.2 mmol) of potassium thioacetate was added at room temperature, and overnight in an 80 ° C oil bath. Stirred. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1-2: 1) to give 3-acetylthio-1- {4- [2- (t-butyldimethyl) as a light brown solid. 773 mg of silyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in a yield of 57%.
[2023]
[2024] Reference Example 40
[2025] 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl} azetidine
[2026]
[2027] (1) [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamic acid benzyl ester
[2028] 1.20 mL (15.0 mmol) of N-methylaminoethanol was dissolved in 36 mL of methylene chloride, 2.56 mL (18.0 mmol) of benzyl chloroformate and 2.52 mL (18.0 mmol) of triethylamine were added under ice-cooling, and then 3 at room temperature. Stirred for time. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added into the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.8 g of (2-hydroxy-ethyl) -methyl-carbamic acid benzyl ester in the form of a pale yellow oil in 90% yield. Subsequently, 2.82 g (13.5 mmol) of (2-hydroxy-ethyl) -methyl-carbamic acid benzyl ester was dissolved in 85 mL of dimethylformamide, and 4.21 mL (16.2 mmol) of t-butyldiphenylsilane chloride under ice-cooling. And imidazole 1.10g (16.2mmol) were added, and it stirred at room temperature after that for 3 hours. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the system, and liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 9: 1) to obtain pale yellow solid [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamic acid benzyl ester. It obtained in 5.7 g, 94% of yield.
[2029]
[2030] (2) 3-t-butyldiphenylsilyloxy-1- (4-{[2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazole-2 Azetidine
[2031] 5.7 g (12.7 mmol) of [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamic acid benzyl ester obtained in Reference Example 40 (1) were dissolved in 285 ml of methanol, and 5.7% of 10% palladium hydroxide was used. In the presence of g, catalytic hydrogen reduction was carried out at room temperature. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 19: 2-ethyl acetate: methanol = 1: 1). [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-amine in the form of a clear oil was obtained at 2.67 g and yield 69%. Subsequently, 1.91 g (4.09 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1). The solution was dissolved in 100 ml of benzene, and 13.6 ml of a 0.67 M [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-amine-trimethylaluminum-benzene solution was added at room temperature under nitrogen atmosphere to reflux overnight. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-{[2- (t-butyldi) as a light brown solid. Phenylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 2.54 g and yield 85%.
[2032]
[2033] (3) 3-hydroxy-1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
[2034] 3-t-butyldiphenylsilyloxy-1- (4-{[2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3 obtained in Reference Example 40 (2). 2.24 g (3.05 mmol) of -thiazol-2-yl) azetidine was dissolved in 70 mL of anhydrous tetrahydrofuran, and 7.32 mL (7.32 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice cooling. Was added and it stirred as it is for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 20: 1 to ethyl acetate: methanol = 15: 1) to give 3-hydroxy-1 -{4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as white solid, 833 mg, yield 94%.
[2035]
[2036] (4) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) -3-hydroxyazetidine
[2037] 576 mg of 3-hydroxy-1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine obtained in Reference Example 40 (3) ( 2.24 mmol) was dissolved in 29 ml of dimethylformamide, 354 mg (2.35 mmol) of t-butyldimethylsilane chloride and 160 mg (2.35 mmol) of imidazole were added under ice cooling, and the mixture was stirred under ice cooling for 2 hours. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added to the system, and liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-ethyl acetate) to give 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl]-as a pale yellow solid. Methyl-carbamoyl} -1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained at 489 mg, yield 60%.
[2038]
[2039] (5) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxyase Tidin
[2040] 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) -3- obtained in Reference Example 40 (4) -3- 442 mg (1.19 mmol) of hydroxyazetidine was dissolved in 15 ml of methylene chloride, 0.12 ml (1.49 mmol) of methanesulfonyl chloride and 0.20 ml (1.49 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour as it is. It was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carrine as a pale yellow solid. Bamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained at 517 mg, yield 97%.
[2041]
[2042] (6) 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) azetidine
[2043] 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) -3- obtained in Reference Example 40 (5) -3- Methanesulfonyloxyazetidine 516 mg (1.14 mmol) was dissolved in 15 ml of dimethylformamide, potassium thioacetate 815 mg (7.14 mmol) was added at room temperature, and it stirred for 3 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl as a light brown solid. ] -Methyl-carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 279 mg, yield 57%.
[2044]
[2045] Reference Example 41
[2046] p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbonylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidine-3- Thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2047]
[2048] (1) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
[2049] 6.73 g (15.3 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (4) was added to dimethylformamide 330. It dissolved in ml, 1.59 ml (18.4 mmol) of allyl bromide and 3.21 ml (18.4 mmol) of diisopropylethylamine were added to the system at room temperature, and stirred for 10 hours in an 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% saline solution were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1) to give 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) in the form of a brown oil. 5-31-g of 3-t-butyldiphenylsilyloxyazetidine was obtained with a yield of 73%.
[2050]
[2051] (2) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine
[2052] 5.31 g (11.1 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 41 (1) It was dissolved in 266 ml of hydrofuran, 13.3 ml (13.3 mmol) of 1M tetrabutylammonium chloride-tetrahydrofuran solution was added under ice-cooling, and stirred overnight at room temperature. After the completion of reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-allyloxycarbonyl-1,3-thiazole- as light brown crystals. 2.91 g of 2-yl) -3-hydroxyazetidine were obtained in a yield of 100%.
[2053]
[2054] (3) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[2055] Reference Example 41 2.91 g (11.1 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in (2) was dissolved in 146 ml of anhydrous methylene chloride. Then, 2.58 ml (33.3 mmol) of methanesulfonyl chloride and 4.67 ml (33.3 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was filtered by adding ethyl acetate and diisopropyl ether, and the filtrate was washed with diisopropyl ether to give 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) as light brown crystals. 3-methanesulfonyloxyazetidine was obtained in 2.71 g and yield 77%.
[2056]
[2057] (4) 3-acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine
[2058] 135 ml of dimethylformamide in 2.70 g (8.51 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 41 (3) Was dissolved in, and potassium thioacetate 5.83 g (51.1 mmol) was added at room temperature, followed by stirring for 10 hours in an 80 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 3-acetylthio-1- (4-allyloxycarbonyl-1,3-thiazole- as a light brown solid. 2-yl) azetidine was obtained in 1.61 g, 63% yield.
[2059]
[2060] (5) p-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] -2- (diphenylphosphoryloxy) -1-methyl-carbafen- 2-m-3-carboxylate
[2061] p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-car Dissolve 5.00 g (8.41 mmol) of carboxylate in 250 ml of dimethylformamide, add 2.54 g (16.8 mmol) of t-butyldimethylsilane chloride and 1.14 g (16.8 mmol) of imidazole under ice-cooling, and under ice-cooling 7 Stirred for time. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Subsequently, ethyl acetate and 10% saline solution were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give p-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1- in the form of a pale yellow oil. t-butyldimethylsilyloxyethyl] -2- (diphenylphosphoryloxy) -1-methyl-carbafen-2-m-3-carboxylate was obtained in 5.27 g and yield 88%.
[2062]
[2063] (6) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-t-Butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2064] Reference Example 41 1.61 g (5.40 mmol) of 3-acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in (4) was dissolved in 80 ml of dimethylformamide. Then, hydrazine acetate 596 mg (6.47 mmol) was added at room temperature under nitrogen atmosphere, and it stirred for 1.5 hours as it is. P-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1-t-butyldimethylsilyloxyethyl] obtained in Reference System 41 (5) in a system under ice-cooling under nitrogen atmosphere after confirmation of completion of reaction. A solution of 190 ml of acetonitrile of 3.83 g (5.40 mmol) of 2- (diphenylphosphoryloxy) -1-methyl-carbafen-2-m-3-carboxylate was added dropwise, followed by diisopropylethylamine. 3.76 ml (21.6 mmol) was added and the mixture was stirred overnight while gradually warming to room temperature. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-allyloxycarbonyl- 1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3 -Carboxylate was obtained as a pale yellow solid at 3.73 g and 97% yield.
[2065]
[2066] (7) p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[( R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2067] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl obtained in Reference Example 41 (6). Dissolve 3.73 g (5.2 mmol) of] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate in 180 ml of methylene chloride 1.46 g (10.4 mmol) of dimethedone, 603 mg (0.522 mmol) of palladium (0) tetrakis (triphenylphosphine), and 205 mg (0.783 mmol) of triphenylphosphine were added thereto, followed by 2 at room temperature under a nitrogen atmosphere. Stirred for time. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1 to methylene chloride: methanol = 10: 1) to obtain a pale brown solid p-nitrobenzyl (1R, 5S, 6S) -2- [ 1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl- Carbafen-2-m-3-carboxylate was obtained in 1.91 g and yield 54%.
[2068] Mass spectrum (FAB ⁺ ): m / z: 675 [M + H] ⁺
[2069] (8) N- (t-butoxycarbonyl) glycine p-nitrobenzyl ester
[2070] 1.51 g (8.62 mmol) of N- (t-butoxycarbonyl) glycine was dissolved in 75 mL of anhydrous methylene chloride, 2.63 mL (17.2 mmol) of p-nitrobenzyl alcohol, 1-ethyl-3- (3-dimethylamino Propyl) -carbodiimide hydrochloride (hereinafter referred to as WSC) 3.3 g (17.2 mmol) and 106 mg (0.87 mmol) of 4-dimethylaminopyridine were added under ice-cooling, and stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 2.67 g of white crystals N- (t-butoxycarbonyl) glycine p-nitrobenzyl ester in 100% yield. Got it.
[2071]
[2072] (9) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbonylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidine -3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2073] Reference Example 41 2.67 g (8.62 mmol) of N- (t-butoxycarbonyl) glycine p-nitrobenzyl ester obtained in (8) was dissolved in 27 ml of 1,4-dioxane and 4N-hydrochloric acid gas- under ice cooling 27 ml of 1, 4- dioxane solution was added, and it stirred at room temperature for 4 hours. After the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether, and dried to yield 1.59 g of white crystal glycine p-nitrobenzyl ester hydrochloride, yield 75 Obtained in%. Next, p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-1,3-thiazol-2-yl) azetidine-3- obtained in Reference Example 41 (7). Yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 207.4 mg (0.31 mmol) and glycine p described above 116 mg (0.47 mmol) of nitrobenzyl ester hydrochloride were suspended in 10.5 mL of dimethylformamide, and 0.072 mL (0.47 mmol) of diethylphosphoryl cyanide and 0.14 mL (1.00 mmol) of triethylamine were added under nitrogen atmosphere under ice-cooling. And it stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (p-nitrobenzyloxycarbine Bonylmethyl) carbamoyl-1,3-thiazol-2yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen -2-M-3-carboxylate was obtained by pale yellow syrup in 209.7 mg, yield 77%.
[2074]
[2075] Reference Example 42
[2076] p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] Azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2077]
[2078] (1) 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine
[2079] 10 g (41.8 mmol) of 1-benzhydryl-3-hydroxyazetidine was dissolved in 300 ml of methanol, and catalytic hydrogen reduction was performed for 3 hours in a 50 ° C water bath in the presence of 10 g of 10% palladium-carbon. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to liquid separation operation by adding ethyl acetate and distilled water, and after washing the water bath with ethyl acetate, the residue obtained by concentrating under reduced pressure was dried under reduced pressure. This crude product was dissolved in 120 ml of methylene chloride and 120 ml of methanol, 8.95 ml (62.7 mmol) of benzyl chloroformate and 8.79 ml (62.7 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain 1.91 g of 1-benzyloxycarbonyl-3-hydroxyazetidine and a yield of 22%. Subsequently, 1.91 g (9.22 mmol) of 1-benzyloxycarbonyl-3-hydroxyazetidine was dissolved in 96 ml of dimethylformamide, 2.88 ml (11.1 mmol) of t-butyldiphenylsilane chloride and imidazole under ice-cooling. 756 mg (11.1 mmol) was added and stirred for 6 hours under ice-cooling in the same manner. After confirming the reaction was completed, ethyl acetate and 10% saline solution were added into the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1) to obtain 4.04 g of 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine in the form of a colorless oil. And yield 98%.
[2080]
[2081] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-thiazole-2 -Yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2082] Reference Example 42 (4) of 4.04 g (9.07 mmol) of 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine obtained in (2) was dissolved in 200 ml of methanol, and in the presence of 4.04 g of 10% palladium carbon, Contact hydrogen reduction was carried out at. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dried under reduced pressure to obtain 2.70 g of a 3-t-butyldiphenylsilyloxyazetidine as a colorless oil in a yield of 96%. Subsequently, p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-1,3-thiazol-2-yl) azetidine-3- obtained in Reference Example 41 (7). Il] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbaphene-2-m-3-carboxylate and 3-71 as described above 947 mg (3.04 mmol) of t-butyldiphenylsilyloxyazetidine was dissolved in 86 ml of dimethylformamide, 461 µl (3.04 mmol) of diethylphosphoryl cyanide and 426 µl (3.04 mmol) of triethylamine under ice-cold cooling under nitrogen atmosphere. mmol) was added and stirred at room temperature for 5.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (3-t-butyldi Phenylsilyloxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1- (t-butyl-dimethylsilyloxy) Ethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained in 789 mg, yield 32%.
[2083]
[2084] Reference Example 43
[2085] p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- (p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazol-2-yl} Azetidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2086]
[2087] (1) (t-butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester
[2088] 3.56 g (40 mmol) of sarcosine are dissolved in 180 ml of methanol and 90 ml of distilled water, and 9.6 g (44.0 mmol) of di-t-butoxycarbonyl anhydride and 80 ml of a 1M sodium hydroxide aqueous solution are added, and the system is ice-cooled. Was added and stirred at room temperature for 1.5 hours. After confirming completion of the reaction, Dowex-50W was added to the system by ice cooling, and the pH of the reaction solution was adjusted to 5-4. Thereafter, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 7.57 g of a crude product of (t-butoxycarbonyl-methyl-amino) -acetic acid. Subsequently, 2.52 g (13.3 mmol) of (t-butoxycarbonyl-methyl-amino) -acetic acid and 4.07 g (26.6 mmol) of p-nitrobenzyl alcohol were dissolved in 125 ml of methylene chloride, and cooled with ice to provide a nitrogen atmosphere. 5.10 g (26.6 mmol) and 252 mg (1.33 mmol) of 4-dimethylaminopyridine were added under the following, and it returned to room temperature after that, and stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to obtain 4.30 g of (t-butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester in the form of a pale yellow oil. Yield was 88%.
[2089]
[2090] (2) Sarcosine p-nitrobenzyl ester hydrochloride
[2091] Reference Example 43 4.30 g (13 3 mmol) of (t-butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester obtained in (1) was dissolved in 43 ml of 1,4-dioxane and 4N- under ice-cooling. 4.3 ml of hydrochloric acid gas-1,4-dioxane solution was added, and it stirred at room temperature for 2.5 hours. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether, and dried to obtain 3.04 g of sarcosine p-nitrobenzyl ester hydrochloride at 88% yield. Got it.
[2092]
[2093] (3) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- (p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazole-2 -Yl} azetidin-3-yl) thio-6-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2094] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio obtained in Reference Example 41 (7). -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate obtained from 1.00 g (1.51 mmol) and Reference Example 43 (2). 590 mg (2.26 mmol) of sarcosine p-nitrobenzyl ester hydrochloride were suspended in 30 ml of dimethylformamide, and 0.37 ml (2.26 mmol) of diethylphosphoryl cyanide and 0.95 ml (6.80 ml) of triethylamine under ice-cooled nitrogen atmosphere. mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- ( p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylate was obtained at 997 mg, yield 76%.
[2095]
[2096] Reference Example 44
[2097] p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- (carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3 -Yl) thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2098]
[2099] (1) Carbamoylmethyl-methyl-carbamic acid t-butyl ester
[2100] 5.03 g (26.6 mmol) of (t-butoxycarbonyl-methyl-amino) -acetic acid obtained in Reference Example 43 (1) was dissolved in 250 ml of anhydrous methylene chloride, and 7.19 g (53.2 mmol) of 1-hydroxybenzotriazole. ), WSC 10.2 g (53.2 mmol) and 4-dimethylaminopyridine 325 mg (2.66 mmol) were added under ice-cooling, and stirred for 2 days at room temperature under a nitrogen atmosphere. After confirming the disappearance of the raw materials, 28% ammonia water was added into the reaction system and stirred for 30 minutes. After confirming the reaction was completed, ethyl acetate and saturated brine were added to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 10: 1) to give 848 mg of carbamoylmethyl-methyl-carbamic acid t-butyl ester in the form of pale yellow oil in a yield of 17%. .
[2101]
[2102] (2) p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- (carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} ase Thidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2103] Reference Example 44 848 mg (4.50 mmol) of carbamoylmethyl-methyl-carbamic acid t-butyl ester obtained in (1) was dissolved in 8.50 ml of 1,4-dioxane, and 4N-HCl-1, under ice-cooling, 8.50 ml of 4-dioxane solution was added and stirred at room temperature for 2.5 hours. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether and dried to yield 421 mg of 2-methylamino-acetamide hydrochloride at 75% yield. Got it. Subsequently, p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-1,3-thiazol-2-yl) azetidine-3- obtained in Reference Example 41 (7). Il] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 1.00 g (1.51 mmol) and 2- of the foregoing description 282 mg (2.26 mmol) of methylamino-acetamide hydrochloride were suspended in 30 ml of dimethylformamide, and 0.37 ml (2.26 mmol) of diethylphosphoryl cyanide and 0.95 ml (6.80 mmol) of triethylamine were added under ice-cooling under nitrogen atmosphere. It was added and stirred at room temperature for 3.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4- [methyl- ( Carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1- (t-butyldimethylsilyloxy) ethyl] 932 mg of 1-methyl-carbafen-2-m-3-carboxylate were obtained in 84% yield.
[2104]
[2105] Reference Example 45
[2106] p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl} thio- 6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2107]
[2108] (1) Carbamoylmethyl-carbamic acid t-butyl ester
[2109] 3.01 g (17.2 mmol) of N- (t-butoxycarbonyl) glycine was dissolved in 150 ml of anhydrous methylene chloride, 4.63 g (34.3 mmol) 1-hydroxybenzotriazole, 6.60 g (34.4 mmol), 4 WSC 210 mg (1.72 mmol) of -dimethylaminopyridine was added under ice-cooling, and stirred overnight at room temperature under a nitrogen atmosphere. After confirming the disappearance of the raw materials, 28% ammonia water was added into the reaction system and stirred for 15 minutes. After confirming completion of the reaction, methylene chloride and saturated brine were added to carry out a liquid separation operation. The aqueous layer was separated and extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 717.7 mg of carbamoylmethyl-carbamic acid t-butyl ester of colorless transparent syrup in a yield of 24%.
[2110]
[2111] (2) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2112] Reference Example 45 717.2 mg (4.12 mmol) of carbamoylmethyl-carbamic acid t-butyl ester obtained in (1) were dissolved in 7.2 ml of 1,4-dioxane, and 4N-hydrochloric acid gas-1,4- under ice-cooling. 7.2 ml of dioxane solution was added and stirred overnight at room temperature. After confirming completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether, and dried to obtain 389 mg of white crystal glycineamide hydrochloride at a yield of 86%.
[2113] Subsequently, p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-1,3-thiazol-2-yl) azetidine-3- obtained in Reference Example 41 (7). Il] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate 566.6 mg (0.85 mmol) and the glycineamides mentioned above 154.3 mg (1.40 mmol) of hydrochloride are suspended in 28.0 ml of dimethylformamide, and 0.2 ml (1.32 mmol) of diethylphosphoryl cyanide and 0.36 ml (2.6 mmol) of triethylamine are added to a room temperature under nitrogen atmosphere under ice-cooling. Stirred for 5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (carbamoyl) as a pale yellow solid. Methyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen The 2-m-3-carboxylate was obtained at 428.6 mg and yield 70%.
[2114]
[2115] Reference Example 46
[2116] p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) -propylcarbamoyl) -1,3 -Thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxyl Rate
[2117]
[2118] (1) N- (t-butoxycarbonyl) -L-valine p-nitrobenzyl ester
[2119] 2.50 g (11.5 mmol) of N- (t-butoxycarbonyl) -L-valine was dissolved in 125 mL of anhydrous methylene chloride, 3.52 g (23.0 mmol) of p-nitrobenzyl alcohol, 4.41 g (23.0 mmol) of WSC, 140 mg (1.15 mmol) of 4-dimethylaminopyridine was added by ice-cooling, and it stirred for 4.5 hours at room temperature under nitrogen atmosphere. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1) to give 3.07 g of white crystals N- (t-butoxycarbonyl) -L-valine p-nitrobenzyl ester. And yield 76%.
[2120]
[2121] (2) L-valine p-nitrobenzyl ester hydrochloride
[2122] 3.07 g (8.71 mmol) of N- (t-butoxycarbonyl) -L-valine p-nitrobenzyl ester obtained in Example 46 (1) was dissolved in 31 ml of 1,4-dioxane and 4N- under ice cooling. 31 mL of hydrochloric acid gas-1,4-dioxane solution was added, and it stirred at room temperature overnight.
