Processes for preparation of bicyclic compounds and intermediates therefor

专利摘要:
The present invention provides a method for producing an intermediate compound (VII), compound (VII), and compound (XIV), which are the starting materials for the synthesis of an antimicrobial compound, from compound (I) or compound (VII) via compound (II) and its It relates to novel compounds useful in the process.
公开号:KR20030031967A
申请号:KR10-2003-7001874
申请日:2001-08-07
公开日:2003-04-23
发明作者:나카야마게이지；무토마코토；사이토다쓰루；다니유이치로；아키바도시후미
申请人:다이이찌 세이야꾸 가부시기가이샤；
IPC主号:

专利说明:

Processes for preparation of bicyclic compounds and intermediates therefor
[2] Compounds of the general formula (VIII) (amino substituted azaspiroalkanes) are conventionally synthesized through a multi-step manufacturing process using ethyl acetoacetate as a starting material (Japanese Patent Laid-Open No. 2-231475).
[3]
[4] In Formula VII above,
[5] n represents the integer of 2-5.
[6] In addition, a colony compound consisting of a single isomer of such a compound converts the racemate of the compound into a diastereomer mixture having an optically active protecting group from which the required isomers are separated by preparative high performance liquid chromatography. After separation, it is obtained by deprotection (Japanese Patent Laid-Open No. 3-95176). However, such a method is complicated to operate, and there is room for improvement as an industrial manufacturing method.
[7] In addition, although a production method using the Strecker reaction or the Dieckmann reaction has been developed, conventional production methods using these have problems such as a long reaction process and difficulty in synthesizing the subsidiary agent. It was not a satisfying way.
[8] It is an object of the present invention to provide a process for producing an amino substituted nitrogen containing heterocyclic compound having a spiro cyclic structure, in particular an optically active amino substituted azaspiro [2.4] heptane derivative, conveniently and industrially advantageously in a single process. To provide.
[9] Disclosure of the Invention
[10] In view of the above circumstances, the present inventors earnestly studied, and the following chemical formula Compounds of (I, in particular, known compounds of which n is 2) can be obtained easily and in high yield, compounds in which one aldehyde group is selectively acetalized to a aldehyde group. It has been found that it can be easily converted to the compound of formula II.
[11]
[12]
[13] The inventors have also found that compounds of formula (II) can be readily obtained by oxidizing and acetalizing compounds of formula (XI), which can be readily converted from compounds of formula (X).
[14]
[15]
[16] In addition, the inventors have found a method for obtaining the compound of the formula VIII from the compound of the formula III obtained by reducing such a compound of the formula II, and the compound of the formula VII.
[17]
[18]
[19] Formula VIII
[20]
[21] In addition, a method of simply converting the protecting group of the amino group of the compound of the formula (VII) to another is found.
[22] On the other hand, in the compound of the formula (II), since the carbon atom to which the amino group is bonded is a subsidiary carbon, diastereomers exist when the substituent R ¹ is a group containing an subsidiary. The present inventors have found that when the compound of formula (II) which is such a diastereomer is produced, a bias occurs in the production rate of the diastereomer, and one diastereomer is obtained superior to the other. Therefore, it was found that by using this, the necessary stereoisomer can be obtained in an advantage.
[23] In addition, the inventors of the present invention show that the diastereomer mixture of the compound of the formula (II) is subjected to heat treatment, in particular, epimerization of one diastereomer by heating in a proton solvent, and the other diastereomer. It has also been found that mixtures can be obtained in which the isomers dominate. That is, such isomerization can also convert unnecessary stereo compounds into necessary stereo compounds, and it is possible to efficiently acquire the required stereoisomers.
[24] This invention is completed based on this knowledge.
[25] That is, this invention relates to the following manufacturing methods.
[26] As a method for preparing a compound of Formula (VIII), a salt thereof, or a hydrate thereof, a compound of Formula (II) is obtained by any one of Step A and Step B shown below, and the cyano group of this compound is reduced to give Formula (III). To obtain a compound of formula III-ALD, which is intramolecularly closed under neutral or basic conditions to give a compound of formula IV; The compound is reduced to give a compound of formula VII, wherein if R ¹ of this compound is not a hydrogen atom, the process comprises the steps of converting R ¹ to a hydrogen atom.
[27] Process A:
[28] Chemical formula Reacting acetalizing agent in the presence of an acid catalyst in the presence of an additive, if desired, to give a compound of formula I, and reacting this compound with a compound of formula VI or a salt thereof and a cyanoating agent;
[29] Process B:
[30] Reacting a compound of formula X with a compound of formula VI or a salt thereof and a cyanoating agent to give a compound of formula XI and oxidizing the compound to give a compound of formula II-ALD, wherein the compound is an acid catalyst The acetalizing agent in the presence of is reacted in the presence of an additive as desired.
[31] Formula VIII
[32]
[33] Formula II
[34]
[35] Formula III
[36]
[37]
[38] Formula IV
[39]
[40]
[41] Formula I
[42]
[43] H ₂ NR ¹
[44] Formula X
[45]
[46] Formula XI
[47]
[48]
[49] In each formula above,
[50] n represents an integer from 2 to 5,
[51] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[52] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be;
[53] The above production method wherein the process for preparing the compound of Formula II is Process A;
[54] The above process for preparing the compound of Formula II is Process B;
[55] The above production method wherein the reduction of the cyano group is a reduction using a catalytic hydrogenation reaction or a metal hydride;
[56] The above production method wherein the reduction of the cyano group is reduction using a catalytic hydrogenation reaction;
[57] The above production method wherein the acid catalyst is hydrochloric acid;
[58] The above production method, wherein the ring closure reaction is a ring closure reaction carried out under neutral or basic conditions;
[59] The above production method wherein R ² and R ³ are an alkoxy group having 1 to 4 carbon atoms;
[60] The above production method wherein R ² and R ³ are an ethoxy group;
[61] The above production method wherein the reduction of the compound of formula IV is a reduction using catalytic hydrogenation or metal hydride;
[62] The above production method wherein the reduction of the compound of formula IV is a catalytic hydrogenation reaction;
[63] The above production method wherein the catalyst is Raney nickel or Raney cobalt;
[64] Reacting a compound of formula (I) with a compound of formula (VI) or a salt thereof and a cyanoating agent to give a compound of formula (II) and reducing the cyano group of such compound to give a compound of formula (III) Hydrolysis in the presence of a catalyst to give a compound of formula III-ALD, which compound is intramolecularly closed under neutral or basic conditions to give a compound of formula IV, which is reduced to give a compound of formula VII obtained, and, when R ¹ is of such a compound other than a hydrogen atom, method of producing the compound or its salt of the formula VIII, characterized by an R ¹ Sikkim hydrogen atom conversion.
[65] Formula I
[66]
[67] Formula VI
[68] H ₂ NR ¹
[69] Formula II
[70]
[71] Formula III
[72]
[73] Formula III-ALD
[74]
[75] Formula IV
[76]
[77] Formula VII
[78]
[79] Formula VIII
[80]
[81] In each formula above,
[82] n represents an integer from 2 to 5,
[83] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[84] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be;
[85] The above production method wherein the compound of formula I is a compound of formula I-R;
[86]
[87] In Formula I-R above,
[88] R represents an alkoxy group having 1 to 4 carbon atoms,
[89] n represents the integer of 2-5.
[90] The compound of formula IR, The above production method wherein the compound obtained by reacting an acetalizing agent in the presence of an acid catalyst with a compound of the present invention wherein n represents an integer of 2 to 5 in the presence of an additive as desired;
[91] The compound of formula IR, A compound obtained by reacting a compound of formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst to a compound of wherein n represents an integer of 2 to 5 Phosphorus preparation method above;
[92] The above additive method is a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, or a dehydrating agent;
[93] The compound of formula IR, Compound obtained by reacting a compound of formula HR, wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst and an additive dehydrating agent, wherein n represents an integer of 2 to 5 Phosphorus preparation method above;
[94] Said manufacturing method whose dehydrating agent is an anhydride of an inorganic salt;
[95] The above production method wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate;
[96] The compound of formula IR, In a compound of formula (H), in the presence of a catalytic amount of a compound of formula HC (R) _{3 which} is an acid catalyst and an additive, wherein R represents an alkoxy group having 1 to 4 carbon atoms, wherein R is a compound having 1 to 4 carbon atoms. The aforesaid production method which is a compound obtained by reacting an alkoxy group of;
[97] The above production method wherein the acid catalyst is a sulfonic acid compound;
[98] The above production method wherein R is an ethoxy group;
[99] The above production method wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin;
[100] The above production method wherein the cyanoating agent is hydrogen cyanide;
[101] The above production method wherein the cyanoating agent is acetone cyanhydrin;
[102] The above production method wherein the reduction of the cyano group of the compound of the formula (II) is reduction by catalytic hydrogenation;
[103] The above production method wherein the reduction of the compound of formula IV is reduction by addition of a metal hydride compound or catalytic hydrogen;
[104] Chemical formula A process for the preparation of compounds of formula (I), characterized in that the acetalizing agent is reacted in the presence of an acid catalyst with a compound of the formula wherein n represents an integer of from 2 to 5.
[105] Formula I
[106]
[107] In Formula I above,
[108] n represents an integer from 2 to 5,
[109] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[110] R ² and R ³ , each independently, the above production method wherein alkoxy group having 1 to 4 carbon atoms;
[111] The compound of formula (I) Is a compound obtained by reacting a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst. The above production method;
[112] The above additive method is a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, or a dehydrating agent;
[113] The compound of formula (I) Compound obtained by reacting a compound of formula HR, wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst and an additive dehydrating agent to a compound of wherein n represents an integer of 2 to 5 Phosphorus preparation method above;
[114] The said manufacturing method whose dehydrating agent is an anhydride of an inorganic base;
[115] The above production method wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate;
[116] The compound of formula (I) In the presence of a catalytic amount of a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, which is an acid catalyst and an additive to the compound of The aforesaid production method which is a compound obtained by reacting alkoxy group);
[117] The above production method wherein the acid catalyst is a sulfonic acid compound;
[118] The above production method wherein R is an ethoxy group;
[119] A process for preparing a compound of formula (II) characterized by reacting a compound of formula (VI) or a salt thereof and a cyanoating agent.
[120] Formula I
[121]
[122] Formula VI
[123] H ₂ NR ¹
[124] Formula II
[125]
[126] In the above formulas (I), (VI) and (II),
[127] n represents an integer from 2 to 5,
[128] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[129] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[130] The above production method wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin;
[131] The above production method wherein the cyanoating agent is hydrogen cyanide;
[132] The above production method wherein the cyanoating agent is acetone cyanhydrin;
[133] Reacting a compound of formula X with a compound of formula VI or a salt thereof and a cyanoating agent to give a compound of formula XI and oxidizing the compound to yield a compound of formula II-ALD, wherein the compound is an acid catalyst Acetalizing agent is reacted in the presence of an additive in the presence of an additive as desired.
[134] Formula X
[135]
[136] Formula VI
[137] H ₂ NR ¹
[138] Formula XI
[139]
[140] Formula II-ALD
[141]
[142] Formula II
[143]
[144] In the above formulas II, II-ALD, VI, X and XI,
[145] n represents an integer from 2 to 5,
[146] R ¹ is a hydrogen atom or a chemical formula [Wherein each independently, R ^a , R ^b and R ^c are a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen At least one group selected from the group consisting of atoms and nitro groups may be substituted), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[147] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[148] The above oxidizing agent is a Collins reagent, pyridinium chlorochromate, pyridinium 2-chromate, Dess-Martin, or pyriodinane;
[149] The above production method wherein the oxidant is pyridinium chlorochromate;
[150] The process of formula II is a compound of formula II-R.
[151]
[152] In Formula II-R above,
[153] n represents an integer from 2 to 5,
[154] R ¹ is a hydrogen atom or a chemical formula [Wherein each independently, R ^a , R ^b and R ^c are a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen At least one group selected from the group consisting of atoms and nitro groups may be substituted), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[155] R represents an alkoxy group having 1 to 4 carbon atoms;
[156] The compound of formula II-R is a compound obtained by reacting a compound of formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst to the compound of formula II-ALD The above production method;
[157] Formula II-ALD
[158]
[159] The above production method wherein R is an ethoxy group;
[160] The above production method wherein the acid catalyst is a sulfonic acid compound;
[161] The above production method wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin;
[162] The above production method wherein the cyanoating agent is hydrogen cyanide;
[163] R ¹ is [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, Or at least one group selected from the group consisting of a halogen atom and a nitro group as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[164] A process for preparing a compound of formula III, characterized by reducing the cyano group of the compound of formula II or a salt thereof.
[165] Formula II
[166]
[167] Formula III
[168]
[169] In the above formulas II and III,
[170] n represents an integer from 2 to 5,
[171] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[172] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[173] The above production method wherein reduction is reduction using catalytic hydrogenation or metal hydride;
[174] The above production method wherein reduction is reduction using catalytic hydrogenation reaction;
[175] The above process wherein the compound of formula III is stereochemically a single compound;
[176] The compound of formula III is The above-mentioned preparation method which is a compound of the stereo configuration of (wherein the definitions of n, R ¹ , R ² and R ³ are as defined above, respectively);
[177] A process for the preparation of a compound of formula IV, characterized in that the compound of formula III or a salt thereof is closed.
[178] Formula III
[179]
[180] Formula IV
[181]
[182] In the above formulas III and IV,
[183] n represents an integer from 2 to 5,
[184] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[185] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[186] A process for producing a compound of formula (III), wherein the compound is hydrolyzed in the presence of an acid catalyst, thereby closing the resulting hydrolysis product.
[187] The above production method wherein the hydrolysis product is a compound of Formula III-ALD.
[188] Formula III-ALD
[189]
[190] In the above formula III-ALD,
[191] n represents an integer from 2 to 5,
[192] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[193] The above production method wherein the acid catalyst is hydrochloric acid;
[194] The above production method, wherein the ring closure reaction is a ring closure reaction carried out under neutral or basic conditions;
[195] The above process wherein the compound of formula IV is a stereochemically single compound;
[196] The compound of formula IV is The preparation method described above, wherein the steric configuration of is a compound wherein n and R ¹ are as defined above;
[197] The above production method wherein R ² and R ³ are an alkoxy group having 1 to 4 carbon atoms;
[198] The above production method wherein R ² and R ³ are an ethoxy group;
[199] A process for preparing a compound of formula VII, characterized by reducing the compound of formula IV.
[200] Formula IV
[201]
[202] Formula VII
[203]
[204] In Formulas IV and VII above,
[205] n represents an integer from 2 to 5,
[206] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[207] The above production method wherein reduction is reduction using catalytic hydrogenation or metal hydride;
[208] The above production method wherein reduction is a catalytic hydrogenation reaction;
[209] The above production method wherein the catalyst is Raney nickel;
[210] The above process wherein the compound of formula VII is stereochemically a single compound;
[211] The compound of formula VII is The above production method, wherein the compound of the stereo configuration of is wherein n and R ¹ are the same as defined above, respectively;
[212] A mixture of isomers based on the subtitle of the carbon atom to which the cyano group of the compound of formula II is bonded, To treat mixtures in which isomers of (where n, R ¹ , R ² and R ³ are each as defined above) are less than the content of the other isomer and increase the content of the compound above that of the other isomer Characterized in that the method for producing an isomer mixture.
[213] Formula II
[214]
[215] In Formula II above,
