Novel Pyrazine Derivatives or Salts Thereof, Pharmaceutical Composition Containing the Same, and Pro

专利摘要:
The pyrazine derivatives or salts thereof represented by the general formula [1] have excellent antiviral activity and are useful as therapeutic agents for the treatment of viral infections. (In the formulas, each symbol is defined in the specification.) In addition, the fluoropyrazine-carboxamide derivatives represented by the general formula [2] or salts thereof are useful as intermediates for the preparation of the compound of the general formula [1], and have 6-fluoro-3-hydroxy- which has antiviral action. The fluoropyrazine-carboxamide derivatives represented by 2-pyrazine-carboxamides are useful as intermediates for industrial production. (In the formulas, each symbol is defined in the specification.)
公开号:KR20030048108A
申请号:KR10-2003-7006077
申请日:2001-02-14
公开日:2003-06-18
发明作者:에가와히로유키；후루타유스케；스기타준；우에하라사유리；하마모토쇼이치；요네자와켄지
申请人:토야마 케미칼 컴퍼니 리미티드；
IPC主号:

专利说明:

Novel Pyrazine Derivatives or Salts Thereof, Pharmaceutical Composition Containing the Same, and Production Intermediates Thereof}
[1] The present invention relates to novel pyrazine derivatives or salts thereof, pharmaceutical compositions containing them, and intermediates for their preparation.
[2] As an antiviral agent used today clinically, Acyclovir and Vidarabine to inhibit herpesvirus, Ganciclovir and Foscarnet to inhibit Cytomegalovirus. ), And interferon for inhibiting Hepatitis virus. In addition, vaccine prevention is widely used to combat influenza virus, and low molecular compounds such as amantadine hydrochloride and ribavirin are also used. Janamivir has also been used recently.
[3] On the other hand, having a pyrazine ring as a base and acting as an antiviral of a nucleoside analogue or a nucleotide analogue, a compound of the following general formula is known so far.
[4]
[5] Wherein R ⁷ is a hydrogen atom, a methyl group or C ₁₀ H ₂₁ .
[6] However, this type of compound is known as "Visna virus activity" [nucleoside & nucleotides, Vol. 15, Nos. 11 and 12, Pages 1849-1861 (1996). In addition, nucleoside analogues and nucleotide analogues having pyrazine rings substituted with carbamoyl groups have not been reported so far.
[7] The problem of amantadine is that the mechanism of action is effective against influenza A but not effective against influenza B, and its resistant virus can be generated, and also cause neuropathy. Ribavirin, on the other hand, exhibits polymerase-inhibitory activity and is effective against influenza A and B, but when used orally, the clinical effect is insufficient.
[8] Therefore, it is desirable to develop antiviral agents that have an infection-preventing effect and exhibit therapeutic effects against various viruses, particularly influenza viruses.
[9] In PCT / JP99 / 04429 (WO00 / 10569), nitrogen-containing heterocyclic carbamoyl derivatives represented by the following general formula [22] and salts thereof are mentioned, which are useful as antiviral agents.
[10]
[11] Wherein A ring is a substituted or unsubstituted parazine, pyrimidine, pyridazine or triazine ring; R ²³ is O or OH; R ²⁴ is a hydrogen atom, an acyl group or a carbamoylalkyl group, and the dotted line is a single bond or a double Indicates a bond)
[12] In the present invention, the method for preparing the compound represented by the general formula [22] and the intermediate used in the preparation are mentioned, but as the intermediate for the preparation of the compound represented by the general formula [22], There is no explanation for usability. In the above specification, among the compounds of the general formula [22], the substituent of the pyrazine ring is a fluorine atom, and mainly the compound represented by the following general formula [23] is described.
[13]
[14] (In formula, A 'ring is a pyrazine ring and R <^23> , R <^24> and a dotted line are as above.)
[15] The compound is a good antiviral agent with strong antiinfluenza virus activity.
[16] In order to solve the above-mentioned problems, the present inventors studied in various ways. As a result, it was found that the pyrazine derivatives represented by the following general formula [1] or salts thereof had excellent antiviral activity. Based on this finding, the present invention has been carried out.
[17]
[18] Wherein R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom or a protected or unprotected monophosphate, diphosphate or triphosphate group; R ³ , R ^4, R ⁵ and R ⁶ may be the same or different; , A hydrogen atom, a halogen atom, an azido group, a substituted or unsubstituted hydroxyl group or an amino group, a protected or unprotected hydroxyl group or an amino group, or a bonding unit of R ⁴ and R ⁶ bonded to each other; A is an oxygen atom or a methylene group; n is 0 or 1; Y represents an oxygen atom, a sulfur atom or an NH group, R ¹ represents a hydrogen atom or a halogen atom; R ² represents a hydrogen atom; R ³ and R ⁵ represent a hydrogen atom; R ⁴ and R ⁶ represent a substituted or unsubstituted hydroxyl group, Or a protected or unprotected hydroxyl group; A is an oxygen atom; n is 0; and Y is an oxygen atom.)
[19] In addition, a fluoropyrazine-carbox which is used as an intermediate in the preparation of a fluoropyrazine derivative represented by the following general formula [21], or a salt thereof, wherein R ¹ is a fluorine atom represented by the general formula [1] It has been found to be used as an excellent intermediate for the industrial preparation of radiantide derivatives. Based on this finding, the present invention has been carried out.
[20]
[21] Wherein R ²¹ represents a hydrogen atom, a methyl group, a halogenated methyl group, a methyl group substituted with a protected or unprotected mercapto group, a formyl group, a nitrile group, a halogenated carbonyl group or a protected or unprotected hydroxymethyl, aminomethyl, carbamoyl or carboxyl group R ²² represents a hydrogen atom, a halogen atom, a protected or unprotected hydroxyl or amino group, a nitro group, an azido group or a substituted or unsubstituted phenylsulfanyl group, a phenylsulfinyl group or a phenylsulfonyl group, and R ²¹ represents a chamoyl group or acyl Carbamoyl group substituted with a group; and R ²² is a hydroxy group and R ²¹ is a hydrogen atom; and R ²² is a hydrogen atom is excluded.)
[22] In addition, the fluoropyrazine derivative represented by the general formula [21] or a salt thereof has an antiviral action and is used as an excellent intermediate for industrial preparation of the fluoropyrazine-carboxamide derivative represented by the general formula [23]. It turned out. Based on this finding, the present invention was carried out.
[23] EMBODIMENT OF THE INVENTION Below, this invention is demonstrated in detail.
[24] The meanings of the following terms used in the present specification are as follows unless otherwise defined. "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; "Halogenated methyl group" includes mono-, di-, or tri-substituted halogenated methyl groups such as fluoromethyl, chloromethyl, bromomethyl, iodine, dichloromethyl, trifluoromethyl and trichloromethyl; "Halogenated carbonyl group" includes a fluorocarbonyl, chlorocarbonyl, bromocarbonyl or iodocarbonyl group; "Lower alkyl group" includes C _1-5 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl; "Lower alkoxycarbonyl group" means methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- C _1-5 alkoxycarbonyl groups such as butoxycarbonyl and pentyloxycarbonyl; "Lower alkylamino group" includes mono- or di-C _1-5 alkylamine groups such as methylamine, ethylamine, propylamine, dimethylamine, diethylamine and methylethylamine; "Halogen-lower alkyl group" includes halogen-C _1-5 alkyl groups such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl and chloropropyl; "Lower alkenyl groups" include C _2-5 alkenyl groups such as vinyl and allyl; "Cycloalkyl group" refers to a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "Aryl group" includes a phenyl group, a naphthyl group, and the like; And “heterocyclic group” means azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolyl Nyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiazolyl, 1,2,4-thiazolyl, tithiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, mother Polyyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, cromenyl, indolinyl, isoindoleyl, indolyl, indazolyl, purinyl, quinolyl , Isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cynolinyl, phthalindinyl, isochromenyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolo Pyridyl, tetrazolopyridazinyl, Trizolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzthiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo [ 4-6 heterocyclic groups or condensed heteros containing at least one heteroatom selected from oxygen, nitrogen and sulfur atoms such as 1,2-b] [1,2,4] -triazinyl and quinuclidinyl It represents a cyclic group.
[25] When the mixture of the present invention and the preparation intermediate thereof have a hydroxyl group, a mercapto group, an amino group, a carbamoyl group or a carboxyl group, their substituents may be protected with known protecting groups.
[26] The term "monophosphate group", "diphosphate group" and "triphosphate group" mean groups represented by the following general formula.
[27]
[28] (Wherein K is 1, 2 and 3, respectively)
[29] As protecting groups for monophosphoric, diphosphoric and triphosphate groups, all groups which can be conventionally used for the protection of the phosphoric acid group can be mentioned. Lower alkyl groups such as methyl, cyclopropylmethyl, tert-butyl and ethane-1,2-diyl; Halogen-lower alkyl groups such as 2,2,2-trichloretyl, 2,2,2-trichloro-1,1-dimethylethyl and 2,2,2-tribromethyl; Acyl lower alkyl groups such as 1-acetylethyl; Cyano lower alkyl groups such as 2-cyanoethyl; Alkylsulfonyl lower alkyl groups such as 2-methylsulfonylethyl; Arylsulfonyl lower alkyl groups such as 2-phenylsulfonylethyl; Alkenyl groups such as allyl; Phenyl, o-hydroxyphenyl, o-chlorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, p-nitrophenyl, 2-dimethylamino-4-nitrophenyl, 2-tert-butylphenyl, 2-chloro Aryl groups such as methyl-4-nitrophenyl and o-phenylene; Ar-lower alkyl groups such as benzyl, o-nitrobenzyl and p-nitrophenylethyl; And heterocyclic groups such as 8-quinolyl and 5-chloro-8-quinolyl. One or more of the aforementioned protecting groups may be used for the protection.
[30] As the protecting group of the carboxyl group, all groups which can be conventionally used for protecting the carboxyl group can be mentioned. Lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl and tert-butyl; Aryl groups such as phenyl and naphthyl; Ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) -methyl; Acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; Oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; Halogen-lower alkyl groups such as 2,2,2-trichloretyl; Lower alkyl-silyl-alkyl groups such as 2- (trimethylsilyl) ethyl; Acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; Nitrogen-containing heterocyclic lower alkyl groups such as phthalimidomethyl and succinimidomethyl; Cycloalkyl groups such as cyclohexyl; Lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; Ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl; Lower alkylthio-lower alkyl groups such as methylthiomethyl and 2-methylthioethyl; Arylthio-lower alkyl groups such as phenylthiomethyl; Lower alkenyl groups of 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl and allyl; And lower alkyl-substituted such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl A silyl group can be mentioned.
[31] As protecting groups for amino and lower alkylamino groups, mention may be made of all groups which can be conventionally used for the protection of amino groups. For example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di- and tri-) Chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbon Carbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl and 8- Acyl groups such as quinolyloxycarbonyl; Ar-lower alkyl groups such as benzyl, diphenylmethyl and trityl; Arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio, alkanes or allen-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; Di-lower alkylamino-lower alkylidine groups such as N, N-dimethylaminomethylene; Ar-lower alkylidine groups such as benzilidine, 2-hydroxybenzylidine, 2-hydroxy-5-chlorobenzylidine and 2-hydroxy-1-naphthylmethylene; Nitrogen-containing heterocyclic alkylidine groups such as 3-hydroxy-4-pyridylmethylene; Cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentyridine, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxycyclohexylidene; Cycloalkylidine groups; Di-aryl or di-ar-lower alkyl phosphoryl groups such as diphenyl phosphoryl and dibenzylphosphoryl; Oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3, -dioxol-4-ylmethyl; And lower alkyl-substituted silyl groups such as trimethylsilyl group.
[32] As protecting groups for the hydroxy group and the mercapto group, any group that can be commonly used for protecting the hydroxy group can be mentioned. For example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl , Ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichlore Oxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) -ethoxycarbonyl, 2- (triphenylphosphonio) Ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbon Bonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxy An acyl group such as cetyl, pivaloyl and benzoyl; Lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichlorethyl and 2-trimethylsilylethyl; Lower alkenyl groups such as allyl; Ar-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; Oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; Lower alkoxy such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichlorethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and 1-ethoxyethyl And lower alkylthio-lower alkyl groups; Alkanes- or allene-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; Substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl; Substituted aryl groups such as hydroquinone and p-methoxyphenol; And enol-ether groups such as (2-methyl-3-oxo-1-cyclopenten-1-yl).
[33] As protecting group for the carbamoyl group, all groups conventionally used for protecting the carbamoyl group can be mentioned. Ar-lower alkyl groups such as benzyl, 4-methoxybenzyl and 2,4-dimethoxybenzyl; Lower alkoxyalkyl groups such as methoxymethyl; Ar-lower alkoxy groups such as benzyloxymethyl; substituted silyl lower alkoxy-lower alkyl groups such as tert-butyldimethylsiloxymethyl; Lower alkoxy groups such as methoxy; Ar-lower alkoxy groups such as benzyloxy; Lower alkylthio groups such as methylthio and triphenylmethylthio; Ar-lower alkylthio groups such as benzylthio; substituted silyl groups such as tert-butyldimethylsilyl; Aryl groups such as 4-methoxymethylphenyl, 4-methoxymethylphenyl and 2-methoxy-1-naphthyl; And acyl groups such as trichloroethoxycarbonyl, trifluoroacetyl and tert-butoxycarbonyl.
[34] As a substituent of the hydroxyl group represented by R <^3> , R <^4> , R <^5> , R <^6> , Z <^2> , Z <^3> , Z <^4> and Z <^5> which may be substituted, Protected or unprotected carboxyl group, lower alkyl group, lower alkoxycarbonyl group, Aryl groups, cycloalkyl groups, lower alkenyl groups, halogen-lower alkyl groups and heterocyclic groups can be mentioned. One or more selected from these substituents may be used for the substitution.
[35] As a substituent of the amino group represented by R ³ , R ⁴ , R ⁵ , R ⁶ , Z ² , Z ³ , Z ⁴ and Z ⁵ which may be substituted, a protected or unprotected carboxyl group, a hydroxyl group, an amino group and a lower alkylamino group , Lower alkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, aryl groups, cycloalkyl groups, lower alkenyl groups, halogen-lower alkyl groups and heterocyclic groups may be mentioned. One or more substituents selected from the aforementioned substituents may be used for the substitution.
[36] As substituents of the phenylsulfanyl group, phenylsulfinyl group and phenylsulfonyl group represented by R ²² , lower alkyl groups such as methyl and ethyl may be mentioned.
[37] As salts of the compounds of the general formulas [1] and [21], salts in basic groups such as amino groups and the like, and salts in acidic groups such as hydroxyl, phosphoryl or carboxyl groups are commonly mentioned. Can be. Salts in the basic group include inorganic acid salts such as hydrochloric acid, hydrobromic acid and sulfuric acid; Salts having organic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts having sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. As a salt in an acidic group, Salt which has alkali metals, such as sodium and potassium; Salts having alkaline earth metals containing calcium and magnesium; Aluminum salts; And trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dichlorohexylamine, procaine, dibenzylamine, N- And salts having a nitrogen-containing organic base such as benzyl-β-phenethylamine, 1-ephenamine and N, N'-dibenzylethylenediamine.
[38] Among the salts mentioned above, pharmacologically acceptable salts are more preferred.
[39] In some cases, the compounds of the general formulas [1] and [21] and salts thereof have isomers such as optical isomers, geometric isomers and tautomers. In such cases, the present invention includes these isomers and also includes solvates, hydrates and various crystals.
[40] Among the pharmaceutical compositions of the present invention, preferred are antiviral agents, more preferred are influenza virus, RS virus, AIDS virus, papilloma virus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, poliovirus, echo Antiviral agents that inhibit viruses, Cooksaki virus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus, and Japanese encephalitis virus. More preferred antiviral agents include antiviruses that inhibit rotavirus, RS virus and influenza virus. Particularly preferred ones include antiviral agents that inhibit influenza virus.
[41] Among the compounds of the present invention, preferred are those in which R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, hydrogen atoms, halogen atoms, substituted or unsubstituted or protected or unprotected hydroxyl groups, R ⁴ and R ⁶ is a compound and salt thereof that bind to each other to form a binding unit; More preferred are compounds wherein R ² is a hydrogen atom, a protected or unprotected monophosphate group, a protected or unprotected triphosphate group; More preferably R ² is a hydrogen atom or a protected or unprotected monophosphate group, R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, a hydrogen atom or a protected or unprotected hydroxyl group, and A is an oxygen atom And n is 0 and a salt thereof; Also particularly preferred are compounds in which R ² is a hydrogen atom and salts thereof.
[42] As the most preferable compound, a compound or a salt thereof, wherein R ¹ is a hydrogen atom, a chlorine atom or a fluorine atom; As a more preferable compound, the compound whose R <^1> is a hydrogen atom or a fluorine atom, and its salt are mentioned.
[43] Among the intermediate compounds of the present invention, preferred are those compounds in which R ²¹ is a hydrogen atom, a methyl group, a halogenated methyl group, a formyl group, a nitrile group, a halogenated carbonyl group or a protected or unprotected hydroxymenyl group, a protected or unprotected carbamoyl group, a protected or unprotected carboxyl group And salts thereof; More preferred are compounds and salts thereof, wherein R ²² is a protected or unprotected hydroxyl group, a protected or unprotected amino group, a halogen atom, a nitro group or an azido group; More preferred are compounds wherein R ²¹ is a methyl group, a halogenated methyl group, a formyl group, a carbamoyl group, a nitrile group, a halogenated carbonyl group, a protected or unprotected hydroxymethyl group or a protected or unprotected carboxyl group and salts thereof; Especially preferred are compounds and salts wherein R ²¹ is a halogenated methyl group, formyl group, carbamoyl group, nitrile group, halogenated carbonyl group, protected or unprotected hydroxymethyl group, or protected or unprotected carboxyl group; Most preferred are compounds and salts thereof in which R ²¹ is a carbamoyl group, a protected or unprotected carboxyl group, a nitrile group or a halogenated carbonyl group. However, among the above-mentioned compounds, compounds in which R ²¹ is a carbamoyl group substituted with a carbamoyl group or an acyl group and R ²² is a hydroxyl group and a compound in which R ²¹ is a hydrogen atom and R ²² is a hydrogen atom are excluded.
[44] Among the compounds of the present invention, typical ones include those listed in Table I-1, wherein "Bn" represents a benzyl group and "-" represents a binding unit.
[45]
[46] Table I-1
[47] R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ ANY HHHOHHOHO0NH HHHOHHOHO0S 6-FHHOHHOHO0NH 6-FHHOHHHO0O HHHOHHHO0O HHHOHHFO0O 6-FHHOHHNH ₂ O0O 6-FHHNH ₂ HOHO0O 6-FHHOHOHHO0O HHHOHHNH ₂ O0O HHHMH ₂ HOHO0O HHHOHOHHO0O HHHOHFHO0O HHHOHN ₃ HO0O 6-FHHN ₃ HHO0O 6-FHHHHHO0O 6-F(HO) ₂ POHOHHOHO0O HHHN ₃ HHO0O HHHHHHO0O H(HO) ₂ POHOHHOHO0O H(BnO) ₂ POHOHHOHO0O 6-FHHOHHOHCH ₂ 0O HHHOHHOHCH ₂ 0O HHHOHOHHCH ₂ 0O HHHHHHCH ₂ 0O HHH-H-CH ₂ 0O HHHOHHHOOneO HHHOHHOHOOneO 6-FH [OP (O) OH] ₃ HOHHOHO0O HH [OP (O) OH] ₃ HOHHOHO0O 6-F[CH ₂ = CHCH ₂ O] P (O)HOHHOHO0O H[CH ₂ = CHCH ₂ O] P (O)HOHHOHO0O
[48] Representative intermediates of the compounds of the present invention are shown in Tables II-1 to 5, wherein "Et" is an ethyl group, "Ac" is an acetyl group, "Ph" is a phenyl group, "Bz" is a benzoyl group, "tBu "Is a tert-butyl group," OPh (p-OH) "is a parahydroxyphenyloxy group, and" C ₆ H ₇ O "represents a 2-methyl-3-oxo-1-cyclopenten-1-yl group. .
[49] TABLE II-1
[50] R ²¹ R ²²HOCH ₃HNH ₂CH ₃ H CH ₃ OH CH ₃ OCH ₃CH ₃ NH ₂CH ₃ F CH ₂ 0HH CH ₂ 0HOH CH ₂ 0HOCH ₃CH ₂ 0HNH ₂CH ₂ 0HF CH ₂ ClH CH ₂ ClOH CH ₂ ClOCH ₃CH ₂ ClNH ₂CH ₂ ClF CH ₂ BrH CH ₂ BrOH CH ₂ BrNH ₂
[51] TABLE II-2
[52] R ²¹ R ²²CHOH CHOOH CHOOCH ₃CHONH ₂CHOF CONH ₂ H CONH ₂ OCH ₃CONH ₂ NH ₂CONH ₂ Cl CONH ₂ F CONH ₂ NO ₂CONH ₂ N ₃COOHH COOHOH COOHOCH ₃COOHNH ₂COOHF COOHNO ₂COOHN ₃
[53] Table II-3
[54] R ²¹ R ²²COOCH ₃ H COOCH ₃ OH COOCH ₃ OCH ₃COOCH ₃ NH ₂COOCH ₃ F COOCH ₃ NO ₂COOEtH COOEtOH COOEtOCH ₃CNH CNOH CNOCH ₃CNNH ₂CNF CNNO ₂CNN ₃CNOCH ₂ Ph CNOCH ₂ CH = CH ₂CNOPh (p-OH) CNSPh CNSOPh CNSO ₂ Ph CNOSO ₂ CH ₃CNOC ₆ H ₇ O COClOH COClOCH ₃COClNH ₂COClF COFOCH ₃COFNH ₂COFF
[55] Table II-4
[56] R ²¹ R ²²CONHAcH CONHAcOCH ₃CONHAcNH ₂CONHAcCl CONHAcF CONHAcNO ₂CONHAcN ₃CONHBzOCH ₃CONHBzNH ₂CONHBzCl CONHBzF CONHBzNO ₂CONHBzN ₃CONHC (O) tBuOCH ₃CONHC (O) tBuNH ₂CONHC (O) tBuCl CONHC (O) tBuF CONHC (O) tBuNO ₂CONHC (O) tBuN ₃
[57] Table II-5
[58] R ²¹ R ²²CONHCH ₂ PhOCH ₃CONHCH ₂ PhNH ₂CONHCH ₂ PhCl CONHCH ₂ PhF CONHCH ₂ PhNO ₂CONHCH ₂ PhN ₃CONHCH ₂ OCH ₂ PhOCH ₃CONHCH ₂ OCH ₂ PhNH ₂CONHCH ₂ OCH ₂ PhCl CONHCH ₂ OCH ₂ PhF CONHCH ₂ OCH ₂ PhNO ₂CONHCH ₂ OCH ₂ PhN ₃
[59] Below, the manufacturing method of the compound of this invention is described.
[60] The compounds of the present invention can be prepared in the following Preparation Methods I-1 to 4.
[61] (Manufacturing Method I-1)
[62]
[63] Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Y and n are the same as defined above; R ⁸ is a lower alkyl group; Z ¹ is a hydrogen atom or a protecting group of a hydroxy group Z ² , Z ³ , Z ⁴ and Z ⁵ may be the same or different and represent a hydrogen atom, a halogen atom, an azido group, a protected hydroxy group or an amino group; and Z ³ and Z ⁵ may be bonded to each other to form a bonding unit. Can form.)
[64] (a) The compound of the general formula [1a] or a salt thereof can be obtained by applying the general formula [2a] or a salt thereof to a de-protecting reaction.
[65] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more.
[66] As a de-protecting agent, reagents used for deprotection of hydroxyl groups, amino groups and phosphoric acid groups can be used. Preferably, bases such as sodium methoxide, hydrogen gas, ammonia gas, ammonia water and butylamine; Acids such as formic acid, aqueous acetic acid, aqueous trifluoroacetic acid and hydrochloric acid; Palladium catalysts such as tetrakis-triphenylphosphine palladium (O); And phosphines such as triphenylphosphine. These deprotectants may be used in combination, or may be prepared in a reaction system. The deprotecting agent is used in an amount of at least 0.01 mol or more per mol of the compound of the formula [2a] or a salt thereof. If necessary, the deprotecting agent may be used as a solvent.