[2123] After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, followed by filtration. The filtrate was washed with ethyl acetate and dried to give 2.21 g of L-valine p-nitrobenzyl ester hydrochloride at 88% yield. Got it.
[2124] Elemental analysis: Found: C, 48.77%, H, 5.63%, N, 9.49%, Cl, 12.38%
[2125] Calculated Value: C, 49.92%, H, 5.93%, N, 9.70%, Cl, 12.28%
[2126] (3) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) -propylcarbamoyl)- 1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3 Carboxylate
[2127] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio obtained in Reference Example 41 (7). -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate obtained from 1.00 g (1.48 mmol) and Reference Example 46 (2). 514 mg (1.78 mmol) of L-valine p-nitrobenzyl ester hydrochloride was dissolved in 50 ml of dimethylformamide, and 275 µl (1.78 mmol) of diethylphosphoryl cyanide under ice-cooled nitrogen atmosphere, diisopropylethylamine 620 Μl (3.56 mmol) was added and stirred at room temperature for 2 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1-1: 1) to obtain p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- ( (1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbaphene-2-m-3-carboxylate was obtained by 1.15 g and yield 86%.
[2128]
[2129] Reference Example 47
[2130] p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazole-2- Yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2131]
[2132] (1) (1S) -1-carbamoyl-2-methyl-carbamic acid t-butyl ester
[2133] 3.00 g (13.8 mmol) of N- (t-butoxycarbonyl) -L-valine are dissolved in 150 ml of anhydrous methylene chloride, 3.73 g (27.6 mmol) of 1-hydroxybenzotriazole, 5.29 g (27.6 mmol) of WSC ) And 4-dimethylaminopyridine 169 mg (1.38 mmol) were added under ice-cooling, and the mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. After confirming the disappearance of the raw materials, 28% ammonia water was added into the reaction system and stirred for 30 minutes. After the reaction was completed, ethyl acetate and saturated brine were added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 9: 1) to give 2.81 g of white crystals (1S) -1-carbamoyl-2-methyl-carbamic acid t-butyl ester. And yield 94%.
[2134]
[2135] (2) 2-amino-3-methyl-butylamide hydrochloride
[2136] Reference Example 47 1.81 g (13.0 mmol) of 1-carbamoyl-2-methyl-carbamic acid t-butyl ester obtained in (1) was dissolved in 28 ml of 1,4-dioxane, and 4N-hydrochloric acid gas was cooled under ice-cooling. 18 ml of -1,4-dioxane solution was added and stirred overnight at room temperature. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the system, the filtration and the filtrate were washed with ethyl acetate and dried to obtain (2S) -2-amino-3-methyl-butylamide hydrochloride. g, yield 98%.
[2137] Elemental analysis: Found: C, 39.21%, H, 8.34%, N, 18.31%, Cl, 23.38%
[2138] Calculated Value: C, 39.35%, H, 8.59%, N, 18.35%, Cl, 23.23%
[2139] (3) p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazole -2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate
[2140] P-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio obtained in Reference Example 41 (7). -6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbafen-2-m-3-carboxylate obtained from 1.00 g (1.48 mmol) and Reference Example 47 (2) 272 mg (1.78 mmol) of L-valineamide hydrochloride were dissolved in 50 ml of dimethylformamide, and 275 µl (1.78 mmol) of diethylphosphoryl cyanide and 620 µl (3.56 mmol) of diisopropylethylamine in ice-cooling under nitrogen atmosphere. Was added and stirred at room temperature for 2.5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate). = 1: 3-- methylene chloride: ethyl acetate = 3: 1), and purified by p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-((1S) -1-carbamoyl-2 -Methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl -Carbafen-2-m-3-carboxylate was obtained in 934 mg, yield 82%.
[2141]
[2142] Reference Example 48
[2143] 3-acetylthio-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidine
[2144] (1) (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester
[2145] 3.03 g (24.1 mmol) of glycine methyl ester hydrochloride was dissolved in 150 mL of methanol, 3.4 mL (24.4 mmol) of triethylamine and 17.7 mL (241.1 mmol) of acetone were added into the system, followed by stirring in a 50 ° C water bath for 1.5 hours. Subsequently, 3.03 g (48.2 mmol) of sodium cyanoborohydride was added to the reaction system under ice-cooling, then a 10% hydrochloric acid gas-methanol solution was added, and the system was adjusted to pH 3-4 and stirred for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was dried under reduced pressure. Subsequently, this crude product was suspended in 45 ml of methanol and 90 ml of methylene chloride, and 10.5 g (48.1 mmol) of di-t-butoxycarbonyl anhydride and 13.5 ml (96.9 mmol) of triethylamine were added under ice cooling. And stirred overnight at room temperature. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 5: 1) to give 3.93 g of (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester of colorless transparent syrup, yield 70 Obtained in%.
[2146]
[2147] (2) (t-butoxycarbonyl-isopropyl-amino) -acetic acid p-nitrobenzyl ester
[2148] 5.59 g (24.2 mmol) of (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester obtained in Reference Example 48 (1) was dissolved in 112 ml of methanol and 56 ml of distilled water, and 37 ml of 1M aqueous sodium hydroxide solution was added. The mixture was added to the system under ice-cooling and stirred at room temperature for 7 hours. After confirming completion of the reaction, Dowex-50W was added to the system by ice cooling, and the reaction solution was adjusted to pH 5-4. Thereafter, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 5.25 g of a crude product of (t-butoxycarbonyl-isopropyl-amino) -acetic acid. Subsequently, 2.05 g (9.44 mmol) of (t-butoxycarbonyl-isopropyl-amino) -acetic acid and 2.89 g (18.9 mmol) of p-nitrobenzyl alcohol were dissolved in 100 ml of methylene chloride and cooled with ice to provide nitrogen. Under the atmosphere, 3.62 g (18.9 mmol) and 120 mg (0.98 mmol) of 4-dimethylaminopyridine were added, and the mixture was returned to room temperature and stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 2) to yield 1.93 g of (t-butoxycarbonyl-isopropyl-amino) -acetic acid p-nitrobenzyl ester of light yellow transparent syrup. The yield was 58%.
[2149]
[2150] (3) isopropylamino-acetic acid p-nitrobenzyl ester hydrochloride
[2151] 1.93 g (5.48 mmol) of (t-butoxycarbonyl-isopropyl-amino) -acetic acid p-nitrobenzyl ester obtained in Reference Example 48 (2) was dissolved in 20 ml of 1,4-dioxane and 4N under ice-cooling. 20 mL of hydrochloric acid gas-1,4-dioxane solution was added, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether, and dried to yield 1.50 of white crystal isopropylamino-acetic acid p-nitrobenzyl ester hydrochloride. g, yield 95%.
[2152]
[2153] (4) 3-t-butyldiphenylsilyloxy-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} ase Tidin
[2154] 500 mg (1.73 mmol) of isopropylamino-acetic acid p-nitrobenzyl ester hydrochloride obtained in Reference Example 48 (3) and 3-t-butyldiphenylsilyloxy-1- (4-carbox obtained in Reference Example 2 (4) 506 mg (1.15 mmol) of carboxyl-1,3-thiazol-2-yl) azetidine was suspended in 15 mL of dimethylformamide, and 0.28 mL (1.73 mmol) of diethylphosphoryl cyanide under ice-cooling under nitrogen atmosphere, 0.60 ml (4.32 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- {4- [isopropyl- (p-nitro) in the form of a pale yellow oil. Benzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 578 mg, yield 75%.
[2155]
[2156] (5) 3-hydroxy-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidine
[2157] 3-t-butyldiphenylsilyloxy-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazole- obtained in Reference Example 48 (4). 2-yl} azetidine 1.81 g (2.69 mmol)
[2158] Was dissolved in 90 ml of anhydrous tetrahydrofuran, and 0.18 ml (3.23 mmol) of acetic acid and 3.23 ml (3.23 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution were added thereto under ice cooling, followed by stirring for 2 hours as it was. . After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 1: 1) to 3-hydroxy-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 968 mg, yield 83%.
[2159]
[2160] (6) 1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine
[2161] 3-hydroxy-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} ase obtained in Reference Example 48 (5). Tidine 968 mg (2.23 mmol) was dissolved in 50 mL of methylene chloride, 0.42 mL (5.34 mmol) of methanesulfonyl chloride and 0.37 mL (2.67 mmol) of triethylamine were added under ice cooling, followed by stirring for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 1: 1) to give 1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl as a pale yellow solid. ] -1,3-thiazol-2-yl} -3-methanesulfonyloxyazetidine was obtained by 835 mg and yield 73%.
[2162]
[2163] (7) 3-acetylthio-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} azetidine
[2164] 1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl} -3-methanesulfonyl obtained in Reference Example 48 (6) 835 mg (1.63 mmol) of oxyazetidine was dissolved in 42 ml of dimethylformamide, 1.12 g (9.77 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for 7 hours in a 90 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- {4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) as a light brown solid. -Carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 312 mg, yield 39%.
[2165]
[2166] Reference Example 49
[2167] 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine
[2168]
[2169] (1) Carbamoylmethyl-isopropyl-carbamic acid t-butyl ester
[2170] 3.20 g (14.7 mmol) of (t-butoxycarbonyl-isopropyl-amino) -acetic acid and 4.0 g (29.6 mmol) of 1-hydroxybenzotriazole obtained in Reference Example 48 (2) were dissolved in 150 ml of methylene chloride. Then, under ice-cooling, 5.6 g (29.2 mmol) of WSC and 200 mg (1.64 mmol) of 4-dimethylaminopyridine were added under nitrogen atmosphere, and then the mixture was returned to room temperature and stirred overnight. After confirming that the raw materials disappeared, 40 ml of 28% aqueous ammonia was added to the system and stirred for 30 minutes. After confirming the completion of the reaction, methylene chloride and saturated brine were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 10: 1) to give 2.67 g of a white solid carbamoylmethyl-isopropyl-carbamic acid t-butyl ester in a yield of 84%. .
[2171]
[2172] (2) 2-isopropylamino-acetamide hydrochloride
[2173] Reference Example 49 2.67 g (12.3 mmol) of carbamoylmethyl-isopropyl-carbamic acid t-butyl ester obtained in (1) were dissolved in 30 ml of 1,4-dioxane and 4N-hydrochloric acid gas-1 under ice-cooling 30 ml of the 4-4-dioxane solution was added and stirred overnight at room temperature. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction solution was filtered, the filtrate was washed with diethyl ether, and dried to yield 1.82 g of white crystals of 2-isopropylamino-acetamide hydrochloride. Yield was 97%.
[2174]
[2175] (3) 3-t-butyldiphenylsilyloxy-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine
[2176] 500 mg (3.28 mmol) of 2-isopropylamino-acetamide hydrochloride obtained in Reference Example 49 (2) and 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-) obtained in Reference Example 2 (4) 961 mg (2.19 mmol) of 1,3-thiazol-2-yl) azetidine was suspended in 29 mL of dimethylformamide, and 0.54 mL (3.29 mmol) of diethylphosphoryl cyanide under ice-cooling under nitrogen atmosphere, triethyl 1.15 mL (8.19 mmol) of amine was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (carbamoylmethyl-isopropyl-carbamoyl)-in the form of a pale yellow oil. 1,3-thiazol-2-yl] azetidine was obtained in 1.18 g and 100% yield.
[2177]
[2178] (4) 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-hydrate
[2179] Roxyazetidine
[2180] 3-t-butyldiphenylsilyloxy-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 49 (3). 6.52 g (11.8 mmol) was dissolved in 326 mL of anhydrous tetrahydrofuran, and 14.2 mL (14.2 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, followed by stirring for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- [4- (carbamoylmethyl-isopropyl-carr). Barmoyl) -1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained as a white solid at 2.35 g, yield 67%.
[2181]
[2182] (5) 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methane
[2183] Sulfonyloxyazetidine and 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl]
[2184] 3-methanesulfonyloxyazetidine
[2185] 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3 obtained in Reference Example 49 (4)
[2186] 2.35 g (7.88 mmol) of -thiazol-2-yl] -3-hydroxyazetidine was dissolved in 120 mL of methylene chloride, 0.91 mL (11.8 mmol) of methanesulfonyl chloride and 1.66 mL of triethylamine under ice-cooling ( 11.8 mmol) was added and stirred as it is for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give a pale yellow solid, 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thia 516 mg of zol-2-yl] -3-methanesulfonyloxyazetidine, yield 17% and 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazole as a pale yellow solid -2-mg] -3-methanesulfonyloxyazetidine was obtained in 634 mg, yield 22%.
[2187] 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine
[2188]
[2189] 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine
[2190]
[2191] (6) 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine
[2192] 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3 obtained in Reference Example 49 (5)
[2193] Dissolve 516 mg (1.37 mmol) of -thiazol-2-yl] -3-methanesulfonyloxyazetidine in 15 ml of dimethylformamide, add 939 mg (8.22 mmol) of potassium thioacetate at room temperature, and The mixture was stirred for 3 hours in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carba) as a light brown solid. Moyl) -1,3-thiazol-2-yl] azetidine in 347 mg, yield 71%.
[2194]
[2195] Reference Example 50
[2196] 3-acetylthio-1- [4- (cyanomethylisopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine
[2197]
[2198] (1) 3-acetylthio-1- [4- (cyanomethylisopropyl-carbamoyl) -1,3-thiazol-2-yl
[2199] ] Azetidine
[2200] 635 mg of 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine obtained in Reference Example 49 (5) mmol) was dissolved in 19 ml of dimethylformamide, 1.21 g (10.6 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 3 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to give 3-acetylthio-1- [4- (cyanomethylisopropyl-carbamoyl) as a light brown solid. 344 mg of -1,3-thiazol-2-yl] azetidine were obtained in a yield of 57%.
[2201]
[2202] Reference Example 51
[2203] 3-acetylthio-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2204]
[2205] (1) 4-hydroxy-1- (p-nitrobenzyloxycarbonyl) -piperidine
[2206] 3.0 g (21.8 mmol) of 4-hydroxypiperidine hydrochloride were dissolved in 90 ml of methylene chloride and 15 ml of pyridine, and 15.4 g (72.0 mmol) of chloroformic acid p-nitrobenzyl and 13.1 ml (93.8 mmol) of chloroformic acid under ice cooling. ) Was added and stirred for 3 days at room temperature. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to give 4-hydroxy-1- (p-nitrobenzyloxycarbonyl) -piperi of pale yellow crystals. Dean was obtained in 2.96 g and yield 48%.
[2207]
[2208] (2) 4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -piperidine
[2209] 2.96 g (14.8 mmol) of 4-hydroxy-1- (p-nitrobenzyloxycarbonyl) -piperidine obtained in Reference Example 51 (1) was dissolved in 90 ml of methylene chloride, and methanesulfonyl chloride was cooled under ice-cooling. 1.15 mL (14.8 mmol) and 2.07 mL (14.8 mmol) triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 6 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -piperidine of pale yellow crystals. Was obtained in 3.31 g, yield 87%.
[2210]
[2211] (3) 4-azide-1- (p-nitrobenzyloxycarbonyl) -piperidine
[2212] 3.31 g (9.24 mmol) of 4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -piperidine obtained in Reference Example 51 (2) was dissolved in 100 ml of dimethylformamide, and the azide was added into the system. 660 mg (10.2 mmol) of sodium sulfate were added, and it stirred for 3 hours in 100 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 1) to give 4-azide-1- (p-nitrobenzyloxycarbonyl) -P as light yellow crystals. Ferridine was obtained in 2.81 g and the yield 100%.
[2213]
[2214] (4) 4-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine
[2215] 2.81 g (9.17 mmol) of 4-azide-1- (p-nitrobenzyloxycarbonyl) -piperidine obtained in Reference Example 51 (3) was dissolved in 84 ml of acetonitrile, and 2.53 g of triphenylphosphine ( 9.63 mmol) was added to the system and stirred for 3 hours in a 70 ° C oil bath. After confirming the disappearance of the raw materials, 3.10 g (9.63 mmol) of sodium sulfate decahydrate was added to the system and stirred for 3 hours. After confirming the completion of the reaction, the reaction solution was filtered, and methylene chloride and 0.1 M hydrochloric acid were added to the filtrate to carry out liquid separation extraction. Methylene chloride and sodium hydrogencarbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to yield 2.33 g of 4-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine as pale yellow crystals, 91% yield. Got it.
[2216]
[2217] (5) 3-t-butyldiphenyloxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2218] 3-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine 382 mg (1.37 mmol) obtained in Reference Example 51 (4) and 3-t-butyldiphenylsilyl obtained in Reference Example 2 (4). Dissolve 500 mg (1.14 mmol) of oxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine in 25 ml of dimethylformamide, and diethylphosphorylcia under ice-cooling under nitrogen atmosphere. 208 microliters (1.37 mmol) of needs and 192 microliters (1.37 mmol) of triethylamine were added, and it stirred at room temperature for 1.5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to give 3-t-butyldiphenyloxy-1- {4- [1- () as a pale yellow solid. p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 574 mg, yield 72%.
[2219]
[2220] (6) 3-hydroxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} ase Tidin
[2221] 3-t-butyldiphenyloxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3 obtained in Reference Example 51 (5). 570 mg (0.820 mmol) of -thiazol-2-yl} azetidine was dissolved in 17 ml of anhydrous tetrahydrofuran, and 56 µl (0.984 mmol) of acetic acid under ice-cooling, 1.0 M tetra-n-butylammonium fluoride-tetrahydro 984 µl (0.984 mmol) of furan solution was added sequentially, followed by stirring for 1 hour. After the reaction was completed, ethyl acetate and saturated water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3-ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4- [1- (p- Nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 360 mg, yield 95%.
[2222]
[2223] (7) 3-methanesulfonyloxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl } Azetidine
[2224] 3-hydroxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazole- obtained in Reference Example 51 (6)- Dissolve 360 mg (0.780 mmol) of 2-yl} azetidine in 18 ml of methylene chloride, add 181 μl (2.34 mmol) of methanesulfonyl chloride and 328 μl (2.34 mmol) of triethylamine under ice-cooling, and after 10 minutes The reaction system was returned to room temperature and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2) to give 3-methanesulfonyloxy-1- {4- [1- (p-nitrobenzyloxy) as a pale yellow solid. 390 mg, yield 93% of carbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained.
[2225]
[2226] (8) 3-acetylthio-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} ase Tidin
[2227] 3-methanesulfonyloxy-1- {4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thia obtained in Reference Example 51 (7) 390 mg (0.723 mmol) of sol-2-yl} azetidine was dissolved in 20 mL of dimethylformamide, 496 mg (4.34 mmol) of potassium thioacetate were added at room temperature, and the mixture was stirred overnight at 80 ° C. in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give 3-acetylthio-1- {4- [1- (p-nitrobenzyloxy) as a light brown solid. 262 mg, yield 70% of carbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained.
[2228]
[2229] Reference Example 52
[2230] 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} Azetidine
[2231]
[2232] (1) (3R) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2233] 7.00 g (56.6 mmol) of (3R) -3-hydroxypyrrolidine hydrochloride was suspended in 210 ml of methylene chloride, and 13.4 g (62.3 mmol) of chloroformate p-nitrobenzyl and 17.4 ml (125 mmol) of triethylamine under ice-cooling. Was added and stirred at room temperature for 5 hours. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to give (3R) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) as pale yellow crystals. ) -Pyrrolidine was obtained at 13.6 g, yield 90%.
[2234]
[2235] (2) (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2236] 9.0 g (33.8 mmol) of (3R) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (1) was dissolved in 270 ml of methylene chloride, and 2.88 mL (37.2 mmol) of sulfonyl chloride and 5.21 mL (37.2 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was for 1.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxy) as a pale yellow solid. 11.5 g of carbonyl) -pyrrolidine was obtained in 99% yield.
[2237]
[2238] (3) (3S) -3-azide-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2239] 4.00 g (11.6 mmol) of (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (2) was dissolved in 120 ml of dimethylformamide, Sodium azide 831 mg (12.8 mmol) was added in the system, and it stirred for 2 hours in 100 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 2) to obtain (3S) -3-azide-1- (p-nitrobenzyloxycarpoxy) as pale yellow crystals. 3.43 g of carbonyl) -pyrrolidine was obtained with a yield of 100%.
[2240]
[2241] (4) (3S) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2242] Reference Example 52 (3S) -3-azide-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine 3.43 g (11.6 mmol) obtained in (3) was dissolved in 103 ml of acetonitrile and triphenylphosphate. 3.19 g (12.2 mmol) of pins were added to the system and stirred for 2 hours in a 70 ° C oil bath. After confirming that the raw materials disappeared, 3.93 g (12.2 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 5 hours. After confirming the completion of the reaction, the reaction solution was filtered, and methylene chloride and 0.1 M hydrochloric acid were added to the filtrate to carry out liquid separation extraction. Methylene chloride and sodium hydrogencarbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to give 2.83 g of (3S) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine as pale yellow crystals. And yield 92%.
[2243]
[2244] (5) 3-t-butyldiphenylsilyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 -Thiazol-2-yl} azetidine
[2245] 363 mg (1.37 mmol) of (3S) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (4) and 3-t- obtained in Reference Example 2 (4) 500 mg (1.14 mmol) of butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine are suspended in 25 ml of dimethylformamide, and the mixture is cooled under ice with nitrogen atmosphere. 208 µl (1.37 mmol) of ethylphosphoryl cyanide and 192 µl (1.37 mmol) of triethylamine were added, followed by stirring at room temperature for 2 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[(3S as a pale yellow solid. ) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 566 mg, yield 72%.
[2246]
[2247] (6) 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2248] 3-t-butyldiphenylsilyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl obtained in Reference Example 52 (5) ] -1,3-thiazol-2-yl} azetidine 560 mg (0.816 mmol) was dissolved in 17 ml of anhydrous tetrahydrofuran, and 56 µl (0.980 mmol) of acetic acid and 1.0 M tetra-n-butylammonium were dissolved under ice-cooling. 980 µl (0.980 mmol) of Floride-tetrahydrofuran were added sequentially, followed by stirring for 1.5 hours. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbine. Bonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 359 mg, yield 98%.
[2249]