[216] n represents an integer from 2 to 5,
[217] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent.), A hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[218] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[219] The above production method wherein the treatment method is heating;
[220] The above production method wherein the treatment method is heating in a polar solvent;
[221] The above production method wherein the polar solvent is an alcohol;
[222] The above production method wherein the alcohol is ethanol;
[223] Formula in a compound of Formula (II) produced by reacting a compound of Formula (I) with a compound of Formula (VI) or a salt thereof and a cyanoating agent The isomeric compound of (wherein n, R ¹ , R ² and R ³ are each as defined above) is separated and then the remaining chemical formula Isomerization of isomer compounds of wherein n, R ¹ , R ² and R ³ are each as defined above A process for the preparation of isomer compounds of wherein n, R ¹ , R ² and R ³ are as defined above;
[224] Formula I
[225]
[226] Formula VI
[227] H ₂ NR ¹
[228] Formula II
[229]
[230] In the above formulas (I), (VI) and (II),
[231] n represents an integer from 2 to 5,
[232] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[233] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; It can be shown).
[234] The above production method wherein the reaction is carried out in alcohol;
[235] The above production method wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin;
[236] The above production method wherein the cyanoating agent is hydrogen cyanide;
[237] The above production method wherein the cyanoating agent is acetone cyanhydrin;
[238] Chemical formula in the compound of formula II The above production method wherein the isomer compound (n, R ¹ , R ² and R ³ are each as defined above) is a method of depositing the isomer by adding water to the reaction mixture;
[239] Formula II
[240]
[241] In Formula II above,
[242] n, R <^1> , R <^2> and R <^3> are as defined above, respectively.
[243] Remaining chemical formula The above-mentioned production method wherein the isomerization method of the isomer compound of (wherein n, R ¹ , R ² and R ³ are the same as defined above) is isomerization by heating;
[244] n is 2, the above production method;
[245] R ^a , R ^b and R ^c are methyl, ethyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 2,4-dinitro The above method for producing a group selected from the group consisting of a phenyl group, a 3,5-dichlorophenyl group, a 3,5-dinitrophenyl group and a naphthyl group;
[246] R ^a , R ^b and R ^c are the different groups from the above production method;
[247] Substituent R ¹ is (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group, (S) -1-phenylpropyl group, (R) -1-phenyl -2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1- (1-naphthyl) ethyl group, (S) -1- (1- Naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group, (R) -1- (4-chlorophenyl) ethyl group, ( S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1- (4-nitrophenyl) ethyl group, (R) -1- (2, 4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group, (S) -1- (2,4 -Dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5- The above production method selected from the group consisting of dinitrophenyl) ethyl group and (S) -1- (3,5-dinitrophenyl) ethyl group;
[248] Said manufacturing method whose substituent R <^1> is (R) -1-phenylethyl group or (S) -1-phenylethyl group; And so on.
[249] Moreover, this invention relates to each following compounds.
[250] Compounds of formula (I).
[251] Formula I
[252]
[253] In Formula I above,
[254] n represents an integer from 2 to 5,
[255] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[256] The above compound wherein R ² and R ³ are an alkoxy group having 1 to 4 carbon atoms;
[257] The above compound wherein R ² and R ³ are an ethoxy group;
[258] Compounds of formula II, salts thereof and hydrates thereof.
[259] Formula II
[260]
[261] In Formula II above,
[262] n represents an integer from 2 to 5,
[263] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[264] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or a combination thereof, a group of the formula -O- (CH ₂ ) _m -O-, wherein m is an integer of 1 to 4 May be represented);
[265] The compound of formula II is A compound of the above configuration wherein n, R ¹ , R ² and R ³ are as defined above, a salt thereof and a hydrate thereof;
[266] Compounds of formula (II-ALD), salts thereof and hydrates thereof.
[267] Formula II-ALD
[268]
[269] In Formula II-ALD above,
[270] n represents an integer from 2 to 5,
[271] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[272] The compound of formula II-ALD is represented by A compound of the above configuration wherein n and R ¹ are each as defined above, a salt thereof and a hydrate thereof;
[273] Compounds of Formula III, salts thereof and hydrates thereof.
[274] Formula III
[275]
[276] In Formula III above,
[277] n represents an integer from 2 to 5,
[278] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group moiety includes an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of halogen atoms and nitro groups may be substituted), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[279] R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, wherein m represents an integer of 1 to 4; May be represented);
[280] The compound of formula III is A compound of the above configuration wherein n, R ¹ , R ² and R ³ are each as defined above, a salt thereof and a hydrate thereof;
[281] The above compound or a salt thereof, wherein R ² and R ³ are an ethoxy group;
[282] Compounds of Formula III-ALD, salts thereof, and hydrates thereof.
[283] Formula III-ALD
[284]
[285] In the above formula III-ALD,
[286] n represents an integer from 2 to 5,
[287] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[288] The compound of formula III-ALD is A compound of the above configuration wherein n and R ¹ are each as defined above, a salt thereof and a hydrate thereof;
[289] Compounds of formula IV, salts thereof and hydrates thereof.
[290] Formula IV
[291]
[292] In Formula IV above,
[293] n represents an integer from 2 to 5,
[294] R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[295] The compound of formula IV is A compound of the above configuration wherein n and R ¹ are each as defined above, a salt thereof and a hydrate thereof;
[296] Compounds of formula (XI), salts thereof and hydrates thereof.
[297] Formula XI
[298]
[299] In the above formula (XI),
[300] n represents an integer from 2 to 5,
[301] R ¹ is a hydrogen atom or a chemical formula [Wherein, independently of each other, R ^a , R ^b and R ^c are a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen) One or more types of groups selected from the group consisting of atoms and nitro groups may be substituted), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[302] the above compounds wherein n is 2, salts thereof, and hydrates thereof;
[303] R ¹ is [Wherein each independently, R ^a , R ^b and R ^c are a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen At least one group selected from the group consisting of atoms and nitro groups may be substituted as a substituent), a hydrogen atom or an alkyl group having 1 to 4 carbon atoms], a salt thereof and a hydrate thereof;
[304] The above compounds, salts thereof, and hydrates thereof, wherein R ^a , R ^b and R ^c are of different groups;
[305] R ^a , R ^b and R ^c are hydrogen, methyl, ethyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 2,4- The above compound, a salt thereof, and a hydrate thereof, which is a substituent selected from the group consisting of dinitrophenyl group, 3,5-dichlorophenyl group, 3,5-dinitrophenyl group, and naphthyl group;
[306] Substituent R ¹ is (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group, (S) -1-phenylpropyl group, (R) -1-phenyl -2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1- (1-naphthyl) ethyl group, (S) -1- (1- Naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group, (R) -1- (4-chlorophenyl) ethyl group, ( S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1- (4-nitrophenyl) ethyl group, (R) -1- (2, 4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group, (S) -1- (2,4 -Dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5- A compound selected from the group consisting of dinitrophenyl) ethyl group and (S) -1- (3,5-dinitrophenyl) ethyl group, salts thereof and hydrates thereof;
[307] Substituent R <^1> is a said (R) -1-phenylethyl group or (S) -1-phenylethyl group, the said compound, its salt, and its hydrate; And so on.
[308] (Embodiment of invention)
[309] EMBODIMENT OF THE INVENTION Below, this invention is demonstrated in detail. In addition, in this specification, an "optically single" or a "stereochemically single" means the compound which consists of any one of these isomers in the compound of the structure in which the some isomer exists. In addition, this includes not only no case containing other isomers, but also a chemically pure degree. That is, other isomers may be included as long as there is no influence on physical constants or physiological activities.
[310] The manufacturing method of this invention is demonstrated below.
[311] First, the manufacturing method of the compound of general formula (II) is demonstrated. Compounds of formula (II) can be prepared by two methods, process A and process B.
[312] Process A
[313] Compound of Formula (I), but Formula It can be obtained by selectively acetalizing one aldehyde group of the compound of.
[314] Formula I
[315]
[316] The compound whose n is 2 among the said dialdehyde compounds is a well-known compound (Unexamined-Japanese-Patent No. 8-133997). Selective acetalization of the present invention allows the acetalizing agent to react with the dialdehyde compound in the presence of a catalyst, in the presence of an additive as desired. As the acetalizing agent, alkyl orthoformates and alcohols can be used, and as additives, dehydrating agents such as anhydrides of inorganic salts can be used, or alkyl orthoformates themselves can be used as reaction promoters as additives.
[317] Although the catalyst used in this reaction may be an acid, any of an organic acid and an inorganic acid may be good. Examples of the inorganic acid include hydrochloric acid and sulfuric acid. Lewis acids such as aluminum chloride, zinc chloride and boron trifluoride can also be used. As an organic acid, the carboxylic acid which may have a substituent, or the sulfonic acid which may have a substituent is mentioned. As carboxylic acids which may have a substituent, trifluoroacetic acid etc. are preferable. On the other hand, as sulfonic acids which may have a substituent, aromatic sulfonic acids which may have a substituent, and aliphatic sulfonic acids which may have a substituent are mentioned. Examples of the aromatic sulfonic acid compound which may have a substituent include benzene sulfonic acid and paratoluene sulfonic acid. Examples of the aliphatic sulfonic acid compound which may have a substituent include methanesulfonic acid, trifluoromethanesulfonic acid and camphorsulfonic acid. Etc. can be mentioned. As the acid catalyst, sulfonic acid compounds are preferable. The amount used is good in the amount of catalyst.
[318] The solvent used in the present reaction is not particularly limited as long as it does not adversely affect the reaction, and any solvent may be used. For example, aromatic hydrocarbons (benzene, toluene, chlorobenzene, etc.), aliphatic hydrocarbons (pentane, hexane, cyclohexane, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2 -Dimethoxy ethane, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane) And esters (ethyl acetate etc.), acetonitrile, etc. are mentioned, In addition, ketones (acetone, methyl ethyl ketone etc.) can also be implemented.
[319] Although this reaction can be performed at the temperature of the range of about -50-100 degreeC, Preferably the range of 0-60 degreeC is favorable.
[320] Although the specific method of selective acetalization is as follows, there are two types of methods largely divided.
[321] Firstly, a dialdehyde compound and alkyl orthoformate are reacted in the presence of an acid catalyst. Alkyl orthoformates here act as acetalizing agents. As the alkyl orthoformate to be used, those having structures corresponding to the substituents R ² and R ³ of the compound of the formula (I) can be used. For example, when R ² and R ³ are methoxy groups, methyl ortho formate may be used. In the case of ethoxy groups, alkyl ortho formate may be selected as ethyl ortho formate. The amount of alkyl orthoformate to be used is preferably in the range of 1 to 2 equivalents relative to the dialdehyde compound, but is preferably in the range of 1 to 1.5 equivalents. This process is carried out in the temperature range of 0 to 30 DEG C, and the desired compound (I) (monoacetal body) can be obtained with excellent yield and selectivity. For example, in toluene, paratoluenesulfonic acid is used as a catalyst, ethyl orthoformate (1.1 equivalents) is used, and reaction with 1,1-cyclopropane dicarboaldehyde is performed. Monoacetalization (meaning that one aldehyde group of the dialdehyde compound is acetalized) proceeds.
[322] Next, a method of obtaining an acetal compound from a dialdehyde compound and an alcohol in the presence of an acid catalyst will be described. This method can achieve good yields and selectivity by performing in the presence of additives.
[323] First, the method of adding a dehydrating agent as an additive is demonstrated. Dehydrating agents remove water from acetalization and are effective at equilibrating the production of acetals.
[324] Any dehydrating agent can be used as long as it does not inhibit the reaction. For example, although anhydrides of inorganic salts can be used, those with high dehydrating ability are preferable, and anhydrous magnesium sulfate is specifically mentioned. In addition, anhydrous sodium sulfate may be used, or a molecular sieve may be used. It is good if it is in the same amount to a very excessive range to replenish the resulting water, but it is simple to use about one mole with the dialdehyde compound.
[325] The alcohol used by such a method can also use the thing corresponding to the substituent R <^2> and R <^3> of the compound of general formula (I) similarly to the above. For example, when R <^2> and R <^3> is a methoxy group, alcohol can be selected as methanol and ethanol when it is an ethoxy group. The amount of alcohol to be used is preferably in the range of 2 equivalents to a very excessive amount (can also serve as a solvent) relative to the dialdehyde compound.
[326] For example, ethanol is used as a solvent, and the reaction is carried out in the presence of anhydrous magnesium sulfate (equivalent molar amount) and a catalytic amount of paratoluenesulfonic acid to obtain the desired compound (I) with a selectivity of 9: 1.
[327] In the method for obtaining an acetal compound from a dialdehyde compound and an alcohol, excellent results can be obtained even if an alkyl orthoformate is added as an additive. In this case, it is considered that alkyl orthoformate acts as a reaction accelerator, alcohol is used stoichiometrically (or higher), and alkyl orthoformate may be added in a catalytic amount. For example, about 0.1-0.2 equivalent can be used with respect to a dialdehyde compound.
[328] The manufacturing method of the compound of general formula (I) demonstrated above is suitable for manufacture of compound (I) whose substituent R <^2> and R <^3> are the same alkoxy group. In addition, the compound whose substituent R <^2> and R <^3> is a different alkoxy group, and the compound of an alkylenedioxy group can be manufactured using the acetal exchange reaction etc. once the acetal compound of the same alkoxy group is produced. Alternatively, hemiacetal can be prepared and further obtained by reacting with another acetalizing agent.
[329] Process from compound (I) to compound (II)
[330] Next, the manufacturing method of the compound of general formula (II) is demonstrated.
[331] Formula II
[332]
[333] In order to obtain such a compound, to the compound of the formula (I), in the presence of the compound of the formula (VI) or a salt thereof, the cyanolating agent can be reacted with a so-called striker reaction.
[334] Formula VI
[335] H ₂ NR ¹
[336] In Formula VI above,
[337] R ¹ may be any substituent as already described.
[338] Acid addition salts may be mentioned as salts of the compounds of the formula (VI), and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide or nitrate. When using such a salt, it is necessary to add the base of the quantity which can make the said salt a free base separately.
[339] In addition, it is preferable that the compound of the formula (VI) is made of a compound having a subsidiary carbon, or, in the case of only one isomer of two optical isomers, that is, an optically single compound.
[340] As the compound of the formula (VI), for example, (R)-or (S) -1-phenylethylamine, (R)-or (S) -1-phenylpropylamine, (R)-or (S) -1 -Phenyl-2- (p-tolyl) ethylamine, (R)-or (S) -1- (1-naphthyl) ethylamine, (R)-or (S) -1- (4-methoxyphenyl ) Ethylamine, (R)-or (S) -1- (4-chlorophenyl) ethylamine, (R)-or (S) -1- (4-nitrophenyl) ethylamine, (R) -or ( S) -1- (2,4-dichlorophenyl) ethylamine, (R) -or (S) -1- (2,4-dinitrophenyl) ethylamine, (R) -or (S) -1- (3,5-dichlorophenyl) ethylamine, (R)-or (S) -1- (3,5-dinitrophenyl) ethylamine, etc. are mentioned.
[341] As the cyanating agent used in this step, hydrogen cyanide or a cyan compound can be used.
[342] When the reaction is performed using hydrogen cyanide, the hydrogen cyanide used may introduce gas generated outside the reaction system into the system, but may be generated directly in the reaction system. When generating in a reaction system, the salt exchange reaction in water with alkali cyanides, such as potassium cyanide, sodium cyanide, and lithium cyanide, and various acidic substances represented by hydrochloric acid can be utilized. Moreover, it can generate | occur | produce by adding a reducing agent, such as sodium hydrogen sulfite, to said alkali cyanide.
[343] Instead of hydrogen cyanide, various cyanide compounds may be used to carry out the reaction. Examples of such cyan compounds include cyanhydrin compounds such as acetone cyanhydrin and cyclohexanone cyanhydrin, organic cyanide compounds such as trimethylsilyl cyanide and diethylphosphoryl cyanide, diethylaluminum cyanide and tributyltin cyanide. And organometallic cyan compounds such as amide. Such cyan compound is advantageous as a process because the reaction proceeds by being added to the reaction mixture, which is simple and has high safety.