[67] The deprotection reaction is generally carried out at a temperature of -50 ° C to 170 ° C, preferably -20 ° C to 100 ° C for 1 minute to 100 hours, preferably 5 minutes to 50 hours.
[68] (b) A compound of formula [1a], or a salt thereof, wherein Y is an oxygen atom, by applying the compound of formula [2b] or a salt thereof to the ammonolysis reaction of a carboxylic ester with or without a catalyst; You can get it.
[69] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more. This reaction can be carried out with the reagents under conditions conventionally used for the ammonolytic reaction of aromatic carboxylic acid esters. However, preferably, ammonia gas, liquid ammonia or ammonia water is used. These reagents use an amount of at least 0.5 moles or more per mole of the compound of the formula [2b] or a salt thereof. In some cases, the reagent may also be used as a solvent. As necessary, catalysts that can be used in the present reaction include ammonium salts such as ammonium chloride; Bases such as sodium methoxide and butyliridium; And alkali metal amides such as sodium amide. The amount of these catalysts used is 0.01 to 100 mol, preferably 0.01 to 20 mol, per mol of the compound of the general formula [2b] or a salt thereof.
[70] The reaction is generally carried out at a temperature of -100 ° C to 250 ° C, preferably -78 ° C to 100 ° C, for 1 minute to 72 hours, preferably for 30 minutes to 50 hours.
[71] (Manufacturing Method I-2)
[72]
[73] Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , Z ² , Z ³ , Z ⁴ , Z ⁵ , A, n and Y are the same as defined above; R ⁹ Is a protected or unprotected monophosphate, or a protected or unprotected monophosphate chloride, and R ¹² represents a protected or unprotected diphosphate group, or a protected or unprotected triphosphate group.)
[74] (a) The compound of formula [2c] or a salt thereof can be obtained by protecting the compound of formula [2b] or a salt thereof with a reagent in the presence or absence of an acidic catalyst or base.
[75] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone; And water. The solvents may be used alone or in a mixture of two or more.
[76] As the reagent, those generally used for the protection of hydroxy groups and amino groups can be used, and preferably 2,2-dimethoxypropane, acetyl chloride and benzoyl chloride are used. If necessary, these reagents are prepared in the reaction system. The amount of the reagent is at least the same amount, preferably 0.01 to 10 moles or more, per mole of the compound of the formula [2b] or a salt thereof.
[77] As the acidic catalyst or base used in the reaction, p-toluenesulfonic acid, triethyleneamine and the like can be mentioned. The amount is used in an amount of 0.01 to 10 mol, preferably 0.05 to 10 mol, per mole of the general formula [2b] compound or salt thereof.
[78] The reaction is generally carried out at a temperature of -50 ° C to 170 ° C, preferably 0 ° C to 150 ° C for 1 minute to 24 hours, preferably 5 minutes to 10 hours.
[79] (b) Compounds of the general formula [2d] or salts thereof include the compounds of the general formula [2c] or salts thereof and phosphorylating agent by Jikken Kagaku Koza, 4th edition, Vol. 22, Pages 313-438 (edited by Chemical Society Japan, 1992) (1) reacted with or without an additive, or (2) after reacting with a phosphating agent, and then again with an oxidizing agent. It can be obtained by reacting.
[80] In the method (1), the solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; And pyridine. These solvents may be used alone or in a mixture of two or more.
[81] As the phosphorylation agent used in the reaction, a reagent generally used for phosphorylation of a hydroxyl group can be used. Examples of such phosphorylating agents include phosphoric acid diesters such as dibenzyl phosphate; Phosphoric acid dithioesters such as monocyclohexyl ammonium S, S'-diphenylphosphorodithioate; And phosphoric acid chlorides such as phosphoryl chloride and diallyl chlorophosphonate. The phosphorylating agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the formula [2c] or a salt thereof. Examples of the additive include azo compounds such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; Phosphines such as triphenylphosphine; Allenesulfonic acid chlorides such as 2,4,6-triisopropylbenzenesulfonic acid chloride; And bases such as pyridine and tert-butylmagnesium chloride. If necessary, these additives may be mixed and used. The additive is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the general formula [2c] or a salt thereof.
[82] The reaction is generally carried out for 1 minute to 72 hours, preferably 5 minutes to 24 hours at a temperature of -50 ° C to 170 ° C, preferably 0 ° C to 100 ° C.
[83] In the method (2), the solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and diethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; And pyridine. These solvents may be used alone or in a mixture of two or more.
[84] As the phosphitizing agent used in the reaction, a reagent generally used in the ignition reaction of a hydroxyl group can be used. Examples of such a phosphorizing agent include phosphoramidites such as diallyl diisopropylphosphoramidite and phosphoric acid chlorides such as diallylphosphorochloridite. The phosphorus agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 3.0 moles or more, per mole of the compound of the formula [2c] and salts thereof. The additives include tetrazole compounds such as 1H-tetrazole and bases such as pyridine and collidine, and these additives may be used in combination depending on the case. The additive may be used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of formula [2c] or a salt thereof.
[85] Examples of the oxidant used in the reaction include peroxides such as m-chloroperbenzoic acid and tert-butyl hydroperoxide and halides such as iodine. The oxidizing agent may be used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of formula [2c] or a salt thereof.
[86] The reaction is carried out at a temperature of -78 ° C to 100 ° C, preferably -50 ° C to 50 ° C for 1 minute to 24 hours, preferably 5 minutes to 6 hours.
[87] (c) The compound of the general formula [1b] and its salt can be obtained through the reaction according to Preparation Method I-1 (b) using the compound of the general formula [2d] and the salt thereof.
[88] (d) The compound of the general formula [1c] and its salt can be obtained through the reaction according to Preparation Method I-1 (a) using the compound of the general formula [1b] and the salt thereof.
[89] (e) The compound of the general formula [1b] and its salt can be obtained through the reaction according to Preparation Method I-2 (b) using the compound of the general formula [1d] and the salt thereof.
[90] (f) Compounds of the general formula [1e] and salts thereof include compounds of the general formula [1c] and salts thereof. Rev., Vol. 100, Pages 2047 to 2049, 2000, by reacting with a phosphating agent in the presence or absence of a condensing agent.
[91] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-diethylacetamide; Sulfoxides such as dimethyl sulfoxide; And pyridine. These solvents may be used alone or in admixture of two or more.
[92] As a phosphorylation agent used for this reaction, the reagent generally used for the phosphorylation reaction of a monophosphate group can be used. Such phosphorylating agents include phosphoric acid such as tri-n-butylammonium phosphate and n-butylammonium phosphate, and these phosphorylating agents can be synthesized in the reaction system as the case may be. The phosphorylating agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 10 moles or more, per mole of the compound of the general formula [1c] or a salt thereof. As the condensing agent, imidazoles such as N, N-carbonyldiimidazole and N-methylimidazole and amines such as morpholine and diisopropylamine may be used, and in some cases, the amines may be mixed and used. have. The condensing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the general formula [1c] or a salt thereof.
[93] The reaction can generally be carried out at a temperature of -50 ° C to 100 ° C, preferably 0 ° C to 50 ° C, for 1 minute to 72 hours, preferably 5 minutes to 24 hours.
[94] (Manufacturing Method I-3)
[95]
[96] Wherein R ¹ , R ⁸ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are the same as defined above; Y ¹ is an oxygen atom or an NH group; R ¹⁰ is halogen Atom, carbonyloxy group or sulfonyloxy group.)
[97] (a) A compound of the general formula [2a] or a salt thereof is prepared by using the compound of the general formula [3a] or a salt thereof in the presence or absence of an additive according to (1) a commonly used silylation method. ] And a salt thereof, followed by reaction with (2) the compound of the general formula [4a] and a salt thereof in the presence or absence of a Lewis acid.
[98] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-diethylacetamide; Sulfoxides such as dimethyl sulfoxide; And halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane. These solvents may be used alone or in admixture of two or more.
[99] As the silylating agent used in the reaction (1), any silylating agent generally used for silylenol etherification of a carbonyl group may be used. Such silylating agents include 1,1,1,3,3,3-hexamethyldisilazane, N, O-bis (trimethylsilyl) acetamide, trimethylsilyl chloride and the like. The silylating agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 10.0 moles or more, per mole of the compound of the general formula [3a] or a salt thereof.
[100] As the additive which can be used in the present reaction as necessary, ammonium sulfate or the like can be mentioned. The amount of 0.01 to 10.0 moles, preferably 0.05 to 5.0 moles, per mole of the general formula [3a] or salt thereof of the additive is used.
[101] The reaction is generally carried out at a temperature of 0 to 200 캜, preferably 0 to 150 캜 for 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
[102] In the reaction (2), the compound of the formula [4a] or a salt thereof is used in an amount of 0.5 to 10 moles, preferably 0.5 to 5 moles per one mole of the compound of the formula [3a] or a salt thereof.
[103] As the Lewis acid which can be used in the present reaction as necessary, trimethylsilyltrifluoromethanesulfonic acid, tin tin (IV) chloride, titanium chloride (IV), zinc chloride and the like can be mentioned. The Lewis acid is used in an amount of at least 0.5 moles or more, preferably 0.5 to 10 moles or more, per mole of the compound of the general formula [3a] or a salt thereof.
[104] The reaction is generally carried out at a temperature of 0 to 100 ° C., preferably 0 to 50 ° C. for 1 minute to 72 hours, preferably 5 minutes to 24 hours.
[105] (b) A compound of the general formula [2a] or a salt thereof is a compound of the general formula [4a] using a base of the general formula [3a] or a salt thereof as a de-acidifying agent in the presence or absence of an additive. Or by reacting with the salt.
[106] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Such solvents include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; And sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more.
[107] As the base used in the reaction, triethylamine, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and the like can be mentioned. In the above reaction, the compound of the formula [4b] or a salt thereof is used in an amount of 0.1 to 5 moles, preferably 0.2 to 2 moles per one mole of the compound of the formula [3a] or the salt thereof. In this reaction, the base is used in an amount of 0.1 to 10 moles, preferably 0.2 to 10 moles per one mole of the compound of the general formula [3a] or a salt thereof.
[108] Additives that can be used in the reaction, if necessary, include palladium catalysts such as tetrakis-triphenylphosphine palladium; Phosphines such as triphenylphosphine; And polyethers such as 18-crown-6-ether and the like. The additive is used in an amount of 0.01 to 10 mol, preferably 0.03 to 5.0 mol, per mol of the compound of the general formula [3a] or a salt thereof.
[109] The reaction is generally carried out at a temperature of -50 ° C to 170 ° C, preferably 0 ° C to 120 ° C for 1 minute to 72 hours, preferably 5 to 24 hours.
[110] (Manufacturing Method I-4)
[111]
[112] (Wherein R ¹ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are the same as above).
[113] Compounds of the general formula [2 g] or salts thereof are prepared by Shin Jikken Kagaku Koza, Vol. 14, a compound or a salt thereof of the general formula [2f] in the presence or absence of a base, according to the method described in the specification of Chemical Society Japan (Edition, 1978), a thionizing agent. It can be obtained by reacting with.
[114] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; And sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more.
[115] As the thiation agent used in the reaction, a reagent generally used in the thiation reaction of amic acid can be used. Examples thereof include hydrogen sulfide gas, phosphorus pentasulphide, and Lawson reagents. The amount of the thionizing agent used in the reaction is used in an amount of 0.1 to 10 mol, preferably 0.2 to 5.0 mol, per mol of the compound of the general formula [2f] or a salt thereof.
[116] Bases used in the reaction include ammonia, triethylamine, morpholine, pyridine and 4-dimethylaminopyridine. In the above reaction, the amount of base is used at least 0.01 mol or more per mol of the compound of the formula [2f] or a salt thereof. If necessary, the base may be used as a solvent.
[117] The reaction is generally carried out at a temperature of -50 ° C to 170 ° C, preferably 0 ° C to 120 ° C for 1 minute to 24 hours, preferably 5 minutes to 6 hours.
[118] Below, the compound of the general formula [2a], [2b], [3a '] and [3j] which are the raw materials which are necessary for the preparation of the compound of this invention, and its manufacturing method are described.
[119] Compounds of the general formulas [2a], [2b], [3a '] and [3j] can be prepared according to known methods as they are or by appropriately mixing the methods. For example, these compounds can be prepared according to the following preparation method I-A.
[120] (Manufacturing Method I-A)
[121]
[122] Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ¹⁰ are as defined above .)
[123] (a) A compound of the general formula [2e] or a salt thereof can be obtained by reacting a compound of the general formula [3c] and a salt thereof with the compound of the general formula [4a] and its salt according to the preparation method I-3 (a). have.
[124] (b) A compound of the general formula [2e] or a salt thereof can be obtained by reacting a compound of the general formula [3c] and a salt thereof with the compound of the general formula [4b] and its salt according to the preparation method I-3 (b). have.
[125] (c) The compound of the general formula [2b] or a salt thereof can be obtained by reacting the compound of the general formula [2e] and the salt thereof according to the preparation method I-1 (a).
[126] Among the reaction raw materials mentioned above, the compound of the general formula [3c] or a salt thereof is described in J. Heterocyclic Chem., Vol. 34, No. 1, Pages 27-32 (1997) or J. Med. Chem., Vol. 12, No. 2, Pages 285-287 (1969); The compound of formula [4a] or a salt thereof is described in J. Med. Chem., Vol. 28, No. 7, Pages 904-910 (1985), and the compounds of the general formula [4b] or salts thereof are described in J. Chem. Soc. PERKIN TRANS. 1, Pages 2419-2425 (1992), J. Med. Chem., Vol. 36, No. 14, Pages 2033-2040 (1993) or Bio. Med. Chem. Lett., Vol. 6, No. 13, Pages 1457-1460 (1996).
[127] (Manufacturing Method I-B)
[128]
[129] (Wherein R ⁸ is the same as defined above; R ^1a is a halogen atom; R ¹¹ is a protecting group of a hydroxyl group; and X represents a halogen atom other than a fluorine atom.)
[130] (a) The compound of the general formula [3f] or a salt thereof can be obtained by reacting the compound of the general formula [3e] or a salt thereof with a diazotizing or alcohol.
[131] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. These solvents include inorganic acids such as sulfuric acid, hydrochloric acid and nitric acid; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amines or amine oxides such as triethylamine, N, N-dimethylaniline and pyridine-N-oxide; Ketones such as acetone; Alcohols such as methanol and ethanol; And water. If necessary, these solvents can be used as a mixture. The diazotization agent used for this invention will not be specifically limited if it is what is normally used for the diazotization reaction of an aromatic amino compound. However, preference is given to using nitrites of alkaline earth metals such as sodium nitrite. The diazotizing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the general formula [3e] or a salt thereof.
[132] As the alcohol used in the reaction, methanol and the like can be mentioned. The alcohol is used in the compound of the formula [3e] or a salt thereof at least the same equivalent or more. Moreover, the said alcohol can also be used as a solvent as needed.
[133] The invention is carried out for 1 minute to 24 hours, preferably 30 minutes to 10 hours at a temperature of -70 ° C to 200 ° C, preferably -50 ° C to 100 ° C.
[134] (b) A compound of the general formula [3g] or a salt thereof is described by Tetrahedron Letters, Vol 38, No. 36, Pages 6367-6370 (1997), which can be obtained by (1) reacting with imine using a base as a deoxidizer in the presence of a catalyst and then (2) hydrolyzing in the presence of an additive.
[135] In the above reaction (1), the solvent used for the reaction is not particularly limited, unless it causes any side effects in the present reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; And ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve. These solvents may be used alone or as a mixture of two or more.
[136] Examples of the catalyst used in the reaction include palladium catalysts such as palladium (II) acetate and tri (dibenzylidene-acetone) dipalladium, nickel catalysts such as bis (1,5-cyclooctadiene) -nickel (O), and 1 Phosphine ligands such as 1'-bis (diphenylphosphino) -ferrocene or (s)-(-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl; Can be selected from combinations. The amount of the catalyst is used in 0.001 to 1.0 mol, preferably 0.002 to 0.5 mol per mol of the compound of the general formula [3f] or a salt thereof.
[137] As the base used in the reaction, alkali metal salts such as sodium tert-butoxide and cesium carbonate may be mentioned. The amount of the base is used in at least the same equivalent or more, preferably 1.0 to 3.0 mol or more, per mol of the compound of the general formula [3f] or a salt thereof.
[138] As the imine used in the reaction, benzophenoneimine and the like can be mentioned. The imine is used in an amount of at least the same equivalent or more, preferably 1.0 to 3.0 moles or more, per mole of the compound of the general formula [3f] or a salt thereof.
[139] The reaction is generally carried out at a temperature of 0 ° C to 120 ° C, preferably 5 ° C to 100 ° C for 1 minute to 48 hours, preferably 5 minutes to 24 hours.
[140] (2) In the reaction (2), the solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Solvents that can be used include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Alcohols such as methanol and ethanol; And water. These solvents may be used alone or as a mixture of two or more.
[141] Examples of the additive used in the reaction include organic or inorganic acid salts such as sodium acetate, hydroxylamine hydrochloride and ammonium formate; Inorganic acids such as hydrochloric acid; Palladium catalysts such as palladium-carbon and the like can be mentioned. If necessary, these additives can be mixed and used. The additive is used in an amount of 0.01 to 50 moles, preferably 0.1 to 20 moles per one mole of the compound of the general formula [3f] or a salt thereof.
[142] The reaction is generally carried out at a temperature of 0 ° C to 120 ° C, preferably 5 ° C to 100 ° C for 1 minute to 48 hours, preferably 3 minutes to 24 hours.
[143] (c) The compound of the general formula [3h] or a salt thereof can be obtained by reacting the compound of the general formula [3g] and the salt thereof according to Preparation Method I-1 (b).
[144] (d) The compound of formula [3i] or a salt thereof may be prepared by the method described in Fusso Kagaku Nyumon, Pages 219-230 (Nippon Gakujutsu Shinkokai, 155 Fluorine Chemistry Comittee, 1997). And in the presence of an acid, in the presence or absence of an additive, an amino group can be obtained by de-amination with a diazotizing agent, and then by adding its fluorination.
[145] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Solvents that can be used include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amine oxides such as triethylamine, N, N-dimethylaniline, pyridine and pyridine-N-oxide; Ketones such as acetone; And water. These solvents may optionally be used in mixtures.
[146] The diazotization agent used for this reaction can be any reagent conventionally used for the diazotization reaction of an aromatic amine compound. As a more preferable diazotizing agent, the alkali metal salt of nitrous acid, such as sodium nitrite, is mentioned. The diazotizing agent may be used in the same equivalent amount, preferably 1.0 to 5.0 mol, and more preferably 1.0 to 1.5 mol, per mol of the compound of the general formula [3h] or a salt thereof.
[147] The acid used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include acids such as hydrochloric acid, hydrofluoric acid and hydrogen fluoride; And base solutions of hydrogen fluoride solutions such as pyridine of hydrogen fluoride solution. If desired, these acids may be used in mixtures.
[148] In the above reaction, the amount of acid used may be used at least 1 ml, preferably 1-50 ml, in a weight capacity ratio (ml / g) relative to the compound of the general formula [3h] or a salt thereof (g).
[149] Examples of the additive used in the reaction include hydrogen borohydride, sodium tetrafluoride and ammonium hydrogen fluoride. The amount of the acid is used at least the same equivalent or more, preferably 1.0 to 20.0 moles or more, per mole of the compound of the general formula [3h] or a salt thereof.
[150] The present reaction is generally carried out at a temperature of -70 ° C to 100 ° C, preferably -60 ° C to 30 ° C, for 50 minutes to 24 hours, preferably 1 hour to 10 hours.
[151] (e) A compound of the general formula [3i] or a salt thereof can be obtained by reacting a compound of the general formula [3f] or a salt thereof according to Production Method I-1 (b).
[152] (f) The compound of the general formula [3a '] or a salt thereof can be obtained by reacting the compound of the general formula [3i] and its salt with a deprotection agent.
[153] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Such as water; Alcohols such as methanol, ethanol and propanol; Thioalcohols such as ethanethiol and thiophenol; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Thio ethers such as dimethyl sulfide; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Inorganic acids such as sulfuric acid and hydrochloric acid; Carboxylic acids such as acetic acid and trifluoroacetic acid; Sulfonic acids such as trifluoromethanesulfonic acid; Organic bases such as pyridine and triethylamine; And water. These solvents may be used alone or in a mixture of two or more.
[154] As the deprotection agent, a reagent generally used for deprotection of a protected aromatic alcohol may be used. Preferred examples include trimethylsilyl iodide and the like. It is also possible to produce deprotectants in the reaction system. The amount of the deprotecting agent is used in an amount of 0.01 to 50 mol, preferably 0.1 to 30 mol, per mol of the compound of the general formula [3i] or a salt thereof.
[155] The reaction is generally carried out at a temperature of -80 ° C to 200 ° C, preferably 0 ° C to 160 ° C for 1 minute to 48 hours, preferably 5 minutes to 20 hours.
[156] The compound of the general formula [3e] or a salt thereof, which is a starting material of the above-mentioned reaction, is described in J. Am. Chem. Soc., Vol. 71, Pages 2798-2800 (1949).
[157] (Manufacturing Method I-C)
[158]
[159] (Wherein R ¹ is the same as defined above and R ¹³ represents a lower alkoxy group or an aryloxy group.)
[160] (a) Compounds of the general formula [3k] or salts thereof are described in Shin Jikken Kagaku Koza, Vol. 14, Pages 1599-1622 (Compiled by Chemical Society Japan, 1978), obtained by reacting a compound of the general formula [3l] or a salt thereof with an alcohol in the presence or absence of an acidic catalyst or base. Can be.
[161] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As these solvents, Aromatic hydrocarbons, such as benzene, toluene, and xylene; Halogenated hydrocarbons of methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; And sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in mixture of two or more.
[162] Alcohols used in the reaction may be mentioned methanol, ethanol, phenol and the like. The alcohol may be used in at least the same equivalent or more based on the compound of the general formula [3] or a salt thereof. If necessary, the alcohol may be used as the solvent.
[163] As the acidic catalyst used in the reaction, a reagent generally used in the imidization reaction of nitrile may be used. For example, hydrogen chloride or the like can be used for this purpose. The acidic catalyst is used in an amount of at least 0.1 mole or more per mole of the compound of the general formula [3l] or a salt thereof.
[164] As a base used for the said reaction, metal alkoxides, such as sodium methoxide, sodium ethoxide, and sodium phenoxide, are mentioned. If necessary, these bases may be prepared in the reaction system. In the present reaction, the base is used at least 0.01 mole, preferably 1.0 mole to 5.0 mole or more, per mole of the compound of the formula [3l] or a salt thereof.
[165] The reaction is generally carried out at a temperature of -78 ° C to 170 ° C, preferably -40 ° C to 120 ° C for 1 minute to 72 hours, preferably 5 minutes to 24 hours.
[166] (b) A compound of the general formula [3j] or a salt thereof is prepared by Shin Jikken Kagaku Koza, Vol. 14, Pages 1614 to 1617 (edited by Chemical Society Japan, 1978) can be obtained by reacting a compound of the general formula [3k] or a salt thereof with a reagent.
[167] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, terahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; And sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in a mixture of two or more.
[168] As the reagent used in the reaction, a reagent generally used for amidation of imidate may be used. Examples of the reagents include acid ammonium salts such as ammonia gas, ammoniacal alcohol solution, ammonia water and ammonium chloride. The reagent is used in at least the same equivalent amount or more based on the compound of formula [3k] or a salt thereof. If necessary, the reagent may be used as a solvent.
[169] The reaction is generally carried out at a temperature of -78 ° C to 170 ° C, preferably 0 ° C to 120 ° C for 1 minute to 72 hours, preferably 5 minutes to 24 hours.
[170] (Manufacturing Method I-D)
[171]
[172] ^Wherein R ^1a is as defined above.