[2250] (7) 3-methanesulfonyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole -2-yl} azetidine
[2251] 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 obtained in Reference Example 52 (6). 350 mg (0.782 mmol) of -thiazol-2-yl} azetidine was dissolved in 18 ml of methylene chloride, and 182 µl (2.35 mmol) of methanesulfonyl chloride and 329 µl (2.35 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2) to give 3-methanesulfonyloxy-1- {4-[(3S) -1- (p) as a pale yellow solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 410 mg, yield 99%.
[2252]
[2253] (8) 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2254] 3-Methanesulfonyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 52 (7). 410 mg (0.780 mmol) of, 3-thiazol-2-yl} azetidine was dissolved in 21 ml of dimethylformamide, 534 mg (4.68 mmol) of potassium thiosacetate was added at room temperature, and the mixture was stirred overnight at 80 ° C. in an oil bath. It was. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate), 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl as a light brown solid ] -1,3-thiazol-2-yl} azetidine was obtained in 287 mg, yield 73%.
[2255]
[2256] Reference Example 53
[2257] 3-acetylthio-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} Azetidine
[2258]
[2259] (1) (3S) -3-acetoxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2260] 7.50 g (21.8 mmol) of (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (2) was dissolved in 225 ml of dimethylformamide, 6.41 g (65.3 mmol) of potassium acetate were added into the system and stirred overnight in an 80 ° C oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 2) to obtain white crystals (3S) -3-acetoxy-1- (p-nitrobenzyloxycarbine). 5.51 g of carbonyl) -pyrrolidine was obtained with a yield of 82%.
[2261]
[2262] (2) (3S) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2263] Reference Example 53 (1S) -3-acetoxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine 5.51 g (17.8 mmol) obtained in (1) was dissolved in 200 ml of methanol, and a catalytic amount of sodium methoxide was obtained. Seeds were added in situ and stirred at room temperature for 4.5 hours. After the reaction was completed, 4N-hydrochloric acid gas-1,4-dioxane solution was added to the system, neutralized, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the water bath was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give (3S) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) as white crystals. ) -Pyrrolidine was obtained in 4.00 g, yield 84%.
[2264]
[2265] (3) (3S) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2266] Reference Example 53 4.00 g (15.0 mmol) of (3S) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in (2) was dissolved in 120 ml of methylene chloride and methane under ice-cooling 1.28 mL (16.5 mmol) of sulfonyl chloride and 2.31 mL (16.5 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2 to ethyl acetate) to give (3S) -3-methanesulfonyloxy-1- (p-nitrobenzyl) as a colorless oil. Oxycarbonyl) -pyrrolidine was obtained in 5.33 g and yield 100%.
[2267]
[2268] (4) (3R) -3-azide-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2269] 5.33 g (15.0 mmol) of (3S) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 53 (3) was dissolved in 159 ml of dimethylformamide, Sodium azide 1.07g (16.5mmol) was added in the system, and it stirred for 3.5 hours in 100 degreeC oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1: 1: 2) to obtain (3R) -3-azide-1- (p-nitrobenzyloxy) as a colorless oil. 4.48 g of carbonyl) -pyrrolidine was obtained with a yield of 100%.
[2270]
[2271] (5) (3R) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine
[2272] 4.48 g (15.4 mmol) of (3R) -3-azide-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 53 (4) was dissolved in 134 ml of acetonitrile and triphenylphosphate 4.22 g (16.1 mmol) of pins were added into the system and stirred for 1.5 hours in a 70 ° C oil bath. After confirming the disappearance of the raw materials, 5.19 g (16.1 mmol) of sodium sulfate decahydrate was added to the system and stirred for 5 hours. After confirming the completion of the reaction, the reaction solution was filtered, and methylene chloride and 0.1 M hydrochloric acid were added to the filtrate to carry out liquid separation extraction. Methylene chloride and sodium hydrogencarbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to afford 3.53 g of (3R) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine as pale yellow crystals. And yield 86%.
[2273]
[2274] (6) 3-t-butyldiphenylsilyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 -Thiazol-2-yl} azetidine
[2275] 363 mg (1.37 mmol) of (3R) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 53 (5) and 3-t- obtained in Reference Example 2 (4) 500 mg (1.14 mmol) of butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine are suspended in 25 ml of dimethylformamide, and the mixture is cooled under ice with nitrogen atmosphere. 208 µl (1.37 mmol) of ethylphosphoryl cyanide and 192 µl (1.37 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[(3R) as a pale yellow solid. ) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 598 mg, yield 51%.
[2276]
[2277] (7) 3-hydroxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2278] 3-t-butyldiphenylsilyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl obtained in Reference Example 53 (6) ] -1,3-thiazol-2-yl} azetidine 590 mg (0.860 mmol) was dissolved in 18 ml of anhydrous tetrahydrofuran, and 59 µl (1.03 mmol) of acetic acid and 1.0 M tetra-n-butylammonium under ice-cooling. 1.03 ml (1.03 mmol) of floride-tetrahydrofuran solution was added sequentially, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbine. Bonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 378 mg, yield 98%.
[2279]
[2280] (8) 3-methanesulfonyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole -2-yl} azetidine
[2281] 3-hydroxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 obtained in Reference Example 53 (7). 370 mg (0.827 mmol) of -thiazol-2-yl} azetidine was dissolved in 19 ml of methylene chloride, and 192 µl (2.48 mmol) of methanesulfonyl chloride and 348 µl (2.48 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours as it was. 192 mL (2.48 mmol) of methanesulfonyl chloride and 348 mL (2.48 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was for 1.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2) to give 3-methanesulfonyloxy-1- {4-[(3R) -1- (p) as a pale yellow solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 422 mg, yield 97%.
[2282]
[2283] (9) 3-acetylthio-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2284] 3-Methanesulfonyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 53 (8). 420 mg (0.799 mmol) of 3,3-thiazol-2-yl} azetidine was dissolved in 21 ml of dimethylformamide, potassium thioacetate 548 mg (4.79 mmol) was added at room temperature, and the mixture was stirred overnight at 80 ° C. in an oil bath. It was. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate: methanol = 99: 1) to give 3-acetylthio-1- {4-[(3R) as a light brown solid. ) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 280 mg, yield 69%.
[2285]
[2286] Reference Example 54
[2287] 3-acetylthio-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2288]
[2289] (1) 3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -azetidine
[2290] 9.00 g (37.6 mmol) of 1-benzhydryl-3-hydroxyazetidine was dissolved in 270 ml of methanol, and contact hydrogen reduction was performed for 5.5 hours in a 50 ° C. water bath in the presence of 9.00 g of 10% palladium carbon. After the completion of reaction, the reaction solution was filtered, the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was washed with ethyl acetate, and then concentrated under reduced pressure, and the obtained residue was dried under reduced pressure. This crude product was dissolved in 82 ml of methylene chloride and 55 ml of methanol, and 8.90 g (41.3 mmol) of chloroformate p-nitrobenzyl and 5.79 ml (41.3 mmol) of triethylamine were added under ice cooling, followed by stirring at room temperature for 1.5 hours. . After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to give 3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -azetidine as pale yellow crystals. Was obtained in 3.52 g, yield 37%.
[2291]
[2292] (2) 3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -azetidine
[2293] 3.52 g (14.0 mmol) of 3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -azetidine obtained in Reference Example 54 (1) was dissolved in 106 ml of methylene chloride, and methanesulfonyl chloride 1.19 under ice-cooling. ML (15.4 mmol) and 2.16 mL (15.4 mmol) triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to give 3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) as pale yellow crystals. Obtained 4.63 g of azetidine in 100% yield.
[2294]
[2295] (3) 3-azide-1- (p-nitrobenzyloxycarbonyl) -azetidine
[2296] 4.63 g (14.0 mmol) of 3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -azetidine obtained in Reference Example 54 (2) was dissolved in 140 ml of dimethylformamide, and the azide was added to the system. Sodium 1.37 g (21.0 mmol) was added and stirred for 4 hours in a 100 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 1) to give 3-azide-1- (p-nitrobenzyloxycarbonyl) -ase of pale yellow crystals. Tidin was obtained in 2.15 g and yield 55%.
[2297]
[2298] (4) 3-amino-1- (p-nitrobenzyloxycarbonyl) -azetidine
[2299] 2.15 g (7.76 mmol) of 3-azide-1- (p-nitrobenzyloxycarbonyl) -azetidine obtained in Reference Example 54 (3) was dissolved in 65 ml of acetonitrile, and 2.14 g (8.14) of triphenylphosphine mmol) was added to the system and stirred for 2 hours in a 70 ° C oil bath. After confirming that the raw materials disappeared, 2.62 g (8.14 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 3 hours. After confirming the completion of the reaction, the reaction solution was filtered, and methylene chloride and 0.1 M hydrochloric acid were added to the filtrate to carry out liquid separation extraction. Methylene chloride and sodium hydrogencarbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 1.87 g of 3-amino-1- (p-nitrobenzyloxycarbonyl) -azetidine as pale yellow crystals in 96% yield.
[2300]
[2301] (5) 3-t-butyldiphenylsilyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl} azetidine
[2302] 3-amino-1- (p-nitrobenzyloxycarbonyl) -azetidine 549 mg (2.18 mmol) obtained in Reference Example 54 (4) and 3-t-butyldiphenylsilyloxy obtained in Reference Example 2 (4). 800 mg (1.82 mmol) of 1- (4-carboxyl-1,3-thiazol-2-yl) azetidine is dissolved in 40 ml of dimethylformamide, and diethylphosphoryl cyanide is ice-cooled under nitrogen atmosphere. 331 microliters (2.18 mmol) and 306 microliters (2.18 mmol) triethylamine were added, and it stirred at room temperature for 5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[(1) as a pale yellow solid. -p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 1.06 g, yield 49%.
[2303]
[2304] (6) 3-hydroxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2305] 3-t-butyldiphenylsilyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3 obtained in Reference Example 54 (5). 1.06 g (1.58 mmol) of -thiazol-2-yl} azetidine was dissolved in 53 mL of anhydrous tetrahydrofuran, and 109 μl (1.90 mmol) of acetic acid under ice-cooling, 1.0 M tetra-n-butylammonium fluoride-tetrahydro 1.90 mL (1.90 mmol) of furan solution was added sequentially, and it stirred for 2 hours as it is. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -ase Thidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 649 mg, yield 95%.
[2306]
[2307] (7) 3-methanesulfonyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} Azetidine
[2308] 3-hydroxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole-2 obtained in Reference Example 54 (6). -Yl} azetidine 640 mg (1.48 mmol) was dissolved in 20 ml of methylene chloride, and 343 µl (4.43 mmol) of methanesulfonyl chloride and 621 µl (4.43 mmol) of triethylamine were added under ice cooling. The mixture was returned to room temperature and stirred overnight. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2) to give 3-methanesulfonyloxy-1- {4-[(1-p-nitrobenzyloxy) as a pale yellow solid. Carbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 611 mg, yield 81%.
[2309]
[2310] (8) 3-acetylthio-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2311] 3-methanesulfonyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole obtained in Reference Example 54 (7). 610 mg (1.19 mmol) of 2-yl} azetidine was dissolved in 81 mL of dimethylformamide, 817 mg (7.15 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight at 80 ° C in an oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2 to ethyl acetate) to give 3-acetylthio-1- {4-[(1-p-nitrobenzyloxy) as a light brown solid. Carbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 405 mg, yield 69%.
[2312]
[2313] Reference Example 55
[2314] 3-acetylthio-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2315]
[2316] (1) 4- (p-nitrobenzyloxycarbonyl) -piperazine hydrochloride
[2317] 1.50 g (8.05 mmol) of 4- (t-butoxycarbonyl) -piperazine was suspended in 68 ml of methylene chloride, and 1.90 g (8.86 mmol) of chloroformic acid p-nitrobenzyl and 1.24 ml (8.86) of triethylamine under ice-cooling. mmol) was added and the resultant was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 3) to give 1- (t-butoxycarbonyl) -4- (p-nitrobenzyloxycarbonyl) in the form of a pale yellow oil. Piperazine was obtained in 2.60 g and 89% yield. Then, 2.60 g (7.12 mmol) of this product was dissolved in 100 ml of acetonitrile, 15.0 ml of 4N-chloride gas-ethyl acetate solution was added under ice cooling, and the mixture was stirred for 2 hours as it was. After confirming completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction system was filtered, and the filtrate was washed with diethyl ether to obtain 2.4 g of 4- (p-nitrobenzyloxycarbonyl) -piperazine hydrochloride as a white solid in a yield of 86%.
[2318] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl } Azetidine
[2319] 874 mg (2.19 mmol) of 4- (p-nitrobenzyloxycarbonyl) piperazine hydrochloride obtained in Reference Example 55 (1) and 3-t-butyldiphenylsilyloxy-1- (obtained in Reference Example 2 (4) 800 mg (1.82 mmol) of 4-carboxyl-1,3-thiazol-2-yl) azetidine are suspended in 40 ml of dimethylformamide, and 0.33 ml of diethylphosphoryl cyanide (2.19) under ice-cooling under nitrogen atmosphere. mmol) and triethylamine 0.30 ml (2.19 mmol) were added and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(4-p-nitrobenzyl) in the form of a pale yellow oil. Oxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 915 mg, yield 73%.
[2320]
[2321] (3) 3-hydroxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2322] 3-t-butyldiphenylsilyloxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thia obtained in Reference Example 55 (2) 1.77 g (1.71 mmol) of zol-2-yl} azetidine was dissolved in 35 mL of anhydrous tetrahydrofuran, and 0.11 mL (1.88 mmol) of acetic acid and 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice cooling. 1.88 mL (1.88 mmol) was added sequentially, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain 3-hydroxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -pipe. Razine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 726 mg, yield 95%.
[2323]
[2324] (4) 3-methanesulfonyloxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2325] 3-hydroxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl obtained in Reference Example 55 (3). } Azetidine 804 mg (1.80 mmol) was dissolved in 40 ml of methylene chloride, 0.30 ml (2.15 mmol) of methanesulfonyl chloride and 0.17 ml (2.15 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-methanesulfonyloxy-1- {4-[(4-p-nitrobenzyloxy) as a pale yellow solid. 550 mg of carbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 58% yield.
[2326]
[2327] (5) 3-acetylthio-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazin-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2328] 3-Methanesulfonyloxy-1- {4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazole-2 obtained in Reference Example 55 (4). 550 mg (1.05 mmol) of -yl} azetidine was dissolved in 40 ml of dimethylformamide, 717 mg (6.28 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 3 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- {4-[(4-p-nitrobenzyloxycarbonyl) -pipe of light brown solid. 345 mg, yield 64% of ragin-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained.
[2329]
[2330] Reference Example 56
[2331] 3-acetylthio-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2332]
[2333] (1) (2-hydroxy-ethyl) -carbamic acid t-butyl ester
[2334] 2.51 g (41.1 mmol) of aminoethanol was dissolved in 50 mL of methylene chloride and 50 mL of methanol, and 13.5 g (61.9 mmol) of di-t-butoxycarbonyl anhydride and 8.6 mL (61.7 mmol) of di-t-butoxycarbonylanhydride under ice cooling. Was added and stirred at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated brine were added to the residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 6.18 g of (2-hydroxy-ethyl) -carbamic acid t-butyl ester of colorless transparent syrup, yield 93%. Got it.
[2335]
[2336] (2) (2-azide-ethyl) -carbamic acid t-butyl ester
[2337] 1.5 g (6.2 mmol) of (2-hydroxy-ethyl) -carbamic acid t-butyl ester was dissolved in 75 ml of tetrahydrofuran, and 3.0 ml (13.9 mmol) of diphenylphosphoryl azide and triphenyl phosphate under ice-cooling. 3.7 g (14.1 mmol) of pins and 5.1 g (13.9 mmol) of diethylazodicarboxylate-40% toluene solution were added under a nitrogen atmosphere, followed by stirring for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1) to yield 1.24 g of (2-azide-ethyl) -carbamic acid t-butyl ester of colorless transparent syrup, yield 72%. Got it.
[2338]
[2339] (3) (2-t-butoxycarbonylamino-ethyl) -carbamic acid p-nitrobenzyl ester
[2340] 1.22 g (6.55 mmol) of (2-azide-ethyl) -carbamic acid t-butyl ester was dissolved in 60 ml of methanol, and catalytic hydrogen reduction was performed at room temperature in the presence of 1.22 g of 20% palladium hydroxide-carbon. After the completion of reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 60 ml of methylene chloride, 2.12 g (9.8 mmol) of chloroformate p-nitrobenzyl and 1.37 mL (9.8 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to obtain 1.2-t-butoxycarbonylamino-ethyl) -carbamic acid p-nitrobenzyl ester of white solid. g, yield 66%.
[2341]
[2342] (4) 3-t-butyldiphenylsilyloxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} ase Tidin
[2343] 1.46 g (4.3 mmol) of (2-t-butoxycarbonylamino-ethyl) -carbamic acid p-nitrobenzyl ester was dissolved in 15 ml of 1,4-dioxane, and 4N-hydrochloric acid gas-1, 15 ml of 4-dioxane solution was added, and it stirred at room temperature for 5.5 hours. After confirming completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction system was filtered, and the filtrate was washed with diethyl ether to obtain 1.18 g of 1- (p-nitrobenzyloxycarbonylamino) ethylamine hydrochloride as a white solid, yield 100%. Subsequently, 490 mg (1.77 mmol) of 2- (p-nitrobenzyloxycarbonylamino) -ethylamine hydrochloride obtained and 3-t-butyldiphenylsilyloxy-1- (4- obtained in Reference Example 2 (4) were obtained. 530 mg (1.21 mmol) of carboxyl-1,3-thiazol-2-yl) azetidine were suspended in 26.5 mL of dimethylformamide, and 0.3 mL (1.98 mmol) of diethylphosphoryl cyanide under ice-cooling under nitrogen atmosphere. 0.5 ml (3.59 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 3-t-butyldiphenylsilyloxy-1- {4- [2- (p-nitrobenzyloxy) as a pale yellow solid. Carbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained at 630 mg, yield 79%.
[2344]
[2345] (5) 3-hydroxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2346] 3-t-butyldiphenylsilyloxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazole obtained in Reference Example 56 (4)- 1.21 g (1.84 mmol) of 2-yl} azetidine was dissolved in 60.6 mL of anhydrous tetrahydrofuran, and 0.13 mL (2.27 mmol) of acetic acid, 2.2 mL of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution under ice-cooling. (2.2 mmol) was added sequentially, and it stirred as it is for 2.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, followed by stirring and washing, followed by filtration to obtain 3-hydroxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3- Thiazol-2-yl} azetidine was obtained as a yellow solid at 667 mg, yield 86%.
[2347]
[2348] (6) 3-methanesulfonyloxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2349] 3-hydroxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} ase obtained in Reference Example 56 (5). Tidin 658.4 mg (1.56 mmol) was dissolved in 33 ml of methylene chloride and 5 ml of pyridine, and 0.31 ml (4.00 mmol) of methanesulfonyl chloride and 0.57 ml (4.09 mmol) of triethylamine were added under ice cooling. The mixture was returned to room temperature and stirred for 4 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added into the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed with 0.5 M hydrochloric acid water, saturated sodium bicarbonate water, and saturated saline solution. It was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to give 3-methanesulfonyloxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) as a pale yellow solid. ) -Ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine in 607.3 mg, yield 78%.
[2350]
[2351] (7) 3-acetylthio-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine
[2352] 3-Methanesulfonyloxy-1- {4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 56 (6). } 607.3 mg (1.22 mmol) of azetidine was dissolved in 33 ml of dimethylformamide, 1.06 g (7.35 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 7 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to give 3-acetylthio-1- {4- [2- (p-nitrobenzyloxycarbonylamino)-as a light brown solid. Ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained at 335.8 mg, yield 58%.
[2353]
[2354] Reference Example 57
[2355] 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2356]
[2357] (1) 1-t-butoxycarbonyl-3- (methanesulfonyloxy) -azetidine
[2358] 3.24 g (18.7 mmol) of 1-t-butoxycarbonyl-3-hydroxyazetidine obtained in Reference Example 31 (1) was dissolved in 160 ml of methylene chloride, and 1.59 ml (20.6 mmol) of methanesulfonyl chloride under ice-cooling. ), Triethylamine 2.89 ml (20.6 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 6 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 2) to obtain 1-t-butoxycarbonyl-3- (methanesulfonyloxy) as light yellow oil. -Azetidine was obtained at 4.71 mg, yield 100%.
[2359]
[2360] (2) 3-azide-1- (t-butoxycarbonyl) -azetidine
[2361] 4.71 g (18.7 mmol) of 1-t-butoxycarbonyl-3- (methanesulfonyloxy) -azetidine obtained in Reference Example 57 (1) was dissolved in 140 ml of dimethylformamide, and sodium azide was added to the system. 3.65 g (56.lmmol) was added and stirred overnight in a 90 ° C. oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1) to give 3.44 g of 3-azide-1- (t-butoxycarbonyl) -azetidine in the form of a colorless oil. And the yield was obtained by 93%.
[2362]
[2363] (3) 1-t-butoxycarbonyl-3- (p-nitrobenzyloxycarbonylamino) -azetidine
[2364] 3.44 g (17.4 mmol) of 3-azide-1- (t-butoxycarbonyl) -azetidine obtained in Reference Example 57 (2) was dissolved in 170 ml of methanol, and in the presence of 3.44 g of 10% palladium carbon, room temperature Contact hydrogen reduction was performed at 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 3-amino-1-t-butoxycarbonylazetidine. This product was dissolved in 170 ml of methylene chloride, 5.63 g (26.1 mmol) of chloroformate p-nitrobenzyl and 3.66 ml (26.1 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1: 1: 2) to give 1-t-butoxycarbonyl-3- (p-nitrobenzyloxy) as a colorless oil. Carbonylamino) -azetidine was obtained in 4.84 g and yield 79%.
[2365]
[2366] (4) 3-t-butyldiphenylsilyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2- Azetidine