[344] In this reaction, any solvent may be used as long as it does not adversely affect the reaction. For example, Alcohol, such as methanol, ethanol, a propanol; Ethers such as tetrahydrofuran and dioxane; Ketones such as acetone; Nitrogen-containing solvents such as acetonitrile; Aromatic hydrocarbons such as toluene; Aliphatic hydrocarbons such as hexane and cyclohexane; Esters such as ethyl acetate; Amides such as dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as dichloromethane and chloroform; Etc. can be mentioned. Moreover, such a solvent is also good as a mixed solvent, and can be used as a water-containing solvent as needed. It is preferable to use alcohols or hydrous alcohols as the solvent.
[345] In the case of carrying out this process with hydrogen cyanide, a compound of the formula (I), a compound of the formula (VI), and a compound which is a source of hydrogen cyanide (the above-mentioned alkali cyanide, organic cyanide compound, and organometallic cyanide compound, etc.) are mixed in a solvent. In addition, it is more simple and preferable to employ | adopt the method of adding the hydrogen cyanide generator here.
[346] When this process is performed using cyan compounds, such as acetone cyanhydrin, addition of the hydrogen cyanide generator is unnecessary, and it is more simple and preferable.
[347] In any case, this step can be carried out at a temperature in the range of about -20 ° C to about 100 ° C, preferably about room temperature to the boiling point of the solvent.
[348] When the present reaction is carried out with optically single amines, the product becomes a mixture of two kinds of diastereomers, but one diastereomer is produced preferentially over the other. In other words, the reaction proceeds selectively to the diastereomer. For example, when (S) -1-phenylethylamine is used as the amine, (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl ] Amino} acetonitrile and its diastereomer (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile And its production ratio is 2: 1 (hence, when (R) -1-phenylethylamine is used, (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1R ) -1-phenylethyl] amino} acetonitrile and its diastereomer (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1R) -1-phenylethyl] amino} Mixture with acetonitrile, but its production ratio is thought to be about 1: 2).
[349] The two diastereomers obtained here can be separated by a conventional method. For example, in addition to what can be separated by crystallization (in the case of a compound to be crystallized), it can be separated using silica gel column chromatography, thin layer chromatography, high performance liquid chromatography, or the like.
[350] Unnecessary isomers of the isolated optically active agents are subjected to epimerization by treatment in polar solvents, ie, to convert the steric arrangement of the carbon atoms to which the amino and cyano groups are bonded, and to a mixture of diastereomers containing the required isomers. You can easily convert it. Then, a compound having the desired steric configuration can be separated and obtained from such a mixture.
[351] As the polar solvent to be used, any solvent can be used as long as it does not adversely affect the reaction, but is preferably a protic solvent, and alcohols such as methanol, ethanol, propanol and isopropanol can be mentioned. It is also possible to use mixed solvents of these protic solvents with other solvents. As another solvent, ethers, such as tetrahydrofuran, ketones, such as acetone, nitrogen-containing solvents, such as acetonitrile, etc. are mentioned.
[352] In addition, such epimerization can be performed by heating. Namely, if (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile was heat-treated in ethanol, it was (2S) -2. -[1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile and (2R) -2- [1- (diethoxymethyl) cyclopropyl]- 2.9: 1 mixture with 2-{[(1S) -1-naphthylethyl] amino} acetonitrile. In this manner, it is possible to easily convert to the optically active substance having the desired steric configuration.
[353] In addition, the present inventors, when one diastereomer tends to precipitate as crystals (solids), the other diastereomer is already converted into one diastereomer, thereby converting the diastereomer and performing crystallization isolation. I think whether it can be performed as a series of processes. That is, after completion of the stretcher reaction, water and the like were added to the reaction mixture in order to reduce the solubility of the solvent used, followed by heat treatment, thereby converting the crystallization and the diastereomers at once and continuously. And by this method, it was successful to obtain the desired diastereomer in high yield. That is, the precipitation of one diastereomer is promoted by lowering the solubility of the solvent of the reaction mixture, while the other diastereomer of high solubility is dissolved in the reaction solution, and this is already one diastereomer by heating. The conversion is carried out, and the resulting diastereomers are precipitated because of their low solubility, and the conversion to the diastereomers is further progressed by such precipitation.
[354] Therefore, in order to carry out this method, it is necessary to add, to the reaction mixture, a substance which reduces the solubility of the solvent used in the same reaction after the completion of the stretcher reaction. The substance for this purpose is not particularly limited as long as it is miscible with the reaction solvent and does not adversely affect the product. For example, water is mentioned as a solvent miscible with water, such as alcohol, dioxane, tetrahydrofuran, acetonitrile, acetone, and hydrocarbons, such as hexane and benzene, regarding solvent which is incompatible with water Can be mentioned. The addition amount of the solvent for decreasing solubility is good as long as unnecessary diastereomers do not precipitate.
[355] The heating temperature of such a process does not re-dissolve the precipitated crystal | crystallization, and it is good as it is a lower temperature. For example, the heating temperature of about 30-60 degreeC is favorable, More preferably, it is about 40-50 degreeC.
[356] In the compound of the formula (II), the compound in which the substituent R ¹ is, for example, alkoxycarbonyl group, aralkyloxycarbonyl group, aliphatic or aromatic acyl group, is usually used from the compound in which R ¹ is a hydrogen atom in the compound of the formula (II). It can be easily converted and obtained by the substitution reaction which takes place.
[357] Process B
[358] Process from compound (VII) to compound (XI)
[359] In order to obtain the compound of the formula (XI), to the compound of the formula (X), a cyanoating agent can be reacted in the presence of the compound of the formula (VI), and a so-called stretcher reaction can be carried out.
[360] Formula VI
[361] H ₂ NR ¹
[362] Also, among the compounds of the formula (X), compounds in which n is 2 are obtained by the methods shown in Reference Examples 2 and 3 (see Japanese Patent Application No. 2001-044405).
[363] As the cyanating agent used in this reaction, hydrogen cyanide or a cyan compound can be used.
[364] When the reaction is performed using hydrogen cyanide, any of a method of introducing gaseous hydrogen cyanide generated outside the reaction system and a method of generating hydrogen cyanide directly in the reaction system may be sufficient. When directly generated in the reaction system, a salt exchange reaction in water with alkali metal cyanide such as potassium cyanide, sodium cyanide and lithium cyanide and various acidic substances can be used. Moreover, it can generate | occur | produce by adding a reducing agent, such as sodium hydrogen sulfite, to said alkali metal cyanide.
[365] When reacting using a cyan compound, cyanhydrin compounds, such as acetone cyanhydrin, organic cyanide compounds, such as trimethylsilyl cyanide, and organometallic cyan compounds, such as diethyl aluminum cyanide, etc. are mentioned.
[366] As the compound of the formula (VI), for example, (R)-or (S) -1-phenylethylamine, (R)-or (S) -1-phenylpropylamine, (R)-or (S) -1 -Phenyl-2- (p-tolyl) ethylamine, (R)-or (S) -1- (1-naphthyl) ethylamine, (R)-or (S) -1- (4-methoxyphenyl ) Ethylamine, (R)-or (S) -1- (4-chlorophenyl) ethylamine, (R)-or (S) -1- (4-nitrophenyl) ethylamine, (R) -or ( S) -1- (2,4-dichlorophenyl) ethylamine, (R) -or (S) -1- (2,4-dinitrophenyl) ethylamine, (R) -or (S) -1- (3,5-dichlorophenyl) ethylamine, (R)-or (S) -1- (3,5-dinitrophenyl) ethylamine, etc. are mentioned.
[367] Any solvent may be used for the solvent used in this reaction as long as it does not adversely affect the reaction. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, nitrogen-containing solvents such as acetonitrile, aromatic hydrocarbons such as benzene and toluene And aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Moreover, such a solvent is good also as a mixed solvent, and also as a water-containing solvent. Of these, hydrous alcohols are preferred.
[368] In any case, the present reaction can be carried out at a temperature in the range of about -20 ° C to about 100 ° C, and a temperature of about the boiling point of the room temperature to the solvent is preferable.
[369] Process from compound (XI) to compound (II-ALD)
[370] In order to obtain a compound of formula II-ALD, an oxidizing agent can be applied to the compound of formula XI and the oxidation of the primary hydroxyl group can be stopped at the stage of the aldehyde.
[371] Any oxidizing agent used in this reaction can be used as long as it can stop the oxidation of the primary hydroxyl group in the step of aldehyde. For example, Collins reagent, pyridinium chlorochromate (PCC), pyridinium 2-chromate (PDC), des martin, pyrique dinan, etc. are mentioned. Among these, pyridinium chlorochromate is preferable. Moreover, the oxidation reaction which converts primary hydroxyl groups, such as Swern oxidation, to an aldehyde, can also be used.
[372] Any solvent may be used for the solvent used in this reaction as long as it does not adversely affect the reaction. For example, ethers, such as diethyl ether, tetrahydrofuran, dioxane, ketones, such as acetone, nitrogen-containing solvents, such as acetonitrile, aromatic hydrocarbons, such as benzene and toluene, aliphatic hydrocarbons, such as hexane and cyclohexane And esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. Of these, halogenated hydrocarbons are preferred, and dichloromethane is particularly preferred.
[373] Although this reaction changes with oxidation reaction conditions, it can carry out at the temperature of the range of about -78 degreeC-the boiling point of a solvent.
[374] Process from compound (II-ALD) to compound (II)
[375] To obtain the compound of formula II, the compound of formula II-ALD can be acetalized by the addition of alcohol as desired, with the action of alkyl orthoformate, in the presence of an acid catalyst.
[376] As the alkyl orthoformate, one having an alkyl moiety having a structure corresponding to the substituents R ² and R ³ of the compound of the formula (II) can be used. For example, alkyl orthoformate can be selected as methyl when R ² and R ³ are methoxy groups and ethyl when ethoxy groups. When the alcohol is added, the same alcohol as that of the alkyl orthoformate can be used. In the case of methyl orthoformate, methyl alcohol and ethyl ortho formate can be selected as ethyl alcohol.
[377] The acid catalyst used in this reaction may be any of an organic acid and an inorganic acid. Examples of the organic acid include carboxylic acids such as acetic acid and trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid. Examples of the inorganic acid include hydrochloric acid and sulfuric acid, and Lewis acids such as titanium tetrachloride and boron trifluoride can also be used. Among these, p-toluenesulfonic acid is preferable. The amount of acid may be sufficient as the amount of the catalyst, and preferably in the range of 1/10 to 1/100 mol relative to the compound II-ALD.
[378] Any solvent may be used for the solvent used in this reaction as long as it does not adversely affect the reaction. For example, ethers, such as diethyl ether, tetrahydrofuran, dioxane, ketones, such as acetone, nitrogen-containing solvents, such as acetonitrile, aromatic hydrocarbons, such as benzene and toluene, aliphatic hydrocarbons, such as hexane and cyclohexane And esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform.
[379] In any case, the present reaction can be carried out at a temperature in the range of room temperature to about 100 ° C.
[380] The manufacturing method of the compound of general formula (II) demonstrated above is suitable for manufacture of compound (II) whose substituents R <^2> and R <^3> are the same alkoxy group. In addition, the compound whose substituents R <^2> and R <^3> are another alkoxy group, and the compound of an alkylenedioxy group can be manufactured using the acetal exchange reaction etc. once the acetal compound of the same alkoxy group is produced. Alternatively, hemiacetal can be prepared and obtained by reacting with another acetalizing agent.
[381] Process from compound (II) to compound (III)
[382] Next, a method for producing the compound of the formula (III) from the compound of the formula (II) is described.
[383] Formula III
[384]
[385] The preparation of such a compound can be carried out by reducing the cyano group of the compound of the formula (II). This reduction can be carried out by a catalytic hydrogenation reaction in a hydrogen atmosphere in the presence of a catalyst, and any reaction can be applied as long as it is inert to R ¹ and the cyano group can be reduced to an aminomethyl group. Examples of the catalyst for the catalytic hydrogenation reaction include palladium-carbon, palladium hydroxide, Raney nickel, Raney cobalt, and the like, and Raney nickel or Raney cobalt is particularly preferable.
[386] The solvent for such a reaction is not particularly limited as long as it does not adversely affect the reaction, and any solvent can be used, but preferably alcohols such as methanol, ethanol, propanol, isopropanol, and ethers such as 1,4-dioxane Etc. can be mentioned. Such a solvent is also suitable as a solvent in which an alkali component, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, or ammonia is dissolved. In this case the solvent can be mixed with water. The solvent containing ammonia can be manufactured by dissolving ammonia gas or mixing ammonia water.
[387] Although reaction of catalytic hydrogenation can be performed at the temperature of the range of 0 degreeC-50 degreeC, Preferably it is about 5 degreeC-about room temperature. The pressure of the hydrogen gas at the time of contact hydrogenation should just be a range of normal pressure-100 atmospheres. In addition, when the catalytic hydrogenation reaction is performed at about room temperature, it may be necessary to continuously heat the ring-closing reaction by heating it at about 50 ° C to 180 ° C.
[388] In addition, the compound of formula III can be obtained by hydride reduction of the compound of formula II. Lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum, sodium cyanoborohydride, and sodium borohydride can be used for hydride reduction according to the method performed normally.
[389] Process from compound (III) to compound (IV)
[390] Next, a method for preparing the compound of formula IV from the compound of formula III is described.
[391] Formula IV
[392]
[393] The preparation of such compounds can be carried out by removing the acetals of the compounds of formula III, leading to the aldehydes of formula III-ALD, and then ring closure.
[394] Formula III-ALD
[395]
[396] Removal of this acetal can be carried out by acting water in the presence of an acid. The acid used here may be any of an organic acid or an inorganic acid, but hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, acetic acid and the like can be used.
[397] The removal of acetal is usually carried out in the presence of a solvent, but this is not particularly limited and may be used as long as it does not adversely affect the reaction. As the solvent, it is preferable to use water or a solvent miscible with water. Examples of the solvent miscible with water include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and nitrogen-containing solvents of acetonitrile. have.
[398] Although such reaction can be performed in the range of -50 degreeC-the boiling point of a solvent, the temperature of the range of about 0 degreeC-about room temperature is preferable.
[399] Next, it is a ring closure of the deacetalized compound, which can be carried out under neutral or basic conditions. The ring closure reaction proceeds even if the reaction solution after deacetalization is neutralized or made basic. In addition, after neutralization, after extraction with a solvent or the like, it can be performed in the presence of a dehydrating agent. The solvent that can be used in the ring-closing step can be used without particular limitation so long as it does not adversely affect the reaction, but for example, aromatic hydrocarbons, aliphatic hydrocarbons, ethers, amides, halogenated hydrocarbons, acetonitrile, acetone, Ethyl acetate and the like can be used. Although ring-closure reaction can be performed in the range of -50 degreeC-the boiling point of a solvent, the temperature of the range of about 0 degreeC-about room temperature is preferable.
[400] Process from compound (IV) to compound (iii)
[401] Next, a method for preparing the compound of formula VII from the compound of formula IV is described.
[402] Formula VII
[403]
[404] Such compounds may be carried out by contact hydrogenation or hydride reduction of the compound of formula IV.
[405] In the catalytic hydrogenation reaction, palladium-carbon, palladium hydroxide, Raney nickel, Raney cobalt and the like can be used as its catalyst, but Raney nickel or Raney cobalt is particularly preferable. Moreover, as a hydride reducing agent, metal aluminum hydride compounds, such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium cyanoborohydride, and sodium borohydride, or a metal borohydride compound Can be mentioned. In these, a metal boron hydride compound is preferable and sodium cyanoborohydride is especially preferable.
[406] Any solvent may be used as long as the solvent of such a reaction does not adversely affect the reaction. Preferably, alcohols such as methanol, ethanol, propanol, isopropanol, and ethers such as tetrahydrofuran are mentioned. Moreover, it can carry out by adding water to such a solvent.
[407] The present reaction can be carried out at a temperature in the range of -50 ° C to 100 ° C, but is preferably in the range of 0 ° C to room temperature. In addition, the pressure of the hydrogen gas at the time of contact hydrogenation can be implemented in 1 atmosphere-100 atmospheres.
[408] Process from compound (iv) to compound (iv)
[409] The compound of the formula (VIII) can be prepared by converting R ¹ (excluding hydrogen atoms) of the compound of the formula (VII) to a hydrogen atom by applying a conventional method such as catalytic hydrogenolysis.
[410] Formula VIII
[411]