[173] (a) A compound of the general formula [3m] or a salt thereof is prepared by Shin Jikken Kagaku Koza, Vol 14, Pages 537 to 538 (the Chemical Society Japan), 1977. Following the process described in), it can be prepared by reacting with a diazotizing agent and a hydroxylating agent in the presence or absence of an additive.
[174] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. These solvents include inorganic acids such as sulfuric acid, hydrochloric acid and nitric acid; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrogen carbonates such as dichloromethane, chloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amines and amine oxides such as triethylamine, N, N-dimethylaniline and pyridine-N-oxide; Ketones such as acetone; And water. These solvents may be used alone or in mixtures.
[175] The diazotizing agent used for the said reaction will not be specifically limited if it is what is normally used for the deamino-hydroxylation reaction of an aromatic amino compound. However, it is preferable to use alkali metal nitrites such as sodium nitrite. The diazotizing agent is used in an amount of at least the same equivalent, preferably 1.0 to 5.0 mol, more preferably 1.0 to 2.0 mol or more, per mol of the compound of the general formula [3n].
[176] As the hydroxide used in the reaction, water and the like can be mentioned. The amount of the hydroxide may be equal to or more than the equivalent of the compound of the general formula [3n], if necessary, but may be used as a solvent.
[177] As an additive used for the said reaction, Copper salts, such as copper sulfate; And inorganic bases such as sodium hydroxide and sodium carbonate and the like. These additives are used in an amount of 0.01 to 100 moles, preferably 0.1 to 50 moles per one mole of the compound of the general formula [3n].
[178] The reaction is generally carried out at a temperature of -70 deg. C to 200 deg. C, preferably -50 deg. C to 100 deg. C for 1 minute to 24 hours, preferably 30 minutes to 10 hours.
[179] (b) The compound of formula [3n] or a salt thereof may be prepared according to the procedure described in (1) Fusso no Kagaku, Pages 28-37 (Kodansha Scientific, 1993). Or reacted with an electrophilic fluorinating agent in the presence or absence of an additive, or (2) Shin Jikken Kagaku Koza, Vol. 14, Pages 354-360 (edited by the Chemical Society Japan, 1977), can be obtained by reacting with a halogenating agent in the presence or absence of additives.
[180] In the above method (1), the solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the present reaction. These solvents include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane and 1,1,2-trichlorotrifluoroethane; Ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether and dimethyl cellosolve; Alcohols such as methanol; Nitriles such as acetonitrile; Organic acids such as acetic acid, formic acid and trifluoroacetic acid; Inorganic acids such as hydrofluoric acid and sulfuric acid; And water. The solvents may be used alone or in a mixture of two or more.
[181] The electrophilic fluorinating agent used in the above reaction is not particularly limited as long as it is commonly used in the reaction of adding fluorine atoms to carbon-carbon multiple bonds. Preferable examples of the electrophilic fluorination agent include fluorine gas, trifluoromethyl hypofluorite, acetyl hypofluorite, difluoride nonfluoride, cesium fluoride, cesium fluorite sulfate, N-fluoropyridinium triflate, N -Fluoro-N-alkylenesulfonamide, N-fluorosaccharin sulfam, N-fluorobis (trifluoromethanesulphone) -imide, N-fluorobis- (benzenesulfon) -imide and N-fluoro-O-benzene Disulfonimide etc. are mentioned. In the said electrophilic fluorination agent, fluorine gas is more preferable. The electrophilic fluorination agent is used in an amount of 0.05 to 50 moles, preferably 0.1 to 20 moles per one mole of the compound of the general formula [3o] or a salt thereof.
[182] The additive which can be used for this reaction as needed is not specifically limited if it is what is normally used for an electrophilic fluorination reaction. Preferable examples include acidic catalysts such as boron trifluoride and hydrofluoric acid; Organic and inorganic bases such as triethylamine and sodium fluoride; And halogens such as chlorine, bromine and iodine. These additives may be used alone or in a mixture of two or more. In the above reaction, the additive is used in an amount of 0.01 to 10 moles, preferably 0.1 to 10 moles per mole of the compound of formula [3o] or a salt thereof.
[183] The reaction is generally carried out at a temperature of -80 ° C to 170 ° C, preferably -80 ° C to 100 ° C for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
[184] The solvent used for the present reaction in the above method (2) is not particularly limited as long as it does not cause any side effects in the reaction. These solvents include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane and 1,1,2-trichlorotrifluoroethane; Ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Organic acids such as acetic acid, formic acid and trifluoroacetic acid; Inorganic acids such as sulfuric acid; And water. The solvents may be used alone or in a mixture of two or more.
[185] The halogenating agent used for the reaction is not particularly limited as long as it is usually used for halogenation of aromatic compounds. Preferred examples of the halogenating agent include bromine, chlorine, sulforyl chloride, N-bromosuccinimide, N-chlorosuccinimide and the like. The halogenating agent is used in an amount of 0.05 to 50 moles, preferably 0.1 to 20 moles per one mole of the compound of the general formula [3o] or a salt thereof.
[186] As needed, as an additive used for the said reaction, if it is what is normally used for the halogenation reaction of an aromatic compound, it will not specifically limit. Preferred examples of the additive include sodium bromide, lead tetraacetate, titanium (IV) chloride, aluminum chloride and silver sulfate. These additives are used alone or in a mixture of two or more. In the above reaction, the additive is used in an amount of 0.01 to 10 moles, preferably 0.1 to 10 moles per one mole of the compound of the general formula [3o] or a salt thereof.
[187] The reaction is usually carried out at a temperature of -80 ° C to 170 ° C, preferably -80 ° C to 100 ° C for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
[188] In the abovementioned preparation process, all compounds can be used in the form of their salts. As the salts, the same ones as those described as salts of the compound of the general formula [1] can be used. As needed, these reactions can be performed in inert gas atmosphere, such as nitrogen gas. Compounds of the general formula [1] or salts thereof obtained by the above-mentioned methods are formulated by known reactions such as oxidation, reduction, potential, substitution, halogenation, dehydration, hydrolysis and appropriate mixing reactions of the above reactions. ] Other compounds or salts thereof.
[189] Some of the compounds mentioned in the above preparation may have isomers such as optical isomers, geometric isomers, tautomers and the like. In such cases, these isomers cannot be used in the present invention, nor can solvates, hydrolysates and various forms of crystals be used. After the reaction is completed, the target compound of the present reaction may optionally proceed to the next step of the reaction without separation.
[190] Some of the compounds mentioned in the above preparation may have an amino group, a hydroxyl group or a carboxyl group. If desired, they are protected by conventional protecting groups, and after the reaction the protecting groups can be detached by well known methods.
[191] The compound of formula [1] or a salt thereof can be separated, purified or recrystallized by conventional methods such as extraction, crystallization and / or column chromatography.
[192] Compounds of the present invention include excipients, binders, disintegrants, disintegrant inhibitors, antiblocking and antifouling agents, lubricants, absorption-adsorbent carriers, solvents, extenders, isotonic agents, dissolution aids, emulsifiers, suspending agents, thickeners, coating agents, adsorption agents Accelerators, gelling-clotting accelerators, photostabilizers, preservatives, desiccants, emulsification-suspension-dispersion stabilizers, colorants, deoxygenation-antioxidants, sweeteners, colorants, foaming agents, antifoams, analgesics, antistatic agents, buffers and pH regulators. Formulated with various pharmaceutical additives, medicines such as oral preparations (tablets, capsules, powders, granules, fine granules, pills and suspensions, emulsions, solvents and syrups), injections, suppositories, external preparations (ointments, plasters, etc.) and aerosols The composition can be formed.
[193] The above-mentioned formulas may be formulated according to conventional methods.
[194] Oral solid preparations such as tablets, powders, and granules are lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous secondary calcium phosphate, and partially pregelatinized according to conventional methods. Pharmaceutical additives such as starch, corn starch and alginic acid; Simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, gum arabic, Binders such as oxypropylmethyl cellulose, hydroxypropyl cellulose, water and ethanol; Disintegrants such as dried starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and sodium starch glycolate; Disintegration inhibitors such as stearyl alcohol, stearic acid, cacao butter and fat hydroxide; Anti-freezing and anti-adherent agents such as aluminum silicate, calcium hydrogen phosphate, magnesium oxide, stone tablets, silicic anhydride and the like; Carnauba wax, light anhydrous silicic acid, aluminum silicate, magnesium silicate, hardened oil, vegetable hardened oil derivative, sesame oil, bleached bees wax, titanium oxide, dry aluminum hydroxide gel, stearic acid, calcium stearate, stearic acid Lubricants such as magnesium lyxate, talc, calcium hydrogen phosphate, sodium lauryl sulfate and polyethylene glycol; Absorption accelerators such as quaternary ammonium salt, sodium lauryl sulfate, urea and enzymes; Prepared according to the usual usage using pharmaceutical additives for solid preparation such as absorption-adsorption carriers such as starch, lactose, kaolin, bentonite, silicic anhydride, hydrous silicate, magnesium metasilicate-aluminate and colloidal silicic acid. .
[195] In addition, if desired, the tablet may be a sugar-skin tablet, a gelatin-coated tablet, a stomach-soluble coated tablet, an intestine It can be prepared from conventional skin-covered tablets such as intestine-soluble coated tablets or water-soluble film coated tablets.
[196] Capsules can be prepared by mixing the aforementioned pharmaceutical ingredients with each other and filling the mixture to obtain hard gelatin capsules, soft capsules and the like.
[197] In addition, using the above-mentioned liquid formulation additives such as solvents, extenders, isotonic agents, emulsifiers, suspending agents, thickeners, etc., according to the conventional method, into aqueous and oily suspensions, solutions, syrups and elixirs It may also be prepared.
[198] Suppositories can be prepared by adding absorption accelerators such as polyethylene glycol, cacao butter, lanolin, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and witepsol, and mixing with pharmaceutical compositions to form suppositories. .
[199] Injectables include diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; PH adjusters and buffers such as sodium citrate, sodium acetate and sodium phosphate; Stabilizers such as sodium pyrosulfite, ethylenediamine-succinic acid, thioglycolic acid, and thiolactate; Isotonic agents, such as sodium chloride, glucose, mannitol and glycerin; Dissolution aids such as sodium carboxymethyl cellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethanes, ethanolamines and glycerin; Analgesics such as calcium gluconate, chlorobutanol, glucose and benzyl alcohol; And pharmaceutical additives for liquid formulation, such as a local anesthetic, can be mixed and molded according to a conventional method.
[200] Ointments in the form of pastes, creams or gels may be prepared according to conventional methods, including pharmaceutical compositions and bases such as white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone and bentonite; Preservatives such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, ethyl paraoxybenzoate and propyl paraoxybenzoate; stabilizator; And a wetting agent and the like, and the mixture can be prepared by ointment.
[201] Plasters can be prepared by applying the aforementioned ointments, creams, gels and pastes to conventional supports using conventional methods. The support may be woven or non-woven fabrics and films made of cotton, staple fibers or chemical fibers, or foamed sheets such as soft vinyl chloride, polyethylene, and polyurethane. have.
[202] The method of administering the above-mentioned pharmaceutical composition is not specifically defined, and an appropriate method may be determined according to the patient's preparation form, age, sex and other matters, and the extent of the patient's symptoms.
[203] The dosage of the active ingredient by the pharmaceutical composition of the present invention is appropriately determined depending on the mixture, age and sex of the patient, the type of disease and other matters. However, depending on the conditions of the active ingredient, the mixture is usually administered once or in several sites at a dose of 0.1-100 mg / kg / day for adults.
[204] In the following, a method for preparing an fluorpyrazine derivative or a salt thereof as an intermediate of the present invention has been described.
[205] (Manufacturing Method II-1)
[206]
[207] Wherein R ²¹ is the same as defined above; R ^22a is a hydrogen atom, a halogen atom, a nitro group, a protected amino group, a protected hydroxy group, a substituted or unsubstituted phenylsulfanyl group, a substituted or unsubstituted phenylsulfinyl group, Substituted or unsubstituted phenylsulfonyl group; X represents other halogen atoms except fluorine atom, except that R ²¹ is a hydrogen atom and R ^{22a is} also a hydrogen atom.)
[208] Compounds of the general formula [24] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 321 to 322 (edited by Chemical Society Japan, 1977) can be obtained by reacting with a fluorinating agent in the presence or absence of an additive.
[209] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as tetrahydrofuran, 1,2-dimethoxyethane and diethylene glycol dimethyl ether; Nitriles such as acetonitrile and benzonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; Sulfoxides such as dimethyl sulfoxide; And sulfones such as sulfolene and dimethyl sulfone; Nitrogen containing heterocyclic compounds, such as collidine, etc. are mentioned.
[210] Fluorinating agents used in the reaction include alkali metal fluorides such as cesium fluoride, rubidium fluoride, potassium fluoride, sodium fluoride and lithium fluoride; Alkali fluoride metals such as calcium fluoride; Other metal fluorides such as zinc fluoride and silver fluoride; Hydrogen fluoride; Ammonium salts such as tetrabutylammonium fluoride; Phosphonium salts; And hydrogen fluoride mixtures. These reagents may optionally be used in admixture. The amount of the fluorinating agent used in the reaction depends on the type of fluorinating agent, but the amount of the fluorinating agent may be used in an amount of at least the same equivalent or more based on the compound of the general formula [25] or a salt thereof, and preferably It may be used in an amount of 1.0 to 20 moles based on the compound of formula [25] or a salt thereof, and more preferably 1.0 to 10 moles based on the compound of formula [25] or a salt thereof.
[211] If desired, additives that can be used in the reaction include quaternary ammonium salts such as tetra-n-butylammonium bromide, tetramethylammonium chloride and tetramethylammonium floride; Polyethers such as 18-crown-6-ether and polyethylene glycol and the like can be mentioned. These additives can be used in mixtures as necessary. The amount of the additive varies depending on the type of the additive, but the additive is used in an amount of 0.01 to 2.0 mol, preferably 0.1 to 1.0 mol per mol of the compound of the general formula [25] or a salt thereof.
[212] The reaction can be carried out under a nitrogen atmosphere if necessary. The reaction is generally carried out for 10 minutes to 24 hours at a temperature of 0 to 300 캜, preferably 20 캜 to 200 캜.
[213] Compounds of the general formula [25] or salts thereof used as raw materials for the above-mentioned reactions are mainly described in J. Med. Chem., Vol. 27, Pages 1634-1639 (1984) or Acta Poloniae Pharmaceutica, Vol. 33, Pages 153-161 (1976).
[214] (Manufacturing Method II-2)
[215]
[216] Wherein R ^21a represents a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl, aminomethyl, carbamoyl or carboxyl group, a methyl group substituted with a protected or unprotected mercapto group, a halogeno-methyl group, a formyl group or a nitrile group And R ^22b represents a protected hydroxy group, protected amino group or halogen atom.)
[217] The compound of formula [26] or a salt thereof is described in Fusso no Kagaku Nyumon, Pages 219-230 (Nippon Gakujutsu Shinkokai, Fluorine Chemistry No. 155 Committee, 1997). Depending on the method, it can be obtained by deamination using a diazotizing agent in the presence of an acid, in the presence or absence of an additive, and then fluorination.
[218] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amines or amine oxides such as triethylamine, N, N-dimethylaniline, pyridine and pyridine-N-oxide; Ketones such as acetone; And water. These solvents can also be used in mixtures as necessary.
[219] The diazotization agent used in the reaction may be any diazotization agent commonly used in the diazotization reaction of an aromatic amino compound. Preferred examples of the diazotizing agent include alkali nitrite metals such as sodium nitrite. The diazotizing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 mol or more, and more preferably 1.0 to 1.5 mol or more, per 1 mol of the compound of the formula [27] or a salt thereof.
[220] The acid used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples include acids such as hydrochloric acid, hydrofluoric acid and hydrogen fluoride; And a basic mixed solution of hydrogen fluoride such as a pyridine solution of hydrogen fluoride. If necessary, these acids and solutions can be mixed and used. The acid can also be used as a solvent.
[221] The amount of acid used in the reaction is used at least 1 ml, preferably 1 to 50 ml, in a weight capacity ratio (ml / g) with respect to the compound of formula [27] or a salt thereof.
[222] As the additive used in the reaction, hydrofluoric acid, sodium tetrafluoride and ammonium hydroborate may be mentioned. The amount of the additive is used in an amount of at least the same equivalent or more, preferably 1.0 to 20.0 moles or more, per mole of the compound of the general formula [27] or a salt thereof.
[223] The reaction is generally carried out at a temperature of -70 to 100 DEG C, preferably -60 to 30 DEG C for 30 minutes to 24 hours, preferably 1 hour to 10 hours.
[224] [Manufacturing Method II-3]
[225]
[226] Wherein R ^21e is a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl group, a protected or unprotected aminomethyl group, a protected or unprotected carbamoyl group, a protected or unprotected carboxyl group, a methyl group substituted with a protected or unprotected mercapto group, or a formyl group R ^22e represents a protected or unprotected hydroxyl group, a protected or unprotected amino group, a halogen atom, a nitrous acid group or azido group.)
[227] The compound of formula [21] or a salt thereof is an additive according to the method described in Fusso no Kagaku, Pages 28-37 (Kodansha Scientific, 1993). It can be obtained by reacting with an electrophilic fluorination agent in the presence or absence of.
[228] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane and 1,1,2-trichlorotrifluoroethane; Ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether and dimethyl cellosolve; Alcohols such as methanol; Nitriles such as acetonitrile; Organic acids such as acetic acid, formic acid and trifluoroacetic acid; Inorganic acids such as hydrofluoric acid and sulfuric acid; And water. These solvents may be used alone or in a mixture of two or more.
[229] The electrophilic fluorinating agent used in the reaction is not particularly limited as long as it is a reagent commonly used to add fluorine atoms to carbon-carbon multiple bonds. Preferred examples of the electrophilic fluorinating agent include fluorine gas, trifluoromethyl hypofluorite, acetyl hypofluorite, difluoride nonfluoride, cesium fluoride sulfate, cesium fluorite, N-fluoropyridinium triflate, and N-fluor- N-alkylenesulfonamide, N-fluorosaccharin sulfam, N-fluorobis (trifluoromethane-sulfon) -imide, N-fluorobis (benzenesulfon) -imide and N-fluoro-O-benzenedisulfone- Imide etc. are mentioned, Among these, a fluorine gas is more preferable. The electrophilic fluorinating agent is used in an amount of 0.05 to 50 moles, preferably 0.1 to 20 moles per one mole of the compound of formula [28] or a salt thereof.
[230] The additive which can be used for this invention as needed is not specifically limited if it is a reagent normally used for an electrophilic fluorination reaction. Preferred examples of the additive include acidic catalysts such as boric trifluoride and hydrofluoric acid; Organic or inorganic bases such as triethylamine and sodium fluoride; And halogens such as chlorine, bromine and iodine. These additives may be used alone or in a mixture of two or more. In this reaction, the additive is used in an amount of 0.01 to 10 mol, preferably 0.1 to 10 mol per mol of the compound of the formula [28] or a salt thereof.
[231] The reaction is generally carried out at a temperature of -80 ° C to 170 ° C, preferably -80 ° C to 100 ° C for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
[232] As a raw material for the above-mentioned reaction, the compound of formula [28] or a salt thereof can be prepared according to a known method, that is, a method described in JP-A-53-119882.
[233] (Manufacturing Method II-4)
[234]
[235] (Wherein R ²¹ is the same as defined above, R ^22c is a halogen atom, and R ^22f represents a protected amino group.)
[236] Compounds of the general formula [21d] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 1333 to 1335 (edited by Chemical Society Japan, 1978), by reacting with a reducing agent in the presence or absence of a catalyst.
[237] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Ketones such as acetone; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Organic acids such as acetic acid; Amines such as hydrazine; And water. These solvents may be used alone or in a mixture of two or more.
[238] The reducing agent used in the reaction is not particularly limited as long as it is conventionally used for nitro group reduction of an aromatic nitro compound. Preferred examples include sodium amide, lithium amide, zinc, aluminum-nickel, tin, tin (II) chloride, iron, sodium borohydride, cyclohexane, hydrogen gas and the like. The reducing agent is used in an amount of 0.01 to 100 mol, preferably 0.01 to 30 mol, per mol of the compound of the general formula [21a] or a salt thereof.
[239] Catalysts that can be used in the present reaction as necessary include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acid such as nickel chloride (II) and tin chloride (II); Metal salts such as bis- (acetylacetone) copper (II); Palladium catalysts such as palladium-carbon and lead-inhibited palladium-calcium carbonate; rhodium; Raney Nickel; Platinum oxide (IV) and the like. The amount of the palladium catalyst and Raney nickel is used in a weight ratio of 0.01 to 100 parts by weight, preferably 0.1 to 10 parts by weight with respect to the compound of the general formula [21a] or a salt thereof. A catalyst other than the palladium catalyst or Raney nickel is used in an amount of 0.01 to 10 moles, preferably 0.01 to 5 moles per mole of the compound of the formula [21a] or a salt thereof.
[240] The reaction is generally carried out at a temperature of -78 ° C to 250 ° C, preferably -50 ° C to 150 ° C for 1 minute to 72 hours, preferably 30 minutes to 24 hours.
[241] Compounds of the general formula [21d] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. It can be obtained by reacting with a reducing agent in the presence or absence of a catalyst according to the method described in 14, Chemical Society Japan (Edition, 1978).
[242] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene and toluene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Ketones such as acetone; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Organic acids such as acetic acid; Amines such as hydrazine; And water. These solvents may be used alone or in a mixture of two or more.
[243] As a reducing agent used for the said reaction, if it is a reagent normally used for azido group reduction of an aromatic azide compound, it will not specifically limit. Preferred examples of the reducing agent include zinc, chromium chloride (II), tributyltin hydride, lithium aluminum hydride and hydrogen gas. The reducing agent is used in an amount of 0.01 to 100 moles, preferably 0.01 to 30 moles per one mole of the compound of the general formula [21b] or a salt thereof.
[244] As a catalyst used for the reaction, inorganic acids such as hydrochloric acid and sulfuric acid; Palladium-carbon, lead- poisoned palladium-calcium carbonate, platinum oxide (IV) and the like can be mentioned. The catalyst is used in an amount of 0.01 to 10 moles, preferably 0.01 to 5.0 moles per one mole of the compound of formula [21b] or a salt thereof. For example, when using a palladium catalyst and Raney nickel, the amount of catalyst may be 0.01 to 10 parts by weight, preferably 0.1 to 5.0 parts by weight, per 1 part by weight of the compound of formula [21b] or a salt thereof.
[245] The reaction is generally carried out at a temperature of -78 ° C to 250 ° C, preferably -50 ° C to 150 ° C for 1 minute to 72 hours, preferably 30 minutes to 24 hours.
[246] Compounds of the general formula [21d] or salts thereof include compounds of the general formula [21c] or salts thereof. Shin Jikken Kagaku Kaza, Vol. It can be obtained by reacting with an aminating agent in the presence or absence of a copper catalyst according to the method described in 14, Pages 1342 to 1351 (edited by Chemical Society Japan, 1978).
[247] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Esters such as ethyl acetate; Amides such as N, N-dimethyl formamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more.
[248] The aminating agent used in the reaction is not particularly limited as long as it is a reagent usually used in the amination reaction by nucleophilic substitution of aromatic halides. Preferred examples of the amination agent include ammonia gas; ammonia; Alkali metal amides such as sodium amide; And ammonium salts such as ammonium carbonate and the like. The aminoating agent is used at least the same equivalent or more, preferably 2.0 to 30 moles or more, per mole of the compound of the formula [21c] or a salt thereof.
[249] Copper powder and cupric chloride etc. are mentioned as a copper catalyst used for the said reaction. The copper catalyst is used in an amount of 0.01 to 30 mol, preferably 0.05 to 2 mol, per mol of the compound of the general formula [21c] or a salt thereof.
[250] The reaction is generally carried out at a temperature of 0 to 250 캜, preferably 0 to 40 캜 for 1 minute to 96 hours, preferably 30 minutes to 7 hours.