[2367] 4.84 g (13.8 mmol) of 1-t-butoxycarbonyl-3- (p-nitrobenzyloxycarbonylamino) -azetidine obtained in Reference Example 57 (3) were dissolved in 50 ml of 1,4-dioxane. 50 ml of 4N hydrochloric acid gas-1,4-dioxane solution was added under ice cooling, and it stirred at room temperature for 2.5 hours. After confirming the completion of the reaction, the reaction system was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the filtrate was washed with ethyl acetate to obtain 2.31 g of pale yellow crystals of 3- (p-nitrobenzyloxycarbonylamino) -azetidine hydrochloride as a yield of 58%. Subsequently, this 3- (p-nitrobenzyloxycarbonylamino) -azetidine hydrochloride 944 mg (3.28 mmol) and 3-t-butyldiphenylsilyloxy-1- (4-) obtained from Reference Example 2 (4). 1.2 g (2.74 mmol) of carboxyl-1,3-thiazol-2-yl) azetidine are suspended in 60 ml of dimethylformamide, and 498 µl (3.28 mmol) of diethylphosphoryl cyanide under ice-cooling under nitrogen atmosphere. 922 microliters (6.58 mmol) of triethylamine were added, and it stirred at room temperature overnight. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer obtained was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -ase as a pale yellow solid. Tidin-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained at 853 mg, yield 53%.
[2368]
[2369] (5) 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2370] 3-t-butyldiphenylsilyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3- obtained in Reference Example 57 (4). 850 mg (1.27 mmol) of thiazol-2-yl} azetidine was dissolved in 43 mL of anhydrous tetrahydrofuran, and 87 μl (1.52 mmol) of acetic acid under ice-cooling, 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran 1.52 mL (1.52 mmol) of the solution was added sequentially and stirred for 0.5 hour as it was. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the filtration and the filtrate were washed with diisopropyl ether to obtain 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino)-. Azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 486 mg, yield 88%.
[2371]
[2372] (6) 3-methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} ase Tidin
[2373] 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2- obtained in Reference Example 57 (5). Dissolve 630 mg (1.45 mmol) of Japanese azetidine in 32 ml of methylene chloride and 12 ml of pyridine, add 377 µl (4.36 mmol) of methanesulfonyl chloride and 611 µl (4.36 mmol) of triethylamine under ice-cooling, After 10 minutes, the reaction system was returned to room temperature and stirred for 4 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and filtration and the filtrate were washed with diisopropyl ether to give 3-methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxy as a white solid). Carbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 766 mg, yield 100%.
[2374]
[2375] (7) 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2376] 3-Methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole obtained in Reference Example 57 (6)- 760 mg (1.45 mmol) of 2-yl} azetidine was dissolved in 38 ml of dimethylformamide, 993 mg (8.70 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for 9 hours in an 80 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carpoxy as a light brown solid. Bonyl] -1,3-thiazol-2-yl} azetidine was obtained in 397 mg, yield 56%.
[2377]
[2378] Reference Example 58
[2379] 3-acetylthio-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine
[2380]
[2381] (1) 3-t-butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxyethyl) carbamoyl] -1,3-thiazol-2-yl} azetidine
[2382] 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) ase obtained from 1.0 ml (12.4 mmol) of N-methylaminoethanol and Reference Example 2 (4) 3.64 g (8.3 mmol) of thydine was suspended in 180 ml of dimethylformamide, and 1.9 ml (12.5 mmol) of diethylphosphoryl cyanide and 1.73 ml (12.4 mmol) of triethylamine were added under nitrogen atmosphere under ice-cooling to room temperature. Stirred for 7 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxy) as a pale yellow transparent syrup. Ethyl) carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 3.41 g and the yield was 83%.
[2383]
[2384] (2) 3-t-butyldiphenylsilyloxy-1- {4-[(2-azideethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
[2385] 3-t-butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxyethyl) carbamoyl] -1,3-thiazol-2-yl} ase obtained in Reference Example 58 (1). Thydine 997.5 mg (2.0 mmol) was dissolved in 50 mL of tetrahydrofuran, and 0.65 mL (3.02 mmol) of diphenylphosphoryl azide, 793 mg (3.02 mmol) of diphenylazodicarboxylate under ice-cooling 1.12 g (3.04 mmol) of a -40% toluene solution was added under a nitrogen atmosphere, followed by stirring overnight. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- {4-[(2-azideethyl) as a colorless transparent syrup. -Methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 1.05 g and 100% yield.
[2386]
[2387] (3) 3-t-butyldiphenylsilyloxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl-1,3-thiazole-2- Azetidine
[2388] 3-t-butyldiphenylsilyloxy-1- {4-[(2-azideethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} obtained in Reference Example 58 (2). 1.05 g (2.02 mmol) of azetidine was dissolved in 60 mL of methanol, and catalytic hydrogen reduction was performed at room temperature in the presence of 1.05 g of 20% palladium hydroxide-carbon. After the completion of reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 52.3 ml of methylene chloride, 650.7 mg (3.02 mmol) of chloroformate p-nitrobenzyl and 0.42 ml (3.01 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 3-t-butyldiphenylsilyloxy-1- (4- {methyl- [2- (p-) as a pale yellow solid. Nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 699.5 mg, yield 52%.
[2389]
[2390] (4) 3-hydroxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine
[2391] 3-t-butyldiphenylsilyloxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3 obtained in Reference Example 58 (3). Dissolve 806.9 mg (1.20 mmol) of -thiazol-2-yl) azetidine in 40 mL of anhydrous tetrahydrofuran, 0.09 mL (1.57 mmol) of acetic acid under ice cooling, 1.0 M tetra-n-butylammonium fluoride-tetrahydro Furan 1.44 mL (1.44 mmol) was added sequentially, and it stirred for 4 hours as it is. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-hydroxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino)- Ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained as a white solid at 428.2 mg, yield 84%.
[2392]
[2393] (5) 3-methanesulfonyloxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) Azetidine
[2394] 3-hydroxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazole-2 obtained in Reference Example 56 (5). -Yl) azetidine 428.2 mg (1.01 mmol) was dissolved in 21.4 ml of methylene chloride, 0.25 ml (3.23 mmol) of methanesulfonyl chloride and 0.45 ml (3.23 mmol) of triethylamine were added under ice cooling, followed by a reaction system after 10 minutes. The mixture was returned to room temperature and stirred for 6 hours as it was. After confirming completion of the reaction, methanol was added to the reaction system and stirred for 30 minutes. Subsequently, ethyl acetate and saturated sodium bicarbonate water were added in the system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-methanesulfonyloxy-1- (4- {methyl- [2- (p-nitrobenzyloxy) as a pale yellow solid. Carbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained at 480.1 mg, yield 93%.
[2395]
[2396] (7) 3-acetylthio-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine
[2397] 3-Methanesulfonyloxy-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazole obtained in Reference Example 56 (6). 480.1 mg (0.93 mmol) of -2-yl) azetidine was dissolved in 24 ml of dimethylformamide, 820 mg (5.69 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for an hour in an 80 ° C oil bath. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-acetylthio-1- (4- {methyl- [2- (p-nitrobenzyloxycarbonyl) as a light brown solid. Amino) -ethyl] carbamoyl-1,3-thiazol-2-yl) azetidine was obtained in 348.9 mg, yield 76%.
[2398]
[2399] Reference Example 59
[2400] 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidine
[2401]
[2402] (1) 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
[2403] 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) obtained from 0.61 ml (1.38 mmol) of N-isopropylaminoethanol and Reference Example 2 (4) Azetidine 500 mg (1.14 mmol) was suspended in 15 ml of dimethylformamide, and 0.23 ml (1.38 mmol) of diethylphosphoryl cyanide and 0.19 ml (0.23 mmol) of triethylamine were added thereto under nitrogen atmosphere under ice-cooling. Stir for 2 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) -isopropyl-carba in the form of a pale yellow oil. Moyl] -1,3-thiazol-2-yl} azetidine in 318 mg, yield 56%.
[2404]
[2405] (2) 3-hydroxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
[2406] 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 59 (1). } 2.49 g (4.75 mmol) of azetidine was dissolved in 100 mL of anhydrous tetrahydrofuran, and 5.70 mL (5.70 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added thereto under ice cooling, followed by stirring for 1 hour. It was. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-hydroxy-1- {4-[(2-hydric acid). Oxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine as 1.33 g as a white solid, yield 98%.
[2407]
[2408] (3) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) -3-hydroxyazetidine
[2409] Reference Example 59 3-hydroxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine obtained in (2) (4.66 mmol) was dissolved in 40 ml of dimethylformamide, 738 mg (4.89 mmol) of t-butyldimethylsilane chloride and 333 mg (4.89 mmol) of imidazole were added under ice cooling, and the mixture was stirred under ice cooling for 2 hours. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated sodium bicarbonate water were added to the system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to obtain 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] as a pale yellow oil. -Isopropyl-carbamoyl} -1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained in 1.26 g, yield 69%.
[2410]
[2411] (4) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxy Azetidine
[2412] 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) -3 obtained in Reference Example 59 (3). 1.24 g (3.23 mmol) of hydroxyazetidine was dissolved in 62 ml of methylene chloride, 0.30 ml (3.88 mmol) of methanesulfonyl chloride and 0.54 ml (3.88 mmol) of triethylamine were added thereto under ice cooling, followed by stirring for 1.5 hours. It was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to yield 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] iso as a pale yellow solid. Propyl-carbamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained at 649 mg, yield 42%.
[2413]
[2414] (5) 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidine
[2415] 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) -3 obtained in Reference Example 59 (4). 649 mg (1.35 mmol) of methanesulfonyloxyazetidine was dissolved in 19 ml of dimethylformamide, 930 mg (8.14 mmol) of potassium thioacetate was added at room temperature, followed by stirring in a 90 ° C oil bath for 3 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1 to ethyl acetate) to give 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) as a light brown solid. ) -Ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidine in 618 mg, yield 100%.
[2416]
[2417] Reference Example 60
[2418] 3-acetylthio-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine
[2419]
[2420] (1) 1- {4-[(2-azide-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3-t-butyldiphenylsilyloxyase Tidin
[2421] 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl obtained in Reference Example 59 (1). } Azetidine 1.46 g (2.79 mmol) is dissolved in 73 mL of tetrahydrofuran, and 0.90 mL (4.18 mmol) of diphenylphosphoryl azide, 1.10 g (4.18 mmol) of diphenylazodicar, under ice-cooling 1.54 g (4.18 mmol) of carboxylate-40% toluene solution was added under nitrogen atmosphere, and the mixture was stirred for 3 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 1- {4-[(2-azide-ethyl) -isopropyl-carbamoyl]-in the form of a pale yellow oil. 1,3-thiazol-2-yl} azetidine-3-t-butyldiphenylsilyloxyazetidine was obtained in 1.33 g and yield 87%.
[2422]
[2423] (2) 3-t-butyldiphenylsilyloxy-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazole-2 Azetidine
[2424] 1- {4-[(2-azide-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3-t-butyl obtained in Reference Example 60 (1) 1.33 g (2.42 mmol) of diphenylsilyloxyazetidine was dissolved in 65 ml of methanol, and catalytic hydrogen reduction was performed at room temperature in the presence of 1.33 g of 20% palladium hydroxide. After the completion of reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 63 ml of methylene chloride, 627 mg (2.90 mmol) of chloroformate p-nitrobenzyl and 0.41 ml (2.90 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give 3-t-butyldiphenylsilyloxy-1- (4- {isopropyl- [in the form of a pale yellow oil. 945 mg of 2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine were obtained in a yield of 56%.
[2425]
[2426] (3) 3-hydroxy-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine
[2427] 3-t-butyldiphenylsilyloxy-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3 obtained in Reference Example 60 (2). 945 mg (1.38 mmol) of -thiazol-2-yl) azetidine was dissolved in 50 mL of anhydrous tetrahydrofuran, and 0.10 mL (1.66 mmol) of acetic acid under ice cooling, 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran 1.66 mL (1.66 mmol) of the solution was added sequentially and stirred for 3 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give 3-hydroxy-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino ) -Ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine as a white solid, 433 mg, yield 66%.
[2428]
[2429] (4) 1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxy Azetidine
[2430] 3-hydroxy-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazole-2 obtained in Reference Example 60 (3). Dissolve 1.43 g (3.09 mmol) of azetidine in 72 ml of methylene chloride, add 0.29 ml (3.70 mmol) of methanesulfonyl chloride and 0.52 ml (3.70 mmol) of triethylamine under ice-cooling, and stir for 1 hour as it is. It was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino)-as a pale yellow solid. Ethyl] -carbamoyl} -1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in 776 mg, yield 46%.
[2431]
[2432] (5) 3-acetylthio-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine
[2433] 1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) -3 obtained in Reference Example 60 (4). 776 mg (1.43 mmol) of methanesulfonyloxyazetidine was dissolved in 23 ml of dimethylformamide, 982 mg (8.60 mmol) of potassium thioacetate was added at room temperature, followed by stirring in a 90 ° C oil bath for 4 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) as a light brown solid. ) -Ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 746 mg, yield 46%.
[2434]
[2435] Reference Example 61
[2436] 3-acetylthio-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazole-2- Azetidine
[2437]
[2438] (1) ((1S) -1-hydroxymethyl-2-methyl-propyl) -carbamic acid t-butyl ester
[2439] 2.00 g (19.4 mmol) of L-valinol were dissolved in 50 ml of methylene chloride and 50 ml of methanol, and 5.08 g (23.3 mmol) of di-t-butoxycarbonyl anhydride was added under ice cooling, and 3 hours at room temperature. Stirred. After confirmation of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the water bath was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give ((1S) -1-hydroxymethyl-2-methyl-propyl) -carbamic acid in the form of a colorless oil. t-butyl ester was obtained at 4.19 mg and yield 100%.
[2440]
[2441] (2) ((1S) -1-azidemethyl-2-methyl-propyl) -carbamic acid t-butyl ester
[2442] Reference Example 61 3.00 g (14.8 mmol) of ((1S) -1-hydroxymethyl-2-methyl-propyl) -carbamic acid t-butyl ester obtained in (1) was dissolved in 150 ml of tetrahydrofuran and ice-cold. Diphenylphosphoryl azide 4.78ml (22.2mmol), triphenylphosphine 5.82g (22.2mmol), diethylazodicarboxylate-40% toluene solution 9.67g (22.2mmol) were added under nitrogen atmosphere, Stir for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 9: 1) to give ((1S) -1-azidemethyl-2-methyl-propyl) -carbamic acid in the form of a colorless oil. 3.26 g of t-butyl esters were obtained by yield 90%.
[2443]
[2444] (3) ((2S) -2-t-butoxycarbonylamino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester
[2445] Reference Example 61 3.26 g (13.3 mmol) of ((1S) -1-azidemethyl-2-methyl-propyl) -carbamic acid t-butyl ester obtained in (2) was dissolved in 160 ml of methanol, and 10% palladium was used. Contact hydrogen reduction was performed at room temperature for 1 hour in the presence of 3.26 g of carbon. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 160 ml of methylene chloride, 4.31 g (20.0 mmol) of chloroformate p-nitrobenzyl and 2.80 ml (20.0 mmol) of triethylamine were added under ice-cooling, and the mixture was stirred at room temperature overnight. After confirmation of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the water bath was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-1: 1) to obtain ((2S) -2-t-butoxycarbonylamino-3-methyl as pale yellow crystals. -Butyl) -carbamic acid p-nitrobenzyl ester was obtained at 3.13 mg and yield 62%.
[2446]
[2447] (4) 3-t-butyldiphenylsilyloxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1 , 3-thiazol-2-yl) azetidine
[2448] 1,4-di ((2S) -2-t-butoxycarbonylamino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester obtained in Reference Example 61 (3) It melt | dissolved in 31 mL of oxanes, 31 mL of 4N hydrochloric acid gas-1, 4- dioxane solutions were added under ice cooling, and it stirred at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue and filtered. The filtrate was washed with ethyl acetate to obtain 1.82 g of pale yellow crystalline ((2S) -2-amino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester hydrochloride in a yield of 70%. Subsequently, 1.29 g (4.05 mmol) of ((2S) -2-amino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester hydrochloride and 3-t-butyldiphenyl obtained in Reference Example 2 (4) were obtained. 1.48 g (3.37 mmol) of silyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine is suspended in 74 ml of dimethylformamide, and diethylphosphoryl is cooled on ice under nitrogen atmosphere. 615 µl (4.05 mmol) of cyanide and 1.14 ml (8.10 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-{(1S) -2-) as a pale yellow solid. Methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 1.55 g, yield 74%.
[2449]
[2450] (5) 3-hydroxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazole -2-yl) azetidine
[2451] 3-t-butyldiphenylsilyloxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcart obtained in Reference Example 61 (4) Bamoyl} -1,3-thiazol-2-yl) azetidine 1.54 g (2.20 mmol) was dissolved in 78 mL of anhydrous tetrahydrofuran and 151 μl (2.64 mmol) of acetic acid under ice-cooling, 1.0 M tetra-n- 2.64 ml (2.64 mmol) of butylammonium fluoride-tetrahydrofuran solution were added sequentially, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-hydroxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl ] -Propylcarbamoyl} -1,3-thiazol-2-yl) azetidine as a white solid, 927 mg, yield 91%.
[2452]
[2453] (6) 3-methanesulfonyloxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3- Thiazol-2-yl) azetidine
[2454] 3-hydroxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1 obtained in Reference Example 61 (5) 920 mg (1.98 mmol) of, 3-thiazol-2-yl) azetidine was dissolved in 46 mL of methylene chloride, and 461 μl (5.95 mmol) of methanesulfonyl chloride and 834 μl (5.95 mmol) of triethylamine under ice-cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 4) to give 3-methanesulfonyloxy-1- (4-{(1S) -2-methyl- [as a pale yellow solid]. 1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 1.06 g and 99% yield.
[2455]
[2456] (7) 3-acetylthio-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazole -2-yl) azetidine
[2457] 3-Methanesulfonyloxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} obtained in Reference Example 61 (6)} 1.06 g (1.96 mmol) of -1,3-thiazol-2-yl) azetidine was dissolved in 53 mL of dimethylformamide, 1.34 mg (11.7 mmol) of potassium thioacetate was added at room temperature, and the mixture was heated in an 80 DEG C oil bath. Stir for 8.5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 3) to give 3-acetylthio-1- (4-{(1S) -2-methyl- [1- as a pale brown solid. (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 785 mg, yield 77%.
[2458]
[2459] Reference Example 62
[2460] 3-acetylthio-1- {4- (p-nitrobenzyloxycarbonylamino) methyl-1,3-thiazol-2-yl} azetidine
[2461]
[2462] (1) 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
[2463] Reference Example 2 1.02 g (2.39 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine obtained in (2) was treated with tetrahydrofuran. Dissolved in 50 ml, 0.8 ml (3.71 mmol) of diphenylphosphoryl azide, 950 mg (3.62 mmol) of triphenylphosphine, and 1.32 g (3.59 mmol) of diethylazodicarboxylate-40% toluene solution under ice-cooling Was added under nitrogen atmosphere and stirred for 2 hours as it is. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 8: 1) to give 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-colorless transparent syrup. t-butyldiphenylsilyloxyazetidine was obtained in 1.06 g and yield 99%.
[2464]
[2465]
[2466] (2) 3-t-butyldiphenylsilyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2467] 53 ml of 1.06 g (2.37 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1) It was dissolved in, and catalytic hydrogen reduction was performed at room temperature in the presence of 1.05 g of 20% palladium hydroxide-carbon. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 53.2 ml of methylene chloride, 0.76 g (3.52 mmol) of chloroformate p-nitrobenzyl and 0.5 ml (3.59 mmol) of triethylamine were added under ice cooling, followed by stirring at room temperature overnight. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 3: 2) to give 3-t-butyldiphenylsilyloxy-1- [4- (p-nitrobenzyloxycarbonylamino) as a yellow solid. -Methyl) -1,3-thiazol-2-yl] azetidine was obtained by 867.2 mg, yield 61%.
[2468]
[2469] (3) 3-hydroxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2470] 3-t-butyldiphenylsilyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine 867.2 obtained in Reference Example 62 (2). Mg (1.44 mmol) was dissolved in 45 mL of anhydrous tetrahydrofuran, and 0.1 mL (1.75 mmol) of acetic acid and 1.72 mL (1.72 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially removed under ice-cooling. It was added and stirred as it was for 4.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-hydroxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3- Thiazol-2-yl] azetidine was obtained as a yellow solid at 457 mg, yield 87%.
[2471]
[2472] (4) 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2473] 3-hydroxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 62 (3) 457 mg (1.25 mmol) Was dissolved in 25 ml of methylene chloride, 0.29 ml (3.75 mmol) of methanesulfonyl chloride and 0.53 ml (3.80 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1) to give 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) as a yellow solid. 49,1 mg, yield 90% of -1,3-thiazol-2-yl] azetidine was obtained.
[2474]
[2475] (5) 3-acetylthio-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2476] 499.4 mg (1.13) of 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 62 (4) mmol) was dissolved in 25 ml of dimethylformamide, 1.0 g (6.93 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 6.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 3-acetylthio-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1 as a light brown solid. , 3-thiazol-2-yl] azetidine was obtained in 265.2 mg, yield 56%.
[2477]
[2478] Reference Example 63
[2479] 3-acetylthio-1- [4- (methoxycarbonylamino) methyl-1,3-thiazol-2-yl] azetidine
[2480]
[2481] (1) 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2482] 106 ml of methanol (12.2 g (4.71 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1)) It was dissolved in, and catalytic hydrogen reduction was performed at room temperature in the presence of 2.12 g of 20% palladium hydroxide. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 100 ml of methylene chloride, 0.43 ml (5.65 mmol) of chloroformmethyl and 0.79 ml (5.65 mmol) of triethylamine were added under ice cooling, followed by stirring at room temperature for 2 hours. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3- in the form of a pale yellow oil. Thiazol-2-yl] azetidine was obtained in 1.88 g and 45% yield.