[412] For example, when using a catalytic hydrogenolysis reaction, palladium-carbon, palladium hydroxide, Raney nickel, etc. can be used as a catalyst, but palladium-carbon, palladium hydroxide is especially preferable. Any solvent may be used as long as the solvent of such a reaction does not adversely affect the reaction. Preferably, alcohols such as methanol, ethanol, propanol, isopropanol, and ethers such as tetrahydrofuran are mentioned. Moreover, it can carry out by adding water to these solvents. In addition, depending on a case, it may carry out by adding acids, such as an acetic acid and hydrochloric acid.
[413] Although this reaction can be implemented in the range of 0 degreeC-100 degreeC, Preferably it is the range of 5 degreeC-50 degreeC. Moreover, although the pressure of the hydrogen gas of this reaction may be in the range of 1 atmosphere-100 atmospheres, it is preferable that it is the range of 1 atmosphere-50 atmospheres.
[414] The compound of the general formula (VIII) obtained by the production method of the present invention can be derived as an excellent antibacterial agent by the methods described in Japanese Patent Application Laid-Open Nos. Hei 2-231475 and Hei 3-95176.
[415] Process from compound (iii) to compound (XII)
[416] The preparation of the compound of the formula XII from the compound of the formula VII is described.
[417]
[418] That is, the acylation, alkoxycarbonylation, aralkylation, etc. can be performed for the amino group which comprises the pyrrolidine ring of the compound of general formula (VII). By such reaction, a substituent can be introduce | transduced into an amino group and an amino group can be protected. R ⁴ is preferably a group different from R ¹ , in particular, a group which can be removed under different conditions.
[419] Examples of the acylating agent used in the acylation reaction include acid anhydrides and acid halides. Examples of the acid anhydrides include acetic anhydride, trifluoroacetic anhydride, phenylacetic anhydride, propionic anhydride, and benzoic anhydride. As acid halide, acetyl chloride, acetyl bromide, propionyl chloride, benzoyl chloride, etc. can be illustrated. Examples of the alkoxycarbonylation reagent include di-tert-butyl dicarbonate, and examples of the aralkyloxycarbonylation reaction agent include benzyloxycarbonyl chloride. Examples of the aralkylation reaction agent include benzyl chloride and benzyl. Bromide and the like.
[420] The amount of the reaction agent for introducing the protecting group is preferably in the range of 1 equivalent to very excess relative to compound (VII), suitably in the range of 1 equivalent to 2 equivalents, and at least 1 equivalent of triethylamine, pyridine, or the like. It is preferable to use together tertiary amine and nitrogen-containing heterocyclic compound.
[421] The solvent used in the present reaction may be any solvent, so long as it does not adversely affect the reaction, for example, aromatic hydrocarbons, aliphatic hydrocarbons, ethers, amides, halogenated hydrocarbons, acetonitrile, Acetone, ethyl acetate and the like can be used.
[422] Although this reaction can be performed at a temperature of about -50-100 degreeC, Preferably it is the range of -20 degreeC-room temperature.
[423] Process from compound (XII) to compound (XII-a)
[424] Next, the manufacturing method of the compound of general formula (XII-a) is demonstrated.
[425]
[426] Such compounds may be prepared by removing R ¹ by, for example, catalytic hydrogenolysis of the compound of formula (XII).
[427] In the case of using a catalytic hydrogenolysis reaction, palladium-carbon, palladium hydroxide, Raney nickel and the like can be used as its catalyst, but palladium-carbon and palladium hydroxide are particularly preferable.
[428] Any solvent may be used as long as the solvent used in such a reaction does not adversely affect the reaction. Preferably, alcohols, such as methanol, ethanol, propanol, isopropanol, and ethers, such as tetrahydrofuran, are mentioned. Moreover, it can carry out by adding water to these solvents. In addition, depending on a case, it may carry out by adding acids, such as an acetic acid and hydrochloric acid.
[429] Although this reaction can be implemented in the range of 0-100 degreeC, Preferably it is the range of the boiling point grade of a room temperature to a solvent. In addition, although this reaction is performed in hydrogen gas atmosphere, the pressure should just be in the range of 1 atmosphere-100 atmospheres, Preferably it is the range of 1 atmosphere-50 atmospheres.
[430] Process from compound (XII-a) to compound (XIII)
[431] Next, a method for producing the compound of formula XIII is described.
[432]
[433] Such a compound can be obtained by converting the primary amino group of the compound of the formula (XII-a) into an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aliphatic or an aromatic acyl group by a commonly used substitution reaction. At this time, R ⁵ is preferably a group which is removed by a group different from R ⁴ , in particular, by other reaction conditions.
[434] Di-tert-butyl dicarbonate etc. are mentioned as an alkoxycarbonylation reaction agent, Benzyloxycarbonyl chloride etc. are mentioned as an aralkyloxycarbonylation reaction agent, As an acylating agent, acetic anhydride and trifluoroacetic anhydride are mentioned. , Phenylacetic anhydride, propionic anhydride, benzoic anhydride, acetyl chloride, acetyl bromide, propionyl chloride, benzoyl chloride, and the like, and benzyl chloride, benzyl bromide and the like as the aralkylation reagent.
[435] The amount of the reactant is preferably in the range of 1 equivalent to very excess relative to compound (XII-a). For example, it is preferable to use a tertiary amine such as triethylamine or pyridine or a nitrogen-containing heterocyclic compound in combination. Do.
[436] In this reaction, any solvent can be used as long as it does not adversely affect the reaction, for example, alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, Nitrogen-containing solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene, aliphatic hydrocarbon solvents such as hexane, esters such as ethyl acetate, amides such as dimethylformamide, halogenated hydrocarbon solvents such as dichloromethane, etc. Can be mentioned. Moreover, such a solvent is used as a water-containing solvent as needed.
[437] The present reaction is carried out at a temperature of about -20 deg. C to about 100 deg. C, preferably at room temperature to the boiling point of the solvent.
[438] Process from compound (XIII) to compound (XIV)
[439] Next, a method for producing the compound of formula XIV is described.
[440]
[441] Such a compound can be obtained by deprotecting R ⁴ from a compound of the formula (XIII). For example, when R ⁴ is an acyl group or an alkoxycarbonyl group, it is hydrolysis, and an aralkyl group or an aralkyloxycarbonyl group. The deprotection can be carried out by hydrogenolysis.
[442] The solvent used for the deprotection reaction can be used as long as it does not adversely affect the reaction, alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, Nitrogen-containing solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene, aliphatic hydrocarbon solvents such as hexane, esters such as ethyl acetate, amides such as dimethylformamide, halogenated hydrocarbon solvents such as dichloromethane, etc. Can be used. In addition, such a solvent is used as a water-soluble solvent as needed. Examples of the solvent miscible with water include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and nitrogen-containing solvents such as acetonitrile.
[443] Although this reaction can be implemented in the range of -50 degreeC-100 degreeC, the temperature of the range of about 0 degreeC-the boiling point of a solvent is preferable.
[444] The compound of the general formula (XIV) obtained here can be derived as an excellent antibacterial agent by the methods described in Japanese Patent Laid-Open Nos. Hei 2-231475 and Hei 3-95176.
[445] Below, the compound of this invention is demonstrated.
[446] Compounds of formula (I) have n of an integer from 2 to 5.
[447] Formula I
[448]
[449] Substituents R ² and R ³ may be a lower alkoxy group having 1 to 4 carbon atoms, or they may together be a methylenedioxy group or a polymethylenedioxy group (alkylenedioxy group). When the substituents R ² and R ³ are alkoxy groups, both may be the same or different, and any of linear or branched chains may be preferable. As R <^2> and R <^3> , it is preferable that it is an alkoxy group, and a methoxy group, an ethoxy group, and a propoxy group are favorable. Moreover, among these, an ethoxy group is the most preferable. Moreover, it is preferable that both are an ethoxy group from the viewpoint of the simplicity of manufacture.
[450] The compound of the formula (I) is a compound of a structure in which one aldehyde group of a gem-dialdehyde compound is selectively acetalized, and one of the characteristics of the present invention is to achieve selective acetalization of one aldehyde group in a dialdehyde compound. In addition, a monoacetal compound (meaning a compound in which one aldehyde group is acetalized in a dialdehyde compound) can be easily obtained.
[451] Compounds of formula (II) of the present invention represent integers where n is 2-5.
[452] Formula II
[453]
[454] Substituent R ¹ is a hydrogen atom or a chemical formula [Wherein, R ^a , R ^b and R ^c each independently represent a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[455] Substituent R ¹ is of the formula In the case of, the group does not change even in the reaction for converting the cyano group of the compound of the formula (II) to an aminomethyl group, and any group can be used as long as it can protect the amino group.
[456] In connection with the substituent R ¹ , the inventors have found that it is preferred that the compound of formula (II) is a compound of the structure in which the diastereomer is present to obtain the isomer of the desired stereoconfiguration. In the compound of the formula (II), since the carbon atom to which the amino group binds is a subtitle carbon, when the substituent R ¹ is a substituent containing the subtitle carbon, the compound of the formula (II) has a diastereomer. And when preparing the compound of Formula (II) which is a diastereomer, this inventor discovered that the formation rate of the two types of diastereoisomers generate | occur | produces, and one diastereomer is obtained superior to the other. . In this case, the control is possible by which the three-dimensional structure of the part of the substituents R ¹ Is a stereoisomeric the advantage, i.e. it is possible to change the structure of the substituent R ¹ produce the desired diastereomer as a lead.
[457] In addition, it has been found that the diastereomeric mixture of the compound of the formula (II) is subjected to heat treatment to change the proportion of the diastereomer present. That is, the present inventors can also produce epimerization of one diastereomer, conversion to the other diastereomer by heat treatment, and obtain a mixture in which the proportion of one diastereomer is increased. It is revealed. In the same manner as described above, which diastereomer is superior in this case can be controlled by changing the structure of the substituent R ¹ . That is, by using such a characteristic, the unnecessary stereoconfiguration can be converted into the required stereoconfiguration, and the isomer of the necessary stereoconfiguration can be obtained efficiently. As mentioned above, as substituent R <^1> , it is preferable that R ^<a> , R <^b> and R <^c> are respectively different.
[458] Specifically, as R ^a , R ^b and R ^c , a hydrogen atom, a methyl group, an ethyl group, a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, 2,4-dichlorophenyl group And 2,4-dinitrophenyl group, 3,5-dichlorophenyl group, 3,5-dinitrophenyl group and naphthyl group.
[459] Moreover, although a methyl group, a methoxy group, a nitro group, and a chlorine atom are mentioned as a specific example of a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogen atom, and a nitro group which are substituents on an aryl group, One or two or more of these may be substituted with one or two or more.
[460] Examples of the substituent R ^{1 in which} R ^a , R ^b and R ^c are different from each other include (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group, and (S) -1- Phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1- (1-naphthyl) Ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group, (R)- 1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1- (4-nitrophenyl) Ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group , (S) -1- (2,4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5-dinitrophenyl) ethyl group or (S) -1- (3,5-dinitrophenyl) ethyl group is mentioned. Among these, as a particularly preferable thing, (R) -1-phenylethyl group or (S) -1-phenylethyl group is mentioned.
[461] The substituent R ¹ may be a protecting group of an amino group, and in this case, it is preferable that the substituent R ¹ does not change even in a reaction for converting the cyano group of the compound of formula II to an aminomethyl group. As a protecting group of such an amino group, the alkoxycarbonyl groups which may have substituents, such as a tert-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxy, for example Aralkyloxycarbonyl groups which may have substituents such as benzyloxycarbonyl group and paranitrobenzyloxycarbonyl group; Aliphatic or aromatic acyl groups which may have substituents such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group and benzoyl group; And aralkyl groups which may have substituents such as a benzyl group, a paranitrobenzyl group, a paramethoxybenzyl group, and a triphenylmethyl group.
[462] Among these protecting groups, aralkyl groups are preferable in view of ease of production. Moreover, a benzyl group is preferable also in an aralkyl group. The phenyl group of such benzyl group may also have a substituent, for example, one or more groups selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom and a nitro group are substituted with at least one group. Can be. Specifically, except for the benzyl group, 4-methoxybenzyl group, 4-chlorobenzyl group, 4-nitrobenzyl group, 2,4-dichlorobenzyl group, 2,4-dinitrobenzyl group, 3,5-dichlorobenzyl group And 3,5-dinitrobenzyl groups.
[463] Among the compounds of the formula (II), the compound whose amino group is the preferred stereoconfiguration is It is a compound shown.
[464] When the compound of formula (II) is an acid addition salt, the acid forming the salt is not particularly limited as long as it does not affect the stability of the compound itself. Such acid may be any of inorganic and organic acids. As a salt with an inorganic acid, hydrochloride, hydrobromide, nitrate, phosphate, a perchlorate, etc. are mentioned, for example, As a salt with an organic acid, a salt with a carboxylic acid compound or a sulfonic acid compound is mentioned. Examples of the carboxylate include acetate, fumarate, lactate, and the like. As sulfonates, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate, and the like can be given. Such salts may also be hydrates. In addition, it is good to think about formation of a salt similarly about the following compounds.
[465] Deacetalization of the compound of formula (II) by acid treatment or the like gives an aldehyde compound of formula (II-ALD).
[466] Formula II-ALD
[467]
[468] The compound of general formula (III) of the present invention will be described.
[469] Formula III
[470]
[471] In formula (III) above, n, substituents R ¹ , R ² and R ³ are the same as described above with respect to compounds of formula (II). This compound can be obtained by reducing the cyano group which is a compound of general formula (II). Stereoconfiguration of the amino groups of these compounds is represented by the general formula This is preferred. Also, by deacetalizing this compound in the same manner as above, an aldehyde compound of formula III-ALDD can be obtained.
[472] Formula III-ALD
[473]
[474] The compound of the formula (IV) of the present invention will be described.
[475] Formula IV
[476]
[477] In formula (IV) above, n and substituent R ¹ are the same as previously described. In addition, the stereoconfiguration of the amino group is It is preferable that it is an arrangement of. Compounds of formula IV can be obtained by ring closure of the compounds in which the acetals of compounds of formula III are aldehyde converted.
[478] The compound of formula VII can be obtained by reducing the imino portion of this compound of formula IV.
[479] Formula VII
[480]
[481] Also in this compound, n of the general formula (VII) and the substituent R ¹ are the same as described above. The stereoconfiguration of the amino groups of these compounds is also as described above. This is preferred.
[482] The desired compound of formula (VIII) can be obtained by converting the substituent R ¹ (excluding hydrogen atoms) of such a compound of formula (VII) to a hydrogen atom in the usual manner.
[483] Formula VIII
[484]
[485] Next, the compound of general formula (XI) is demonstrated.
[486] Formula XI
[487]
[488] n represents the integer of 2-5. Substituent R ¹ is a hydrogen atom or a chemical formula [Wherein, R ^a , R ^b and R ^c each independently represent a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen) One or more types of groups selected from the group consisting of atoms and nitro groups may be substituted), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[489] Substituent R ¹ is of the formula In the case of, the group does not change even in the reaction for converting the cyano group, which is a compound of the formula (XI), to an aminomethyl group, and any group can be used as long as it can protect the amino group.
[490] With regard to the substituent R ¹ , it is preferred that the compound of the formula (XI) is a compound of the structure in which the diastereomer is present, to obtain the variant of the stereoconfiguration required. In the compound of the formula (XI), since the carbon atom to which the amino group is bonded is a subtitle carbon, when the substituent R ¹ is a substituent containing the subtitle carbon, the compound of the formula (XI) has a diastereomer. And when manufacturing the compound of general formula (XI) which is a diastereomer, a bias arises in the production | generation ratio of the 2 types of diastereomers produced | generated, and one diastereomer is obtained superior to the other. In this case, any possible diastereoisomers is controlled by the steric structure of the substituents R ¹ Is the lead, i.e., it is possible to change the structure of the substituent R ¹ produce the desired diastereomer as a lead.
[491] Therefore, as substituent R ¹ , it is preferable that R ^a , R ^b and R ^c are different from each other.
[492] Specifically, as R ^a , R ^b and R ^c , a hydrogen atom, a methyl group, an ethyl group, a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, 2,4-dichlorophenyl group And 2,4-dinitrophenyl group, 3,5-dichlorophenyl group, 3,5-dinitrophenyl group and naphthyl group.