[251] Compounds of the general formula [21b] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 1655-1666 (edited by Chemical Society Japan, 1978), and can be obtained by reacting with an azide-forming agent.
[252] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Esters such as ethyl acetate; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more.
[253] The azide molding agent used for the above reaction is not particularly limited as long as it is a reagent normally used for azide molding by nucleophilic substitution of aromatic halides. Preferred examples of the azide molding agent include sodium azide and the like. The azide agent is used at least the same equivalent or more, preferably 1.0 to 30 moles, more preferably 1.0 to 1.5 moles per mole of the compound of formula [21c] or a salt thereof.
[254] The reaction is generally carried out at a temperature of 0 to 250 캜, preferably 0 to 40 캜 for 1 minute to 96 hours, preferably 5 minutes to 6 hours.
[255] Compounds of the general formula [21d] or salts thereof may be prepared according to conventional methods, ie Theodora W. Green: Protective Groups in Organic Synthesis, 3rd Edition, Pages 494-653 (John Wiley & Sons). , Inc. Edit, 1999), by reacting with a de-protecting agent in the presence or absence of a catalyst.
[256] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. The solvent includes water; Alcohols such as methanol, ethanol and propanol; Thioalcohols such as ethanethiol and thiophenol; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; Dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Thioethers such as dimethyl sulfide; Ketones such as acetone; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Inorganic acids such as sulfuric acid and hydrochloric acid; Carboxylic acids such as acetic acid and trifluoroacetic acid; Sulfonic acids such as trifluoromethanesulfonic acid; Nitroalkanes such as nitromethane; Organic bases such as pyridine and diethylamine; Etc. can be mentioned. These solvents may be used alone or in a mixture of two or more.
[257] The deprotection agent used for the reaction is not particularly limited as long as it is conventionally used for deprotection of a protected amino group. Preferred examples of the deprotecting agent include hydrogen gas; Ammonium formate; zinc; salt; Hydrochloric acid such as vinyl chloroform acid and acetyl chloride; Organosilanes such as triethylsilane and trimethylsilyl iodine; Tributyltin hydride; Alkali metal alkoxides such as potassium tert-butoxide; Alkali metal thioalkoxides such as sodium thiomethoxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Sodium borohydride; Alkali metal salts such as potassium fluoride and sodium iodide; Lewis acids such as boric trifluoride, aluminum chloride, ruthenium chloride and zinc chloride; Inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; Organic acids such as trifluoroacetic acid, methane sulfonic acid and p-toluenesulfonic acid; Inorganic bases such as potassium carbonate, sodium bicarbonate and sodium hydrogen dioxide; Organic bases such as piperidine; Amines such as ammonia and hydrazine; Organolithium compounds such as methyllithium; Diammonium cerium nitrate; Peroxides, such as hydrogen peroxide, ozone, and a manganese acid, etc. are mentioned. The deprotecting agent is used in an amount of 0.01 to 1,000 moles, preferably 0.1 to 100 moles per one mole of the compound of the general formula [21t] or a salt thereof.
[258] The catalyst used as necessary in the reaction is not particularly limited as long as it is conventionally used for deprotection of a protected amino group. Preferred examples of the catalyst include palladium catalysts such as palladium-carbon; rhodium; Raney nickel and platinum (IV) etc. are mentioned. For example, the palladium-carbon and Raney nickel are used in an amount of 0.01 to 10 parts by weight, preferably 0.01 to 5 parts by weight per 1 part by weight of the compound of the general formula [21t] or a salt thereof. The catalyst other than palladium-carbon and Raney nickel is used in an amount of 0.01 to 10 moles, preferably 0.01 to 5 moles per one mole of the compound of the general formula [21t] or a salt thereof.
[259] The reaction is generally carried out at a temperature of -80 ° C to 200 ° C, preferably 0 ° C to 160 ° C for 1 minute to 48 hours, preferably 5 minutes to 12 hours.
[260] (Manufacturing Process II-5)
[261]
[262] Wherein R ^22c is the same as defined above; R ^21b is substituted with a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl group, a protected or unprotected aminomethyl group, a protected or unprotected carboxyl group, a protected or unprotected mercapto group Methyl group, halogenated methyl group, form group, protected carbamoyl group, nitrile group or halogenated carbonyl group; R ²⁵ represents a group protected with a hydroxyl group; except when R ^21b is a carbamoyl group protected with an acyl group. )
[263] A mixture of the general formula [21h] or a salt thereof may be prepared by Shin Jikken Kagaku Koza, Vol. 14, Pages 537 to 538 (edited by Chemical Society Japan, 1977), which can be obtained by reacting with a diazotizing agent and a hydroxide in the presence or absence of an additive.
[264] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid and nitrous acid; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amines and amine oxides such as triethylamine, N, N-dimethylanilyl and pyridine-N-oxide; Ketones such as acetone; And water. If desired, these solvents can be used as a mixture.
[265] The diazotizing agent used for the above reaction is not particularly limited as long as it is usually used for deaminoating hydroxylation of aromatic amino compounds. Preferred examples of the diazotizing agent include alkali metal nitrites such as sodium nitrite and the like. The diazotizing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, more preferably 1.0 to 2.0 moles or more, per mole of the compound of the general formula [21e] or a salt thereof.
[266] As the hydroxylating agent used in the reaction, water and the like can be mentioned. The hydroxyl agent is used at least the same equivalent or more relative to the compound of the general formula [21e] or a salt thereof. The hydroxide can also be used as a solvent.
[267] As the catalyst used in the reaction, copper salts such as copper sulfate and inorganic bases such as sodium hydroxide and sodium carbonate may be mentioned. The additive is used in an amount of 0.01 to 100 moles, preferably 0.1 to 50 moles per one mole of the compound of the general formula [21e] or a salt thereof.
[268] The reaction is generally carried out at a temperature of -70 deg. C to 200 deg. C, preferably -50 deg. C to 100 deg. C for 1 minute to 24 hours, preferably 30 minutes to 10 hours.
[269] Compounds of the general formula [21h] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 535-536 (edited by Chemical Society Japan, 1977).
[270] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Ketones such as acetone; Amides such as N, N-dimethylformamide and N, N-diketylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more.
[271] The hydroxyl agent used in the present reaction is not particularly limited as long as it is commonly used for hydroxylation by nucleophilic substitution of aromatic halides. Preferred examples of the hydroxide include inorganic and organic bases such as sodium hydroxide, lithium hydroxide, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and sodium acetate; Inorganic and organic acids such as hydrochloric acid, phosphoric acid and formic acid aqueous solution. The hydroxide is used in an amount of at least 0.01 mol or more, preferably 0.05 to 20 mol, per mol of the compound of the general formula [21f] or a salt thereof.
[272] The reaction is generally carried out at a temperature of -78 ° C to 180 ° C, preferably -20 ° C to 100 ° C for 1 minute to 96 hours, preferably 10 minutes to 72 hours.
[273] Compounds of the general formula [21g] or salts thereof (1) Compounds of the general formula [21f] or the salts thereof are described in Shin Jikken Kagaku Koza, Vol. Obtained by reacting with a nucleophilic substituent in the presence or absence of a copper catalyst according to the method described in 14, Pages 570-571 (Chemical Society Japan, 1977) or (2) a compound of the general formula [21f]. Or the salt can be obtained by reacting with a nucleophilic substituent in the presence of a base.
[274] In the above method (1), the solvent used is not particularly limited, unless it causes any side effects in the present reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in a mixture of two or more.
[275] The nucleophilic substituent used in the reaction is not particularly limited as long as it is a reagent normally used for nucleophilic substitution of aromatic halides. Examples thereof include alkali metal-C _1-6 lower alkoxides such as sodium methoxide; Alkali metal-ar-C _1-6 lower alkoxides such as potassium benzyl oxide; And alkali metal salts of organic carboxylic acids such as sodium acetate. If desired, these nucleophilic substituents can be synthesized in the reaction system. The nucleophilic substituent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of [21f] or a salt thereof. If necessary, the copper catalyst that can be used is not particularly limited as long as it is a reagent commonly used for nucleophilic substitution of aromatic halides. Preferred examples of the copper catalyst include copper powder, cupric iodide and the like. The copper catalyst is used in an amount of 0.01 to 30 mol, preferably 0.05 to 2 mol per mol of the compound of the general formula [21f] or a salt thereof.
[276] The reaction is generally carried out at a temperature of -70 deg. C to 200, preferably -20 deg. C to 50 deg. C for 1 minute to 24 hours, preferably 5 minutes to 6 hours.
[277] In the above method (2), the solvent used is not particularly limited, unless it causes any side effects in the present reaction.
[278] Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in a mixture of two or more.
[279] The nucleophilic substituent used in the reaction is not particularly limited as long as it is commonly used in nucleophilic substitution of aromatic halides. Preferred examples of nucleophilic substituents include C _1-6 lower alcohols such as methanol, ethanol, isopropyl alcohol and allyl alcohol; Lower alcohols such as ar-C _1-6 such as benzyl alcohol; Substituted phenols such as hydroquinone and p-methoxyphenol; Alpha-diketones such as 3-methyl-1,2-cyclopentanedione; Beta-diketones such as 2-methyl-1,3-cyclopentanedione; Etc. can be mentioned. The nucleophilic substituent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the general formula [21f] or a salt thereof. The base used for this reaction will not be specifically limited if it is what is normally used for the nucleophilic substitution reaction of an aromatic halide. Examples of the base include organic bases such as triethylamine and pyridine; Inorganic bases, such as sodium carbonate and potassium carbonate, etc. are mentioned. The base is used in an amount of 0.01 to 30 moles, preferably 0.5 to 2 moles per one mole of the compound of formula [21f] or a salt thereof.
[280] The reaction is generally carried out at a temperature of -70 ° C to 200 ° C, preferably -20 ° C to 100 ° C for 1 minute to 24 hours, preferably 5 minutes to 6 hours.
[281] Compounds of formula [21h] or salts thereof include compounds of formula [21g] or salts thereof Theodora W. Greene: PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd Edition, Pages 75 and 249-287 (John Wiley & Sons, Inc.). Edited, 1999), by reacting with a deprotectant in the presence or absence of a catalyst.
[282] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. The solvent includes water; Alcohols such as methanol, ethanol and propanol; Thio alcohols such as ethanethiol and thiophenol; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Thio ethers such as dimethyl sulfoxide; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Inorganic acids such as sulfuric acid and hydrochloric acid; Carboxylic acids such as acetic acid and trifluoroacetic acid; Sulfonic acids such as trifluoromethanesulfonic acid; Organic bases such as pyridine and triethylamine; And water. These solvents may be used alone or in a mixture of two or more.
[283] The deprotection agent used for the reaction is not particularly limited as long as it is conventionally used in the deprotection reaction of the protected aromatic alcohol. Preferred examples of the deprotecting agent include hydrogen gas; Lewis acids such as aluminum, trichloride, boron tribromide and iodine-magnesium composites; Inorganic acids such as hydrobromic acid; Acid salts such as pyridine hydrochloride; Inorganic bases such as potassium carbonate, sodium bicarbonate and sodium hydroxide; And oxidizing agents such as cerium diammonium nitrate, iron (III) chloride, 2,3-dichloro-5,6-isocyan-1,4-benzoquinone, and the like. The deprotecting agent is used in an amount of 0.01 to 50 mol, preferably 0.01 to 30 mol, per mol of the compound of the general formula [21 g] or a salt thereof.
[284] The catalyst that can be used as needed in the reaction is not particularly limited as long as it is conventionally used in the deprotection reaction of the protected aromatic alcohol. Preferred examples of the catalyst include palladium catalysts such as palladium-carbon; rhodium; Raney Nickel; Platinum oxide (IV) and the like. The palladium-carbon and raney nickel are used in an amount of 0.001 to 10 parts by weight, preferably 0.01 to 5 parts by weight, per 1 part by weight of the compound of the general formula [21 g] or a salt thereof. The catalyst other than palladium-carbon and Raney nickel is used in an amount of 0.001 to 10 mol, preferably 0.01 to 5 mol per mol of the compound of the general formula [21 g] or a salt thereof.
[285] The reaction is generally carried out at a temperature of -80 ° C to 200 ° C, preferably 0 ° C to 160 ° C for 1 minute to 48 hours, preferably 5 minutes to 12 hours.
[286] The compound of the general formula [21g] and its salt can be obtained by reacting the compound of the general formula [21e] and its salt with a diazotizing agent and alcohol or sulfonic acid.
[287] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid and nitrous acid; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimenyl sulfoxide; Amines and amine oxides such as triethylamine, N, N-dimethylaniline and pyridine-N-oxide; Alcohols such as methanol and ethanol; And water. These solvents may optionally be used as a mixture.
[288] The diazotization agent used for the said reaction will not be specifically limited if it is a reagent normally used for the diazotization reaction of an aromatic amino compound. Preferred examples of the diazotizing agent include alkali metal nitrites such as sodium nitrite. The diazotizing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the general formula [21e] or a salt thereof.
[289] As the alcohol used for the reaction, for example, methanol and the like can be mentioned. The alcohol is used in at least the same equivalent or more with respect to the compound of the general formula [21e] or a salt thereof. The alcohol may optionally be used as a solvent.
[290] The sulfonic acid used in the reaction includes methanesulfonic acid, p-toluenesulfonic acid and the like. The sulfonic acid is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of formula [21e] or a salt thereof. The sulfonic acid may optionally be used as a solvent.
[291] The reaction is generally carried out at a temperature of -70 deg. C to 200 deg. C, preferably -50 deg. C to 100 deg. C for 1 minute to 24 hours, preferably 30 minutes to 10 hours.
[292] (Manufacturing Method II-6)
[293]
[294] Wherein R ²² is the same as defined above; R ^21c is a methyl group, a halogenated methyl group or a formyl group substituted with a methyl group, a protected or unprotected hydroxymethyl group, a protected or unprotected aminomethyl group, a protected or unprotected mercapto group; R ²⁶ represents a protecting group of a carboxy group; and R ²⁷ represents a halogen atom.)
[295] Compounds of the general formula [21j] or salts thereof include compounds of the general formula [21i] or salts thereof Shin Jukken Kagaku Koza, Vol. 15, Pages 922-926 (edited by Chemical Society Japan, 1977) or Vol. It is obtained by reacting with an oxidizing agent according to the method described in 14, Pages 1,051-1,053 (Chemical Society Japan, 1988).
[296] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Alcohols such as methanol, ethanol and propanol; Ketones such as acetone; Organic bases such as pyridine; Organic acids such as acetic acid; Inorganic acids such as nitrous acid and sulfuric acid; And water. These solvents may be used alone or in a mixture of two or more.
[297] The oxidizing agent used in the reaction is not particularly limited as long as it is a reagent commonly used as an oxidizing agent of aromatic carboxylic acid. Preferred examples of the oxidizing agent include potassium permanganate, chromium (VI) oxide, sodium dichromate, selenium dioxide, silver oxide and molybdenum oxide (VI). The oxidizing agent is used in an amount of 0.01 to 20 mol, preferably 0.5 to 10 mol per mol of the compound of [21i] or a salt thereof.
[298] The reaction is generally carried out at a temperature of -50 ° C to 170 ° C, preferably 0 to 150 ° C, for 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
[299] Compounds of the general formula [21m] can be prepared by Shin Jikken Kagaku Koza, Vol. 14, Pages 1,002 to 1,016 and 1,106 to 1,119 (Chemical Society Japan, 1977, 1977).
[300] Specifically speaking, methods that can be taken include (1) a dehydration condensation reaction with an alcohol in the presence or absence of a catalyst or a dehydrating agent, (2) a reaction of an alkylating agent, (3) a general formula [21j] A method of reacting an alkali metal salt or an ammonium salt with dialkyl sulfate or alkyl halide, and (4) the activity of an acid halide [21 l] by reacting a compound of the general formula [21j] or a salt thereof with a halogenating agent in the presence or absence of a catalyst After obtaining an intermediate, the method of making it react with alcohol in presence or absence of a base, etc. are mentioned.
[301] In the above method (1), the solvent used in the present reaction is not particularly limited as long as it does not cause any adverse reaction to the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Alcohols such as methanol, ethanol and propanol, and the like. These solvents may be used alone or in a mixture of two or more.
[302] As needed in the reaction, catalysts that can be used include inorganic acids such as hydrochloric acid and sulfuric acid; Organic acids such as aromatic sulfonic acids; Lewis acids, such as boron trifluoride ester acid, etc. are mentioned. The catalyst is used in an amount of 0.01 to 20 moles, preferably 0.01 to 10 moles per one mole of the compound of formula [21j] or a salt thereof.
[303] Examples of the dehydrating agent that can be used as necessary in the above reaction include carbodiimide such as dicyclohexy carbodiimide and diisopropyl carbodiimide. The dehydrating agent may be used in an amount of at least the same equivalent or more, preferably 1 to 20 moles per mole of the compound of formula [21j] or a salt thereof.
[304] The reaction can generally be carried out for 5 minutes to 10 days, preferably 30 minutes to 6 days at a temperature of -20 ° C to 200 ° C, preferably 0 to 180 ° C.
[305] In the above reaction (2), the solvent used in the present reaction is not particularly limited as long as it does not cause any adverse reaction to the reaction. Examples of the solvent include ethers such as diethyl ether, dioxane and tetrahydrofuran; Aromatic hydrocarbons such as benzene and toluene; Ortho esters such as triethyl ortho formic acid and the like. These solvents may be used alone or in a mixture of two or more.
[306] As an alkylating agent used for the said reaction, diazo compounds, such as diazomethane, ortho ester, such as triethyl ortho formic acid, etc. are mentioned. The alkylating agent is used in an amount of at least the same equivalent or more, preferably 1 to 20 moles or more, per mole of the compound of formula [21j] or a salt thereof.
[307] The reaction is generally carried out at a temperature of -20 ° C to 200 ° C, preferably 0 to 180 ° C, for 5 minutes to 72 hours, preferably 30 minutes to 48 hours.
[308] In the above method (3), the solvent used in the present reaction is not particularly limited as long as it does not cause any adverse reaction to the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Alcohols such as methanol, ethanol and propanol; Ketones such as acetone; Amides, such as N, N- dimethylformamide, etc. are mentioned. These solvents may be used alone or in a mixture of two or more.
[309] Examples of alkali metal salts used in the reaction include sodium salts and potassium salts. Organic base salts such as ammonium salts or tetramethylammonium salts and the like can also be mentioned. If desired, these salts can be generated in the reaction system.
[310] Dialkyl sulfates, such as dimethyl sulfate and diethyl sulfate, are mentioned as dialkyl sulfate used for the said reaction. As the halogenated alkyl used in the reaction, halogenated alkyl such as methyl iodide and ethyl iodide may be mentioned. The dialkyl sulfate and halogenated alkyl are used in an amount of at least the same equivalent or more, preferably 1 to 20 moles or more, per mole of the compound of the formula [21j] or a salt thereof.
[311] The reaction is generally carried out at a temperature of -20 ° C to 250 ° C, preferably 0 to 180 ° C for 5 minutes to 72 hours, preferably 30 minutes to 48 hours.
[312] In the above method (4), the solvent used in the present reaction is not particularly limited as long as it does not cause any adverse reaction to the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Ketones, such as acetone, etc. are mentioned. These solvents may be used alone or in a mixture of two or more. As a halogenating agent used for the said reaction, Inorganic halides, such as thionyl chloride, phosphorus hexachloride, phosphorus trichloride, phosphorus chloride; Halogenated oxalic acids such as oxaryl chloride, oxaryl bromide and the like can be mentioned. The halogenating agent is used in an amount of at least the same equivalent or more, preferably 1 to 10 moles or more, per mole of the compound of formula [21j] or a salt thereof.
[313] Catalysts that can be used in the reaction, if necessary, include organic bases such as triethylamine and pyridine; Lewis acids such as zinc chloride; iodine; N, N-dimethylformamide and the like can be mentioned. The catalyst is used in an amount of 0.001 to 10 mol, preferably 0.001 to 0.5 mol per mol of the compound of the formula [21j] or a salt thereof.
[314] As the base used in the reaction, organic and inorganic bases such as pyridine, dimethylaniline and metal magnesium may be mentioned. The base is used in an amount of at least the same equivalent or more, preferably 1 to 10 moles or more, per mole of the compound of formula [21j] or a salt thereof.
[315] The reaction is generally carried out at a temperature of -20 deg. C to 200 deg. C, preferably -10 deg. C to 120 deg. C for 1 minute to 72 hours, preferably 10 minutes to 24 hours.
[316] The compound of formula [21m] or a salt thereof collects the compound of formula [21k] or a salt thereof. Czech. Chem. Commun., Vol. 54, No. 5, Pages 1,306-1,310 (1989), which can be obtained by reacting with esters in the presence or absence of a catalyst.
[317] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include sulfuric acid and water. These solvents may be used alone or in a mixture of two or more.
[318] As the ester used in the reaction, esters such as methyl pyruvate and ethyl pyruvate may be mentioned. The ester may be used in an amount of 0.1 to 10 moles, preferably 0.2 to 5 moles per one mole of the compound of formula [21k] or a salt thereof.
[319] Examples of the catalyst used as necessary in the reaction include copper sulfate and hydrogen peroxide. These catalysts are used in amounts of 0.01 to 10 moles, preferably 0.1 to 5 moles per one mole of the compound of the formula [21k] or a salt thereof.
[320] The reaction is generally carried out at a temperature of -50 ° C to 150 ° C, preferably -20 ° C to 100 ° C for 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
[321] (Manufacturing Method II-7)
[322]
[323] Wherein R ²⁶ and R ²⁷ are the same as defined above; R ^22d represents a protected hydroxy group, a protected or unprotected amino group, a halogen atom, a nitrous acid group or azido group.
[324] Compounds of the general formula [21q] or salts thereof include the compounds of the general formula [21n] or salts thereof Shin Jikken Kagaku Koza, Vol. 14, Pages 1,106 to 1,119 and 1,136 to 1,147 (edited by Chemical Society Japan, 1977).
[325] Specifically, a method that can be taken includes (1) dehydration of compound [21n] or a salt thereof with ammonia in the presence or absence of a catalyst or dehydrating agent, and (2) amidating agent of compound [21n] or a salt thereof. ) And (3) a method of reacting the compound [21n] or a salt thereof with a halogenated compound to obtain an active intermediate such as an acid halogen compound [21o], and then reacting with ammonia.
[326] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Ketones such as acetone; Amides such as N, N-dimethylformamide; And water. These solvents are used alone or in mixture of two or more. If necessary, as the catalyst used in the reaction (1), organic acids such as activated alumina and aromatic sulfonic acid may be mentioned. The amount of the catalyst is used in an amount of 0.01 to 20 mol, preferably 0.1 to 10 mol per mol of the compound of the general formula [21n] or a salt thereof. As dehydrating agent used for the said reaction (1), carbodiimide, such as dicyclohexyl carbodiimide and diisopropyl carbodiimide, is mentioned. Amidating agents which can be used in the reaction (2) include amidating agents such as urea. Halides that can be used in the reaction (3) include halogenating agents such as oxalyl chloride and thionyl chloride. In these reactions, the dehydrating agent, the amidating agent and the halide are used at least the same equivalent or more, preferably 1 to 20 moles per mole of the compound of the general formula [21n] or a salt thereof.
[327] These reactions are generally carried out for 5 minutes to 72 hours, preferably 30 minutes to 48 hours at a temperature of -20 ° C to 200 ° C, preferably 0 to 180 ° C.
[328] The compound of the general formula [21q] or a salt thereof may be prepared by the method described in Shin Jikken Kagaku Koza, Vol 14, Pages 1,147-1,151 (Chemical Society Japan, 1977). Can be obtained through ammonolysis of carboxyl esters in the presence or absence of a catalyst.
[329] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; And water. These solvents may be used alone or in a mixture of two or more. This reaction is carried out under the conditions normally used for the ammonolytic reaction of aromatic carboxylic acid esters, but a method using ammonia gas or aqueous ammonia or liquid ammonia is also preferred. As a catalyst used as needed in the said reaction, Acidic ammonium salts, such as ammonium chloride and butyllithium; Alkali metal amides such as sodium amide and the like can be mentioned. The catalyst is used in an amount of 0.01 to 100 mol or more, preferably 0.01 to 20 mol, per mol of the compound of the general formula [21p] or a salt thereof.