[2483]
[2484] (2) 3-hydroxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2485] 1.88 g of 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 63 (1). mmol) was dissolved in 94 mL of anhydrous tetrahydrofuran, and 0.27 mL (4.68 mmol) of acetic acid and 4.68 mL (4.68 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution were added sequentially under ice cooling. Stirred for 30 minutes. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3-hydroxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine Was obtained as a white solid at 426 mg, yield 45%.
[2486]
[2487] (3) 3-methanesulfonyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2488] Methyl chloride, 426 mg (1.75 mmol) of 3-hydroxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 63 (2) It melt | dissolved in 20 mL, 0.16 mL (2.10 mmol) of methanesulfonyl chlorides, and 0.29 mL (2.10 mmol) of triethylamines were added under ice cooling, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-methanesulfonyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazole-2 as a pale yellow solid. -Yl] azetidine was obtained at 448 mg, yield 80%.
[2489]
[2490] (4) 3-acetylthio-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2491] 4-48 mg (1.39 mmol) of 3-methanesulfonyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 63 (3) It was dissolved in 13 ml of dimethylformamide, 952 mg (8.34 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred for 6 hours in a 90 ° C oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- [4- (methoxycarbonylamino-methyl) -1,3- pale brown solid. 441 mg of a thiazol-2-yl] azetidine was obtained in a yield of 100%.
[2492]
[2493] Reference Example 64
[2494] 3-acetylthio-1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2495]
[2496] (1) 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-t-butyldiphenylsilyloxyazetidine
[2497] 120 ml of 1.53 g (5.60 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1) It was dissolved in, and contact hydrogen reduction was carried out at room temperature in the presence of 2.53 g of 20% palladium hydroxide. After the reaction was completed, the reaction solution was filtered. 1.90 mL (8.40 mmol) of benzoic anhydrides were added to the filtrate under ice-cooling, and the mixture was stirred for 2.5 hours as it was. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-ethyl acetate) to give 1- [4- (benzoylamino-methyl) -1,3-thiazole-2 in the form of a pale yellow oil. -Yl] -3-t-butyldiphenylsilyloxyazetidine was obtained in 1.49 g and 50% yield.
[2498]
[2499] (2) 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-hydroxyazetidine
[2500] 1.49 g (2.82 mmol) of 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 64 (1) It was dissolved in 75 ml of anhydrous tetrahydrofuran, and 3.39 ml (3.39 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were added sequentially under ice cooling, and it stirred as it is for 1 hour. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2-ethyl acetate: methanol = 9: 1) to obtain 1- [4- (benzoylamino-methyl) -1,3-thiazole. 2-yl] -3-hydroxyazetidine was obtained as a white solid at 582 mg, yield 71%.
[2501]
[2502] (3) 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine
[2503] 582 mg (2.01 mmol) of 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-hydroxyazetidine obtained in Reference Example 64 (2) was added to 30 ml of methylene chloride. The solution was dissolved, and 0.19 ml (2.41 mmol) of methanesulfonyl chloride, 0.34 ml (2.41 mmol) of triethylamine, and 5.8 ml of pyridine were added under ice cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxy as a pale yellow solid. Azetidine was obtained in 739 mg, yield 100%.
[2504]
[2505] (4) 3-acetylthio-1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine
[2506] 739 mg (2.01 mmol) of 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine obtained in Reference Example 64 (3) was used as dimethylformamide. It dissolved in 20 mL, 1.38 g (12.1 mmol) of potassium thioacetate was added at room temperature, and it stirred for 3.5 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to give 3-acetylthio-1- [4- (benzoylamino-methyl) -1,3- pale brown solid. Thiazol-2-yl] azetidine was obtained with 698 mg of yield 100%.
[2507]
[2508] Reference Example 65
[2509] 3-acetylthio-1- [4-benzoylsulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2510]
[2511] (1) 3-t-butyldiphenylsilyloxy-1- [4- (benzoylsulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2512] 106 ml of 1.12 g (4.71 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1) It was dissolved in, and catalytic hydrogen reduction was performed at room temperature in the presence of 2.12 g of 20% palladium hydroxide. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 100 ml of methylene chloride, 0.90 ml (7.07 mmol) of benzenesulfonyl chloride and 0.98 ml (7.07 mmol) of triethylamine were added under ice cooling, followed by stirring at room temperature for 2 hours. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (benzenesulfonyl-amino) methyl-1,3-thia in the form of a pale yellow oil. Zol-2-yl] azetidine was obtained in 755 mg, yield 28%.
[2513]
[2514] (2) 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine
[2515] 2.79 g (4.95 mmol) of 3-t-butyldiphenylsilyloxy-1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in Reference Example 65 (1) ) Was dissolved in 140 ml of anhydrous tetrahydrofuran, and 5.94 ml (5.94 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added sequentially under ice cooling, followed by stirring for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine. It obtained 1.06g and yield 66% as a white solid.
[2516]
[2517] (3) 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -33-methanesulfonyloxyazetidine
[2518] 1.06 g (3.26 mmol) of 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine obtained in Reference Example 65 (2) The solution was dissolved in mL, 0.38 mL (4.89 mmol) of methanesulfonyl chloride and 0.68 mL (4.89 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-methane sulfide as a pale yellow solid. Ponyloxyazetidine was obtained in 1.16 mg and the yield of 91%.
[2519]
[2520] (4) 3-acetylthio-1- [4- (benzoylsulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2521] 1.16 g (2.98 mmol) of 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine obtained in Reference Example 65 (3). It dissolved in 35 ml of dimethylformamide, added 2.04 g (17.9 mmol) of potassium thioacetate at room temperature, and stirred for 4 hours in a 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 5: 1) to give 3-acetylthio-1- [4- (benzenesulfonyl-amino) methyl-1,3- as a light brown solid. 1.00 g of thiazol-2-yl] azetidine was obtained in 91% yield.
[2522]
[2523] Reference Example 66
[2524] 3-acetylthio-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2525]
[2526] (1) 3-t-butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2527] 120 ml of methanol 1.47 g (5.50 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1) It dissolved in, and contact hydrogen reduction was performed at room temperature in the presence of 2.47 g of 20% palladium hydroxide. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. This residue was dissolved in 115 ml of methylene chloride, 0.71 ml (6.60 mmol) of thienyl chloride and 0.92 ml (6.60 mmol) of trimethylamine were added under ice cooling, followed by stirring at room temperature for 1 hour. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to 3-t-butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl in the form of a pale yellow oil. -Amino) methyl-1,3-thiazol-2-yl] azetidine was obtained in 1.88 g and 64% yield.
[2528]
[2529] (2) 3-hydroxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2530] 3-t-butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in Reference Example 66 (1). 2.18 g (4.08 mmol) was dissolved in 110 mL of anhydrous tetrahydrofuran, and 4.90 mL (4.90 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was sequentially added under ice cooling, followed by stirring for 1 hour as it is. . After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 3-hydroxy-1- [4- (thiophene-2-carbonyl-amino) methyl-1,3- Thiazol-2-yl] azetidine was obtained as a white solid at 571 mg, yield 47%.
[2531]
[2532] (3) 3-methanesulfonyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2533] Reference Example 66 571 mg (1.93 mmol) of 3-hydroxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in (2) Was dissolved in 28 ml of methylene chloride, and 0.18 ml (2.32 mmol) of methanesulfonyl chloride and 0.33 ml (2.32 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 1: 1) to give 3-methanesulfonyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl as a pale yellow solid. 490 mg of -1,3-thiazol-2-yl] azetidine were obtained in 91% yield.
[2534]
[2535] (4) 3-acetylthio-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2536] 623 mg of 3-methanesulfonyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in Reference Example 66 (3). mmol) was dissolved in 18 ml of dimethylformamide, 1.14 g (10.0 mmol) of potassium thioacetate was added at room temperature, followed by stirring in a 90 ° C oil bath for 4 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to give 3-acetylthio-1- [4- (thiophene-2-carbonyl-amino) as a light brown solid. Methyl-1,3-thiazol-2-yl] azetidine was obtained in 490 mg, yield 91%.
[2537]
[2538] Reference Example 67
[2539] 3-acetylthio-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2540]
[2541] (1) 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2542] 120 ml of methanol 1.47 g (5.50 mmol) of 1- (4-azidemethyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 62 (1) It dissolved in, and contact hydrogen reduction was performed at room temperature in the presence of 2.47 g of 20% palladium hydroxide. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. This residue was dissolved in 115 ml of methylene chloride, 0.65 ml (6.60 mmol) of 2-furoyl chloride and 0.92 ml (6.60 mmol) of triethylamine were added under ice cooling, followed by stirring for 1 hour. After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate water were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-carbonyl-) in the form of a pale yellow oil. Amino) methyl-1,3-thiazol-2-yl] azetidine was obtained in 1.60 g and 60% yield.
[2543]
[2544] (2) 1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine
[2545] Reference Example 67 (1) To 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine 1.90 g (3.68 mmol) was dissolved in 95 mL of anhydrous tetrahydrofuran, and 4.41 mL (4.41 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was sequentially added under ice cooling, followed by stirring for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- [4- (furan-2-carbonyl-amino-methyl) -1,3-thiazole-2- Il] -3-hydroxyazetidine was obtained as a white solid at 426 mg, yield 47%.
[2546]
[2547] (3) 1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine
[2548] 426 mg (1.72 mmol) of 1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine obtained in Reference Example 67 (2) It was dissolved in 20 ml of methylene chloride, 0.16 ml (2.07 mmol) of methanesulfonyl chloride and 0.29 ml (2.07 mmol) of triethylamine were added under ice cooling, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 20: 1) to yield 1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazole- as a pale yellow solid. 2-81] -3-methanesulfonyloxyazetidine was obtained with 481 mg and yield 78%.
[2549]
[2550] (4) 3-acetylthio-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
[2551] 481 mg (1.34 mmol) of 1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine obtained in Reference Example 67 (3) ) Was dissolved in 14 ml of dimethylformamide, potassium thioacetate 921 mg (8.07 mmol) was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 6 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- [4- (furan-2-carbonyl-amino) methyl-1, a light brown solid. 3-thiazol-2-yl] azetidine was obtained in 341 mg, yield 83%.
[2552]
[2553] Reference Example 68
[2554] 3-acetylthio-1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidine
[2555]
[2556] (1) 3-t-butyldiphenylsilyloxy-1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidine
[2557] 1.50 g (3.53 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (2) were treated with tetrahydrofuran. It was dissolved in 75 ml, and under nitrogen cooling, 519 mg (5.30 mmol) of phthalimide, 1.39 g (5.30 mmol) of triphenylphosphine, and 2.03 ml (5.30 mmol) of diethylazodicarboxylate-40% toluene solution were added to a nitrogen atmosphere. It was added under stirring as it was for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 5) to give 3-t-butyldiphenylsilyloxy-1- (4-phthalimidemethyl-1,3 in the form of a pale yellow oil. -Thiazol-2-yl) azetidine was obtained at 1.52 mg, yield 78%.
[2558]
[2559] (2) 1- (4-phthalimidemethyl-1,3-thiazol-2-yl] -3-hydroxyazetidine
[2560] 1.52 g (2.57 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 68 (1) was substituted with anhydrous tetra It was dissolved in 76 ml of hydrofuran, and 3.29 ml (3.29 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution were added sequentially under ice-cooling, followed by stirring for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- (4-phthalimidemethyl-1,3-thiazol-2-yl] -3-hydroxyazetidine as a white solid. Mg, yield 100%.
[2561]
[2562] (3) 1- (4-phthalimidemethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine
[2563] 864 mg (2.74 mmol) of 1- (4-phthalimidemethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 68 (2) were dissolved in 35 ml of methylene chloride, and Under ice-cooling, 0.25 ml (3.29 mmol) of methanesulfonyl chloride and 0.46 ml (3.29 mmol) of triethylamine were added thereto, and the mixture was stirred for 1 hour as it was. After confirming completion of the reaction, diethyl ether was added to the reaction system and stirred for 30 minutes. The reaction system was filtered, and the filtrate was washed with diethyl ether to give 1- (4-phthalimidemethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine as a white solid. Mg, yield 67%.
[2564]
[2565] (4) 3-acetylthio-1- (4-phthalimidemethyl-1,3-thiazol-2-yl) azetidine
[2566] 726 mg (1.85 mmol) of 1- (4-phthalimidemethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 68 (3). It dissolved in mL, added 1.26 g (11.1 mmol) of potassium thioacetate at room temperature, and stirred for 6.5 hours in 90 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-phthalimidemethyl-1,3-thiazole-2- as a light brown solid. I) to 599 mg, yield 87% of azetidine.
[2567]
[2568] Reference Example 69
[2569] 3-acetylthio-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine
[2570]
[2571] (1) 3-t-butyldiphenylsilyloxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine
[2572] 1.50 g (3.53 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (2) were treated with tetrahydrofuran. It was dissolved in 75 ml, and succinimide 525 mg (5.30 mmol), triphenylphosphine 1.39 g (5.30 mmol) and diethylazodicarboxylate-40% toluene solution 2.03 ml (5.30 mmol) were dissolved in ice-cold nitrogen atmosphere. It was added under stirring as it was for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated brine were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-succinimidemethyl-1,3 in the form of a pale yellow oil. -Thiazol-2-yl) azetidine was obtained in 1.79 g, yield 100%.
[2573]
[2574] (2) 3-hydroxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine
[2575] 1.79 g (3.53 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 69 (1) was substituted with anhydrous tetra It was dissolved in 141 ml of hydrofuran, 4.24 ml (4.24 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added sequentially under ice-cooling, and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 3-hydroxy-1- (4-succinimidemethyl-1,3-thiazole-2- Il) azetidine was obtained as a white solid at 456 mg, yield 49%.
[2576]
[2577] (3) 3-methanesulfonyloxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine
[2578] Reference Example 69 459 mg (1.72 mmol) of 3-hydroxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine obtained in (2) were dissolved in 50 ml of methylene chloride, Under ice-cooling, 0.16 ml (2.06 mmol) of methanesulfonyl chloride and 0.29 ml (2.06 mmol) of triethylamine were added thereto, and the mixture was stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-methanesulfonyloxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine as a pale yellow solid. Was obtained in 515 mg, yield 87%.
[2579]
[2580] (4) 3-acetylthio-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine
[2581] 15 ml of dimethylformamide in 515 mg (1.49 mmol) of 3-methanesulfonyloxy-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 69 (3) Was dissolved in, and potassium thioacetate 1.02 g (8.95 mmol) was added at room temperature, followed by stirring in a 90 ° C oil bath for 8 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- (4-succinimidemethyl-1,3-thiazol-2-yl) azetidine as a pale yellow solid. Mg, yield 49%.
[2582]
[2583] Reference Example 70
[2584] 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine
[2585]
[2586] (1) (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanate-propionic acid methyl ester
[2587] Reference Example 39 32.0 g (65.1 mmol) of t-butyldiphenylsilyloxy-N-carbenzyloxy-L-celine methyl ester obtained in (1) was dissolved in 960 ml of methanol, and 32.0 g of 10% palladium carbon was present. , Contact hydrogen reduction was performed at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5) to give t-butyldiphenyl as a colorless oil. Silyloxy-L-celine methyl ester was obtained by 19.7 g and yield 85%. Subsequently, 19.7 g (55.0 mmol) of t-butyldiphenylsilyloxy-L-celine methyl ester obtained was dissolved in 590 mL of methylene chloride, 6.62 mL (110 mmol) of carbon disulfide and 19.3 mL (138 mmol) of triethylamine were dissolved at room temperature. Add and stir overnight. Next, 13.2 ml (138 mmol) of ethyl chloroformate and 19.3 ml (138 mmol) of triethylamine were added, and also it stirred for 1 hour. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Ethyl acetate and saturated brine were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene) to give 14.8 g of yellow crystals (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanate-propionic acid methyl ester, yield. Obtained at 67%.
[2588]
[2589] (2) (2S) -3- (t-butyldiphenylsilyloxy) -2-[(3-hydroxyazetidine-1-carbothioyl) -amino] -propionic acid methyl ester
[2590] 13.4 g (33.5 mmol) of (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanate-propionic acid methyl ester obtained in Reference Example 70 (1) was dissolved in 245 ml of tetrahydrofuran, A 50 ml aqueous solution of 4.90 g (67.1 mmol) of 3-hydroxyazetidine obtained in Reference Example 31 (1) was added to the system at room temperature and stirred as it was overnight. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene to toluene: acetonitrile = 3: 1) to give a yellow solid of (2S) -3- (t-butyldiphenylsilyloxy) -2-[(3- 9.60 g of hydroxyazetidine-1-carbothioyl) -amino] -propionic acid methyl ester was obtained in a yield of 61%.
[2591]
[2592] (3) (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl] -amino} -3- (t-butyldiphenylsilyloxy) -propionic acid methyl ester
[2593] 21.1 g of (2S) -3- (t-butyldiphenylsilyloxy) -2-[(3-hydroxyazetidine-1-carbothioyl) -amino] -propionic acid methyl ester obtained in Reference Example 70 (2) (44.6 mmol) was dissolved in 630 ml of pyridine, 30.0 g (133 mmol) of benzoic anhydride and 545 mg (4.46 mmol) of 4-dimethylaminopyridine were added to the reaction system under ice-cooling, followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5N hydrochloric acid, saturated sodium bicarbonate water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1) to give a pale yellow solid (2S) -2-{[3- (benzoyloxy) -azetidine-1-carboti. Oil] -amino} -3- (t-butyldiphenylsilyloxy) -propionic acid methyl ester was obtained with 23.3 g of yield 91%.
[2594]
[2595] (4) (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl] -amino} -3-hydroxy-propionic acid methyl ester
[2596] (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl] -amino} -3- (t-butyldiphenylsilyloxy) -methyl propionate obtained in Reference Example 70 (3). 23.3 g (40.0 mmol) of the ester were dissolved in 700 mL of tetrahydrofuran, and 48.4 mL (48.4 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, followed by stirring overnight. After confirming the completion of the reaction, ethyl acetate and saturated brine were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to give a white solid of (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl]. -Amino} -3-hydroxy-propionic acid methyl ester was obtained at 12.6 g and yield 92%.
[2597]
[2598] (5) 3- (benzoyloxy) -1-[(4S) -4-methoxycarbonyl-1,3-oxazolin-2-yl] azetidine
[2599] (2S) -2-{[3- (benzoyloxy)-obtained in Reference Example 70 (4) to a solution of 15.1 g (55.9 mmol) of acetonitrile in 2-chloro-3-ethylbenzooxazole tetrafluoroborate Azetidine-1-carbothioyl] -amino} -3-hydroxypropionic acid methyl ester 12.6 g (37.2 mmol) of acetonitrile was added dropwise under ice-cooling and nitrogen atmosphere, and stirred for 1 hour after completion of dropwise addition. It was. Next, 10.4 ml (74.4 mmol) of triethylamine was added to the system, and further stirred for 1.5 hours. After confirming the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-benzoyloxy-1-[(4S) -4-methoxycarbonyl-1, 3-oxazolin-2-yl] azetidine was obtained in 9.12 g, yield 81%.
[2600]
[2601] (6) 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine
[2602] 450 ml of toluene and 9.00 g (30.0 mmol) of 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazolin-2-yl) azetidine obtained in Reference Example 70 (5) It dissolved in ml, 63.8 g of manganese dioxide was added in the system, and it heated and refluxed for 5 hours. After the completion of reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1) to give 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazole-2- as pale yellow crystals. I) 5.24 g of azetidine was obtained in a yield of 58%.
[2603]
[2604] (7) 3-hydroxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine
[2605] 5.24 g (17.3 mmol) of 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (6) was diluted with 260 ml of methanol and 80 ml of methylene chloride. It dissolved in mL, added the catalytic amount of sodium methoxide at room temperature, and stirred as it is for 1 hour. After confirming the completion of the reaction, the mixture was neutralized by adding 4N hydrochloric acid gas-dioxane solution under ice cooling, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5) to give 3-hydroxy-1- (4-methoxycarbonyl-1,3-oxazole-2- as light brown crystals. I) 2.65g of azetidine, yield 77% was obtained.
[2606]
[2607] (8) 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine
[2608] 2.64 g (13.4 mmol) of 3-hydroxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (7) were dissolved in 80 ml of dimethylformamide. Then, 6.97 ml (26.8 mmol) of t-butyldiphenylsilane chloride and 1.82 g (26.8 mmol) of imidazole were added under ice-cooling, and the mixture was stirred overnight under ice-cooling. After the reaction was completed, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and 10% saline solution were added to the system, followed by extracting liquids. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1-3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-methoxycarpoxy as a pale yellow solid. 4.95 g of carbonyl-1,3-oxazol-2-yl) azetidine were obtained in yield 85%.
[2609]
[2610] (9) 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-oxazol-2-yl) azetidine