[493] Moreover, although a methyl group, a methoxy group, a nitro group, and a chlorine atom are mentioned as a specific example of a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogen atom, and a nitro group which are substituents on an aryl group, One or two or more of these may be substituted with one or two or more.
[494] Examples of the substituent R ^{1 in which} R ^a , R ^b and R ^c are different from each other include (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group, and (S) -1- Phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1- (1-naphthyl) Ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group, (R)- 1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1- (4-nitrophenyl) Ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitrophenyl) ethyl group , (S) -1- (2,4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl) ethyl group, (R) -1- (3,5-dinitrophenyl) ethyl group or (S) -1- (3,5-dinitrophenyl) ethyl group is mentioned. Among these, as an especially preferable thing, (R) -1-phenylethyl group or (S) -1-phenylethyl group is mentioned.
[495] The substituent R ¹ may be a protecting group of an amino group other than the above, and in this case, the substituent R ¹ is good if it does not change even in the reaction for converting the cyano group of the compound of the formula (XI) into an aminomethyl group. As a protecting group of such an amino group, the alkoxycarbonyl groups which may have substituents, such as a tert-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxy, for example Aralkyloxycarbonyl groups which may have substituents such as benzyloxycarbonyl group and paranitrobenzyloxycarbonyl group; Aliphatic or aromatic acyl groups which may have substituents such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group and benzoyl group; And aralkyl groups which may have substituents such as a benzyl group, a paranitrobenzyl group, a paramethoxybenzyl group, and a triphenylmethyl group.
[496] Among these protecting groups, aralkyl groups are preferable in view of ease of production. Moreover, a benzyl group is preferable also in an aralkyl group. The phenyl group of such benzyl group may also have a substituent, for example, one or more groups selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom and a nitro group are substituted with at least one group. Can be. Specifically, except for the benzyl group, 4-methoxybenzyl group, 4-chlorobenzyl group, 4-nitrobenzyl group, 2,4-dichlorobenzyl group, 2,4-dinitrobenzyl group, 3,5-dichlorobenzyl group And 3,5-dinitrobenzyl groups.
[497] Among the compounds of the formula (XI), compounds in which the amino group is a preferred stereoconfiguration are Compound.
[498] The compound of formula (XI) may be an acid addition salt, but the acid forming the salt is not particularly limited as long as it does not affect the stability of the compound itself. Such acid may be any of inorganic and organic acids. As a salt with an inorganic acid, hydrochloride, hydrobromide, nitrate, phosphate, a perchlorate, etc. are mentioned, for example, As a salt with an organic acid, a salt with a carboxylic acid compound or a sulfonic acid compound is mentioned. Examples of the carboxylate include acetate, fumarate, lactate, and the like. Methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate, and the like can be given. Such salts may also be hydrates. In addition, regarding the formation of a salt, the following compounds can also be considered.
[499] In the compound of the formula (II-ALD), n and the substituent R ¹ , and more preferred stereoconfiguration can be considered in the same manner as the compound of the formula (XI).
[500] Compounds of formula (VII) are useful because they can carry out more substitution reactions by converting the protecting group of an amino group to a compound of formula (XII) converted to another protecting group. Compounds of formula (XII) are those wherein n is an integer from 2 to 5.
[501] Formula XII
[502]
[503] R ¹ may be the same as that described for the compound of formula (II). R ⁴ does not change even in the deprotection reaction of R ¹ , and any one may be used as long as it can protect the amino group. Moreover, R <^4> and R <^1> is another group (protecting group), Especially the combination which group which differs in reaction conditions for removing these is favorable.
[504] As R <^4> , an aliphatic or aromatic acyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aralkyl group, etc. are mentioned, for example. As the acyl group, for example, formyl group, acetyl group, propanoyl group, butyloyl group, benzoyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, dichloroacetyl A group, a trichloroacetyl group, etc. are mentioned, As an alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2- trichloroethoxy carbon And an alkyl group. Examples of the aralkyloxycarbonyl group include benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, and paranitrobenzyloxycarbonyl group. Examples of the aralkyl group include, for example, an aralkyl group. , Benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group and the like.
[505] The compound of formula (XII-a) is an integer where n is 2 to 5, and R ⁴ is preferably the same group as described for the compound of formula (XII).
[506] Formula XII-a
[507]
[508] Compounds of formula (XIII) represent integers where n is 2-5.
[509] Formula XIII
[510]
[511] R ⁴ may be the same as that described for the compound of formula (XII). R ⁵ does not change even in the deprotection reaction of R ⁴ , and any one may be used as long as it can protect the amino group.
[512] As R ⁵ , an aliphatic or aromatic acyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aralkyl group, etc. are mentioned, for example. As the acyl group, for example, formyl group, acetyl group, propanoyl group, butyloyl group, benzoyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, dichloroacetyl A group, a trichloroacetyl group, etc. are mentioned, As an alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2- trichloroethoxy carbon And an alkyl group. Examples of the aralkyloxycarbonyl group include benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, and paranitrobenzyloxycarbonyl group. Examples of the aralkyl group include, for example, an aralkyl group. , Benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group and the like.
[513] The compound of the preferable stereoconfiguration of the above compound is shown below.
[514] ; ;
[515] Preferred compounds in the present invention are compounds wherein n is 2 and these are shown below.
[516]
[517] Best Mode for Carrying Out the Invention
[518] Next, although an Example is given and this invention is demonstrated, this invention is not limited to this.
[519] Example 1 1- (diethoxymethyl) cyclopropane carboaldehyde (monoacetal body)
[520] 1,1-cyclopropane dicarboaldehyde (49 mg, 0.5 mmol) was dissolved in toluene (0.5 ml), and under ice-cooled stirring, p-toluenesulfonate monohydrate (1.9 mg, 0.01 mmol), ethyl orthoformate (74 mg) , 0.5 mmol) and ethanol (23 mg, 0.5 mmol) were added sequentially and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered and distilled off under reduced pressure to give a colorless oil (67.9 mg, 78.9%). The ratio of monoacetal body and diacetal body is about 40: 1 by the integral ratio of ¹ H-NMR.
[521] ¹ H-NMR (C ₆ D ₆ ) δ: 0.87-1.08 (m, 4H), 1.01 (t, J = 6.9 Hz, 6H), 3.25 (q, J = 6.9 Hz, 1H), 3.29 (q, J = 6.9 Hz, 1H), 3.45 (q, J = 6.9 Hz, 1H), 3.48 (q, J = 6.9 Hz, 1H), 4.74 (s, 1H), 9.29 (s, 1H).
[522] Reference: 1,1-bis (diethoxymethyl) cyclopropane (diacetal)
[523] ¹ H-NMR (C ₆ D ₆ ) δ: 0.91 (s, 4H), 1.10 (t, J = 6.9 Hz, 12H), 3.39 (q, J = 6.9 Hz, 2H), 3.42 (q, J = 6.9 Hz, 2H), 3.61 (q, J = 6.9 Hz, 2H), 3.64 (q, J = 6.9 Hz, 2H), 4.93 (s, 1H).
[524] Example 2 1- (diethoxymethyl) cyclopropane carboaldehyde
[525] 1,1-cyclopropane dicarboaldehyde (30 g, 306 mmol) is dissolved in toluene (260 ml) and stirred at 20 ° C. To this solution, a solution of p-toluenesulfonate monohydrate (153 mg, 0.77 mmol) toluene (10 ml) was added dropwise and cooled to an internal temperature of 5 ° C. or lower. Subsequently, a solution of ethyl orthoformate (49.7 g, 335 mmol) toluene (30 ml) was slowly added dropwise. After completion of the dropwise addition, stirring is continued for 1 hour in an ice bath. The internal temperature is raised to 25 ° C. and stirred for 1 hour. After confirming the completion of the reaction, the internal temperature was adjusted to 15 ° C., 2 mol / 1-NaOH (3.75 ml) was added, and the mixture was stirred for 1 hour. Water (50 ml) was added, the mixture was extracted and then toluene was distilled off under reduced pressure to give a colorless oil (55.8 g, quantitative). 95% or more of the ratio of a monoacetal body and a diacetal body is a monoacetal body. The instrument data is the same as that shown in Example 1.
[526] Example 3 1- (diethoxymethyl) cyclopropane carboaldehyde
[527] Dissolve 1,1-cyclopropane dicarboaldehyde (200 mg, 2.04 mmol) in ethanol (2.0 ml), and dry magnesium sulfate (246 mg, 2.04 mmol) and p-toluenesulfonate monohydrate (19.4 mg, 0.1 mmol). In addition, it is stirred for 1 hour at 50 ℃. At this point, the reaction mixture was checked by gas chromatography, and the ratio of monoacetal to diacetal was about 90:10. The instrument data is the same as that shown in Example 1.
[528] Example 4 1- (diethoxymethyl) cyclopropane carboaldehyde
[529] 1,1-cyclopropane dicarboaldehyde (200 mg, 2.04 mmol) was dissolved in ethanol (2.0 ml), ethyl orthoformate (59.0 mg, 0.41 mmol) and p-toluenesulfonate monohydrate (19.4 mg, 0.1 mmol) ) Is added and stirred at 50 ° C for 1 hour. At this point, the reaction mixture was checked by gas chromatography, and the ratio of monoacetal to diacetal was about 90:10. The instrument data is the same as that shown in Example 1.
[530] Example 5 2- (benzylamino) -2- [1- (diethoxymethyl) cyclopropyl] acetonitrile
[531] 1,1-cyclopropane dicarboaldehyde (2.94 g, 30 mmol) was dissolved in toluene (30 ml) and ethanol (138 mg, 3.0 mmol) in p-toluenesulfonate monohydrate (5.7 mg, 0.03 mmol) under ice-cooling stirring. The solution is added, then ethyl orthoformate (4.67 g, 31.5 mmol) is added and stirred at an external temperature of 40 ° C. for 1 hour. Saturated aqueous sodium bicarbonate solution (3 ml) was added to the reaction solution, and under ice-cooled stirring, benzyl amine (3.54 g, 33 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Potassium cyanide (2.15 g, 33 mmol) and sodium hydrogen sulfite (4.69 g, 45 mmol) are then added sequentially, then water (30 ml) is added and stirred at room temperature for 13 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered and then distilled off under reduced pressure. The pale yellow oil obtained is treated with silica gel column chromatography (150 g of silica gel, hexanes: ethyl acetate = 10: 1) to give the title compound (6.16 g, 71.2%) as a colorless oil.
[532] ¹ H-NMR (C ₆ D ₆ ) δ: 0.33-1.00 (m, 4H), 0.97 (t, J = 6.9 Hz, 6H), 3.10-3.29 (m, 2H), 3.31-3.47 (m, 2H) , 3.46 (s, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 4.69 (s, 1H), 7.09-7.27 (m, 5H).
[533] FABMS (m / z); 289 (M ⁺ + H), 2443, 217
[534] Example 6 (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[535] 1,1-cyclopropane dicarboaldehyde (1.96 g, 20 mmol) was dissolved in toluene (20 ml) and ethanol (276 mg, 6.0 mmol) of p-toluenesulfonate monohydrate (19.2 mg, 0.1 mmol) under ice-cooling stirring. The solution is added, then ethyl orthoformate (3.11 g, 21 mmol) is added and stirred at an external temperature of 40 ° C. for 1 hour. Saturated aqueous sodium bicarbonate solution (0.3 ml) was added to the reaction solution, followed by (S) -1-phenylethylamine (2.67 g, 22 mmol) under ice-cooled stirring, followed by stirring at room temperature for 30 minutes. Subsequently, potassium cyanide (1.43 g, 22 mmol) and sodium hydrogen sulfite (3.12 g, 30 mmol) are added sequentially, then water (20 ml) is added and stirred at 50 ° C. for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered and then distilled off under reduced pressure. The yellow oil (6.23 g) obtained was treated with silica gel column chromatography (100 g of silica gel, hexane: ethyl acetate = 10: 1 to 5: 1), and the title compound and its diastereomer (2R) -2- A mixture of [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile (3.86 g, 63.9%) is obtained as colorless crystals. The production ratio of the two diastereomers is 2: 1 in the integral ratio of ¹ H-NMR (the title compound is the main product).
[536] ¹ H-NMR (C ₆ D ₆ ) δ: 0.14-0.60 (m, 4H), 0.88-1.05 (m, 6H), 1.14 (d, J = 6.4 Hz, 3H × 2/3), 1.16 (d, J = 6.4 Hz, 3H × 1/3), 3.07-3.50 (m, 4H), 3.17 (s, 1H × 2/3), 3.59 (s, 1H × 1/3), 4.01-4.13 (m, 1H ), 4.61 (s, 1H × 1/3), 4.79 (s, 1H × 2/3), 7.05-7.34 (m, 5H).
[537] FABMS (m / z); 303 (M ⁺ + H), 257, 230, 105
[538] Example 7 (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile
[539] 1,1-cyclopropane dicarboaldehyde (294 mg, 3.0 mmol) was dissolved in toluene (3.0 ml) and, under ice-cooled stirring, p-toluenesulfonate monohydrate (2.9 mg, 0.015 mmol) in ethanol (41.5 mg, 0.9 mmol) solution is added, and then ethyl orthoformate (467 mg, 3.2 mmol) is added and stirred at an external temperature of 40 ° C. for 1 hour. Saturated aqueous sodium bicarbonate solution (0.3 ml) was added to the reaction solution, followed by (S) -1-naphthylethylamine (565 mg, 3.3 mmol) under ice-cooled stirring, followed by stirring at room temperature for 30 minutes. Potassium cyanide (215 mg, 3.3 mmol) and sodium hydrogen sulfite
[540] (469 mg, 4.5 mmol) was added sequentially, followed by addition of water (3.0 ml) and stirring at 50 ° C. for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over sodium sulfate, filtered and then distilled off under reduced pressure. The yellow oil (1.19 g) obtained was treated by silica gel column chromatography (36 g silica gel, hexane: ethyl acetate = 10: 1 to 5: 1), and the title compound and its diastereomer (2R) -2- A mixture (732 mg, 69.2%) of [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile is obtained as a colorless oil. The production ratio of the two diastereomers is 1.6: 1 by the integral ratio of ¹ H-NMR (the title compound is the main product).
[541] ¹ H-NMR (C ₆ D ₆ ) δ: 0.14-0.97 (m, 4H), 0.89-1.04 (m, 6H), 1.33 (d, J = 6.6 Hz, 3H × 1.6 / 2.6), 1.34 (d, J = 6.6 Hz, 3H × 1.0 / 2.6), 3.06-3.50 (m, 4H), 3.18 (s, 1H × 1.6 / 2.6), 3.67 (s, 1H × 1.0 / 2.6), 4.59 (s, 1H × 1.0 /2.6), 4.83 (s, 1H x 1.6 / 2.6), 4.93-4.97 (m, 1H), 7.24-8.42 (m, 7H).
[542] FABMS (m / z); 353 (M ⁺ + H), 307, 280, 155
[543] Example 8 (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2 {[(1S) -1-phenyl-2- (p-tolyl) ethyl] amino} acetonitrile
[544] 1,1-cyclopropane dicarboaldehyde (294 mg, 3.0 mmol) was dissolved in toluene (3.0 ml) and, under ice-cooled stirring, p-toluenesulfonate monohydrate (2.9 mg, 0.015 mmol) in ethanol (41.5 mg, 0.9 mmol) solution is added, followed by ethyl orthoformate (467 mg, 3.2 mmol) and stirred at an external temperature of 40 ° C. for 1 hour. Saturated aqueous sodium bicarbonate solution (0.3 ml) was added to the reaction solution, followed by (S) -1-phenyl-2- (p-tolyl) ethylamine (697 mg, 3.3 mmol) under ice-cooling stirring, followed by 30 minutes at room temperature. Stir. Subsequently, potassium cyanide (215 mg, 3.3 mmol) and sodium hydrogen sulfite (469 mg, 4.5 mmol) are added sequentially, then water (3.0 ml) is added and stirred at 50 ° C. for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate.
[545] The organic layer was washed sequentially with water and saturated brine, dried over sodium sulfate, filtered and then distilled off under reduced pressure. The yellow oil (1.22 g) obtained was treated by silica gel column chromatography (36 g silica gel, hexane: ethyl acetate = 10: 1 to 5: 1), and the title compound and its diastereomer (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenyl
[546] A mixture of -2- (p-tolyl) ethyl] amino} acetonitrile (715 mg, 60.7%) is obtained as a colorless oil. The production ratio of the two diastereomers is 2.2: 1 by the integral ratio of ¹ H-NMR (the title compound is the main product).
[547] ¹ H-NMR (C ₆ D ₆ ) δ: 0.03-0.54 (m, 4H), 0.85-1.04 (m, 6H), 2.06 (s, 3H × 1.0 / 3.2), 2.08 (s, 3H × 2.2 / 3.2 ), 2.73-2.92 (m, 2H), 3.03-4.63 (m, 4H and 1H), 4.18 (m, 1H × 1.0 / 3.2), 4.39 (m, 1H × 2.2 / 3.2), 4.46 (s, 1H × 1.0 / 3.2), 4.76 (s, 1H × 2.2 / 3.2), 6.90-7.39 (m, 9H).
[548] FABMS (m / z); 393 (M ⁺ + H), 347, 320, 195
[549] Example 9 Epimerization of (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[550] A mixture of the title compound and its diastereomer (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile (16 mg, mix ratio = 1: 1.8, (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile is anhydrous ethanol (1.Oml) After the addition, the mixture was stirred at 60 DEG C for 30 minutes under argon stream, and the reaction solution was concentrated under reduced pressure. The mixture ratio of the diastereomer of the obtained colorless crystals (16 mg) was 3.4: 1 by the integral ratio of ¹ H-NMR ((2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile).
[551] Example 10 Purification of (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[552] (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile and (2R) -2- [1- (diethoxymethyl) Anhydrous ethanol (1.5 ml) in a diastereomeric mixture (300 mg, diastereomer ratio = 2: 1, the title compound is the main component) of cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile The mixture was added, stirred at 60 ° C. for 30 minutes under an argon stream, then cooled to room temperature, and further stirred for 1 hour under ice-cooling. The precipitated crystals are filtered to give the title compound (200 mg of first crystals, 66.6%) as colorless needles. In addition, the crystalline residue (93 mg) obtained by concentrating the mother liquor under reduced pressure was operated in the same manner as above, and the title compound (37 mg of second crystals, 12.4%) was obtained as colorless needles. The optical purity of the obtained crystal is 99% de by HPLC analysis.
[553] Melting point (EtOH); 96-97 ℃
[554] ¹ H-NMR (C ₆ D ₆ ) δ: 0.14-0.60 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H), 1.00 (t, J = 6.9 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 3.07-3.31 (m, 2H), 3.17 (s, 1H), 3.36-3.50 (m, 2H), 4.12 (q, J = 6.6 Hz, 1H), 4.79 (s, 1H) , 7.05-7.34 (m, 5 H).
[555] FABMS (m / z); 303 (M ⁺ + H), 257, 230, 105
[556] (HPLC condition)
[557] column; CHIRALCEL-OJ (4.6mmΦ × 250mm)
[558] Mobile phase; Hexane: isopropanol = 98: 2
[559] Flow rate; 0.5ml / min
[560] Temperature; Room temperature
[561] detection; UV 254nm
[562] Holding time; (S) type: 9.4 minutes, (R) type: 10.4 minutes
[563] Analysis of the obtained compound; 9.4 minutes:> 99% ((S, S) type)
[564] 10.4 minutes: <1% ((R, S) type)