[330] The reaction is generally carried out at a temperature of -100 ° C to 250 ° C, preferably -78 ° C to 100 ° C for 1 minute to 78 hours, preferably 30 minutes to 50 hours.
[331] Compounds of the general formula [21q] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 1,151-1,154 (edited by Chemical Society Japan, 1977), obtained by amidation under (1) acidic conditions, (2) basic conditions, or (3) neutral conditions. Can be.
[332] In the method (1), the solvent used in the present reaction is not particularly limited, unless it causes any adverse reaction to the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Inorganic acids such as hydrochloric acid, sulfuric acid and polyphosphoric acid; Organic acids such as acetic acid and formic acid; And water. These solvents may be used alone or in a mixture of two or more.
[333] Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid and polyphosphoric acid; Chloride water; Hydrogen bromide; Organic acids saturated with Lewis acids such as boron trifluoride; Etc. can be mentioned. The amount of the acid used is 0.1 to 100 ml / g, preferably 0.5 to 50 ml / g, as a weight capacity ratio (ml / g) to the compound of the general formula [21r] or a salt thereof. If necessary, these acids can also be used as a solvent.
[334] The reaction is generally carried out at a temperature of 0 to 200 캜, preferably 0 to 160 캜 for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
[335] In the above method (2), the solvent used is not particularly limited, unless it causes any side effects in the present reaction. Examples of the solvent include alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide; Esters such as ethyl acetate; And water. These solvents may be used alone or in a mixture of two or more.
[336] The base used in the reaction is not particularly limited as long as it is commonly used in carbamoylation of aromatic nitriles. Preferred examples of the base include an alkali metal base such as sodium hydroxide and an aqueous amine solution such as aqueous ammonia. The base is used in an amount of 0.1 to 20 moles, preferably 0.5 to 10 moles per one mole of the compound of the general formula [21r] or a salt thereof.
[337] As the peracid used in the reaction, hydrogen peroxide and the like can be mentioned. The peracid is used in an amount of 0.1 to 20 moles, preferably 0.5 to 10 moles per one mole of the compound of the general formula [21r] or a salt thereof.
[338] The reaction is generally carried out at a temperature of -20 ° C to 170 ° C, preferably 0 to 160 ° C for 1 minute to 72 hours, preferably 5 minutes to 48 hours.
[339] In the above method (3), the solvent used is not particularly limited as long as it does not cause any side effects in the present reaction. As said solvent, Halogenated hydrocarbons, such as methylene chloride; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; Nitriles such as acetonitrile; And water. These solvents may be used alone or in a mixture of two or more.
[340] The reagent used for the reaction is not particularly limited as long as it is a reagent commonly used for carbamoyl reaction of aromatic nitriles. Preferred examples of the reagents include manganese dioxide. The reagent is used in an amount of at least the same equivalent or more, preferably 1 to 100 moles or more, per mole of the compound of formula [21r] or a salt thereof.
[341] The reaction is generally carried out at a temperature of -20 ° C to 170 ° C, preferably 0 to 160 ° C for 5 minutes to 72 hours, preferably 30 minutes to 48 hours.
[342] The compound of formula [21q] or a salt thereof collects the compound of formula [21s] or a salt thereof. Czech. Chem. Commun., Vol. 54, No. According to the method described in 5, Pages 1,306-1,310 (1989), it can be obtained by reacting with an amide in the presence or absence of a catalyst.
[343] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include sulfuric acid and water. These solvents may be used alone or in a mixture of two or more.
[344] As the amide used in the reaction, formamide and the like can be mentioned. The amide is used in an amount of 0.1 to 100 moles, preferably 0.2 to 50 moles per one mole of the mixture of the general formula [21s] or a salt thereof.
[345] As needed, examples of the catalyst that can be used in the present reaction include copper sulfate and hydrogen peroxide. The catalyst is used in an amount of 0.01 to 10 moles, preferably 0.1 to 5 moles per one mole of the compound of formula [21s] or a salt thereof.
[346] The reaction is generally carried out at a temperature of -50 ° C to 150 ° C, preferably -20 ° C to 100 ° C for 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
[347] (Manufacturing Method II-8)
[348]
[349] ^Wherein R ^22c is the same as defined above; R ^21d is a methyl group, protected or unprotected hydroxymethyl group, protected or unprotected aminomethyl group, protected or unprotected carbamoyl group, protected or unprotected carboxyl group, protected or unprotected mercap Methyl group, halogen-methyl group, formyl group, nitrile group or halogenated carbonyl group substituted with earthenware.)
[350] Compounds of the general formula [21v] or salts thereof include compounds of the general formula [21u] or salts thereof Shin Jikken Kagaku Koza, 4th edition, Vol. It can be obtained by reacting with an oxidizing agent in the presence or absence of a catalyst according to the method described in 23 (Chemical Society Japan Edit, 1991).
[351] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ketones such as acetone; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Nitriles such as acetonitrile and benzonitrile; Organic acids such as acetic acid and trifluoroacetic acid; And water. These solvents may be used alone or in a mixture of two or more.
[352] The oxidizing agent used in the reaction is not particularly limited as long as it is a reagent commonly used in the oxidation reaction of tertiary amines. Preferable examples of the oxidizing agent include inorganic peracids such as hydrogen peroxide; organic peracids such as m-perchloric acid, peracetic acid and pertrifluoroacetic acid; Dioxysilanes such as dimenyldioxysilane; Peroxides such as potassium persulfate and sodium perborate; ozone; And oxygen gas. If desired, these oxidants can be synthesized in the reaction system. The oxidizing agent is used in an amount of 0.01 to 10 moles, preferably 0.1 to 5.0 moles per one mole of the compound of the general formula [21 u] or a salt thereof.
[353] If necessary, molybdenum oxide, iron (III) oxide, or the like may be mentioned as a catalyst that can be used in the reaction. The catalyst is used in an amount of 0.01 to 100 parts by weight, preferably 0.1 to 10 parts by weight, per 1 part by weight of the compound of the general formula [21 u] or a salt thereof.
[354] The reaction is generally carried out at a temperature of -78 deg. C to 200 deg. C, preferably 0 to 150 deg. C for 1 minute to 24 hours, preferably 30 minutes to 8 hours.
[355] The compound of formula [21w] or a salt thereof is reacted with a halogenating agent by using the method described in Heterokan Kagoubutsu no Kagaku, Pages 177-201 (Kodansha Scientific, 1988). You can get it.
[356] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Etc. can be mentioned. These solvents may be used alone or in a mixture of two or more.
[357] The reagent used for the reaction is not particularly limited as long as it is a halogenating agent. Preferred halogenating agents include phosphorus oxychloride and thionyl chloride. The halogenating agent is used in an amount of 0.3 to 100 mol, preferably 1 to 30 mol, per mol of the compound of the general formula [21v] or a salt thereof.
[358] The reaction is generally carried out at a temperature of -20 deg. C to 200 deg. C, preferably 0 to 120 deg. C for 1 minute to 24 hours, preferably 30 minutes to 6 hours.
[359] (Manufacturing Method II-9)
[360]
[361] ( ^Wherein R ^21c is the same as defined above; R ²⁶ is a substituted or unsubstituted phenyl group; and n represents 1 or 2).
[362] Compounds of the general formula [21y] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. 14, Pages 1,749 to 1,756 and 1,759 to 1,763 (Chemical Society Japan, 1978).
[363] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ketones such as acetone; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Alcohols such as methanol, ethanol and propanol; Nitriles such as acetonitrile and benzonit; Organic acids such as acetic acid and trifluoroacetic acid; Organic bases such as pyridine and quinoline; And water. These solvents may be used alone or in a mixture of two or more.
[364] The oxidizing agent used in the reaction is not particularly limited as long as it is a reagent commonly used in the oxidation reaction of sulfides. Examples of the oxidizing agent include peracids such as hydrogen peroxide, peracetic acid, perbenzoic acid, and m-chloride perbenzoic acid; Metaguadioic acid, hydroperoxide, ozone, selenium dioxide, chromic acid, dinitrogen pentoxide, acyl nitrite, iodine, bromine, N-bromosuccinimide, iodosylbenzene, iodosylbenzene, sulfonyl chloride added with silica gel, butyl tert- hypopochlorite, ruthenium oxide, osmium oxide, and the like. These oxidants can optionally be synthesized in the reaction system. These oxidizing agents are used in an amount of 0.01 to 10 mol, preferably 1.0 to 5.0 mol, per mol of the compound of the general formula [21x] or a salt thereof. The reaction is generally carried out at a temperature of -78 deg. C to 200 deg. C, preferably 0 to 150 deg. C for 1 minute to 24 hours, preferably 30 minutes to 8 hours.
[365] Below, the synthesis | combining method of general formula [25] and general formula [27] or its salt used for manufacture reaction II-1 and II-2 was described.
[366] (Manufacturing Method II-A)
[367]
[368] ^Wherein R ²¹ , R ^22a , R ^22c and X are as defined above.
[369] Compounds of the general formula [25] or salts thereof (1) Compounds of the general formula [29] or salts thereof according to Shin Jikken Kagaku Koza, Vol. 14, Pages 383 to 387 (edited by Chemical Society Japan, 1977), followed by deamination of an amino group with a diazotizing agent in the presence of an additive, followed by halogenation, or (2 ) A compound of formula [29] or a salt thereof is obtained by reacting with a protective agent in the presence or absence of an additive according to the method described in Theodora W. Green: PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd edition, Pages 503-615 (1999). Can be.
[370] In the reaction (1), the solvent used is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid and nitrous acid; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Halogenated hydrocarbons such as dichloromethane, dichloroform and dichloroethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide; Amines or amine oxides such as triethylamine, N, N-dimethylaniline and pyridine-N-oxide; Ketones such as acetone; And water. These solvents may optionally be used as a mixture.
[371] The diazotization agent used for the said reaction is not specifically limited if it is a reagent normally used for the diazotization reaction of an aromatic amino acid. Preferred examples of the dioxidizer include alkali nitrite metals such as sodium nitrite. The diazotizing agent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, more preferably 1.0 to 2.0 moles or more, per mole of the compound of the formula [29] or a salt thereof.
[372] As an additive used for the said reaction, Copper salts, such as copper chloride and copper bromide; And iron salts such as iron chloride and iron bromide. The additive is used in an amount of 0.01 to 100 moles, preferably 1 to 50 moles per one mole of the compound of formula [29] or a salt thereof.
[373] The present reaction is generally carried out at a temperature of -70 ° C to 200 ° C, preferably -50 ° C to 100 ° C for 1 minute to 24 hours, preferably 30 minutes to 10 hours.
[374] In the method (2), the solvent used is not particularly limited as long as it does not cause any side effects in the present reaction. The solvent includes water; Alcohols such as methanol, ethanol and propanol; aliphatic hydrocarbons such as n-hexane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Thioethers such as dimethyl sulfide; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Acetals such as N, N-dimethylformamide dimethyl acetal; Inorganic acids such as sulfuric acid and hydrochloric acid; Carboxylic acids such as acetic acid and trifluoroacetic acid; Organic bases such as pyridine and triethylamine; and the like. These solvents may be used alone or in a mixture of two or more.
[375] The protecting agent used in the reaction is not particularly limited as long as it is a reagent commonly used for protecting aromatic amino acids. Preferred examples of the protective agent include organic halides such as benzoyl chloride, benzyl chloroformic acid and trityl chloride; Acid anhydrides such as acetic anhydride and di-tert-butyl dicarbonate; Aldehydes such as benzaldehyde; Acetals, such as N, N- dimethylformamide dimethyl acetal, etc. are mentioned. The protecting agent is at least the same equivalent or more, preferably 1.0 to 5.0 moles per mole of the compound of formula [29] or a salt thereof, except that N, N-dimethylformamide dimethyl acetal is used as the solvent as the protecting agent. As mentioned above, More preferably, it is used in the quantity of 1.0-3.0 mol or more.
[376] In the reaction, the additive may include inorganic bases such as sodium bicarbonate, sodium hydride and sodium hydroxide; Carboxylates such as sodium acetate; Organic bases such as pyridine and triethylamine; organolithium compounds such as n-butyllithium; Organo-silicon compounds such as trimethylsilyl chloride; Alkali metal salts such as sodium sulfate; Ortho acids such as ethyl ortho formate; Organic acids such as acetic acid, p-toluenesulfonic acid and N-hydrosuccinimide; Inorganic acids such as hydrochloric acid and boric acid fluoride; Alkali metals such as sodium; Carbodiimides such as N, N'-dichlorohexyl carbodiimide; Crown ethers such as 18-crown-6; Ammonium salts such as tetra-n-butylammonium iodine; Copper salts such as copper chloride; Palladium salts, such as a palladium chloride, etc. are mentioned. The additive is used in an amount of 0.01 to 100 moles, preferably 1 to 50 moles per one mole of the compound of formula [29] or a salt thereof.
[377] The reaction is generally carried out at a temperature of -70 ° C to 200 ° C, preferably -50 ° C to 160 ° C for 1 minute to 24 hours, preferably 10 minutes to 10 hours.
[378] The compound of formula [29] or a salt thereof, which is the starting material of the above-mentioned reaction, is described in J. Med. Chem., Vol. 8, Pages 638-642 (1965).
[379] The compound of formula [25] or a salt thereof can be obtained by halogenating the compound of formula [30] in the presence or absence of an additive.
[380] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. As said solvent, Aromatic hydrocarbons, such as toluene; Ethers such as tetrahydrofuran and the like. These solvents can optionally be used in mixtures.
[381] The halogenating agent used for the reaction is not particularly limited as long as it is a normal halogenating agent. As said halogenating agent, Phosphorus halides, such as phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, dichlorotriphenylphosphorane; And compounds having halogenated ions such as phosgene, thionyl chloride and benzenesulfonyl chloride. If desired, these reagents can be used in mixtures. The amount of the halogenating agent used varies depending on the type of halogenating agent, but is used in at least the same equivalents or more with respect to the compound of the general formula [30] or a salt thereof. In some cases, the halogenating agent may also be used as a solvent. For example, when phosphorus oxychloride is used, it can also be used as a solvent, and is used in an amount of 2.0 to 100 moles, preferably 2.0 to 30 moles per mole of the compound of formula [30] or a salt thereof. .
[382] As the additive that can be used in the present reaction as necessary, bases such as pyridine, N, N-diethylaniline and the like can be mentioned. The amount of the additive used varies depending on the type of the additive, but an amount of 0.1 to 30 moles, preferably 1.0 to 10 moles, per mole of the compound of Formula [30] or a salt thereof may be used.
[383] The reaction is generally carried out at a temperature of 0 to 300 ° C, preferably 20 to 120 ° C for 30 minutes to 48 hours, preferably 1 hour to 24 hours.
[384] Compounds of the general formula [30] or salts thereof include those of Shin Jikken Kagaku Koza, Vol. It is obtained by reacting with a nitrating agent according to the method described in 14 (III), Pages 1,266-1,277 (Chemical Society Japan, 1978).
[385] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid; Aliphatic carboxylic acids and acid anhydrides such as acetic acid; Ethers such as diethyl ether; Halogenated hydrocarbons such as methylene chloride; And water. These solvents can optionally be used in mixtures. The nitrating agent used in the reaction may be an inorganic acid such as nitric acid; Alkali metal nitrates such as potassium nitrate; Mention may be made of nitronium salts such as nitronium tetrafluoroborate and nitronium trifluoromethanesulfonate. These reagents are optionally used in mixtures.
[386] The amount of the nitrating agent used in the reaction varies depending on the type of nitrating agent, but at least the same equivalent or more, preferably 1.0 to 10 moles or more, more preferably 1.0 to the compound of the general formula [31] or a salt thereof. It may be used in an amount of ˜3.0 mol or more.
[387] The reaction is generally carried out at a temperature of -60 deg. C to 200 deg. C, preferably 0 to 100 deg. C for 10 minutes to 48 hours, preferably 1 hour to 24 hours.
[388] Compounds of the general formula [25] or salts thereof include compounds of the general formula [34] or salts thereof. Shin Jikken Kagaku Koza, Vol. It can be obtained by reacting with a halogenating agent in the presence or absence of a catalyst according to the method described in 14, Pages 1,106 to 1,119 (edited by Chemical Society Japan, 1977).
[389] The solvent used for the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Ketones such as acetone; Etc. can be mentioned. These solvents may be used alone or in a mixture of two or more.
[390] The halogenating agent used in the reaction is not particularly limited as long as it is a conventional halogenating agent. As said halogenating agent, Inorganic halides, such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphoryl chloride; Oxalic acid halides such as oxalyl chloride and oxalyl bromide; Etc. can be mentioned. The halogenating agent is used in an amount of at least the same equivalent or more, preferably 1 to 10 moles or more, per mole of the compound of the formula [34] or a salt thereof.
[391] As a catalyst which can be used in this reaction as needed, Organic bases, such as thioethylamine and a pyridine; Lewis acids such as zinc chloride; iodine; N, N-dimethylformamide and the like can be mentioned. The catalyst is used in an amount of 0.001 to 10 mol, preferably 0.001 to 0.5 mol per mol of the compound of the formula [34] or a salt thereof.
[392] The reaction is generally carried out at a temperature of -20 deg. C to 200 deg. C, preferably -10 deg. C to 120 deg. C for 1 minute to 72 hours, preferably 10 minutes to 24 hours.
[393] The compound of formula [25] or a salt thereof can be obtained by reacting a compound of formula [35] or a salt thereof with a nucleophilic substituent in the presence of a base.
[394] The solvent used in the reaction is not particularly limited as long as it does not cause any side effects in the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used alone or in a mixture of two or more.
[395] The nucleophilic substituent used in the reaction is not particularly limited as long as it is a reagent commonly used for nucleophilic substitution of aromatic halides. Preferred examples of the nucleophilic substituent include substituted phenols such as hydroquinone and p-methoxyphenol; Aryl mercaptan, such as thiophenol, etc. are mentioned. The nucleophilic substituent is used in an amount of at least the same equivalent or more, preferably 1.0 to 5.0 moles or more, per mole of the compound of the general formula [35] or a salt thereof. The base used for the reaction is not particularly limited as long as it is a reagent commonly used for nucleophilic substitution of aromatic halides. Preferred examples of the base include organic bases such as triethylamine and pyridine; And inorganic bases such as sodium carbonate and potassium carbonate. The base is used in an amount of 0.01 to 30 moles, preferably 0.5 to 2 moles per one mole of the compound of formula [35] or a salt thereof.
[396] The reaction is generally carried out at a temperature of -70 ° C to 200 ° C, preferably -20 ° C to 50 ° C for 1 minute to 24 hours, preferably 5 minutes to 6 hours.
[397] (Manufacturing Method II-B)
[398]
[399] ^Wherein R ^21a and R ^22b are the same as defined above.
[400] The compound of formula [27] or a salt thereof can be obtained by reacting the compound of formula [32] or a salt thereof with the same reaction as mentioned in preparation method II-4-1.
[401] The compound of formula [32] or a salt thereof can be obtained by reacting the compound of formula [33] or a salt thereof with the same reaction as mentioned in preparation method II-A-2.
[402] The following describes a method for producing a compound of formula [23] using a compound of formula [21] or a salt thereof as a starting compound.
[403]
[404] Wherein A ′, R ²¹ , R ²² , R ²³ , R ²⁴ and the dotted line are the same as defined above; R ²¹ is a carbamoyl group substituted with a carbamoyl group or an acyl group, and R ²² is a hydroxy group Is excluded.)
[405] The compound of formula [23] or a salt thereof can be prepared by subjecting the compound of formula [21] or a salt thereof to hydroxylation and / or carbamoyl reaction.
[406] In the above reaction, the hydroxylation method is prepared by the compound of formula [21] or a salt thereof in II-4-1, II-4-2, II-4-3, II-4-4, II-5-1. Through known reactions such as reduction reactions, substitution reactions, sandmeyer reactions, hydrolysis reactions and / or deprotection reactions described in the above, II-5-2, II-5-3 and II-5-4. Or by appropriately mixing these reactions.
[407] In the above reaction, the carbamoyl reaction is carried out in the compounds of the general formula [21] or salts thereof in II-6-1, II-6-2, II-6-3, II-7-1, II-7-2, Through known reactions such as oxidation reactions, reduction reactions, substitution reactions, addition reactions, halogenation reactions, dehydration reactions and / or hydrolysis reactions mentioned in II-7-3 and II-7-4, or these reactions are May be mixed.
[408] When both the hydroxylation and carbamoyl reactions are carried out within these reactions, any of the hydroxylation and carbamoyl reactions can be carried out before others.
[409] Salts of the compounds of the general formulas [21] to [35] in the above-mentioned methods for the preparation of intermediates are salts in conventionally known basic groups such as amino groups and salts in acidic groups such as hydroxyl groups, carboxyl groups and the like. Can be mentioned. Salts in the basic group include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; Salts formed with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, taphthalenesulfonic acid and the like. As a salt in an acidic group, Salt formed from alkali metals, such as sodium and potassium; Salts formed of alkaline earth metals such as calcium and magnesium; Trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dichlorohexylamine, procaine, dibenzylamine, N-benzyl salts formed with nitrogen-containing organic bases such as -β-pentylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, and the like.
[410] Further, in the above-mentioned preparation method, salts of the compounds of the general formulas [21] to [35] can be used in place of the compounds of the general formulas [21] to [35], and as the salts, the same as mentioned above Salts can be used.
[411] In some cases, the compounds of the general formulas [21] to [35] and salts thereof may have tautomers, optical isomers, regioisomers and the like and solvates. In some cases, all such isomers and solvates may be used in the present invention. After the reaction is completed, the target compound of the reaction can be used on its own in the next step of the production process without separation.
[412] In particular, the compound of the general formula [21], in which R ²² is OH, includes the following keto or enol type tautomers, and these tautomers are substantially the same compounds.
[413]
[414] In the above-mentioned production method, the compound of the general formula [21] to [35] or a salt thereof has an amino group, carbamoyl group, hydroxy group, mercapto group or carboxyl group. In some cases, these groups are previously protected with conventional protecting groups, and after the reaction the protecting groups can be detached according to known methods.
[415] In the following, the antiviral and cytotoxic action of the pyrazine derivative represented by the compound of the general formula [1] of the present invention and salts thereof will be described.
[416] Sample: A pyrazine derivative represented by formula [1] or a salt thereof was dissolved in dimethyl sulfoxide to prepare a solution having a concentration of 10 mg / ml. In use, the solution was used diluted to the appropriate concentration in the medium.
[417] Culture medium: 10% of the right when proliferating MDCK cells (derived from the dog's stomach), MA-104 cells (derived from the monkey's stomach) and HEp-2 cells (derived from human laryngeal cancer cells) and subjected to cytotoxicity testing E'-MEM with fetal serum was used.
[418] MDCK cells were used as host cells of influenza virus and also in cytotoxicity tests. MA-104 cells were used as host cells for rotavirus and HEp-2 cells were used as host cells for RS virus.
[419] (Test Example 1 [anti-influenza virus action])
[420] MDCK cells were plated at 5 × 10 ⁵ cell / well in a 6-well plate (manufactured by CORNING) and incubated overnight at 35 ° C. under 5% carbon dioxide conditions. Influenza virus (A / PR / 8/34 strains) was diluted to 200 PFU / ml in serum-free culture medium and hepatitis and absorbed for 1 hour at a rate of 0.5 ml / well. After complete hepatitis and absorption, it was added to E'-MEM medium containing 0.6% agar noble, 1% bovine serum albumin and 3 μg / ml acetized trypsin with a predetermined concentration of test compound. . After sufficient coagulation, the plates were turned upside down and the medium was left for 3 days. After the medium was completed, the living cells were stained with 1% Neutral Red, the cells were fixed with 10% formalin, the agar medium was removed with water, and the plaques were counted. The plaque-inhibition rate was expressed as a percentage of the control sample containing no test compound.
[421] The above results are shown in Table I-2. Here, the number of test compounds was the same as that of the sample.