[2611] 4.95 g (11.3 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (8) It melt | dissolved in 100 ml of hydrofuran, it dripped at the suspension of 250 ml of anhydrous tetrahydrofuran 1.29 g (33.9 mmol) of lithium aluminum hydride previously adjusted under nitrogen atmosphere by ice-cooling, and stirred for 5 minutes on the same conditions after completion | finish of dripping. After confirmation of reaction completion, magnesium sulfate decahydrate was gradually added into the system under the same conditions, and when foaming from the system subsided, the mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was slowly added into the system, followed by saturated brine. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-oxa as a white solid. Zol-2-yl) azetidine was obtained in 3.88 g and 84% yield.
[2612]
[2613] (10) 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-oxazol-2-yl) azetidine
[2614] 3.88 g (9.50 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (9) was dried with anhydrous methylene chloride. It was dissolved in 190 ml, 19.4 g of active manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3- pale yellow crystals. 3.09 g of oxazol-2-yl) azetidine was obtained in 80% yield.
[2615]
[2616] (11) 3-t-butyldiphenylsilyloxy-1- (4-carboxy-2-yl) azetidine
[2617] 3.09 g (7.60 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (10) was dissolved in anhydrous methylene chloride 18. Dissolved in mL, 93 mL of t-butanol and 5.70 mL (11.4 mmol) of 2M 2-methyl-2-butene tetrahydrofuran solution were added into the system. Subsequently, an 18 ml aqueous solution of 1.72 g (15.2 mmol) of sodium chlorite and 1.82 g (15.2 mmol) of sodium dihydrogen phosphate was added dropwise into the system under ice-cooling and stirred for 1 hour. After the reaction was completed, ethyl acetate and 1M hydrochloric acid (pH: 2-3) were added to the system. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 9: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3) as a brown solid. 1.90 g of -thiazol-2-yl) azetidine was obtained with a yield of 59%.
[2618]
[2619] Reference Example 71
[2620] 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine
[2621]
[2622] (1) 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
[2623] 3.00 g (4.58 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (8) was added to toluene 100 The solution was dissolved in ml, and 13.7 ml of a 0.67 M azetidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, followed by stirring in a 100 ° C oil bath for 5.5 hours. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1-ethyl acetate) to give 1- (4-azetidinocarbonyl-1,3-oxazole-2 as a pale brown solid. -Yl) -3-t-butyldiphenylsilyloxyazetidine was obtained in 875 mg, yield 41%.
[2624]
[2625] (2) 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-hydroxyazetidine
[2626] 870 mg (1.88 mmol) of 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine obtained in Reference Example 71 (1) was dried. It was dissolved in 44 ml of tetrahydrofuran, 2.26 ml (2.26 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred as it is for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to obtain 1- (4-azetidinocarbonyl-1,3- Oxazol-2-yl) -3-hydroxyazetidine was obtained as white crystals at 396 mg, yield 94%.
[2627]
[2628] (3) 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-methanesulfonylazetidine
[2629] 390 mg (1.75 mmol) of 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 71 (2) was dissolved in 20 ml of methylene chloride. 406 µl (5.24 mmol) of methanesulfonyl chloride and 734 µl (5.24 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the filtrate was washed with diisopropyl ether and dried under reduced pressure to obtain 1- (4-azetidinocarbonyl-1,3-oxazole as a pale yellow solid. 2-yl) -3-methanesulfonylazetidine 449 mg, yield 85%.
[2630]
[2631] (4) 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine
[2632] 25 ml of 470 mg (1.56 mmol) of 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-methanesulfonylazetidine obtained in Reference Example 71 (3) It dissolved in, and potassium thioacetate 1.07g (9.36mmol) was added at room temperature, and it stirred for 8.5 hours in 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxa as a pale brown solid. Zol-2-yl) azetidine was obtained in 330 mg, yield 75%.
[2633]
[2634] Reference Example 72
[2635] 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine
[2636]
[2637] (1) 3-t-butyldiphenylsilyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine
[2638] 1.00 g (2.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (8) was added to toluene 50. It dissolved in ml, and added 6.87 ml of 0.67M morpholine-trimethylaluminum-toluene solution at room temperature under nitrogen atmosphere, and stirred in 80 degreeC oil bath for 4 hours. After confirming completion of the reaction, 50 ml of 10% acetic acid water and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-morpholinocarbonyl-1) as a light brown solid. , 3-oxazol-2-yl) azetidine was obtained in 400 mg, yield 36%.
[2639]
[2640] (2) 3-hydroxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine
[2641] 730 mg (1.48 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 72 (1) was anhydrous. It was dissolved in 37 ml of tetrahydrofuran, 1.78 ml (1.78 mmol) of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred for 1.5 hours as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to give 3-hydroxy-1- (4-mor). Polynocarbonyl-1,3-oxazol-2-yl) azetidine was obtained as white crystals in 377 mg, yield 100%.
[2642]
[2643] (3) 3-methanesulfonyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine
[2644] 370 mg (1.48 mmol) of 3-hydroxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 72 (2) were dissolved in 19 ml of methylene chloride. Then, 344 µl (4.44 mmol) of methanesulfonyl chloride and 622 µl (4.44 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7) to give 3-methanesulfonyloxy-1- (4-morpholinocarbonyl-1,3-oxazole as pale yellow crystals. 2-yl) azetidine was obtained in 404 mg, yield 100%.
[2645]
[2646] (4) 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine
[2647] 400 mg (1.21 mmol) of 3-methanesulfonyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 72 (3) was converted to dimethylformamide 20. It dissolved in mL, added 827 mg (7.24 mmol) of potassium thiosionate at room temperature, and stirred for 6 hours in an 80 degreeC oil bath. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxa as a pale brown solid. Zol-2-yl) azetidine was obtained with 266 mg, yield 71%.
[2648]
[2649] Reference Example 73
[2650] 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2651]
[2652] (1) 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2653] 1.57 g (3.60 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (8) was added to toluene 80. It dissolved in ml, and 10.8 ml of 0.67M 3-methoxyazetidine (obtained in Reference Example 31 (2))-trimethylaluminum-toluene solution was added under nitrogen atmosphere at room temperature, and stirred for 30 minutes in a 60 degreeC oil bath. After confirming the reaction was completed, 100 ml of 10% acetic acid water and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl)-as a pale brown solid. 1.50 g of 1,3-oxazol-2-yl] azetidines were obtained in a yield of 90%.
[2654]
[2655] (2) 3-hydroxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2656] 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] ase obtained in Reference Example 72 (1). Tidine 1.49 g (3.23 mmol) was dissolved in 75 mL of anhydrous tetrahydrofuran, 1.088 mL (3.88 mmol) of 1.0M tetra-n-butylammonium chloride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1 hour as it was. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to give 3-hydroxy-1- [4- ( 3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine was obtained as a white solid at 486 mg, yield 60%.
[2657]
[2658] (3) 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2659] Reference Example 73 480 mg of 3-hydroxy-1- [4- (3-methoxy-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidine obtained in (2) mmol) was dissolved in 24 ml of methylene chloride, 439 µl (5.67 mmol) of methanesulfonyl chloride and 795 µl (5.67 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 30 minutes as it was. . After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the filtrate was washed with diisopropyl ether to give 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-) as a pale yellow solid. 1-carbonyl) -1,3-oxazol-2-yl] azetidine was obtained in 586 mg, yield 94%.
[2660]
[2661] (4) 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2662] Reference Example 73 3-Methanesulfonyloxy-1- [4- (3-methoxy-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidine 580 mg obtained in (3). (1.75 mmol) was dissolved in 30 ml of dimethylformamide, 1.20 g (10.5 mmol) of potassium thioacetate was added at room temperature, followed by stirring in an 80 ° C oil bath for 6 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 97: 3) to give 3-acetylthio-1- [4- (3-methoxy-azetidine-1-) as a light brown solid. 336 mg, yield 62% of carbonyl) -1,3-oxazol-2-yl] azetidine was obtained.
[2663]
[2664] Reference Example 74
[2665] 3-acetylthio-1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2666]
[2667] (1) 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] -3-hydroxyazetidine
[2668] 500 mg (2.52 mmol) of 3-hydroxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (7) were dissolved in 25 ml of toluene, 0.63 M 3-t-butyldiphenylsilyloxyazetidine (obtained in Reference Example 42 (2))-11.3 ml of trimethylaluminum-toluene solution was added under nitrogen atmosphere at room temperature, and stirred for 15 minutes in an 80 ° C oil bath. . After confirming completion of the reaction, 20 ml of 10% acetic acid water and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 0.5 hour. Subsequently, ethyl acetate was further added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5-9: 1) to give 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1- as a light brown solid. Carbonyl) -1,3-oxazol-2-yl] -3-hydroxyazetidine was obtained in 1.24 g and 100% yield.
[2669]
[2670] (2) 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] -3-methanesulfonyloxyazetidine
[2671] 1- [4- (3-t-butyldiphenylsilyloxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] -3-hydroxyazetidine obtained in Reference Example 74 (1). 1.68 g (3.53 mmol) was dissolved in 84 ml of methylene chloride, 820 µl (10.6 mmol) of methanesulfonyl chloride and 1.49 ml (10.6 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature. It stirred for 0.5 hours. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 1: 1) to give a pale yellow solid, 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl). -1,3-oxazol-2-yl] -3-methanesulfonyloxyazetidine was obtained in 1.56 g and 80% yield.
[2672]
[2673] (3) 3-acetylthio-1- [4- (3-t-butyldiphenylsilyloxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidine
[2674] 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] -3-methanesulfonyloxy obtained in Reference Example 74 (2). 1.56 g (2.81 mmol) of azetidine were dissolved in 80 ml of dimethylformamide, 1.92 g (16.8 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 7.5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1: 1: 1) to give 3-acetylthio-1- [4- (3-t-butyldiphenyl) as a light brown solid. Silyloxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidine was obtained in 863 mg, yield 57%.
[2675]
[2676] Reference Example 75
[2677] 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-carbonyl] -1,3-oxazol-2-yl} azetidine
[2678]
[2679] (1) 3-t-butyldiphenylsilyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2- Azetidine
[2680] 1.39 g (4.83 mmol) of 3- (p-nitrobenzyloxycarbonylamino) azetidine hydrochloride obtained in Reference Example 57 (4) and 3-t-butyldiphenylsilyloxy-1- obtained in Reference Example 70 (11) 1.70 g (4.02 mmol) of (4-carboxyl-1,3-oxazol-2-yl) azetidine was suspended in 85 ml of dimethylformamide, and 801 µl of diethylphosphoryl cyanide was cooled under ice with nitrogen atmosphere. 4.83 mmol) and 1.70 mL (12.1 mmol) of triethylamine were added and stirred overnight at room temperature. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- {4- [3- ( p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 596 mg, yield 23%.
[2681]
[2682] (2) 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2683] 3-t-butyldiphenylsilyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3- obtained in Reference Example 75 (1). 640 mg (0.976 mmol) of thiazol-2-yl} azetidine was dissolved in 32 ml of anhydrous tetrahydrofuran, and 67 µl of acetic acid, (1.17 mmol), 1.0 M tetra-n-butylammonium fluoride-tetrahydro under ice-cooling 1.17 mL (1.17 mmol) of furan solution was added sequentially and stirred for 1.5 hours as it was. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5-9: 1) to give 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino). -Azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained as a white solid at 360 mg, yield 88%.
[2684]
[2685] (3) 3-methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} ase Tidin
[2686] 3-hydroxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2- obtained in Reference Example 75 (2). Dissolve 360 mg (0.863 mmol) of Japanese azetidine in 18 ml of methylene chloride, add 200 µl (2.59 mmol) of methanesulfonyl chloride and 363 µl (2.59 mmol) of triethylamine under ice-cooling, and after 10 minutes The mixture was returned to room temperature and stirred for 2 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 95: 5) to give 3-methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxy) as a pale yellow solid. Carbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 390 mg, yield 91%.
[2687]
[2688] (4) 3-acetylthio-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine
[2689] 3-Methanesulfonyloxy-1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole obtained in Reference Example 75 (3)- 390 mg (0.787 mmol) of 2-yl} azetidine was dissolved in 20 ml of dimethylformamide, 539 mg (4.72 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an 80 ° C oil bath for 10.5 hours. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate) to give 3-acetylthio-1- {4- [3- (p-nitrobenzyloxy) as a light brown solid. Carbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl} azetidine was obtained in 195 mg, yield 52%.
[2690]
[2691] Reference Example 76
[2692] 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} Azetidine
[2693]
[2694] (1) 3-t-butyldiphenylsilyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 -Oxazol-2-yl} azetidine
[2695] 905 mg (3.41 mmol) of (3S) -3-amino-1-p-nitrobenzyloxycarbonylpyrrolidine obtained in Reference Example 52 (4) and 3-t-butyldiphenyl obtained in Reference Example 70 (11). 1.20 g (2.84 mmol) of silyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine is suspended in 36 ml of dimethylformamide, and diethylphosphoryl is cooled on ice under nitrogen atmosphere. 556 µl (3.41 mmol) of cyanide and 478 µL (3.41 mmol) of triethylamine were added, and the mixture was stirred overnight at room temperature. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[( 3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained in 936 mg, yield 49%.
[2696]
[2697] (2) 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2 -Yl} azetidine
[2698] 3-t-butyldiphenylsilyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl obtained in Reference Example 76 (1) ] -1,3-oxazol-2-yl} azetidine 1.10 g (1.64 mmol) is dissolved in 55 ml of anhydrous tetrahydrofuran, and 113 µl of acetic acid, (1.97 mmol), 1.0 M tetra-n-butyl under ice-cooling 1.97 ml (1.97 mmol) of an ammonium floride-tetrahydrofuran solution were added sequentially and stirred as it was overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbine. Bonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained as a white solid at 687 mg, yield 97%.
[2699]
[2700] (3) 3-methanesulfonyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole -2-yl} azetidine
[2701] 3-hydroxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 obtained in Reference Example 76 (2). 680 mg (1.58 mmol) of -oxazol-2-yl} azetidine was dissolved in 34 ml of methylene chloride, and 366 µl (4.73 mmol) of methanesulfonyl chloride and 663 µl (4.73 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 96: 4) to give 3-methanesulfonyloxy-1- {4-[(3S) -1- (p) as a pale yellow solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine in 760 mg, yield 95%.
[2702]
[2703] (4) 3-acetylthio-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2 -Yl} azetidine
[2704] 3-Methanesulfonyloxy-1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 76 (3). 760 mg (1.49 mmol) of, 3-oxazol-2-yl} azetidine was dissolved in 38 ml of dimethylformamide, 1.02 g (8.95 mmol) of potassium thioacetate was added at room temperature, followed by 10.5 hours in an 80 ° C oil bath. Stirred. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 6 to ethyl acetate) to give 3-acetylthio-1- {4-[(3S) -1- (p) as a light brown solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine in 533 mg, yield 73%.
[2705]
[2706] Reference Example 77
[2707] 3-acetylthio-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} Azetidine
[2708]
[2709] (3) 3-t-butyldiphenylsilyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 -Oxazol-2-yl} azetidine
[2710] 798 mg (3.01 mmol) of (3R) -3-amino-1-p-nitrobenzyloxycarbonylpyrrolidine obtained in Reference Example 53 (5) and 3-t-butyldiphenyl obtained in Reference Example 70 (11). 1.06 g (2.51 mmol) of silyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine is dissolved in 50 ml of dimethylformamide, and diethylphosphoryl is cooled on ice under nitrogen atmosphere. 464 µl (3.01 mmol) of cyanide and 422 µl (3.01 mmol) of triethylamine were added, and the mixture was stirred overnight at room temperature. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-1: 3) to give 3-t-butyldiphenylsilyloxy-1- {4-[(3R) as a light brown solid. ) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine in 813 mg, yield 48%.
[2711]
[2712] (2) 3-hydroxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2 -Yl} azetidine
[2713] 3-t-butyldiphenylsilyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl obtained in Reference Example 77 (1) ] -1,3-oxazol-2-yl} azetidine 810 mg (1.21 mmol) was dissolved in 40 ml of anhydrous tetrahydrofuran, and 83 µl of acetic acid, (1.45 mmol), 1.0 M tetra-n-butyl under ice-cooling 1.45 mL (1.45 mmol) of ammonium floride-tetrahydrofuran solution was added sequentially and stirred as it was overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- {4-[(3R) -1- (p-) as a pale yellow oil. Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained in 507 mg, yield 97%.
[2714]
[2715] (3) 3-methanesulfonyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole -2-yl} azetidine
[2716] Reference Example 77 3-hydroxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3 obtained in (2). -Oxazol-2-yl} azetidine 500 mg (1.16 mmol) was dissolved in 25 ml of methylene chloride, and 269 µl (3.48 mmol) of methanesulfonyl chloride and 488 µl (3.48 mmol) of triethylamine were added under ice cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 3 hours as it was. After the reaction was completed, ethyl acetate and saturated sodium bicarbonate water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 96: 4) to give 3-methanesulfonyloxy-1- {4-[(3R) -1- (p) as a pale yellow solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine in 546 mg, yield 92%.
[2717] Mass Spectrum (FAB ⁺ ): m / z: 510 [M + H] ⁺
[2718] (4) 3-acetylthio-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2 -Yl} azetidine
[2719] 3-Methanesulfonyloxy-1- {4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 77 (3). 540 mg (1.06 mmol) of, 3-oxazol-2-yl} azetidine was dissolved in 27 ml of dimethylformamide, 726 mg (6.36 mmol) of potassium thioacetate was added at room temperature, followed by 9 hours in an 80 ° C oil bath. Stirred. After confirming the reaction was completed, ethyl acetate and 10% brine were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 6-ethyl acetate) to give 3-acetylthio-1- {4-[(3R) -1- (p) as a light brown solid. -Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained in 281 mg, yield 54%.
[2720]
[2721] Test Example 1 in vitro antimicrobial activity
[2722] Antimicrobial activity was measured by agar plate dilution, and the minimum growth inhibition concentration (µg / ml) for various pathogens was determined. The results are shown in Table 6. In the table, test bacteria A, B, and C are as follows.
[2723] A: Staphylococcus aureus 209P strain
[2724] B: 10664 pneumococcal strains (penicillin resistant strains)
[2725] C: 9787 strains of Haemophilus and influenza (β-lactamase producing strain)
[2726] compoundMinimal developmental concentration (µg / ml) Test bacterium ABC Compound of Example 30.050.200.10 Compound of Example 40.050.200.20 Compound of Example 50.050.200.20 Compound of Example 60.050.200.20 Compound of Example 190.050.200.10 Compound of Example 220.050.200.10 Compound of Example 24≤0.0120.0250.05 Compound of Example 250.0250.100.39 Compound of Example 560.050.200.20 Compound of Example 570.0250.200.20 Compound of Example 58≤0.0120.200.20 Compound of Example 59≤0.0120.200.20 Compound of Example 600.0250.390.39 Compound of Example 610.0250.200.39 Compound of Example 67≤0.0120.390.20 Compound of Example 69≤0.012≤0.0120.78 Compound of Example 70≤0.012≤0.0120.78 Compound of Example 71≤0.012≤0.0120.39 Compound of Example 72≤0.0120.0250.20 Compound of Example 760.050.200.39 Compound of Example 800.0250.200.39 Compound of Example 81≤0.0120.200.39
[2727] The above results indicate that the compound of the present invention has a strong antimicrobial activity.
[2728] Test Example 2 Body Dynamics
[2729] Compound (20 mg / kg) was subcutaneously administered to mice (n = 3, ddy males, SLC) and plasma concentrations at 5, 15, 30, 1, 1.5 and 2 hours after administration were determined. It was measured by bioassay. The obtained pharmacokinetic parameters are shown in Table 7. In the table, C _max is the peak plasma concentration, T _1/2 is the _half-life of the plasma concentration, and AUC _all is the area under the plasma concentration curve (for time).
[2730] compoundC _max (μg / ml)T _1/2 (hr)AUC _all (μghr / ml) Compound of Example 3127.170.2583.90 Compound of Example 4157.381.02165.19 Compound of Example 1156.560.3340.38 Compound of Example 5748.150.3845.31 Compound of Example 5863.880.4147.38 Compound of Example 6046.140.3027.88 Compound of Example 6740.200.4534.13 Compound of Example 7652.800.1927.88
[2731] Test Example 3 in vivo antibacterial activity (mouse infection treatment test)
[2732] Four-week-old ddY male mice (Nihon SLC) were inoculated with 0.2 ml of S.pneumoniae 9605 (PRSP) intraperitoneally (containing 5% mucin, 1-5 x 10 ³ cfu / mouse) and subcutaneously subcutaneously with the test compound. 0.1 ml was administered once. Mice using the group 1 and 7, test compound was calculated from the ED ₅₀ with probit (probit) method from the survival rate 7 days after using the one-step two-fold dilution. The test results are shown in Table 8.
[2733] compoundED ₅₀ (mg / kg / dose) Compound of Example 570.855 Compound of Example 580.899 Compound of Example 591.08 Compound of Example 601.41 Compound of Example 611.79 Compound of Example 671.60 Compound of Example 760.534
[2734] Formulation Example 1 (Injectable)
[2735] 500 mg of the compound of Example 3 was dissolved in 5 ml of distilled water for injection, passed through a sterile filter, and lyophilized to obtain a freeze-dried preparation for injection.
[2736] Formulation Example 2 (Capsule)
[2737] 50 mg of the compound of Example 24
[2738] Lactose 128mg
[2739] Corn Starch 70mg
[2740] Magnesium stearate 2mg
[2741] 250mg
[2742] The powder of the said prescription is mixed, it passes through a 60-mesh sieve, and this powder is put into 250 mg No. 3 gelatin capsule, and it is set as a capsule.
[2743] Formulation Example 3 (Tablet)
[2744] 50 mg of the compound of Example 24
[2745] Lactose 126 mg
[2746] Corn Starch 23mg
[2747] Magnesium Stearate 1mg
[2748] 200mg
[2749] The powder of the above formula is mixed, wet granulated with corn starch paste, dried, tableted with a tableting machine, and tablets of 200 mg per tablet. This tablet can be sugared as needed.
[2750] The 1-methylcarbapenem compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent antibacterial activity, is stable against dihydropeptidase I and β-lactamase, and has a high urine recovery. In addition, the toxicity to the kidneys is low, so it is useful as a medicine, especially an antibacterial agent.