[565] Example 11 (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[566] 1- (diethoxymethyl) cyclopropane carboaldehyde (30.0 g, 306 mmol) is dissolved in ethanol (240 ml) and stirred at 0 ° C. for 30 minutes. (S) -phenylethylamine (43.5 ml, 336 mmol) was added dropwise and the temperature was raised to 40 ° C. After stirring for 30 minutes at the same temperature, acetone cyanhydrin (33.4 ml, 367 mmol) was added dropwise and stirred for 30 minutes at the same temperature. At the end of the reaction, the ratio of the title compound and its diastereomer (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile was determined by HPLC. Analysis was 77:23 (54% de) (title compound as main product). Then water (240 ml) was added dropwise at 40 ° C. and stirred for 3 hours while maintaining the temperature at 40 ° C. The reaction solution is cooled to 20 ° C., water (30 ml) is added and stirred at 20 ° C. for 14 hours. It is also cooled to 0 ° C. and stirred for 3 hours. The precipitated crystals are filtered to give the title compound (86.2 g, 93%) as colorless needles. The optical purity of the obtained crystal is 99% de by HPLC analysis.
[567] Instrument data of the product is the same as described in Example 6.
[568] Example 12 Epimerization of (2R) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile
[569] A mixture of the title compound and (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-naphthylethyl] amino} acetonitrile (30 mg, diastereomeric ratio = 1O Anhydrous ethanol (1.0 ml) was added to the title compound as a main component, and the mixture was heated and stirred for 1 hour at 60 ° C. under an argon stream, and then concentrated under reduced pressure. The diastereomeric mixing ratio of the obtained colorless oil (28 mg) was 2.9: 1 by the integral ratio of ¹ H-NMR ((2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S ) -1-naphthylethyl] amino} acetonitrile).
[570] Example 13 N- {2-amino- (1S) -1- [1- (diethoxymethyl) cyclopropyl] ethyl} -N-[(1S) -1-phenylethyl] amine
[571] (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile (150 mg, 0.496 mmol) was dissolved in ethanol (9.0 ml) , 5 mol / l-sodium hydroxide aqueous solution (0.5 ml, 2.5 mmol) and Raney nickel (R-100, 1.5 g) were added and stirred for 5 hours at room temperature under hydrogen stream. The catalyst is filtered off, washed with ethanol, the filtrate is concentrated under reduced pressure, water and chloroform are added to the residue, and the mixture is separated. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (150 mg, 98.4%) as a pale yellow oil.
[572] ¹ H-NMR (CDCl ₃ ) δ: 0.18-0.58 (m, 4H), 1.07-1.28 (m, 6H), 1.31 (d, J = 6.4 Hz, 3H), 1.98 (t, J = 6.4 Hz, 1H ), 2.82 (dd, J = 3.0 and 6.4 Hz, 2H), 3.35-3.72 (m, 4H), 3.93 (q, J = 6.4 Hz, 1H), 4.32 (s, 1H), 7.19-7.32 (m, 5H).
[573] EIMS (m / z); 276 (M ⁺ -CH ₂ NH ₂ ), 230, 105
[574] Example 14 (S) -N-[(S) -1-phenylethyl] -5-azaspiro [2,4] hepto-4-en-7-amine
[575] (S) -N- {2-amino-1- [1- (diethoxymethyl) cyclopropyl] ethyl} -N-[(S) -1-phenylethylamine] (136 mg) in acetone (1.0 ml) Dissolve and add 1 mol / l hydrochloric acid (2.0 ml) under ice-cooled stirring and stir at room temperature for 1 hour. Toluene was added to the reaction solution and the mixture was separated. After cooling with ice, saturated aqueous sodium bicarbonate solution was added to the aqueous layer to make alkaline and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (85 mg, 90.0%) as a pale yellow oil.
[576] ¹ H-NMR (CDCl ₃ ) δ: 0.67-0.74 (m, 1H), 0.82-0.97 (m, 2H), 1.18-1.26 (M, 1H), 1.30 (d, J = 6.4 Hz, 3H), 2.85 (dd, J = 4.0 and 6.9 Hz, 1H), 3.82 (q, J = 6.4 Hz, 1H), 3.86 (dd, J = 4.0 and 15.8 Hz, 1H), 4.09 (dd, J = 6.9 and 15.8 Hz, 1H), 6.98 (s, 1H), 7.18-7.35 (m, 5H).
[577] EIMS (m / z); 214 (M ⁺ ), 109, 105
[578] Example 15 (S) -N-[(S) -1-phenylethyl] -5-azaspiro [2,4] heptan-7-amine
[579] (S) -N-[(S) -1-phenylethyl] -5-azaspiro [2.4] hepto-4-en-7-amine (85 mg, 0.40 mmol) was dissolved in ethanol (2.6 ml) Nickel (R-100, 427 mg) is added and stirred at room temperature under hydrogen stream for 2 hours. The catalyst is filtered off, washed with ethanol, the filtrate is concentrated under reduced pressure, and the residue is separated by addition of 0.5 mol / l-sodium hydroxide aqueous solution and chloroform. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to yield the title compound (71 mg, 82.9%) as a pale yellow oil.
[580] ¹ H-NMR (CDCl ₃ ) δ: 0.41-0.50 (m, 3H), 0.68-0.80 (m, 1H), 1.32 (d, J = 6.6 Hz, 3H), 2.47 (dd, J = 3.3 and 5.0 Hz , 1H), 2.68 (d, J = 10.9 Hz, 1H), 2.93 (dd, J = 3.3 and 11.2 Hz, 1H), 3.07 (d, J = 10.9 Hz, 1H), 3.10 (dd, J = 5.0 and 11.2 Hz, 1H), 3.74 (q, J = 6.6 Hz, 1H), 7.19-7.35 (m, 5H).
[581] EIMS (m / z); 216 (M ⁺ ), 187, 111, 105
[582] Example 16
[583] From (S) -N-[(S) -1-phenylethyl] -5-azaspiro [2.4] heptan-7-amine obtained in Example 15, 5-azaspiro [2.4] heptane according to Reference Example 1 -(S) -7-amine is synthesized and the optical purity is measured. The measurement of optical purity is performed as follows.
[584] The obtained compound and racemate are dissolved in tetrahydrofuran and 3,5-dinitrobenzoyl chloride is added. Under ice-cooling, triethylamine is added dropwise thereto and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was analyzed by HPLC.
[585] (HPLC condition)
[586] column; SUMICHIRALOA-4600 (4.6mmΦ × 250mm)
[587] Mobile phase; Hexane: 1,2-dichloroethane: ethanol = 60: 40: 5
[588] Flow rate; 1.Oml / min
[589] Temperature; Room temperature
[590] detection; UV 254nm
[591] Holding time; (S) type: 6.8 minutes, (R) type: 10.0 minutes
[592] Analysis of the obtained compound; 6.8 minutes: 99% ((S) type)
[593] 10.0 minutes: 1% ((R) type)
[594] Reference Example 1 5-Azaspiro [2.4] heptane- (S) -7-amine dihydrochloride
[595] (S) -N-[(S) -1-phenylethyl] -5-azaspiro [2.4] heptan-7-amine (79 mg, 0.36 mmol), 20% Pd (OH) ₂ -C (50% wet, 37 mg), ethanol (2.0 ml), water (1.0 ml) and concentrated hydrochloric acid (0.5 ml) are placed in an autoclave and stirred overnight at room temperature under hydrogen atmosphere (3.92 MPa (40 kgf / cm 2)). After the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give colorless crystals (72 mg, 82%).
[596] Reference Example 2 [1- (Diethoxymethyl) cyclopropyl] methanol
[597] A tetrahydrofuran (190 mL) solution of 1- (diethoxymethyl) cyclopropane carboaldehyde (37.78 g) is cooled to 0 ° C., to which lithium aluminum hydride (2 g, 52.7 mmol) is added and stirred for 40 minutes. Water was added to stop the reaction. The mixture was extracted with chloroform, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 34.60 g (91%) of the title compound as a colorless oil.
[598] ¹ H-NMR (CDCl ₃ ) δ: 4.30 (1H, s), 3.79-3.68 (2H, m), 3.60-3.49 (2H, m), 3.54 (2H, d, J = 5.6 Hz), 2.79 (1H , t, J = 5.6 Hz), 1.22 (3H, t, J = 7.0 Hz), 0.67-0.63 (2H, m), 0.50-0.46 (2H, m).
[599] Reference Example 3 1- (hydroxymethyl) cyclopropane carboaldehyde
[600] An acetone (73 mL) solution of [1- (diethoxymethyl) cyclopropyl] methanol (34.6 g, 199 mmol) was cooled to 0 ° C., and 1.2 mol / l-hydrochloric acid (10 mL) was added thereto and stirred for 30 minutes. 1 mol / l-sodium hydroxide aqueous solution (12 mL) was added to stop the reaction. The mixture was extracted with chloroform, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 16.6 g (83%) of the title compound as a pale yellow oily substance.
[601] ¹ H-NMR (CDCl ₃ ) δ: 8.77 (1H, s), 3.74 (2H, s), 3.13 (1H, brs), 1.28-1.21 (2H, m), 1.19-1.12 (2H, m).
[602] Example 17 2- [1- (hydroxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[603] To a solution of 1- (hydroxymethyl) cyclopropane carboaldehyde (683 mg, 6.82 mmol) in ethanol (4.9 mL) in water (2.1 mL), (S)-(-)-1-phenylethylamine (0.94 mL, 7.50 mmol ), Potassium cyanide (489 mg, 7.50 mmol) and sodium hydrogen sulfite (1.45 g, 13.6 mmol) were added and stirred at 50 ° C. for 30 minutes. Cool to 0 ° C., stop the reaction with saturated aqueous sodium hydrogen carbonate solution, extract with ethyl acetate, wash with water and dry with magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound as a pale yellow oily substance (1.55 g, crude product).
[604] ¹ H-NMR (CDCl ₃ , Main Product) δ: 7.38-7.30 (5H, m), 4.05 (1H, q, J = 6.6 Hz), 3.56 (2H, s), 3.44 (1H, s), 1.43 ( 3H, d, J = 6.6 Hz), 0.71-0.54 (4H, m).
[605] Example 18 2- (1-formylcyclopropyl) -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[606] Pyridinium chlorochloromate (3.74) in a dichloromethane (20 mL) solution of 2- [1- (hydroxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile (2.08 g) g, 17.4 mmol) is added and stirred at room temperature for 2 hours. The solvent was distilled off after removing the insolubles by silica gel filtration, and the residue was purified by column chromatography to give the title compound as pale yellow crystals (508 mg, 1- (hydroxymethyl) cyclopropane carboaldehyde from 20%). do.
[607] ¹ H-NMR (CDCl ₃ , Main Product) δ: 8.79 (1H, s), 7.36-7.26 (5H, m), 4.07 (1H, q, J = 6.4 Hz), 2.04 (1H, s), 1.39 ( 3H, d, J = 6.4 Hz), 1.38-1.07 (4H, m).
[608] Example 19 2- (benzylamino) -2- (1-formylcyclopropyl) acetonitrile
[609] Benzylamine (107 mg, 1.0 mmol) is suspended in a mixture of ethanol (0.5 ml) and water (1.5 ml), and potassium cyanide (65 mg, 1.0 mmol) and sodium hydrogen sulfite (104 mg, 1.0 mmol) are sequentially added under ice-cooled stirring. Add, dropwise add 1,1-cyclopropane dicarboaldehyde (98 mg, 1.0 mmol) solution of ethanol (1.5 ml) and stir at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over sodium sulfate, filtered and then distilled off under reduced pressure. The obtained oily residue was treated with silica gel column chromatography (silica gel 8.0 g; hexanes: ethyl acetate = 5: 1) to give the title compound (109 mg, 50.8%) as pale yellow oil.
[610] ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.38 (m, 4H), 3.52 (s, 1H), 3.83 (d, J = 13.2 Hz, 1H), 4.11 (d, J = 13.2 Hz, 1H), 7.27-7.38 (m, 5 H), 8.82 (s, 1 H).
[611] EI MS (m / z); 214 (M ⁺ ), 187, 159, 123
[612] In addition, 2- (benzylamino) -2- {1- [1- (benzylamino) -2-nitroethyl] cyclopropyl} acetonitrile (53.8 mg, 16.3%) is obtained as colorless crystals.
[613] ¹ H-NMR (C ₆ D ₆ ) δ: 0.81-1.01 (m, 4H), 3.73 (d, J = 12.9 Hz, 2H), 4.03 (d, J = 12.9 Hz, 2H), 4.19 (s, 2H ), 7.21-7.35 (m, 10 H).
[614] Example 20 (2S) -2- [1- (diethoxymethyl) cyclopropyl] -2-{[(1S) -1-phenylethyl] amino} acetonitrile
[615] 2- (1-formylcyclopropyl) -2-{[(1S) -1-phenylethyl] amino} acetonitrile (
[616] To a solution of 102 mg, 0.447 mmol) of ethanol (2.5 mL) was added triethyl orthomorphate (0.2 mL, 1.20 mmol) and p-toluenesulfonate monohydrate (1 mg, 0.0053 mmol) and stirred at room temperature for 2 hours 30 minutes. And also stirred at 50 ° C. for 4 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the organic layer was washed with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure and purified by column chromatography to give the title compound as white crystals (40 mg, 30%, diastereomer ratio = 81/19).
[617] ¹ H-NMR (CDCl ₃ , Main Product) δ: 0.14-0.60 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H), 1.00 (t, J = 6.9 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 3.07-3.31 (m, 2H), 3.17 (s, 1H), 3.36-3.50 (m, 2H), 4.12 (q, J = 6.6 Hz, 1H), 4.79 (S, 1H ), 7.05-7.34 (m, 5H).
[618] Example 21 7- (S)-[1- (S) -phenylethylamino] -5-N-acetylazaspiro [2.4] heptane
[619] 7- (S)-[(S) -1-phenylethylamino] -5-azaspiro [2.4] heptane (2.16 g, 10 mmol) was dissolved in ethyl acetate (20 ml) and acetic anhydride (1.02) under ice-cooling stirring. g, 10 mmol) is added dropwise and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture to separate the organic layer. The organic layer was washed sequentially with water and brine. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (2.53 g, 98%) as a pale yellow oil.
[620] ¹ H-NMR (CDCl ₃ ) δ: 0.45-0.57 (m, 3H), 0.65-0.71 (m, 1H), 1.30 and 1.33 (d, J = 6.6 Hz, 3H, rotamers), 2.00 and 2.06 (s , 3H, rotamers), 2.52 and 2.64 (m, 1H, rotamers), 3.11-3.67 (m, 4H), 3.77 and 3.79 (q, J = 6.6 Hz, 1H, rotamers), 7.19-7.36 (m , 5H).
[621] FAB MS (m / z); 259 (M ⁺ + H), 217, 155, 105
[622] Example 22 7- (S) -Amino-5-N-acetylazaspiro [2.4] heptane (method 1)
[623] 7- (S)-[1- (S) -phenylethylamino] -5-N-acetylazaspiro [2.4] heptane (517 mg, 2.0 mmol) was dissolved in ethanol (8.0 ml) and 5% Pd-C (50% wet, 1.03 g) is added and stirred at room temperature under hydrogen stream for 5 hours and then at 50 ° C. for 3 hours. The catalyst is filtered off, washed with ethanol and the filtrate is concentrated under reduced pressure to give the title compound (365 mg, quantitative) as a colorless oil.
[624] ¹ H-NMR (CDCl ₃ ) δ: 0.51-0.80 (m, 4H), 2.02 and 2.07 (s, 3H, rotamers), 3.03-3.46 (m, 3H), 3.60-3.89 (m, 2H).
[625] FAB MS (m / z); 155 (M ⁺ + H), 138, 96
[626] Example 23 7- (S) -amino-5-N-acetylazaspiro [2.4] heptane (method 2)
[627] 7- (S) -amino-5-azaspiro [2.4] heptane (586 mg, 5.0 mmol) was dissolved in dichloromethane (12 ml), cooled to -75 ° C, and stirred with acetic anhydride (510 mg, 5.0 mmol). Dichloromethane solution is added dropwise for 15 minutes and stirred at room temperature for 30 minutes. The solvent is distilled off, and hydrochloric acid and chloroform are added to the residue for separation. An aqueous sodium hydroxide solution is added to the aqueous layer to make alkaline and extracted with chloroform. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (707 mg, 92%) as a yellow oil.
[628] Example 24 7- (S)-[tert-Butoxycarbonylamino] -5-N-acetylazaspiro [2.4] heptane
[629] 7- (S) -amino-5-N-acetylazaspiro [2.4] heptane (365 mg, 2.0 mmol) was dissolved in ethanol (6.0 ml), triethylamine (304 mg, 3.0 mmol) was added at room temperature, and then Di-tert-butyldicarbonate (524 mg, 2.4 mmol) was added and stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the residue is separated by adding chloroform and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (586 mg, quantitative) as a crystalline residue.
[630] ¹ H-NMR (CDCl ₃ ) δ: 0.53-0.95 (m, 4H), 1.44 and 1.45 (s, 9H, rotamers), 2.02 and 2.06 (s, 3H, rotamers), 3.19-3.30 (m, 1H ), 3.60-3.84 (m, 4H).
[631] FAB MS (m / z); 255 (M ⁺ + H), 213, 199, 157, 155, 96
[632] m.p .: 141-142 ° C. (toluene)
[633] Example 25 7- (S)-[tert-Butoxycarbonylamino] -5-azaspiro [2.4] heptane
[634] 7- (S)-[tert-butoxycarbonylamino] -5-N-acetylazaspiro [2.4] heptane (386 mg, 1.5 mmol) is dissolved in ethanol (4.Oml) and 1 mol / l at room temperature -Aqueous sodium hydroxide solution (4.0 ml) is added, it is stirred for 3 hours at 50 degreeC, 5 mol / l- sodium hydroxide aqueous solution (2.2 ml) is added, and it stirred at 70 degreeC for 20 hours. The ethanol was distilled off under reduced pressure, and the residue was separated by adding chloroform and water. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give the title compound (231 mg, 72%) as a crystalline residue. Its ¹ H-NMR spectrum is consistent with the standard.
[635] Example 26
[636] 7- (S)-[tert-Butoxycarbonylamino] -5-azaspiro obtained in Example 25
[637] [2.4] The optical purity of heptane was measured as follows.
[638] The obtained compound and racemate are dissolved in tetrahydrofuran and 3,5-dinitrobenzoyl chloride is added. Under ice-cooling, triethylamine is added dropwise thereto and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution and chloroform were added to the reaction mixture, and the organic layer was analyzed by HPLC.
[639] (HPLC condition)
[640] column; SUMICHIRAL OA-440O (4.6mmΦ × 250mm)
[641] Mobile phase; Hexane: 1,2-dichloroethane: ethanol = 75: 25: 1
[642] Flow rate; 1.Oml / min
[643] Temperature; Room temperature
[644] detection; UV 254nm
[645] Holding time; (S) type: 9.0 minutes, (R) type: 10.4 minutes
[646] Analysis of the obtained compound; (S) Form: 99.2%
[647] (R) type: 0.8%
[648] Example 27 7- (S)-[benzyloxycarbonylamino] -5-N-acetylazaspiro [2.4] heptane
[649] Dissolve 7- (S) -amino-5-N-acetylazaspiro [2.4] heptane (2.44 g, 15.8 mmol) in dichloromethane (24 ml) and triethylamine (1.76 g, 17.4 mmol) under ice-cooling stirring. Then, dichloromethane solution of benzyloxycarbonyl chloride (2.70 g, 15.8 mmol) was added dropwise and stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer is dried over sodium sulfate, filtered and distilled off under reduced pressure to give a yellow oil (2.64 g). This was purified by silica gel column to give the title compound (1.87 g, 41%).
[650] ¹ H-NMR (CDCl ₃ ) δ: 0.55-0.91 (m, 4H), 2.01 and 2.04 (s, 3H, rotamers), 3.19-3.30 (m, 1H), 3.59-3.85 (m, 4H), 5.08 And 5.10 (s, 2H, rotamers), 7.31-7.40 (m, 5H).
[651] FAB MS (m / z); 289 (M ⁺ + H), 245, 199, 152, 135, 91
[652] Example 28 7- (S)-[benzyloxycarbonylamino] -5-azaspiro [2.4] heptane
[653] 7- (S)-[benzyloxycarbonylamino] -5-N-acetylazaspiro [2.4] heptane (288 mg, 1.0 mmol) is dissolved in ethanol (5.0 ml) and 5 mol / l-sodium hydroxide aqueous solution at room temperature. (10 ml) is added and stirred for 72 hours at room temperature. Toluene and water are added to the reaction mixture for separation, and the organic layer is washed with water. The organic layer was dried over sodium sulfate, filtered and distilled off under reduced pressure to yield a yellow oil (165 mg). This was purified by silica gel column to give the title compound (97.4 mg, 40%).
[654] ¹ H-NMR (CDCl ₃ ) δ: 0.50-0.82 (m, 4H), 2.74 (d, J = 10.7 Hz, 1H), 2.94-3.02 (m, 2H), 3.34 (dd, J = 5.5 and 11.5 Hz , 1H), 3.71 (m, 1H), 5.07 (s, 2H), 7.28-7.39 (m, 5H).
[655] FAB MS (m / z); 247 (M ⁺ + H), 185, 157, 135, 91
[656] Example 29 7- (S)-[benzyloxycarbonylamino] -5-azaspiro [2.4] heptane p-toluenesulfonate
[657] 7- (S)-[benzyloxycarbonylamino] -5-azaspiro [2.4] heptane (123 mg, 0.5 mmol) is dissolved in toluene (1.2 ml) and p-toluenesulfonate monohydrate (95.1 mg) at room temperature , 0.5 mmol) of ethanol is added and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, ethyl acetate (2.0 ml) was added to the residue, the slurry was stirred at 50 ° C. for 30 minutes, diisopropyl ether (2.0 ml) was added, and the slurry stirred at room temperature for 30 minutes. The precipitated crystals were filtered off and washed with a mixture of ethyl acetate and diisopropyl ether (1: 1). The crystals are dried under reduced pressure at room temperature to give the title compound (150 mg, 71%) as white crystals.
[658] ¹ H-NMR (CDCl ₃ ) δ: 0.55-0.98 (m, 4H), 2.32 (s, 3H), 3.04-3.12 (m, 1H), 3.54-3.64 (m, 3H), 3.91 (m, 1H) , 5.02 (dd, J = 12.5 and 15.5 Hz, 2H), 6.59 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 7.27-7.34 (m, 5H), 7.70 ( d, J = 7.9 Hz, 2H), 9.06 (br. s, 1H), 9.35 (br. s, 1H).
[1] The present invention relates to amino substituted aza having a spiro cyclic structure for use as a raw material for the production of quinolone derivatives (see Japanese Patent Application Laid-Open Nos. Hei 2-231475 and Hei 3-95176) which are expected to be excellent antimicrobial agents. A novel process for the preparation of spiroalkane compounds and intermediate compounds useful in the process.
[659] According to the present invention, an amino-substituted azaspiroalkane compound having a spiro cyclic structure, which is an intermediate compound serving as a synthetic raw material of a synthetic antimicrobial compound, can be easily produced.