[422] Table I-2
[423] Sample No.Test compound concentration added (μg / ml)% Inhibition Ⅰ-410080 Ⅰ-810042 Ⅰ-910031 Ⅰ-1010026 Ⅰ-1210028 Ⅰ-1310039
[424] In addition, the anti-influenza virus action of the nitrogen-containing heterocyclic carbamoyl derivative represented by the general formula [23] and the derivative salt which can be separated from the compound of the present invention can be obtained by the same method as in Test Example 1. As the test compound, 6-fluoro-3-hydroxy-2-pyrazinecarboxyamide was dissolved in dimethyl sulfoxide to prepare a 10 mg / ml medium, which was used in a medium solution at a predetermined concentration immediately before use. Diluted. As a result, the anti-influenza virus action was found to be 100% in terms of plaque inhibition at a test compound concentration of 1 µg / ml, demonstrating the superiority of the test compound as an anti-viral agent.
[425] (Test Example 2 [Anti-Rotavirus Action])
[426] MA-104 cells were plated in 6-well plates (CORNING Co., Ltd.) at a density of 5 × 10 5 cells / well and incubated overnight at 37 ° C. under 5% carbon dioxide. Rotavirus (Ku species) activated with 10 μg / ml of acecetylated trypsin for 30 minutes was diluted to 140 PFU / ml in serum-free medium and harvested and absorbed at a rate of 0.5 ml / well for 1 hour. After complete hepatitis and absorption, the hepatitised medium was removed and E'MEM medium containing 30 μg / ml test compound, 5 μg / ml trypsin and 1.4% agarose were added. Rotavirus infected MA-104 cells were incubated for 3 days at 37 ° C. under 5% carbon dioxide, after which the agarose containing 0.005% of Neutral Red was superimposed, and the medium was subjected to the same conditions as above. I put another day. After the medium was completed, the test plate was fixed with 3% formaldehyde solution, the test medium solidified with agar was removed, and the plaques were counted. Inhibition rate for rotavirus was calculated from the number of plaques in the compound-treated groups.
[427] Test Example 3 [Anti-RS virus (respiratory syncytial virus) action]
[428] HEp-2 cells were sprinkled in 6-well plates (CORNING Co.) at a density of 5 × 10 5 cells / well and incubated overnight at 37 ° C. under 5% carbon dioxide. RS virus (A-2 species) was diluted in serum-free medium at 140 PFU / ml and hepatitis and absorbed for one hour at a rate of 0.5 ml / hole. After complete hepatitis and absorption, the hepatitised medium was removed and added to E'MEM medium containing 30 μg / ml of test compound, 0.12% glutamine, 2% fetal bovine serum and 1% methyl cellulose. HEp-2 cells infected with RH virus were incubated at 35 ° C. for 3 days under 5% carbon dioxide. After the medium was completed, the test plate was fixed with 3% formaldehyde solution and the test medium containing methylcellulose was removed. The test plates were then stained with 5% Giemza Solution and the plaques counted. Inhibition rate for the RS virus was calculated from the number of plaques in the compound treated and untreated groups.
[429] As a result, the compound of Examples I-14 was found to have anti-RS viral action.
[430] Test Example 4 [Cytotoxic Activity]
[431] The medium containing the test compound at a predetermined concentration was added to a 96-well plate (manufactured by CORNING) in an amount of 100 µl / well. Subsequently, MDCK cells were prepared in a dispersion having a concentration of 2 × 10 ⁴ cells / μl in the medium, sprinkled at a rate of 100 μl / hole, and then incubated at 37 ° C. under 5% carbon dioxide for 3 days. When the medium was completed, the viable cells were counted according to the XXT method (CANCER RESEARCH, Vol. 48, Pages 4,827-4,833 (1988), etc.).
[432] As a result, all the compounds listed in Table I-2 were found to exhibit a 50% cell growth inhibitory concentration (IC ₅₀ ) of 100 µg / ml or more.
[433] (Example)
[434] Hereinafter, the compounds of the present invention and the intermediates of the present invention will be described with reference to Examples and Examples, but are not limited thereto.
[435] In the following Reference Examples and Examples, the mixing ratio in the eluent all means the "volume ratio". Packages for column chromatography were silica gel BW-127ZH (manufactured by Fuji Silysia Chemical Co.); Packages for reverse phase chromatography were YMC GEL ODS-AM 120-S50 (manufactured by YMC Co., Ltd.); And the package for ion exchange column chromatography is DEAE cellulose (manufactured by Wako Pure Chemical Industries).
[436] Indications used in Reference Examples and Examples mean the following.
[437] DMSO-d ₆ : Deuterated dimethyl sulfoxide
[438] (Reference Example I-1)
[439] 17.0 g of methyl 3-amino-6-bromo-2-pyrazinecarboxylate was dissolved in 100 ml of concentrated sulfuric acid. Under ice-cooling, 10.1 g of sodium nitrite was added and stirred for 30 minutes. The reaction mixture was poured into 920 mL of methanol and heated at reflux for 5 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure, and the obtained residue was added to a mixture of 500 ml of ice water and 600 ml of chloroform, and then the obtained mixture was separated in layers. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and the solvent was removed under reduced pressure. As a result, 6.30 g of methyl-6-bromo-3-methoxy-2-pyrazinecarboxylate as a light yellow oily product was obtained.
[440] IR (KBr) cm ^-1 : 1735
[441] ¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 4.06 (3H, s), 8.37 (1H, s)
[442] (Reference Example I-2)
[443] In a nitrogen gas atmosphere, 11.4 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was dissolved in 227 ml of toluene, 10.3 g of benzophenoneimine, 0.42 g of tris (dibenzylideneacetone) dipalladium, 0.86 g of (s)-(-)-2,2'-bis (diphenylphosphino) -1,1'-binafthyl and 6.20 g of sodium tert-butoxide were added successively. The resulting mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled down and then filtered. The filtrate was purified by column chromatography [eluent; Toluene: ethyl acetate = 20: 1]. The obtained oil-fat product was dissolved in 140 ml of tetrahydrofuran, 7 ml of 2 mol / L hydrochloric acid was added, and the obtained mixture was stirred at room temperature for 15 minutes. A mixture of 20 ml of chloroform and 50 ml of water was added to the reaction mixture, and then 1 mol / l of sodium hydroxide was added to alkalinize the mixture, and the organic layer was separated. The organic layer obtained was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Toluene: ethyl acetate = 1: 1] to give 3.64 g of methyl-6-amino-3-methoxy-2-pyrazinecarboxylate as a yellow oil.
[444] IR (KBr) cm ^-1 : 1716, 1670
[445] ¹ H-NMR (DMSO-d ₆ ) δ: 3.80 (3H, s), 3.82 (3H, s), 7.20 (2H, brs), 7.77 (1H, s)
[446] Reference Example I-3
[447] 3.5 g of methyl-6-amino-3-methoxy-2-pyrazinecarboxylate was dissolved in 70 ml of methanol. After injecting ammonia gas into the solution to prepare a saturated solution, the solution was stirred for 14 hours at room temperature. By removing the solvent from the reaction solution under reduced pressure, 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide as a solid was obtained.
[448] IR (KBr) cm ^-1 : 1684
[449] ¹ H-NMR (DMSO-d ₆ ) δ: 3.79 (3H, s), 5.87 (2H, brs), 7.30-7.75 (3H, m)
[450] (Reference Example I-4)
[451] Under a nitrogen gas atmosphere, 1.50 g of 6-amino-3-methoxy-2pyrazinecarboxamide was dissolved in 12 ml of a 70% hydrogen fluoride-pyridine solution under ice-cooling. Thereafter, sodium nitrite was added at -50 ° C, and the obtained mixture was stirred at 10 ° C for 1 hour. After the mixture was stirred for an additional hour, a mixture of 50 ml of ice water and 100 ml of chloroform was added, and the obtained mixture was separated in layers. The organic layer obtained was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. As a result, 1.29 g of 6-fluoro-3-methoxy-pyrazinecarboxamide as a solid was obtained.
[452] IR (KBr) cm ^-1 : 1707
[453] ¹ H-NMR (DMSO-d ₆ ) δ: 3.95 (3H, s), 7.55 to 8.15 (2H, m), 8.39 (1H, d, J = 8.3 Hz)
[454] (Reference Example I-5)
[455] Under a nitrogen gas atmosphere, 1.51 g of sodium iodide was dissolved in 22 ml of acetonitrile. After addition of 1.10 g of trimethylsilyl chloride, the resulting mixture was stirred at room temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was added, and the obtained mixture was added to a mixture of 10 ml of water and 20 ml of chloroform, and then separated in layers. The obtained organic layer was successively washed with a 5% aqueous solution of sodium thiosulfate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Hexane: ethyl acetate = 2: 1] to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white solid.
[456] IR (KBr) cm ^-1 : 1685, 1658
[457] ¹ H-NMR (CDCl ₃ ) δ: 5.40 to 7.80 (2H, m), 8.31 (1H, d, J = 7.8 Hz), 12.33 (1H, s)
[458] (Reference Example I-6)
[459] 1.0 g of 6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 40 ml of dichloroethane. Under a nitrogen gas atmosphere, 1.0 ml of 1,1,1,3,3,3-hexamethyldisilazane and 0.54 ml of chlorotrimethylsilane were added successively and heated to 90 ° C. for 2 hours. The mixture was cooled down and the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of dichloroethane and 2.68 g of β-D-ribofuranose-1-acetate-2,3,5-tribenzoate and tin (IV) were added successively, and then the mixture obtained was Stir at room temperature for 16 hours. The reaction mixture was added to 30 ml of ice water, the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution, and the layers were separated. The organic layer obtained was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Hexane: ethyl acetate = 4: 1] to give the yellow oil, 4-{(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5-[(benzoyloxy) methyl] tetrahydro- 1.76 g of 2-furanyl} -6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[460] IR (neat) cm ^-1 : 1728
[461] ¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.5 to 4.9 (3H, m), 5.6 to 6.0 (2H, m), 6.3 to 6.5 (1H, m), 7.1 to 8.2 (16H, m)
[462] (Reference Example I-7)
[463] Methyl-4-{(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5-[(benzoyloxy) methyl] tetrahydro-2-furanyl} -6-chloro in 16 ml methanol 0.80 g of 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was suspended. The suspension was added under ice cooling to 0.73 g of a 28% methanol solution of sodium methoxide, and the resulting mixture was stirred for 1 hour at the same temperature as above. The mixture was further stirred at room temperature for an additional 3 hours, after which the pH was adjusted to 7 with 6 mol / l hydrochloric acid and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Purified with chloroform: methanol = 10: 1] to give a yellow oil, methyl 6-chloro-4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro- 0.29 g of 2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[464] IR (neat) cm ^-1 : 1728
[465] ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 3.6 to 5.6 (11 H, m), 5.99 (1 H, s), 8.67 (1 H, s)
[466] (Reference Example I-8)
[467] 0.39 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 4.0 ml of N, N-dimethylformamide. Under a nitrogen gas atmosphere, 90 mg of sodium hydride was added and stirred at room temperature for 2 hours. Then, a suspension of 0.50 g of 4-[(trityloxy) methyl] -2-cyclopenten-l-yl acetate, 0.62 g of tetrakis-triphenylphosphine palladium and 50 mg of triphenylphosphine was added with tetrahydrofuran. To 4 ml, the resulting mixture was stirred for 1 hour at room temperature and 4 hours at 60 ° C. The reaction mixture was cooled, diluted with 30 ml of ethyl acetate and 20 ml of water, then adjusted to pH 4 with 1 mol / l hydrochloric acid, and then separated into layers. The organic layer was washed successively with saturated aqueous sodium carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Hexane: ethyl acetate = 1: 1] to give a pale yellow oil, methyl 3-oxo-4- {4-[(trityloxy) methyl] -20cyclopenten-l-yl} -3,4-dihydro- 0.23 g of 2-pyrazinecarboxylate was obtained.
[468] IR (neat) cm ^-1 : 1735
[469] ¹ H-NMR (CDCl ₃ ) δ: 1.2 to 1.6 (2H, m), 2.8 to 3.4 (3H, m), 3.98 (3H, s), 5.6 to 5.8 (1H, m), 5.8 to 6.1 (1H, m), 6.2 to 6.4 (1H, m), 7.0 to 7.6 (17H, m)
[470] (Reference Example I-9)
[471] 0.20 Methyl 3-oxo-4- {4-[(triloxy) methyl] -2-cyclopenten-l-yl} -3,4-dihydro-2-pyrazinecarboxylate 0.20 in 80 ml of 80% acetic acid aqueous solution g was dissolved and the resulting solution was heated at 80 ° C. for 1 h. The reaction mixture was cooled and diluted with 10 mL of water, after which the precipitate precipitated out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [eluent; Ethylacetate], 77 mg of methyl 4- [4- (hydroxymethyl) -2-cyclopenten-1-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a pale yellow oil. Got.
[472] IR (neat) cm ^-1 : 1738
[473] ¹ H-NMR (CDCl ₃ ) δ: 1.4 to 1.7 (1H, m), 2.2 to 3.2 (3H, m), 3.5 to 3.9 (2H, m), 3.96 (3H, s), 5.6 to 5.8 (1H, m), 5.8 to 6.1 (1H, m), 6.2 to 6.5 (1H, m), 7.43 (1H, d, J = 4.2 Hz), 7.70 (1H, d, J = 4.2 Hz)
[474] (Reference Example I-10)
[475] 0.24 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 6.0 ml of N, N-dimethylformamide. After addition of 82 mg of 18-crown-6-ether and 62 mg of sodium hydride, the obtained mixture was heated to 80 ° C. for 1 hour. Then, a solution of 3.0 g of (4aR, 7R, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] -dioxin-7-yl 4-methylbenzenesulfonate was dissolved in N. Dropwise was added dropwise to 3.0 ml of N-dimethylformamide and the resulting mixture was heated to 100 ° C. for 4 hours. The reaction mixture was cooled, diluted with 50 ml of ethyl acetate and 25 ml of water and separated into layers. Further, ethyl acetate was added three times by 25 ml each to extract an aqueous layer. All organic layers obtained were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Toluene: ethyl acetate = 3: 1]. Isopropyl ether and diethyl ether were added to the purified product, and then the solid was filtered through filtration. Thus, methyl 4-[(4aR, 7S, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3-oxo-3, which is a white solid, 84 mg of 4-dihydro-2-pyrazinecarboxylate was obtained.
[476] IR (neat) cm ^-1 : 1732
[477] ¹ H-NMR (DMSO-d ₆ ) δ: 1.97 to 2.37 (2H, m), 3.22 to 4.36 (6H, m), 3.95 (3H, s), 5.4 to 5.6 (1H, m), 5.67 (1H, s), 7.3 to 7.5 (5H, m), 8.35 (1H, d, J = 10 Hz), 8.37 (1H, d, J = 10 Hz)
[478] (Reference Example I-11)
[479] 0.38 ml of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 5.7 ml of N, N-dimethylformamide. After adding 0.10 g of sodium hydride, the obtained mixture was heated to 80 ° C. for 30 minutes. Thereafter, 0.19 g of (1aS, 3aR, 7aR, 7bS) -6-phenylhexahydro-1,3,5,7-tetraoxacyclopropa [a] naphthalene was added and heated at 100 ° C. for an additional 4.5 hours. . After cooling the reaction mixture and diluting with 30 ml of ethyl acetate and 20 ml of water, the obtained mixture was separated into layers. In addition, the aqueous layer was extracted with 30 ml of ethyl acetate. All organic layers obtained were combined and washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Toluene: ethyl acetate = 2: 1], and after adding isopropyl ether and diethyl ether, the solid was filtered through filtration. This gives methyl 4-[(4aR, 7R, 8S, 8aS) -8-hydroxy-2-phenyl-hexahydroxypyrano [3,2-d] [1,3] dioxine-7- as a yellow solid. 65 mg of il] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[480] IR (neat) cm ^-1 : 3447, 1740
[481] ¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, d, J = 2.2 Hz), 3.98 (3H, s), 3.52 to 4.62 (7H, m), 4.6 to 5.0 (1H, m), 5.59 (1H) s), 7.2 to 7.6 (5H, m), 7.52 (1H, d, J = 4.0 Hz), 8.17 (1H, d, J = 4.0 Hz)
[482] (Reference Example I-12)
[483] Suspension 1.52 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate in 12 ml of 1,1,1,3,3,3-hexamethyldisilazane, and the obtained suspension was refluxed. Under heating for 1 h. The mixture was cooled down and the solvent was removed under reduced pressure. Under a nitrogen gas atmosphere, the obtained residue was dissolved in 30 ml of dichloroethane, and 4.98 g of β-D-ribofuranose-1-acetate-2,3,5-tribenzoate and 1.73 ml of tin (IV) chloride were added thereto. After addition continuously, the resulting mixture was stirred for 14 hours at room temperature. The reaction mixture was diluted with 30 ml of chloroform and 30 ml of saturated aqueous sodium hydrogen carbonate solution, the precipitate was filtered off, and the organic layer was extracted. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Purified by n-hexane: ethyl acetate = 1: 1], methyl-4-{(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5-[(benzoyloxy) methyl as a white solid ] 3.4 g of tetrahydro-2-furanyl} -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[484] IR (KBr) cm ^-1 : 1728
[485] ¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 4.55 to 5.00 (3H, m), 5.75 to 6.00 (2H, m), 6.42 (1H, d, J = 3.0 Hz), 7.20 to 8.20 (17H, m)
[486] (Reference Example I-13)
[487] Methyl 4-{(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5-[(benzoyloxy) methyl] methyl] tetrahydro-2-furanyl} -3-oxo-3, 4-Dihydro-2-pyrazinecarboxylate was treated in the same manner as in Reference Example I-7 to give methyl 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxy Methyl) tetrahydro-2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[488] IR (KBr) cm ^-1 : 1740
[489] ¹ H-NMR (DSMO-d ₆ ) δ: 3.60 to 4.20 (5H, m), 3.83 (3H, s), 5.00 to 5.50 (2H, m), 5.61 (1H, d, J = 4.6 Hz), 5.91 (1H, s), 7.47 (1H, d, J = 4.4 Hz), 8.29 (1H, d, J = 4.4 Hz)
[490] (Reference Example I-14)
[491] To 5 ml of acetone, methyl 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4- 0.50 g of dihydro-2-pyrazinecarboxylate was suspended. Thereafter, 1 ml of trimethylorthoformate and 33 mg of p-toluenesulfonic acid monohydrate were added successively, and the obtained mixture was heated under reflux for 1 hour, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Purification with ethyl acetate] yielded white solid, methyl 4-[(3aR, 4R, 6R, 6aR) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d] [ 1,3] dioxol-4-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[492] IR (KBr) cm ^-1 : 1728
[493] ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, s), 1.59 (3H, s), 3.10 (1H, brs), 3.65-4.25 (2H, m), 3.95 (3H, s), 4.49 (1H s), 4.92 (2H, s), 5.91 (1H, s), 7.48 (1H, d, J = 4.3 Hz), 7.89 (1H, d, J = 4.3 Hz)
[494] (Reference Example I-15)
[495] 4 ml of pyridine methyl 4-[(3aR, 4R, 6R, 6aR) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol- 0.22 g of 4-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved. Thereafter, 0.17 g of dibenzyl phosphate, 0.40 g of triphenylphosphine and 0.30 ml of diisopropyl azodicarboxylate were added successively, stirred at room temperature for 15 hours, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Purification with ethyl acetate] gave an orange solid, methyl 4-[(3aR, 4R, 6R, 6aR) -6-({[bis (benzyloxy) -phosphoryl] oxy} methyl) -2,2-dimethyl 0.37 g of tetrahydropuro [3,4-d] dioxol-4-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained.
[496] R (KBr) cm ^-1 : 1734
[497] ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, s), 1.56 (3H, s), 3.96 (3H, s), 4.10-4.30 (2H, m), 4.30-4.45 (1H, m), 4.55 4.70 (2H, m), 4.90-5.15 (4H, m), 5.85-5.95 (1H, m), 7.10-7.85 (12H, m)
[498] (Reference Example I-16)
[499] J. Heterocycl. Chem., Vol. 1,1 g of 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile synthesized according to the method described in 19, Pages 1,397-1,402 (1982) was dissolved in 33 ml of methanol. While the solution was cooled under ice-cooling, hydrogen chloride gas was injected to saturation and the solution was stirred at the same temperature for 8 hours. The solvent was removed under reduced pressure, and the obtained residue was dissolved in 55 mL of 7 mol / L ammonia solution under ice cooling, and then the obtained solution was stirred at the same temperature as above for 5 minutes. The formed solid was taken as filtration to obtain 1.1 g of 3-oxo-3,4-dihydro-2-pyrazine-carboxyimidamide as a pale yellow solid.
[500] IR (KBr) cm ^-1 : 3379, 3000, 1698
[501] 1 H-NMR (DMSO-d ₆ ) δ: 7.50 (1H, d, J = 2.0 Hz), 8.33 (1H, brs), 8.18 (1H, d, J = 2.0 Hz), 8.33 (2H, brs)
[502] (Reference Example I-17)
[503] 0.30 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved in a mixture of 0.5 ml of ethanol and 1.9 ml of diethyl ether. While the solution was cooled under ice-cooling, hydrogen chloride gas was injected to saturation, and then the solution was stirred for 5 hours. The reaction mixture was mixed with 5.0 ml of diethyl ether, and the precipitated solid was taken through filtration, then successively with a mixture consisting of 10 ml of diethyl ether, 2.5 ml of ethanol and 2.5 ml of diethyl ether, and 5 ml of diethyl ether. Washed with water. As a result, 0.28 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidoate as a yellow solid was obtained.
[504] IR (KBr) cm ^-1 : 3041, 1670
[505] ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 1.43 (3H, t, J = 7.0 Hz), 4.50 (2H, q, J = 7.0 Hz), 8.49 (1H, d, J = 8.0 Hz )
[506] (Reference Example I-18)
[507] Under ice-cooling, ammonia gas was injected into 2.0 ml of ethanol to prepare a saturated solution, and 0.10 g of 6-fluor-3-oxo-3,4-dihydro-2-pyrazinecarboxymididoate and 2.0 ml of ethanol were added. After warming to room temperature, the mixture was left for 17 hours. The precipitated solid was taken through filtration and washed with ethanol. The obtained residue was subjected to silica gel column chromatography [eluent; Chloroform: methanol = 10: 1], and ethanol was added to the purified product, followed by filtration to give a solid. As a result, 20 mg of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidamide was obtained.
[508] IR (KBr) cm ^-1 : 3445, 3030, 1684
[509] ¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 8.26 (1H, d, J = 8.6 Hz)
[510] (Reference Example I-19)
[511] 1.0 g of 3-pydoxy-2-pinazinecarboxamide was suspended in 5.0 ml of 1,1,1,3,3,3-hexamethyldisilazane. The suspension was heated at reflux for 30 minutes, cooled and the solvent was removed under reduced pressure. The residue was dissolved in 5.0 ml of dichloroethane under nitrogen gas, followed by the continuous addition of 3.11 g of β-D-ribofuranose-1-acetate-2,3,5-tribenzoate and tin (IV). The resulting mixture was stirred at rt for 22 h. The reaction mixture was diluted with 30 ml of ethyl acetate and 20 ml of water, the pH was adjusted to 8 with saturated sodium bicarbonate solution, the precipitate was filtered off, and the organic layer was separated. The organic layer obtained was washed successively with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; Ethyl acetate: methanol = 10: 1], and after adding isopropyl ether, the solid material was taken through filtration. As such, the white solid [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetra 0.41 g of hydro-2-furanyl] methylbenzoate was obtained.
[512] IR (KBr) cm ^-1 : 1734, 1685
[513] ¹ H-NMR (CDCl ₃ ) δ: 4.6 to 5.1 (3H, m), 5.8 to 6.2 (3H, m), 6.39 (1H, d, J = 2.5 Hz), 7.2 to 8.2 (17H, m), 8.95 (1h, brs)
[514] (Reference Example I-20)
[515] To 4 ml of methanol [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro 0.37 g of 2-furanyl] methyl benzoate was dissolved. While the solution was cooled under ice cooling, ammonia gas was injected to saturation. The reaction solution was stirred at room temperature for 15 hours, and the solvent was removed under reduced pressure. Methanol is added to the residue and the precipitate is taken through filtration to give a light brown solid, 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro- 0.12 g of 2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained.