权利要求:
Claims (38)
[1" claim-type="Currently amended] 1-methylcarbapenem compound represented by formula (I) or a pharmacologically acceptable salt or ester derivative thereof:
[Formula I]
[Wherein, R ¹ is,
(1) the group represented by the formula COOR ³
[Wherein, R ³ represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group],
(2) the group represented by the formula CONR ⁴ R ⁵
[Wherein, R ⁴ and R ⁵ are the same or different, a hydrogen atom, a C1-C6 alkyl group (which may be substituted with the same or different 1 or 2 groups selected from Substituent Group A below), a C3-C6 cycloalkyl group, A 3-6 membered heterocyclic group or a C6-C10 aryl group (which may be substituted with the same or different 1 or 2 groups selected from Substituent Group B below), or integrally with the nitrogen atom to which they are bonded Group which forms a six-membered nitrogen-containing heterocycle (may be substituted with the same or different 1 or 2 groups selected from Substituent Group B below),
(3) cyano groups,
(4) groups represented by the formula CH ₂ OR ⁶
[Wherein R ⁶ is a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group] or
(5) group represented by the formula CH ₂ NR ⁷ R ⁸
[Wherein, R ⁷ represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, R ⁸ represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, C6-C10 Arylcarbonyl group (may be substituted with the same or different 1 or 2 groups selected from Substituent Group B), C1-C6 alkoxycarbonyl group, 5- or 6-membered aromatic heterocyclic carbonyl group, C1-C6 alkylsulfonyl group or C6-C10 An arylsulfonyl group, or R ⁷ and R ⁸ are integral with the nitrogen atom to which they are bonded to represent a succinimide group (which may be condensed with a phenyl group);
Indicates,
R ² represents a hydrogen atom or a C1-C6 alkyl group,
n represents 1, 2 or 3,
X represents a sulfur atom or an oxygen atom,
Substituent group A may be a hydroxyl group, an amino group (which may be substituted with one or two C1-C6 alkyl groups), a carbamoyl group (the amino moiety may be substituted with one or two C1-C6 alkyl groups), a carboxyl group, a cyano group , A group containing a C1-C6 alkoxy group,
Substituent group B includes a hydroxy C1-C4 alkyl group, an amino C1-C4 alkyl group (the amino portion may be substituted with 1 or 2 C1-C6 alkyl groups), a carbamoyl group (the amino portion is 1 or 2 C1-C6 Alkyl group), carboxyl group, hydroxyl group, amino group (may be substituted with one or two C1-C6 alkyl groups), C1-C6 alkoxy group, C1-C6 alkyl group.
[2" claim-type="Currently amended] The 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ , a cyano group or a group represented by the formula CH ₂ NR ⁷ R ⁸ . .
[3" claim-type="Currently amended] The 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ or a group represented by the formula CH ₂ NR ⁷ R ⁸ .
[4" claim-type="Currently amended] The 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ .
[5" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 4, wherein R ² is a hydrogen atom or a C1-C3 alkyl group.
[6" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 4, wherein R ² is a hydrogen atom.
[7" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 6, wherein R ³ is a hydrogen atom or a C1-C3 alkyl group.
[8" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 6, wherein R ³ is a hydrogen atom, a methyl group or an ethyl group.
[9" claim-type="Currently amended] The 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 8, wherein R ⁴ is a hydrogen atom or a C1-C3 alkyl group.
[10" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 8, wherein R ⁴ is a hydrogen atom, a methyl or isopropyl group.
[11" claim-type="Currently amended] The compound of any one of claims 1 to 10, wherein R ⁵ is a hydrogen atom, a C1-C6 alkyl group (may be substituted with the same or different 1 or 2 groups selected from substituent group A) or 4 to 6 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof, which is a desired nitrogen-containing heterocyclic group.
[12" claim-type="Currently amended] Azetidinyl according to any one of claims 1 to 10, wherein R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted with the same or different 1 or 2 groups selected from substituent group A) , 1-methylcarbapenem compound, or a pharmacologically acceptable salt or ester derivative thereof, which is a pyrrolidinyl or piperidinyl group.
[13" claim-type="Currently amended] 9. A group according to any one of claims 1 to 8, wherein R ⁴ and R ⁵ are integrated with the nitrogen atom to which they are bonded to form a 4 to 6 membered nitrogen-containing heterocycle (selected from substituent group B). 1-methylcarbapenem compound, or a pharmacologically acceptable salt or ester derivative thereof, which may be substituted by the same or different 1 or 2 groups.
[14" claim-type="Currently amended] 9. An azetidino, piperazino, morpholino or thiomorpholino group according to any one of claims 1 to 8, wherein R ⁴ and R ⁵ are integrated with the nitrogen atom to which they are attached. Group may be substituted with the same or different 1 or 2 groups selected from substituent group B) or a pharmacologically acceptable salt or ester derivative thereof.
[15" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 14, wherein R ⁶ is a hydrogen atom or a C1-C3 alkyl group.
[16" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 14, wherein R ⁶ is a hydrogen atom.
[17" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16, wherein R ⁷ is a hydrogen atom or a C1-C3 alkyl group.
[18" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16, wherein R ⁷ is a hydrogen atom or a methyl group.
[19" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 16, wherein R ⁷ is a hydrogen atom.
[20" claim-type="Currently amended] 20. The compound of any one of claims 1 to 19, wherein R ⁸ is a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkanoyl group, a benzoyl group (the same or different one or two selected from substituent group B). 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof, which may be substituted with a group), a C1-C3 alkoxycarbonyl group, a thiophencarbonyl group, a furancarbonyl group or a pyridinecarbonyl group.
[21" claim-type="Currently amended] 20. The compound of any one of claims 1 to 19, wherein R ⁸ is a hydrogen atom, a benzoyl group (which may be substituted with the same or different 1 or 2 groups selected from substituent group B), thiophen-2- 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof which is a carbonyl group, furan-2-carbonyl group or pyridine-3-carbonyl group.
[22" claim-type="Currently amended] 22. The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 21, wherein n is 1.
[23" claim-type="Currently amended] The 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 22, wherein X is an oxygen atom.
[24" claim-type="Currently amended] 2. A group according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ is a hydrogen atom or a C1-C3 alkyl group, R ⁵ is a hydrogen atom, a C1-C6 alkyl group (selected in substituent group A) Or a 4 to 6 membered nitrogen-containing heterocyclic group), R ² is a hydrogen atom, n is 1, X is an oxygen atom or a sulfur atom Bafenem compound or a pharmacologically acceptable salt or ester derivative thereof.
[25" claim-type="Currently amended] 2. A group according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ is a hydrogen atom, a methyl or an isopropyl group, R ⁵ is a hydrogen atom, a C1-C6 alkyl group (in the substituent group A Or azetidinyl, pyrrolidinyl or piperidinyl group), n is 1, X is an oxygen atom or a sulfur atom, and is a 1-methylcarbapenem compound Or a pharmacologically acceptable salt or ester derivative thereof.
[26" claim-type="Currently amended] A group according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are united with the nitrogen atom to which they are bonded to form a 4-6 membered nitrogen-containing heterocycle) Or a 1-methylcarbapenem compound wherein R ² is a hydrogen atom, n is 1, X is an oxygen atom or a sulfur atom, or Pharmacologically acceptable salts or ester derivatives thereof.
[27" claim-type="Currently amended] 2. A group according to claim 1, wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are integrated with the nitrogen atom to which they are bonded to azetidino, piperazino, morpholino or thio) Morpholino group (these groups may be substituted with the same or different 1 or 2 groups selected from substituent group B), R ² is a hydrogen atom, n is 1 and X is an oxygen atom or a sulfur atom -Methylcarbapenem compounds or pharmacologically acceptable salts or ester derivatives thereof.
[28" claim-type="Currently amended] The 1-methylcarbapenem compound or pharmacologically acceptable salt or ester derivative thereof according to claim 1, wherein R ¹ is a cyano group, R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom.
[29" claim-type="Currently amended] A group according to claim 1, wherein R ¹ is a group represented by the formula CH ₂ NR ⁷ R ⁸ , wherein R ⁷ is a hydrogen atom or a C 1-3 alkyl group, and R ⁸ is a hydrogen atom, a C 1-3 alkyl group, C 1-3 Alkanoyl group, benzoyl group (which may be substituted with the same or different 1 or 2 groups selected from substituent group B), C1-C3 alkoxycarbonyl group, thiophencarbonyl group, furancarbonyl group or pyridinecarbonyl group, and R ² is hydrogen 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof, wherein the atom is n is 1 and X is an oxygen atom or a sulfur atom.
[30" claim-type="Currently amended] A group according to claim 1, wherein R ¹ is a group represented by the formula CH ₂ NR ⁷ R ⁸ (wherein R ⁷ is a hydrogen atom or a methyl group, and R ⁸ is a hydrogen atom, a benzoyl group (the same selected from substituent group B or May be substituted with other 1 or 2 groups), thiophene-2-carbonyl group, furan-2-carbonyl group or pyridine-3-carbonyl group), R ² is a hydrogen atom, n is 1 and X is an oxygen atom Or a 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof.
[31" claim-type="Currently amended] 1-methylcarbapenem compound or a pharmacologically acceptable salt or ester derivative thereof selected from the group of compounds
(1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hide Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydrate Oxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1 -Hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (4-aminoazetidino) carbonyl-1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (4-aminoazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [ (1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (4-hydroxyazetidino) carbonyl-1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (4-hydroxyazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [(1R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl } Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (piperazin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (piperazin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[( R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((1S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4-((1S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-oxazol-2-yl] azetidine- 3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-oxazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-oxazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R)- 1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R ) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio -6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid,
(1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid, and
(1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio- 6-[(R) -1-hydroxyethyl] -1-methyl-carbafen-2-m-3-carboxylic acid.
[32" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to any one of claims 1 to 31, a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt thereof as an active ingredient.
[33" claim-type="Currently amended] The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is a composition for preventing or treating bacterial infection.
[34" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 31, a pharmacologically acceptable ester or salt thereof, for the manufacture of a pharmaceutical composition.
[35" claim-type="Currently amended] 35. The use according to claim 34, wherein the pharmaceutical composition is a composition for the prevention or treatment of bacterial infections.
[36" claim-type="Currently amended] 32. A method for preventing or treating a disease, wherein a pharmacologically effective amount of the compound according to any one of claims 1 to 31, a pharmacologically acceptable ester or salt thereof is administered to a warm-blooded animal.
[37" claim-type="Currently amended] The method of claim 36, wherein the disease is bacterial infection.
[38" claim-type="Currently amended] 38. The method of claim 36 or 37, wherein the warm-blooded animal is a human.