权利要求:
Claims (111)
[1" claim-type="Currently amended] As a method for preparing a compound of formula (VII), a salt thereof, or a hydrate thereof, a compound of formula (II) is obtained by any one of step A and step B shown below, and the cyano group of this compound is reduced to give formula (III). To obtain a compound of formula III-ALD, which is intramolecularly closed under neutral or basic conditions to give a compound of formula IV; Reducing the compound to give a compound of formula (VII), wherein if R ¹ of the compound is not a hydrogen atom, the process comprises the steps of converting R ¹ to a hydrogen atom.
Process A:
Chemical formula Reacting an acetalizing agent in the presence of an acid catalyst with a compound of, in the presence of an additive as desired to give a compound of formula (I), and reacting this compound with a compound of formula (VI) or a salt thereof and a cyanoating agent;
Process B:
Reacting a compound of formula (VI) with a compound of formula (VI) or a salt thereof and a cyanoating agent to give a compound of formula (XI), and oxidizing the compound to give a compound of formula (II-ALD), to which the acid catalyst The acetalizing agent in the presence of is reacted in the presence of an additive as desired.
Formula VIII

Formula II

Formula III

Formula III-ALD

Formula IV

Formula VII

Formula I

Formula VI
H ₂ NR ¹
Formula X

Formula XI

Formula II-ALD

In each formula above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[2" claim-type="Currently amended] The process according to claim 1, wherein the process for preparing the compound of formula II is process A.
[3" claim-type="Currently amended] The process according to claim 1, wherein the process for preparing the compound of formula II is process B.
[4" claim-type="Currently amended] The production method according to any one of claims 1 to 3, wherein the reduction of the cyano group is reduction using a catalytic hydrogenation reaction or a metal hydride.
[5" claim-type="Currently amended] The production method according to any one of claims 1 to 3, wherein the reduction of the cyano group is reduction using a catalytic hydrogenation reaction.
[6" claim-type="Currently amended] The process according to any one of claims 1 to 5, wherein the acid catalyst is hydrochloric acid.
[7" claim-type="Currently amended] The production method according to any one of claims 1 to 6, wherein the ring closure reaction is a ring closure reaction carried out under neutral or basic conditions.
[8" claim-type="Currently amended] The manufacturing method of any one of Claims 1-7 whose R <^2> and R <^3> is a C1-C4 alkoxy group.
[9" claim-type="Currently amended] The production method according to claim 8, wherein R ² and R ³ are ethoxy groups.
[10" claim-type="Currently amended] The process according to any one of claims 1 to 9, wherein the reduction of the compound of formula IV is a reduction using a catalytic hydrogenation reaction or a metal hydride.
[11" claim-type="Currently amended] 10. The process according to claim 1, wherein the reduction of the compound of formula IV is a catalytic hydrogenation reaction.
[12" claim-type="Currently amended] The process of claim 11 wherein the catalyst is Raney nickel or Raney cobalt.
[13" claim-type="Currently amended] Reacting a compound of formula (I) with a compound of formula (VI) or a salt thereof and a cyanoating agent to give a compound of formula (II) and reducing the cyano group of such compound to give a compound of formula (III) Hydrolysis in the presence of a catalyst to give a compound of formula III-ALD, which compound is intramolecularly closed under neutral or basic conditions to give a compound of formula IV, which reduces the compound and gives a compound of formula VII And when R ¹ of such a compound is not a hydrogen atom, R ¹ is converted to a hydrogen atom.
Formula I

Formula VI
H ₂ NR ¹
Formula II

Formula III

Formula III-ALD

Formula IV

Formula VII

Formula VIII

In each formula above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[14" claim-type="Currently amended] The process according to claim 13, wherein the compound of formula I is a compound of formula I-R.
Formula I-R

In Formula I-R above,
R represents an alkoxy group having 1 to 4 carbon atoms,
n represents the integer of 2-5.
[15" claim-type="Currently amended] The compound of claim 14, wherein the compound of formula IR is A compound obtained by reacting an acetalizing agent in a presence of an acid catalyst in the presence of an acid catalyst with a compound of (wherein n represents an integer of 2 to 5).
[16" claim-type="Currently amended] The compound of claim 15, wherein the compound of formula IR is A compound obtained by reacting a compound of formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst to a compound of wherein n represents an integer of 2 to 5 Phosphorus manufacturing method.
[17" claim-type="Currently amended] The method according to claim 15, wherein the additive is a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, or a dehydrating agent.
[18" claim-type="Currently amended] 18. The compound of claim 15 or 17, wherein the compound of formula IR is Compound obtained by reacting a compound of formula HR, wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst and an additive dehydrating agent to a compound of wherein n represents an integer of 2 to 5 Phosphorus manufacturing method.
[19" claim-type="Currently amended] The process according to claim 17 or 18, wherein the dehydrating agent is an anhydride of an inorganic salt.
[20" claim-type="Currently amended] The method according to any one of claims 17 to 19, wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.
[21" claim-type="Currently amended] 18. The compound of claim 15 or 17, wherein the compound of formula IR is In a compound of formula (H), in the presence of a catalytic amount of a compound of formula HC (R) _{3 which} is an acid catalyst and an additive, wherein R represents an alkoxy group having 1 to 4 carbon atoms, wherein R is a compound having 1 to 4 carbon atoms. To alkoxy group).
[22" claim-type="Currently amended] The production method according to any one of claims 14 to 21, wherein the acid catalyst is a sulfonic acid compound.
[23" claim-type="Currently amended] The production method according to any one of claims 14 to 22, wherein R is an ethoxy group.
[24" claim-type="Currently amended] The production process according to any one of claims 13 to 23, wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin.
[25" claim-type="Currently amended] The production process according to any one of claims 13 to 23, wherein the cyanoating agent is hydrogen cyanide.
[26" claim-type="Currently amended] The production process according to any one of claims 13 to 23, wherein the cyanoating agent is acetone cyanhydrin.
[27" claim-type="Currently amended] 27. The process according to any one of claims 13 to 26, wherein the reduction of the cyano group of the compound of formula (II) is reduction by catalytic hydrogenation.
[28" claim-type="Currently amended] The production method according to any one of claims 13 to 27, wherein the reduction of the compound of formula IV is reduction by addition of a metal hydride compound or catalytic hydrogen.
[29" claim-type="Currently amended] Chemical formula A process for the preparation of compounds of formula (I), characterized in that the acetalizing agent is reacted in the presence of an acid catalyst with a compound of the formula wherein n represents an integer of from 2 to 5.
Formula I

In Formula I above,
n represents an integer from 2 to 5,
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[30" claim-type="Currently amended] The production method according to claim 29, wherein R ² and R ³ are each independently alkoxy groups having 1 to 4 carbon atoms.
[31" claim-type="Currently amended] The compound of claim 29 or 30, wherein the compound of formula I is Is a compound obtained by reacting a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst. Manufacturing method.
[32" claim-type="Currently amended] The production method according to claim 29 or 30, wherein the additive is a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, or a dehydrating agent.
[33" claim-type="Currently amended] 33. The compound of claim 29, 30 or 32, wherein the compound of formula I is Compound obtained by reacting a compound of formula HR, wherein R represents an alkoxy group having 1 to 4 carbon atoms, in the presence of an acid catalyst and an additive dehydrating agent to a compound of wherein n represents an integer of 2 to 5 Phosphorus manufacturing method.
[34" claim-type="Currently amended] 34. The process according to claim 29, 30, 32 or 33, wherein the dehydrating agent is an anhydride of an inorganic base.
[35" claim-type="Currently amended] 35. The process according to claim 32, 33 or 34, wherein the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.
[36" claim-type="Currently amended] The compound of claim 29 or 30, wherein the compound of formula I is In the presence of a catalytic amount of a compound of the formula HC (R) ₃ , wherein R represents an alkoxy group having 1 to 4 carbon atoms, which is an acid catalyst and an additive to a compound of the formula, wherein the compound of the formula HR, wherein R A compound obtained by reacting an alkoxy group).
[37" claim-type="Currently amended] 37. The process according to any one of claims 29 to 36, wherein the acid catalyst is a sulfonic acid compound.
[38" claim-type="Currently amended] 38. The process according to any one of claims 31 to 37, wherein R is an ethoxy group.
[39" claim-type="Currently amended] A process for preparing a compound of formula (II), characterized by reacting a compound of formula (VI) or a salt thereof and a cyanoating agent.
Formula I

Formula VI
H ₂ NR ¹
Formula II

In the above formulas (I), (VI) and (II),
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[40" claim-type="Currently amended] 40. The process of claim 39, wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin.
[41" claim-type="Currently amended] 40. The process of claim 39, wherein the cyanoating agent is hydrogen cyanide.
[42" claim-type="Currently amended] 40. The process according to claim 39, wherein the cyanoating agent is acetone cyanhydrin.
[43" claim-type="Currently amended] Reacting a compound of formula X with a compound of formula VI or a salt thereof and a cyanoating agent to give a compound of formula XI and oxidizing the compound to give a compound of formula II-ALD, wherein the compound is an acid catalyst Acetalizing agent is reacted in the presence of an additive in the presence of an additive as desired.
Formula X