[516] IR (KBr) cm ^-1 : 1654
[517] ¹ H-NMR (DMSO-d ₆ ) δ: 3.73 (2H, dd, J = 5.4,5.4 Hz), 3.8-4.2 (3H, m), 5.08 (1H, brs), 5.24 (1H, t, J = 5.4 Hz), 5.61 (1H, brs), 5.92 (1H, s), 7.54 (1H, d, J = 4.2 Hz), 7.71 (1H, brs), 8.27 (1H, d, J = 4.2 Hz), 8.30 (1H, brs)
[518] (Reference Example I-21)
[519] 6-Fluoro-3-hydroxy-2-pyrazinecarboxamide was treated in the same manner as in Reference Example I-19 to give [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5 -Fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2-furanyl] methyl benzoate was obtained.
[520] IR (KBr) cm ^-1 : 1726, 1690
[521] ¹ H-NMR (DMSO-d ₆ ) δ: 4.6 to 5.0 (3H, m), 5.9 to 6.1 (2H, m), 6.33 (1H, s), 7.3 to 8.2 (17H, m), 8.53 (1H, brs)
[522] (Reference Example I-22)
[523] To 2.0 ml of methanol [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyl 0.15 g of oxy) tetrahydro-2-furanyl] methyl benzoate was dissolved. Thereafter, 0.14 g of a 28% methanol solution of sodium methoxide was added thereto, and the resultant was stirred for 20 minutes under ice cooling and 30 minutes at room temperature. The reaction mixture was acidified with 0.75 mL of 1 mol / L hydrochloric acid and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent; After purification with chloroform: methanol = 5: 1], isopropanol and diethyl ether were added and the solid was collected by filtration to obtain 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 40 mg of-(hydroxymethyl) tetrahydro-2-furanyl] -6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained.
[524] IR (KBr) cm ^-1 : 1693
[525] (Reference Example I-23)
[526] To 4 ml of methanol, methyl 6-chloro-4-[(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo- 0.26 g of 3,4-dihydro-2-pyrazinecarboxylate was dissolved. While the solution was cooled under ice cooling, ammonia gas was injected to saturation. The reaction mixture was stirred for 1 hour under ice cooling, and then the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Purification with chloroform: methanol = 7: 1] yields a pale yellow solid, 6-chloro-4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro- 0.06 g of 2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained.
[527] IR (KBr) cm ^-1 : 1693
[528] (Example I-3)
[529] 0.62 g of 3-hydroxy-2-pyrazinecarboxamide was suspended in 5.0 ml of 1,1,1,3,3,3-hexamethyldisilazane. The suspension was heated at reflux for 1 h. After cooling the reaction mixture, removing the solvent under reduced pressure, the residue was dissolved in 2 ml of dichloroethane under a nitrogen gas atmosphere, and thereafter, J. Med. Chem., Vol. 28, No. 7, (2R, 3S) -5- (acetyloxy) -2-[(acetyloxy) methyl] tetrahydro-3-furanyl acetate, prepared according to the method described in Pages 904-910 (1985). And 3 ml of dichloroethane and titanium (IV) chloride were added to 1.0 g of a mixture of (3R, 4S) -4,6-bis (acetyloxy) tetrahydro-2H-furan-3-yl acetate. Further 5.0 mL of dichloroethane was added thereto, and the obtained mixture was stirred for 17 hours. The reaction mass was diluted with 100 ml of chloroform and 25 ml of saturated aqueous sodium hydrogen carbonate solution, the precipitate was filtered off, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography [eluent; Purified with ethyl acetate: methanol = 10: 1] to give a light brown oil, {(2R, 3S) -3- (acetyloxy) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyra 0.43 g of genyl) tetrahydro-2-furanyl} methyl acetate was obtained.
[530] IR (KBr) cm ^-1 : 1735,1685
[531] ¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H, s), 2.14 (3H, s), 1.8 to 2.6 (2H, m), 4.0 to 4.6 (2H, m), 5.0 to 5.4 (2H, m) , 6.33 (1H, d, J = 5.9 Hz), 6.64 (1H, brs), 7.76 (1H, d, J = 4.2 Hz), 7.83 (1H, d, J = 4.2 Hz), 9.06 (1H, brs)
[532] (Example I-4)
[533] To 2 ml of methanol {(2R, 3S) -3- (acetyloxy) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -tetrahydro-2-furanyl} 0.20 g of methyl acetate was dissolved. Under ice-cooling, the solution was added with 0.23 g of a 28% methanol solution of sodium methoxide and stirred for 20 minutes. Thereafter, 1.2 ml of 1 mol / l hydrochloric acid was added to the reaction mixture. The residue obtained was purified by column chromatography [eluent; Purified by chloroform: methanol = 10: 1] to give a yellow oil, 4-[(4S, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3, 90 mg of 4-dihydro-2-pyrazinecarboxamide was obtained.
[534] IR (KBr) cm ^-1 : 1684
[535] ¹ H-NMR (DMSO-d ₆ ) δ: 1.8 to 2.2 (2H, m), 3.0 to 4.4 (4H, m), 4.50 to 5.20 (2H, m), 6.13 (1H, d, J = 5.9 Hz) , 7.59 (1H, d, J = 4.2 Hz), 7.70 (1 H, brs), 7.92 (1 H, d, J = 4.2 Hz), 8.45 (1 H, brs)
[536] (Example I-8)
[537] 75 mg of methyl 4- [4- (hydroxymethyl) -2-cyclopenten-1-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 1 ml of methanol. At room temperature, 25% aqueous ammonia solution was added and stirred for 13 hours, after which the solvent was removed under reduced pressure. Isopropanol was added to the residue, and the solid was collected by filtration to give 4- [4- (hydroxymethyl) -2-cyclopenten-1-yl] -3-oxo-3,4-dihydro- as a white solid. 20 mg of 2-pyrazinecarboxamide was obtained.
[538] IR (KBr) cm ^-1 : 1668
[539] ¹ H-NMR (DMSO-d ₆ ) δ: 1.2 to 3.8 (5H, m), 4.92 (1H, brs), 5.8 to 6.1 (2H, m), 6.2 to 6.4 (1H, m), 7.4 to 8.1 ( 3H, m), 8.20 (1H, brs)
[540] (Example I-9)
[541] In 5.0 ml of 80% acetic acid aqueous solution, methyl 4-[(4aR, 7S, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3-oxo 80 mg of -3,4-dihydro-2-pyrazinecarboxylate was dissolved. The solution was heated to 80 ° C. for 2 hours, then cooled and the solvent was removed under reduced pressure. The residue was diluted with 20 mL of water and washed with diethyl ether and then water was removed from the aqueous layer. The obtained residue was dissolved in 4.0 ml of methanol, and ammonia gas was introduced to saturated state under ice cooling. The reaction mixture was stirred at room temperature for 2 hours and then depressurized to remove the solvent. The residue obtained was purified by column chromatography [eluent; Purified by chloroform: methanol = 10: 1] to give a solid 4-[(3S, 5S, 6R) -5-hydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] -3- 24 mg of oxo-3,4-dihydro-2-pyrazinecarboxamide was obtained.
[542] IR (KBr) cm ^-1 : 3451, 1676
[543] ¹ H-NMR (DMSO-d ₆ ) δ: 1.45 to 1.85 (1H, m), 2.10 to 2.30 (1H, m), 2.95 to 4.05 (6H, m), 4.47 (1H, t, J = 5.6 Hz) , 4.83 (1H, d, J = 5.4 Hz), 5.20 to 5.30 (1 H, m), 7.67 (1 H, brs), 7.80 (1 H, brs), 8.24 (1 H, d, J = 7.0 Hz), 8.27 ( 1H, d, J = 7.0Hz)
[544] (Example I-10)
[545] Methyl 4-[(4aR, 7R, 8S, 8aS) -8-hydroxy-2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3-oxo- 3,4, -dihydro-2-pyrazinecarboxylate was treated in the same manner as in Example I-9 to 4-[(3R, 4S, 5S, 6R) -4,5-dihydroxy-6- ( Hydroxymethyl) tetrahydro-2H-pyran-3-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide.
[546] IR (KBr) cm ^-1 : 3404, 1670
[547] ¹ H-NMR (DMSO-d ₆ ) δ: 3.42 to 3.67 (4H, m), 3.95 (1H, dd, J = 3.1,13 Hz), 3.90 to 3.95 (1H, m), 4.02 (1H, dd, J = 3.7,13 Hz), 4.56 (1H, t, J = 6.1 Hz), 4.68 (1H, q, J = 4.8 Hz), 4.75 (1H, d, J = 6.1 Hz), 5.37 (1H, d, J = 4.5 Hz), 7.49 (1 H, d, J = 4.3 Hz), 7.66 (1 H, brs), 8.21 (1 H, d, J = 4.3 Hz), 8.34 (1 H, brs)
[548] (Example I-11)
[549] Methyl 4-[(3aR, 4R, 6R, 6aR) -6-({[bis (benzyloxy) phosphoryl] oxy} methyl) -2,2-dimethyltetrahydropuro [3,4-d] [1 , 3] dioxol-4-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate was treated in the same manner as in Reference Example I-23 to obtain {(3aR, 4R, 6R, 5aR) -6- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4 -Yl} methyl dibenzyl phosphate was obtained.
[550] IR (KBr) cm ^-1 : 1685, 1654
[551] ¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, s), 1.59 (3H, s), 4.00 to 4.65 (5H, m), 4.80 to 5.50 (4H, m), 5.93 (1H, d, J = 2.2 Hz), 6.15 (1 H, brs), 7.10 to 7.80 (10 H, m), 7.59 (1 H, d, J = 4.3 Hz), 7.67 (1 H, d, J = 4.3 Hz), 9.15 (1 H, brs)
[552] (Example I-12)
[553] 60 mg of {(3aR, 4R, 6R, 6aR) -6- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl in 3 ml of 90% aqueous solution of trifluuroacetic acid under ice cooling ] -2,2-dimethyltetrahydropuro [3,4-d] [1,3] dioxol-4-yl] methyl dibenzyl phosphate was dissolved. The obtained solution was stirred at the same temperature as above for 30 minutes and at room temperature for 2 hours, and then the solvent was removed under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was taken by filtration and washed with methanol. As a result, the light red solid {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro 2-furanyl} methyl dihydrogen phosphate was obtained.
[554] IR (KBr) cm ^-1 : 1654
[555] ¹ H-NMR (DMSO-d ₆ ) δ: 2.80 to 4.80 (9H, m), 5.90 to 6.00 (1H, m), 7.47 (1H, d, J = 4.5 Hz), 7.68 (1H, brs), 7.97 (1H, d, J = 4.5Hz), 8.30 (1H, brs)
[556] (Example I-13)
[557] To a mixture of 2 mL tetrahydrofuran and 1 mL water, {(3aR, 4R, 6R, 6aR) -6- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2,2 100 mg of dimethyltetrahydropuro [3,4-d] [1,3] dioxol-4-yl] methyl dibenzyl phosphate was dissolved. After adjusting the pH value to 0.5 with 6 mol / l hydrochloric acid, the mixture was left at room temperature for 2 days. The precipitated solid material was taken by filtration and washed with ethanol to obtain the solid {(2R, 3S, 4R, 5R) -5 [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3 40 mg of, 4-dihydroxytetrahydro-2-furanyl} methyl dibenzyl phosphate was obtained.
[558] IR (KBr) cm ^-1 : 1676, 1660
[559] ¹ H-NMR (DMSO-d ₆ ) δ: 3.70 to 4.60 (5H, m), 5.04 (2H, s), 5.12 (2H, s), 5.30 to 5.45 (1H, m), 5.71 (1H, d, J = 4.6 Hz), 5.85 to 6.00 (1H, m), 7.10 to 7.60 (11H, m), 7.76 (1H, brs), 7.78 (1H, d, J = 3.9 Hz), 8.30 (1H, brs)
[560] (Example I-14)
[561] In 20 ml of 1,1,1,3,3,3-hexamethyldisilazane, 0.02 g of 3-oxo-3,4-dihydro-2-pyrazinecarboxymidamide and 10 mg of ammonium sulfate were suspended. Under a nitrogen gas stream, the suspension was heated at reflux for 10 minutes. After addition of 9.0 mg of ammonium sulfate, the mixture was heated at reflux for an additional 2 hours. After cooling the obtained reaction mixture, the solvent was removed under reduced pressure. The obtained residue was dissolved in 4.0 ml of acetonitrile, 0.46 g of β-D-ribofuranose-1,2,3,5-tetraacetate and 0.34 ml of tin chloride (IV) were added sequentially, and the mixture obtained was Stir at room temperature for 3 hours. Then 10 μl of trifluoroacetic acid and 10 mL of water were added to the reaction mixture, and the solvent was removed under reduced pressure. In addition, the same reaction was repeated using 0.05 g of 3-oxo-3,4-dihydro-2-pyrazinecarboxymidamide. The obtained reaction mixture was combined with the above reaction mixture, and the obtained product was subjected to reverse phase silica gel column chromatography [eluent; Purification with acetonitrile: water = 1: 4] yielded pale yellow solid (2R, 3R, 4R, 5R) -4- (acetyloxy) -2-[(acetyloxy) methyl] -5- [3- [ 0.34 g of amino (imino) methyl] -2-oxo-1 (2H) -pyrazinyl] tetrahydro-3-furanyl acetate was obtained.
[562] IR (KBr) cm ^-1 : 3392, 1750, 1685
[563] ¹ H-NMR (DMSO-d ₆ ) δ: 2.11 (3H, s), 2.16 (6H, s), 4.4 to 4.7 (3H, m), 5.31 (1H, t, J = 5.0 Hz), 5.5 to 5.6 (1H, m), 6.22 (1H, d, J = 3.0 Hz), 7.8-8.0 (1H, m), 8.1-8.3 (1H, m), 8.67 (1H, brs), 10.45 (2H, brs)
[564] (Example I-15)
[565] Under ice-cooling, in 5.0 ml of 25% aqueous ammonia solution (2R, 3R, 4R, 5R) -4- (acetyloxy) -2-[(acetyloxy) methyl] -5- [3- [amino (imino) methyl ] 0 oxo-1 (2H) -pyrazinyl] tetrahydro-3-furanyl acetate was added and the resulting mixture was stirred for 2 h at room temperature as above. After adding 4.9 mL of acetic acid to the reaction mixture, the solvent was removed under reduced pressure. Furthermore, (2R, 3R, 4R, 5R) -4- (acetyloxy) -2 [(acetyloxy) methyl] -5- [3- [amino (imino) methyl] -2-oxo-1 (2H) The same reaction was repeated using 20 mg of -pyrazinyl] tetrahydro-3-furanyl acetate, and the obtained mixture was combined with the above reaction mixture. The combined mixtures were reversed-phase silica gel column chromatography [eluent; Water]. 5.0 mL of 1 mol / L hydrochloric acid was added to the obtained solid, and then the solvent was removed under reduced pressure. Again, 5.0 ml of 1 mol / l hydrochloric acid was added and the solvent was removed under reduced pressure. Ethanol was added to the obtained residue, and the solid was collected by filtration to obtain 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro- as a pale yellow solid. 30 mg of 2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxymidamide hydrochloride was obtained.
[566] IR (KBr) cm ^-1 : 3374, 3281, 1690
[567] ¹ H-NMR (DMSO-d ₆ ) δ: 3.7-3.9 (2H, m), 3.9-4.2 (3H, m), 5.1-5.3 (1H, m), 5.3-5.6 (1H, m), 5.6- 5.8 (1H, m), 5.90 (1H, s), 7.86 (1H, d, J = 4.0Hz), 8.76 (1H, d, J = 4.0Hz), 9.44 (3H, brs)
[568] (Example I-16)
[569] 4-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4- in 2.0 ml of trimethylphosphate 0.11 g of dihydro-2-pyrazinecarboxamide was suspended. Under ice-cooling, 0.11 ml of phosphorus oxychloride was added and stirred for 2 hours at room temperature as above. A solution of 1.2 ml of tributylamine and 0.56 g of tributylammonium phosphate in 6.0 ml of dimethylformamide was added to the reaction and stirred for 1 hour at the same temperature as above. 0.1 mol / l of triethylammonium hydrogen carbonate solution was added to the reaction solution, and the mixture was left at room temperature for 12 hours. The solvent was removed under reduced pressure, and the obtained residue was subjected to ion exchange column chromatography [eluent; 0.07 mol / l triethylammonium hydrogen carbonate solution] to obtain {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H)- Fragments containing triethylamine salt of pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl diphosphate and {(2R, 3S, 4R, 5R) -5- [3 Containing a triethylamine salt of-(aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl triphosphate A fragment was obtained. Solid products 143 mg and 113 mg were obtained here, respectively. {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl } In 143 mg of the triethylamine salt of methyl diphosphate, 110 mg was extracted and dissolved in 3.0 ml of methanol, where a solution of 0.28 g of sodium perchlorate in 7.5 ml of acetone was added. The solid was obtained by centrifugation, washed with acetone to obtain a white solid {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] 64 mg of sodium salt of -3,4-dihydroxytetrahydro-2-furanyl} methyl diphosphate was obtained.
[570] IR (KBr) cm ^-1 : 3418, 1682, 1236, 983, 905
[571] ¹ H-NMR (D ₂ O) δ: 4.2 to 4.5 (5H, m), 6.12 (1H, s), 7.83 (1H, d, J = 3.7 Hz), 8.35 (1H, d, J = 3.7 Hz)
[572] (Example I-17)
[573] {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxy obtained in Examples I-16 In 113 mg of triethylamine salt of tetrahydro-2-furanyl} methyl triphosphate, 46 mg were taken and dissolved in 1.0 mL of methanol, and a solution of 92 mg of sodium perchlorate was added thereto in 5.0 mL of acetone. The solid was obtained by centrifugation and washed with acetone to obtain {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3, 21 mg of sodium salt of 4-dihydroxytetrahydro-2-furanyl} methyl triphosphate were obtained.
[574] IR (KBr) cm ^-1 : 3436, 1692, 1284, 1103, 997
[575] ¹ H-NMR (D ₂ O) δ: 4.2 to 4.5 (5H, m), 6.14 (1H, s), 7.85 (1H, d, J = 3.0 Hz), 8.36 (1H, d, J = 3.0 Hz)
[576] (Example I-18)
[577] Under a nitrogen gas stream, 5.3 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide was suspended in 53 ml of acetonitrile. To this, 8.4 ml of N, O-bis (trimethylsilyl) acetamide was added under ice cooling, and the obtained mixture was stirred at room temperature for 1.5 hours. The reaction mixture was cooled under ice cooling, followed by Carbohydr. Res., Vol. 203, No. (2R, 3R, 4R) -4,5-bis (acetyloxy) -2- (hydroxymethyl) -tetrahydro-3-fue prepared according to the process described in 9, Pages 324-329 (1990). 7.2 ml of ranyl acetate and tin (IV) chloride were successively added to the reaction mixture, and the obtained mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a mixture of 100 ml of ethyl acetate and 300 ml of saturated aqueous sodium bicarbonate solution, the organic layer was separated, and the aqueous layer was extracted with 700 ml of ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of methanol, and 100 ml of 80% acetic acid aqueous solution was added thereto, and the obtained mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica road column chromatography [eluent; Chloroform: methanol = 40: 1]. To this was added chloroform and isopropyl ether, followed by filtration to give a solid, which was a pale yellow solid (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl 9.3 g of) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -5- (hydroxymethyl) tetrahydro-3-furanyl acetate was obtained.
[578] IR (KBr) cm ^-1 : 3411, 1752, 1686
[579] ¹ H-NMR (DMSO-d ₆ ) δ: 2.04 (3H, s), 2.10 (3H, s), 3.64 (1H, ddd, J = 2.5,5.0,13 Hz), 3.86 (1H, ddd, J = 2.5 , 5.0, 13 Hz), 4.29 (1H, d, J = 6.0 Hz), 5.35 (1H, t, J = 6.0 Hz), 5.49 (1H, dd, J = 3.0, 5.0 Hz), 5.65 (1H, t, J = 5.0Hz), 6.11 (1H, d, J = 3.0Hz), 7.96 (1H, brs), 8.42 (1H, d, J = 5.0Hz), 8.49 (1H, brs)
[580] (Example I-19)
[581] Under nitrogen gas stream, (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluor-2-oxo-1 (2H) -pyrazinyl]- 1.5 g of 5- (hydroxymethyl) -tetrahydro-3-furanyl acetate and 0.84 g of 1H-tetrazole were dissolved in 30 ml of acetonitrile. While cooling the solution under ice cooling, a solution of 1.4 ml of diallyl diisopropyl phosphoramidite in 20 ml of acetonitrile was added and stirred for 20 minutes. To this was added a solution of 1.4 g of m-chloroperbenzoic acid in 10 ml of acetonitrile and stirred for 10 minutes. After adding 60 ml of ethyl acetate to the reaction mixture, the obtained mixture was incorporated into 60 ml of water, the organic layer was separated, and the aqueous layer was extracted with 90 ml of ethyl acetate. All organic layers were combined, 30 ml of water was added, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent; Chloroform: methanol = 40: 1] to give a yellow solid (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo- 1.3 g of 1 (2H) -pyrazinyl] -5-({[bis (allyloxy) phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate was obtained.
[582] IR (KBr) cm ^-1 : 3403, 1753, 1694, 1244, 1024
[583] ¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.15 (3H, s), 4.32 to 4.35 (1H, m), 4.47 to 4.52 (2H, m), 4.58 to 4.64 (4H, m) , 5.27 (2H, dt, J = 1.0, 10.5 Hz), 5.37-5.44 (4H, m), 5.90-6.00 (2H, m), 6.28 (1H, d, J = 4.0 Hz), 6.32 (1H, brs ), 7.99 (1H, d, J = 6.0 Hz), 9.02 (1H, brs)
[584] (Example I-20)
[585] To 4.0 ml of methanol (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluor-2-oxo-1 (2H) -pyrazinyl] -5 0.23 g of-({[bis (allyloxy) -phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate was dissolved. While cooling the solution under ice cooling, 0.17 g of a 28% methanol solution of sodium methoxide was added and stirred for 5 minutes. 0.15 ml of acetic acid was added here and the solvent was removed under reduced pressure. On the other hand, (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluor-2-oxo-1 (2H) -pyrazinyl] -5- 1.0 g of ({[bis (allyloxy) -phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate was reacted in the same manner as above. Combine the two reactants and silica gel column chromatography [eluent; Chloroform: methanol = 40: 1]. This gave {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydrate as a yellow solid. 0.35 g of oxytetrahydro-2-furanyl} methyl diallyl phosphate was obtained.
[586] IR (KBr) cm ^-1 : 3417, 1684, 1264, 1025, 1000
[587] ¹ H-NMR (DMSO-d ₆ , D ₂ O) δ: 3.1 to 4.7 (10H, m), 5.1 to 5.5 (4H, m), 5.7 to 6.2 (2H, m), 7.94 (1H, d, J) = 6.0 Hz)
[588] (Example I-21)
[589] Under a nitrogen gas stream, a mixture of 8.2 ml of methanol and 8.2 ml of tetrahydrofuran was added to {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluor-2-oxo-1 ( 0.82 g of 2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl diallyl phosphate was dissolved. 0.11 g of tetrakis-triphenylphosphine palladium (0) and 0.28 g of triphenylphosphine were added successively, and the obtained mixture was stirred at room temperature for 30 minutes. While cooling the reaction mixture under ice-cooling, a solution of 0.68 mL of formic acid in 1.9 mL of tetrahydrofuran and 0.25 mL of n-butylamine in 8.2 mL of tetrahydrofuran were added successively. The resulting mixture was stirred at 30-35 ° C. for 1 hour and at 40-45 ° C. for 2 hours. The reaction mixture was diluted with 10 mL of water and the organic solvent was removed under reduced pressure. The aqueous solution obtained was washed with 20 ml of chloroform, and the washed water was extracted with 30 ml of water. All aqueous layers were combined and the solvent was removed under reduced pressure. The obtained residue was subjected to reverse phase silica gel column chromatography [eluent; Water]. This gave {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydrate as a yellow solid. 0.29 g of oxytetrahydro-2-furanyl} methyl dihydrogen phosphate n-butylamine salt was obtained.