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同族专利:

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CN1486317A|2004-03-31|

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HU0303204A3|2010-04-28|

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IL155931D0|2003-12-23|

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US7001897B2|2006-02-21|

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CZ20031325A3|2003-10-15|

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NZ525934A|2004-09-24|

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CN1289498C|2006-12-13|

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AU1521202A|2002-05-27|

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US20040014962A1|2004-01-22|

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MXPA03004372A|2003-08-19|

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ES2273902T3|2007-05-16|

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CA2429346A1|2002-05-23|

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CZ300137B6|2009-02-18|

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ZA200303796B|2004-08-16|

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SK5982003A3|2004-05-04|

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KR100832287B1|2008-05-26|

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TWI242013B|2005-10-21|

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EP1340757A1|2003-09-03|

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DE60123827T2|2007-05-31|

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BR0115454A|2003-09-23|

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HU0303204A2|2003-12-29|

---

NO20032198L|2003-07-16|

---

DK1340757T3|2007-02-12|

---

RU2247725C2|2005-03-10|

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AU2002215212B2|2004-10-14|

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EP1340757A4|2005-01-26|

---

EP1340757B1|2006-10-11|

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PL362132A1|2004-10-18|

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WO2002040483A1|2002-05-23|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-11-16|Priority to JPJP-P-2000-00350063

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2000-11-16|Priority to JP2000350063

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2001-11-14|Application filed by 상꾜 가부시키가이샤

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2001-11-14|Priority to PCT/JP2001/009960

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2003-06-18|Publication of KR20030048151A

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2008-05-26|Application granted

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2008-05-26|Publication of KR100832287B1

优先权:

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申请号 | 申请日 | 专利标题

---

JPJP-P-2000-00350063|2000-11-16|

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JP2000350063|2000-11-16|

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PCT/JP2001/009960|WO2002040483A1|2000-11-16|2001-11-14|1-methylcarbapenem derivatives|