Formula VI
H ₂ NR ¹
Formula XI

Formula II-ALD

Formula II

In each formula above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[44" claim-type="Currently amended] The method of claim 43, wherein the oxidizing agent is Collins reagent, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin or Periodinane.
[45" claim-type="Currently amended] The method of claim 43, wherein the oxidant is pyridinium chlorochromate.
[46" claim-type="Currently amended] 46. The process of any one of claims 43-45, wherein the compound of formula II is a compound of formula II-R.
Formula II-R

In Formula II-R above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R represents an alkoxy group having 1 to 4 carbon atoms.
[47" claim-type="Currently amended] 47. The compound of any one of claims 43-46, wherein the compound of formula II-R is a compound of formula HC (R) ₃ , wherein R is C 1 in the presence of an acid catalyst to the compound of formula II-ALD. To alkoxy groups of 4 to 4).
Formula II-ALD

[48" claim-type="Currently amended] 48. The process according to claim 46 or 47, wherein R is an ethoxy group.
[49" claim-type="Currently amended] 49. The process of any one of claims 43-48, wherein the acid catalyst is a sulfonic acid compound.
[50" claim-type="Currently amended] 50. The process according to any of claims 43 to 49, wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin.
[51" claim-type="Currently amended] The production process according to any one of claims 43 to 49, wherein the cyanoating agent is hydrogen cyanide.
[52" claim-type="Currently amended] The compound of any one of claims 43-51, wherein R ¹ is [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, And at least one group selected from the group consisting of a halogen atom and a nitro group as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[53" claim-type="Currently amended] A process for preparing a compound of formula III, characterized by reducing the cyano group of the compound of formula II or a salt thereof.
Formula II

Formula III

In the above formulas II and III,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[54" claim-type="Currently amended] 54. The process of claim 53 wherein the reduction is a reduction using catalytic hydrogenation or metal hydride.
[55" claim-type="Currently amended] 54. The method of claim 53, wherein the reduction is reduction using a catalytic hydrogenation reaction.
[56" claim-type="Currently amended] 56. The process of any one of claims 53-55, wherein the compound of formula III is stereochemically a single compound.
[57" claim-type="Currently amended] The compound of any one of claims 53-56 wherein the compound of Formula III is Wherein the definitions of n, R ¹ , R ^2, and R ³ are the same as the above definitions, respectively.
[58" claim-type="Currently amended] A process for the preparation of a compound of formula IV, characterized in that the compound of formula III or a salt thereof is closed.
Formula III

Formula IV

In Formulas III and IV above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[59" claim-type="Currently amended] 59. The process according to claim 58, wherein the compound of formula III is hydrolyzed in the presence of an acid catalyst, thereby closing the hydrolysis product obtained.
[60" claim-type="Currently amended] 60. The process of claim 59, wherein the hydrolysis product is a compound of Formula III-ALD.
Formula III-ALD

In the above formula III-ALD,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[61" claim-type="Currently amended] 61. The process of claim 60, wherein the acid catalyst is hydrochloric acid.
[62" claim-type="Currently amended] The production method according to any one of claims 58 to 61, wherein the ring closure reaction is a ring closure reaction carried out under neutral or basic conditions.
[63" claim-type="Currently amended] 63. The method of any one of claims 58-62, wherein the compound of formula IV is stereochemically a single compound.
[64" claim-type="Currently amended] 64. The compound of any of claims 58-63, wherein the compound of Formula IV is Wherein the definitions of n and R ¹ are the same as the definitions above, respectively.
[65" claim-type="Currently amended] 65. The process according to any one of claims 53 to 64, wherein R ² and R ³ are alkoxy groups having 1 to 4 carbon atoms.
[66" claim-type="Currently amended] 65. The process according to any one of claims 53 to 64, wherein R ² and R ³ are ethoxy groups.
[67" claim-type="Currently amended] A process for preparing a compound of formula VII, characterized by reducing the compound of formula IV.
Formula IV

Formula VII

In Formulas IV and VII above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [In the above formula, R ^a , R ^b and R ^c are each independently a phenyl group, benzyl group, naphthyl group (The aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, One or more kinds of groups selected from the group consisting of an alkoxy group, a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[68" claim-type="Currently amended] 67. The method of claim 67, wherein the reduction is a reduction using catalytic hydrogenation or metal hydride.
[69" claim-type="Currently amended] The method of claim 67, wherein the reduction is a catalytic hydrogenation reaction.
[70" claim-type="Currently amended] 68. The method of claim 67, wherein the catalyst is Raney nickel.
[71" claim-type="Currently amended] The method of any one of claims 67-70, wherein the compound of Formula VII is stereochemically a single compound.
[72" claim-type="Currently amended] The compound of any one of claims 67-71, wherein the compound of Formula VII is Wherein the definitions of n and R ¹ are the same as the definitions above, respectively.
[73" claim-type="Currently amended] A mixture of isomers based on the subtitle of the carbon atom to which the cyano group of the compound of formula II is bound, To treat mixtures in which the isomers of (where n, R ¹ , R ² and R ³ are the same as the above definitions) are less than the content of the other isomer and the content of the compound Method for producing an isomer mixture, characterized in that to increase the content of the isomer of.
Formula II

In Formula II above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[74" claim-type="Currently amended] 74. The method of claim 73, wherein the processing method is heating.
[75" claim-type="Currently amended] 75. The process of claim 73 or 74 wherein the treatment is heating in a polar solvent.
[76" claim-type="Currently amended] 76. The method of claim 75, wherein the polar solvent is an alcohol.
[77" claim-type="Currently amended] 77. The method of claim 76, wherein the alcohol is ethanol.
[78" claim-type="Currently amended] A compound of formula (II) is formed by reacting a compound of formula (VI) with a compound of formula (VI) or a salt thereof The isomeric compound remaining after separation of the isomeric compounds wherein n, R ¹ , R ² and R ³ are the same as defined above Isomerization of an isomer compound, wherein n, R ¹ , R ² and R ³ are the same as defined above, respectively. Wherein n, R ¹ , R ² and R ³ are the same as defined above, respectively.
Formula I

Formula VI
H ₂ NR ¹
Formula II

In the above formulas (I), (VI) and (II),
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[79" claim-type="Currently amended] 79. The process of claim 78, wherein the reaction is carried out in alcohol.
[80" claim-type="Currently amended] 79. The process of claim 78 or 79, wherein the cyanoating agent is hydrogen cyanide or acetone cyanhydrin.
[81" claim-type="Currently amended] 80. The process of claim 78 or 79, wherein the cyanoating agent is hydrogen cyanide.
[82" claim-type="Currently amended] 80. The method of claim 78 or 79, wherein the cyanoating agent is acetone cyanhydrin.
[83" claim-type="Currently amended] 84. The compound of any one of claims 78-82, wherein the compound of formula II The method for isolating isomer compounds, wherein n, R ¹ , R ^2, and R ³ are the same as defined above, is a method for depositing the isomer by adding water to the reaction mixture.
Formula II

In Formula II above,
n, R ¹ , R ² and R ³ are the same as defined above.
[84" claim-type="Currently amended] 84. The chemical formula of any one of claims 78-83, wherein The isomerization method of the isomer compound [where n, R <^1> , R <^2> and R <^3> is the same as the above definition, respectively] is a isomerization by heating.
[85" claim-type="Currently amended] 85. The method of any one of claims 13-84, wherein n is two.
[86" claim-type="Currently amended] The compound according to any one of claims 13 and 39 to 85, wherein R ^a , R ^b and R ^c are a methyl group, an ethyl group, a phenyl group, a 4-methylphenyl group, 4-methoxyphenyl group, 4-chlorophenyl group, A method for producing a group selected from the group consisting of 4-nitrophenyl group, 2,4-dichlorophenyl group, 2,4-dinitrophenyl group, 3,5-dichlorophenyl group, 3,5-dinitrophenyl group and naphthyl group.
[87" claim-type="Currently amended] 87. The method of any one of claims 13 and 39-86, wherein R ^a , R ^b and R ^c are different groups.
[88" claim-type="Currently amended] The substituent R ¹ is a (R) -1-phenylethyl group, (S) -1-phenylethyl group, or a (R) -1-phenylpropyl group according to any one of claims 13 and 39 to 87. , (S) -1-phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1 -(1-naphthyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl ) Ethyl group, (R) -1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1 -(4-nitrophenyl) ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2, 4-dinitrophenyl) ethyl group, (S) -1- (2,4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3, A method for producing a group selected from the group consisting of 5-dichlorophenyl) ethyl group, (R) -1- (3,5-dinitrophenyl) ethyl group and (S) -1- (3,5-dinitrophenyl) ethyl group.
[89" claim-type="Currently amended] The production method according to any one of claims 13 and 39 to 87, wherein the substituent R ¹ is a (R) -1-phenylethyl group or a (S) -1-phenylethyl group.
[90" claim-type="Currently amended] Compounds of formula (I).
Formula I

In Formula I above,
n represents an integer from 2 to 5,
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[91" claim-type="Currently amended] 91. The compound of claim 90, wherein R ² and R ³ are alkoxy groups having 1 to 4 carbon atoms.
[92" claim-type="Currently amended] 91. The compound of claim 90, wherein R ² and R ³ are ethoxy groups.
[93" claim-type="Currently amended] Compounds of formula II, salts thereof and hydrates thereof.
Formula II

In Formula II above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[94" claim-type="Currently amended] 95. The compound of claim 93, wherein the compound of formula II Compounds, salts thereof, and hydrates thereof, which are compounds of a stereo configuration of (wherein the definitions of n, R ¹ , R ^2, and R ³ are the same as defined above).
[95" claim-type="Currently amended] Compounds of formula (II-ALD), salts thereof and hydrates thereof.
Formula II-ALD

In Formula II-ALD above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[96" claim-type="Currently amended] 97. The compound of claim 95, wherein the compound of formula II-ALD is Compounds, salts thereof, and hydrates thereof, which are compounds of a stereo configuration of (wherein the definitions of n and R ¹ are the same as defined above, respectively).
[97" claim-type="Currently amended] Compounds of Formula III, salts thereof and hydrates thereof.
Formula III

In Formula III above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group can be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
R ² and R ³ each independently represent an alkoxy group having 1 to 4 carbon atoms, or together they represent a group of the formula -O- (CH ₂ ) _m -O-, where m represents an integer of 1 to 4 May be).
[98" claim-type="Currently amended] 98. The compound of claim 97, wherein the compound of formula III is Compounds, salts thereof, and hydrates thereof, which are compounds of a stereo configuration of (wherein the definitions of n, R ¹ , R ^2, and R ³ are the same as defined above).
[99" claim-type="Currently amended] 99. The compound or salt thereof according to claim 93, 94, 97 or 98, wherein R ² and R ³ are alkoxy groups having 1 to 4 carbon atoms.
[100" claim-type="Currently amended] 99. The compound or salt thereof according to claim 93, 94, 97 or 98, wherein R ² and R ³ are ethoxy groups.
[101" claim-type="Currently amended] Compounds of Formula III-ALD, salts thereof, and hydrates thereof.
Formula III-ALD

In the above formula III-ALD,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[102" claim-type="Currently amended] 102. The compound of claim 101, wherein the compound of Formula III-ALD is Compounds, salts thereof, and hydrates thereof, which are compounds of a stereo configuration of (wherein the definitions of n and R ¹ are the same as defined above, respectively).
[103" claim-type="Currently amended] Compounds of formula IV, salts thereof and hydrates thereof.
Formula IV

In Formula IV above,
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[104" claim-type="Currently amended] 107. The compound of claim 103, wherein the compound of formula IV is Compounds, salts thereof, and hydrates thereof, which are compounds of a stereo configuration of (wherein the definitions of n and R ¹ are the same as the above definitions respectively).
[105" claim-type="Currently amended] Compounds of formula (XI), salts thereof and hydrates thereof.
Formula XI

In the above formula (XI),
n represents an integer from 2 to 5,
R ¹ is a hydrogen atom or a chemical formula [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, benzyl group, naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen) At least one member selected from the group consisting of atoms and nitro groups may be used as a substituent), a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms.
[106" claim-type="Currently amended] 105. The compound of any one of claims 90-105, wherein n is 2, salts thereof and hydrates thereof.
[107" claim-type="Currently amended] 107. The compound of any of claims 93-106, wherein R ¹ is [Wherein R ^a , R ^b and R ^c are each independently a phenyl group, a benzyl group, a naphthyl group (the aryl group portion of these groups is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, At least one group selected from the group consisting of a halogen atom and a nitro group as a substituent), a hydrogen atom or an alkyl group having 1 to 4 carbon atoms], a salt thereof and a hydrate thereof.
[108" claim-type="Currently amended] 107. The compound of claim 107, ^a salt thereof and a hydrate thereof, wherein R ^a , R ^b and R ^c are of different groups.
[109" claim-type="Currently amended] 109. The method according to claim 107 or 108, wherein R ^a , R ^b and R ^c are hydrogen atom, methyl group, ethyl group, phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, 2 A compound, a salt thereof and a hydrate thereof, which is a substituent selected from the group consisting of a 4-dichlorophenyl group, a 2,4-dinitrophenyl group, a 3,5-dichlorophenyl group, a 3,5-dinitrophenyl group, and a naphthyl group.
[110" claim-type="Currently amended] The substituent R ¹ is a (R) -1-phenylethyl group, (S) -1-phenylethyl group, (R) -1-phenylpropyl group, or (S) according to any one of claims 107 to 109. -1-phenylpropyl group, (R) -1-phenyl-2- (p-tolyl) ethyl group, (S) -1-phenyl-2- (p-tolyl) ethyl group, (R) -1- (1- Naphthyl) ethyl group, (S) -1- (1-naphthyl) ethyl group, (R) -1- (4-methoxyphenyl) ethyl group, (S) -1- (4-methoxyphenyl) ethyl group, ( R) -1- (4-chlorophenyl) ethyl group, (S) -1- (4-chlorophenyl) ethyl group, (R) -1- (4-nitrophenyl) ethyl group, (S) -1- (4- Nitrophenyl) ethyl group, (R) -1- (2,4-dichlorophenyl) ethyl group, (S) -1- (2,4-dichlorophenyl) ethyl group, (R) -1- (2,4-dinitro Phenyl) ethyl group, (S) -1- (2,4-dinitrophenyl) ethyl group, (R) -1- (3,5-dichlorophenyl) ethyl group, (S) -1- (3,5-dichlorophenyl ) A group selected from the group consisting of an ethyl group, (R) -1- (3,5-dinitrophenyl) ethyl group and (S) -1- (3,5-dinitrophenyl) ethyl group, salts thereof, and their Luggage.
[111" claim-type="Currently amended] 109. The compound, a salt thereof, and a hydrate thereof according to any one of claims 107 to 109, wherein the substituent R ¹ is a (R) -1-phenylethyl group or a (S) -1-phenylethyl group.

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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:
2000-08-08|Priority to JPJP-P-2000-00239246

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2000-08-08|Priority to JP2000239246

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2001-02-05|Priority to JPJP-P-2001-00027632

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2001-02-05|Priority to JP2001027632

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2001-02-13|Priority to JP2001034779

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2001-02-13|Priority to JPJP-P-2001-00034779

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2001-02-21|Priority to JP2001044402

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2001-02-21|Priority to JPJP-P-2001-00044402

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2001-06-08|Priority to JP2001173426

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2001-06-08|Priority to JPJP-P-2001-00173426

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2001-08-07|Application filed by 다이이찌 세이야꾸 가부시기가이샤

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2001-08-07|Priority to PCT/JP2001/006786

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2003-04-23|Publication of KR20030031967A

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2009-05-07|Application granted

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2009-05-07|Publication of KR100895421B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-2000-00239246|2000-08-08|

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JP2000239246|2000-08-08|

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JPJP-P-2001-00027632|2001-02-05|

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JP2001027632|2001-02-05|

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JP2001034779|2001-02-13|

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JPJP-P-2001-00034779|2001-02-13|

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JP2001044402|2001-02-21|

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JPJP-P-2001-00044402|2001-02-21|

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JP2001173426|2001-06-08|

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JPJP-P-2001-00173426|2001-06-08|

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PCT/JP2001/006786|WO2002014278A1|2000-08-08|2001-08-07|Processes for preparation of bicyclic compounds and intermediates therefor|