[590] IR (KBr) cm ^-1 : 3382, 1685, 1183, 1110
[591] ¹ H-NMR (DMSO-d ₆ ) δ: 0.75 to 0.90 (3H, m), 1.25 to 1.42 (2H, m), 1.45 to 1.70 (2H, m), 2.70 to 2.80 (2H, m), 3.3 to 4.7 (9H, m), 5.33 (1H, d, J = 10Hz), 5.42 (1H, d, J = 17Hz), 5.90 (2H, brs), 7.95 (1H, brs), 8.34 (1H, d, J = 5.0 Hz), 8.63 (1 H, brs)
[592] (Example I-22)
[593] To a mixture of 4.2 ml of acetonitrile and 8.4 ml of N, N-dimethylformamide, {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H 0.21 g))-pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl dihydrogen phosphate n-butylamine salt was suspended. 0.15 g of N, N-carbonyldiimidazole was added thereto and stirred at room temperature for 2 hours. Thereafter, 19 µl of methanol was added to the reaction mixture, which was stirred for 30 minutes. In addition, a solution of 0.86 g of tri-n-butylammonium pyrophosphate in 2.0 ml of N, N-dimethylformamide was added and stirred for an additional 14 hours. The solvent was removed under reduced pressure, and the obtained residue was subjected to ion exchange column chromatography [eluent; 0.10 mol / l solution of hydrogen triethylammonium carbonate] and reverse phase column chromatography [eluent; Water]. To the solid obtained was successively added a solution of 0.90 mL of methanol and 0.17 g of sodium perchloride in 4.5 mL of acetone. The precipitate was taken by centrifugation, washed with acetone and washed with pale yellow solid {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluor-2-oxo-1 (2H)- 60 mg of sodium salt of pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl] methyl triphosphate was obtained.
[594] IR (KBr) cm ^-1 : 3422, 1686, 1252, 1108
[595] ¹ H-NMR (D ₂ O) δ: 4.3 to 4.5 (5H, m), 6.09 (1H, s), 8.41 (1H, d, J = 5.1 Hz)
[596] (Example I-23)
[597] See (2R, 3R, 4R) -5- (acetyloxy) -2-[(benzoyloxy) methyl] -4-fluorotetrahydro-3-furanyl benzoate prepared according to WO 93/10137. (2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2-[(benzoyloxy) methyl ] -4-fluorotetrahydro-3-furanyl benzoate was obtained.
[598] IR (KBr) cm ^-1 : 3422, 1718, 1685
[599] ¹ H-NMR (CDCl ₃ ) δ: 4.1 to 6.2 (6H, m), 7.3 to 8.2 (12H, m), 8.1 to 8.3 (1H, m), 8.8 to 9.1 (2H, m)
[600] (Example I-24)
[601] (2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2-[(benzoyloxy) methyl] -4-fluorotetrahydro 3-furanyl benzoate was treated in the same manner as in Reference Example I-22 to give 4-[(2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetra Hydro-2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide.
[602] IR (KBr) cm ^-1 : 3376, 1684, 1654
[603] ¹ H-NMR (CDCl ₃ , CD ₃ OD) δ: 3.7 to 4.4 (4H, m), 4.96 (1H, dd, J = 4.0,52 Hz), 6.22 (1H, d, J = 16 Hz), 7.6 (1H) , d, J = 4.0Hz), 8.42 (1H, d, J = 4.0Hz)
[604] (Reference Example II-1)
[605] 8.0 g of methyl 3-amino-6-chloro-2-pyrazinecarboxylate was suspended in a mixture of 14 mL of 12 mol / L hydrochloric acid and 14 mL of tetrahydrofuran. After adding 5.9 g of sodium nitrate at 5 to 12 ° C., the obtained mixture was stirred under ice cooling for 50 minutes. Then, 8.4 g of copper chloride (I) was added to 6 mol / L hydrochloric acid, followed by stirring for 10 minutes at the same temperature as above. The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and mL of water to separate an organic layer. The obtained organic layer was washed with water continuously in 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent; n-hexane: ethyl acetate = 6: 1] to obtain 6.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate as a colorless oil.
[606] IR (neat) cm ^-1 : 1747
[607] ¹ H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 8.54 (1H, s)
[608] (Reference Example II-2)
[609] 2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate was dissolved in 10 ml of methanol. Thereafter, 10.2 ml of 1 mol / L aqueous sodium hydrogen chloride solution was added under ice-cooling, and stirred for 1 hour. The reaction mixture was mixed with a mixture of 200 ml of ethyl acetate and 200 ml of water to separate an organic layer. The organic layer was washed successively with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was washed with hexane to obtain 1.6 g of 3,6-dichloro-2-perazinecarboxylic acid as a white solid.
[610] IR (KBr) cm ^-1 : 1718
[611] ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (1H, s), 8.84 (1H, s)
[612] (Reference Example II-3)
[613] 208.0 g of 3-hydroxy-2-pyrazinecarboxamide was dissolved in 1.2 L of 97% sulfuric acid, and the solution was cooled under ice-cooling to maintain a temperature of 10 to 25 ° C. 185 g of sodium nitrite was added to the obtained solution, and the obtained mixture was stirred at room temperature for 15 minutes and at 40 ° C for 2 hours. The reaction mixture was cooled to 20 ° C., then mixed with 6 L of ice water, stirred for 1 hour at room temperature, then precipitated through filtration and washed twice with 50 ml of water each time. The solid obtained was suspended in 1 L of water, the pH was adjusted to 1.5 with 5 mol / L aqueous sodium hydroxide solution, and the solid was taken out by filtration. The solid was successively washed with 500 ml of water and 500 ml of acetone to obtain 180.0 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide as a solid.
[614] IR (KBr) cm ^-1 : 1707, 1685, 1654
[615] ¹ H-NMR (DSMO-d ₆ ) δ: 5.60 (1H, brs), 8.10 (1H, brs), 8.35 (1H, brs), 8.96 (1H, s)
[616] (Reference Example II-4)
[617] To 400 ml of phosphorus oxychloride 88.7 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide was added at a temperature of 55-60 ° C. After the mixture was reacted for 15 minutes at the same temperature as above, 150 ml of pyridine was added dropwise at a temperature of 40 to 60 ° C. The reaction mixture was first stirred at 60 ° C. for 1 hour, then at 80 ° C. for 1 hour and finally at 100 ° C. for 4 hours, then mixed with 600 ml of toluene and kept at room temperature. After filtering out the precipitate, the filtrate was concentrated to dryness under reduced pressure. 500 ml of toluene and 1 liter of water were continuously added to the obtained residue, and the obtained mixture was stirred at 40 ° C for 30 minutes to separate an organic layer. The organic layer was first washed twice with 50 ml of water, washed once with 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: toluene = 1: 1] to give 64.5 g of 3,6-dichloro-2-pyrazinecarbonitrile as a solid.
[618] IR (KBr) cm ^-1 : 2236, 2252
[619] ¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s)
[620] (Reference Example II-5)
[621] In 1.19 L of water, 80.0 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide and 47.5 g of sodium hydroxide were dissolved. After heating at reflux for 1.5 hours, 400 ml of ethanol was added at 40 ° C. and stirred for 30 minutes, and then 400 ml of ethanol was added at 30 ° C. and stirred for 3 minutes. After addition of 400 ml of ethanol at 20 ° C., the mixture was cooled to 10 ° C. and the precipitate was taken through filtration. The precipitate was washed with 160 mL of ethanol and dried at 40 ° C. for 15 minutes to give 78.8 g of a solid. The solid (78.8 g) was suspended in 1.5 L of methanol, and dry hydrogen chloride gas was injected for 1 hour until saturation. The mixture was heated at reflux for 1 hour and cooled, then the precipitated salts were filtered off and the filtrate was concentrated to dryness under reduced pressure. Ethanol (500 ml) was added to the residue, concentrated to dryness under reduced pressure, and then washed with 250 ml of isopropyl alcohol to obtain methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazine as a solid. 48.8 g of carboxylate were obtained.
[622] IR (KBr) cm ^-1 : 1736
[623] ¹ H-NMR (CDCl ₃ ) δ: 2.45 (1H, brs), 3.87 (3H, s), 8.98 (1H, s)
[624] (Reference Example II-6)
[625] Suspend 48.7 g of methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate in 2.0 liters of dioxane, followed by 42.4 ml of N-ethyldiisopropyl amine and 9.9 ml of methanol in succession. By adding. Thereafter, 122 ml of 2.0 mol / l trimethylsilyldiazomethane in hexane was added at room temperature, and the obtained mixture was stirred at the same temperature as above for 15 minutes, and the solvent was removed under reduced pressure. 500 ml of ethyl acetate and 250 ml of water were added to the residue obtained above, and the organic layer was separated by adjusting the pH to 1.5 with 6 mol / l hydrochloric acid. The remaining aqueous layer was extracted twice with 200 ml of ethyl acetate. All organic layers were combined, washed successively with 200 mL of water and 200 mL of saturated aqueous sodium chloride solution, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate as a solid.
[626] IR (KBr) cm ^-1 : 1729
[627] ¹ H-NMR (DMSO-d ₆ ) δ: 4.03 (3H, s), 4.22 (3H, s), 9.25 (1H, s)
[628] (Reference Example II-7)
[629] At room temperature and 1 atm, no further absorption of hydrogen gas is seen in the mixture of 24.3 g of methyl 3-methoxy-6-nitro-pyrazinecarboxylate, 480 ml of acetic acid and 1.2 g of lead-pyrided palladium-calcium carbonate. Hydrogen gas was injected until. After insoluble materials were filtered out of the reaction mixture, the solvent was removed under reduced pressure, and the obtained solid was washed with ethyl acetate and diethyl ether. This obtained 15.0 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate which is a solid. The solvent was removed from the filtrate under reduced pressure, and the solid was washed with ethyl acetate to obtain 2.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a solid.
[630] IR (KBr) cm ^-1 : 1717
[631] ¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 3.99 (3H, s), 4.38 (2H, brs), 7.79 (1H, s)
[632] (Reference Example II-8)
[633] In 80 ml of tetrahydrofuran was dissolved 4.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile synthesized according to the method mentioned in US Pat. No. 3341540. While cooling the solvent under ice-cooling, 1.2 g of 60% sodium hydroxide and 2.8 g of benzoyl chloride were continuously added, followed by 0.8 g of 60% sodium hydride. The resulting mixture was stirred under ice cooling for 1 hour. An additional 0.4 g of 60% sodium hydride was added and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled under ice-cooling, then mixed into a liquid mixture consisting of 50 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 5 with 6 mol / l hydrochloric acid. The precipitate was taken through filtration, and the obtained residue was dissolved in a mixture of 50 ml of ethyl acetate and 100 ml of tetrahydrofuran, treated with activated charcoal, and filtered, and then the solvent was removed under reduced pressure. The obtained residue was washed with diisopropyl ether to obtain 1.7 g of N- (5-bromo-3-cyano-2-pyrazinyl) -benzamide as a pale yellow solid. The organic layer was separated from the obtained filtrate, and the separated filter layer was washed successively with water and saturated aqueous sodium chloride solution, treated with activated carbon, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was washed with diisopropyl ether to give 2.9 g of N- (5-bromo-3-cyano-2-pyrazinyl) -benzamide as a yellow solid.
[634] IR (KBr) cm ^-1 : 2238, 1667
[635] ¹ H-NMR (CDCl ₃ ) δ: 7.41 to 7.74 (3H, m), 8.04 to 8.15 (2H, m), 8.76 (1H, s), 11.31 (1H, brs)
[636] (Reference Example II-9)
[637] 0.50 g of 3-amino-6-bromo-2-pyrazinecarbonitrile was dissolved in 10 ml of tetrahydrofuran. After addition of 0.15 g of 60% sodium hydride, the mixture was stirred at room temperature for 15 minutes. Thereafter, 0.7 ml of di-t-butyl dicarbonate and 0.10 g of 60% sodium hydride were added successively, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a liquid mixture consisting of 30 ml of ethyl acetate and 60 ml of water, and the organic layer was separated by adjusting the pH to 5 with 2 mol / l hydrochloric acid. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to obtain 0.30 g of t-butyl 5-bromo-3-cyano-2-pyrazinylcarbamate as a white solid.
[638] IR (KBr) cm ^-1 : 2239, 1708
[639] ¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.57 (9H, s), 7.41 (1H, brs), 8.62 (1H, s)
[640] (Reference Example II-10)
[641] 1.0 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 10 ml of dimethylformamide. After adding 0.7 g of hydroquinone and 1.74 g of potassium carbonate, the obtained mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with a mixture of 10 ml of ethyl acetate and 30 ml of water, the pH was adjusted to 7 with 2 mol / l hydrochloric acid, and the organic layer was separated. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to give 1.0 g of 6-chloro-3 (4-hydroxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.
[642] IR (KBr) cm ^-1 : 3384, 2250
[643] ¹ H-NMR (CDCl ₃ ) δ: 6.82 to 7.05 (4H, m), 8.27 (1H, s), 8.88 (1H, s)
[644] (Reference Example II-11)
[645] 1.5 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 15 ml of dimethylformamide. After addition of 1.2 g of 4-methoxyphenol and 1.8 g of potassium carbonate, the obtained mixture was stirred at room temperature for 30 minutes. A mixture of 20 mL of ethyl acetate and 60 mL of water was added to the reaction mixture, and the organic layer was separated. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to give 2.1 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.
[646] IR (KBr) cm ^-1 : 2236
[647] ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.95 (2H, d, J = 9.2 Hz), 7.11 (2H, d, J = 9.2 Hz), 8.26 (1H, s)
[648] (Reference Example II-12)
[649] 2.5 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 25 ml of dimethylformamide. After adding 3.2 g of 4- (benzyloxy) phenol and 3.0 g of potassium carbonate, the mixture was stirred at room temperature for 1 hour. A mixture of 25 mL ethyl acetate and 100 mL water was added to the reaction mixture, and the organic layer was separated. The organic layer obtained was washed sequentially with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, the insoluble material was filtered off and the filtrate was concentrated. The obtained residue was washed with n-hexane to obtain 3.84 g of 3-[(4- (benzoyl) phenoxy)]-6-chloro-2-pyrazinecarbonitrile as a pale brown solid.
[650] IR (KBr) cm ^-1 : 2238
[651] ¹ H-NMR (CDCl ₃ ) δ: 5.12 (2H, s), 7.03 to 7.48 (9H, m), 8.65 (1H, s)
[652] (Reference Example II-13)
[653] 0.4 g of 6-chloro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile was dissolved in 8 ml of dimethylformamide. After addition of 0.5 ml of iodine methane and 0.89 g of potassium carbonate, the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a mixture of 10 ml of ethyl acetate and 30 ml of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was separated under reduced pressure. This obtained 0.43 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile which is a yellowish-brown solid.
[654] IR (KBr) cm ^-1 : 2236
[655] ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.95 (2H, d, J = 9.2 Hz), 7.11 (2H, d, J = 9.2 Hz), 8.26 (1H, s)
[656] (Reference Example II-14)
[657] 1.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile was dissolved in 4 ml of dimethylformamide dimethyl acetal. The solution was heated at reflux for 3 hours and cooled to room temperature, 5 ml of n-hexane and 5 ml of diisopropyl ether were added and stirred at room temperature for 10 minutes. The precipitate was taken through filtration and washed with a mixture of 5 ml of n-hexane and 5 ml of diisopropyl ether, and the tan solid N '-(5-bromo-3-cyano-2-pyrazinyl) -N, N 1.0 g of '-dimethyliminoformamide was obtained.
[658] IR (KBr) cm ^-1 : 2234
[659] ¹ H-NMR (CDCl ₃ ) δ: 3.21 (6H, s), 8.32 (1H, s), 8.60 (1H, s)
[660] (Reference Example II-15)
[661] 10.0 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 50 ml of N, N-dimethylformamide. After successively adding 6.40 mL of thiophenol and 11.91 g of potassium carbonate, the obtained mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was placed in a mixture of 100 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 2 with 6 mol / l hydrochloric acid. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; Toluin: n-hexane = 1: 3] to obtain 3.80 g of 6-chloro-3- (phenylsulfanyl) -2-pyrazinecarnitrile as a pale yellow oil.
[662] IR (neat) cm ^-1 : 2238
[663] ¹ H-NMR (CDCl ₃ ) δ: 7.00 to 7.70 (5H, m), 8.39 (1H, s)
[664] (Example II-1)
[665] (a) 2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate was dissolved in 20 ml of acetonitrile. After addition of 2.8 g sodium fluoride and 0.51 g of 18-crown-6-ether, the resulting mixture was heated under reflux in a nitrogen gas atmosphere for 9.5 hours. After cooling, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography [eluent; Hexane: ethyl acetate = 15: 1] to give 1.1 g of methyl 3,6-difluoro-2-pyrazinecarboxylate as a colorless oil.
[666] IR (neat) cm ^-1 : 1743
[667] ¹ H-NMR (CDCl ₃ ) δ: 4.05 (3H, s), 8.28 (1H, dd, J = 1.6 Hz, 8.4 Hz)
[668] (b) 0.2 g of 3,6-dichloro-2-pyrazinecarboxylic acid was suspended in 2.0 ml of methylene chloride. Thereafter, 0.001 ml of N, N-dimethylformamide and 0.14 ml of oxalyl chloride were added successively under ice cooling, and the obtained mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated to dryness under reduced pressure, and then dissolved in 3.0 ml of acetonitrile. Thereafter, 0.3 g of sodium fluoride and 0.056 g of 18-crown-6-ether were added, and the obtained mixture was stirred for 2.5 hours at a temperature of 60 ° C. under a nitrogen gas atmosphere. The reaction mixture was poured into 3.0 ml of methanol, the insolubles were filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 9: 1] to give 0.15 g of methyl 3,6-difluoro-2-pyrazinecarboxylate as a colorless oil.
[669] The physical properties of this compound were consistent with those of the compound obtained in Example II-1 (a).
[670] (Example II-2)
[671] 0.3 g of methyl 3,6-difluoro-2-pyrazinecarboxylate was dissolved in 3.0 ml of N, N-dimethylformamide. After adding 0.16 g of sodium acetate under ice-cooling, the obtained mixture was stirred at 50 ° C. for 2.5 hours. After adding the reaction mixture to a mixture of 50 ml of ethyl acetate and 30 ml of water, the organic layer was separated. The remaining aqueous phase was adjusted to pH 1.5 with 1 mol / l hydrochloric acid and extracted three times with 25 ml of ethyl acetate. The organic layers were combined, washed successively with 15 mL of water and 15 mL of saturated aqueous sodium chloride solution, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent; n-hexane: ethyl acetate = 1: 2] to obtain 0.03 g of methyl 6-fluoro-oxo-3,4-dihydro-2-pyrazinecarboxylate as a colorless solid.
[672] IR (KBr) cm ^-1 : 1677
[673] ¹ H-NMR (CDCl ₃ ) δ: 4.09 (3H, s), 8.35 (1H, d, J = 8.2 Hz), 11.1 (1H, brs)
[674] (Example II-3)
[675] (a) 90.1 g of 3,6-dichloro-2-pyrazinecarbonitrile was suspended in 1.1 L of dimethyl sulfoxide. After addition of 180.5 g of potassium fluoride and 66.8 g of tetra-n-butylammonium bromide, the mixture was stirred at 50-55 ° C. for 6 hours. The reaction mixture was brought back to room temperature, added to a mixture of 1.1 liter of ethyl acetate and 2.2 liter of water, and then the organic layer was separated. Water (1 L) was added to the organic layer and the pH was adjusted to 2.5 with 1 mol / L hydrochloric acid to separate the organic layer. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 58.3 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid.
[676] IR (KBr) cm ^-1 : 2250
[677] ¹ H-NMR (CDCl ₃ ) δ: 8.34 (1H, dd, J = 1.3, 7.9 Hz)
[678] (b) 0.40 g of 6-fluor-3- (phenylsulfonyl) -2-pyrazinecarbonitrile was added to 4 ml of dimethyl sulfoxide. After adding 0.44 g of potassium fluoride and 0.10 g of tetra-n-butylammonium bromide successively, the obtained mixture was stirred at 60 ° C. for 1.5 hours. The reaction mixture was poured into a mixture of 20 ml of ethyl acetate and 20 ml of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 20: 1] to give 0.06 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid.
[679] (Example II-4)
[680] 57.3 g of 3,6-difluoro-2-pyrazinecarbonitrile was suspended in a mixture of 570 ml of 12 mol / l hydrochloric acid and 57 ml of tetrahydrofuran. The suspension was stirred at 30-35 ° C. for 6.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, 100 ml of ethanol was added, and then the solvent and hydrochloric acid were removed under reduced pressure. The obtained residue was washed with ethanol and diisopropyl ether to give 53.7 g of 3,6-difluoro-2-pyrazinecarboxamide as a colorless solid.
[681] IR (KBr) cm ^-1 : 1708, 1692
[682] ¹ H-NMR (CDCl ₃ ) δ: 8.00 (1 H, brs), 8.25 (1 H, brs), 8.57 (1 H, dd, J = 1.7, 8.1 Hz)
[683] (Example II-5)
[684] (a) 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of N, N-dimethylformamide. Under ice-cooling, 0.64 g of sodium acetate was added and stirred for 6 hours. The reaction mixture was added to a mixture of 20 ml of ethyl acetate and 20 ml of water and the pH was adjusted to 1.5 with 6 mol / l hydrochloric acid to separate the organic layer. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 1: 1] to obtain 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile as a yellow solid.
[685] IR (KBr) cm ^-1 : 2238, 1655
[686] ¹ H-NMR (DSMO-d ₆ ) δ: 8.52 (1H, d, J = 7.6 Hz), 12.70 (1H, brs)
[687] (b) 1.0 g of 3- (benzyloxy) -6-fluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of toluene. To this, 0.64 g of aluminum chloride was added under ice cooling, and the obtained mixture was stirred at room temperature for 2 hours. Thereafter, 10 ml of water was added to the solution, the aqueous layer was separated, and the oil layer was extracted twice with 2 ml of water. The aqueous layers were combined and extracted twice with 5 ml of ethyl acetate. The oily layer obtained was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. As a result, 0.51 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.
[688] The physical properties of the compound were consistent with that of the compound obtained in Example II-5 (a).
[689] (c) 1.0 g of 3- (allyloxy) -6-fluor-2-pyrazinecarbonitrile was dissolved in 5 ml of toluene. After addition of 0.82 g of aluminum chloride, the mixture was stirred at rt for 1.5 h. Water (5 mL) was added to the reaction solution to separate the aqueous layer, and the organic layer was extracted with 3 mL of water and again 2 mL of water. The aqueous layers were combined, washed with 5 ml of toluene and extracted with 15 ml of ethyl acetate. The organic layer obtained was washed with 3 ml of water, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile which is a yellow solid.
[690] The physical properties of the compound were consistent with that of the compound obtained in Example II-5 (a).
[691] (d) 1.0 g of 6-fluoro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile was dissolved in a mixture of 30 ml of acetonitrile and 20 ml of water. After addition of 11.2 g of diammonium cerium nitrate, the mixture was heated at reflux for 3 hours. The reaction mixture was brought to room temperature and a mixture consisting of 50 ml of toluene, 50 ml of water and 50 ml of 5% aqueous sodium thiosulfate solution was added to separate the aqueous layer. Ethyl acetate (50 mL) was added to the obtained aqueous layer, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium chloride solution, treated with activated carbon, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile which is a yellow solid.
[692] (e) 1.0 g of 3- [4- (benzyloxy) phenoxy] -6-fluor-2-pyrazinecarbonitrile was dissolved in a mixture of 30 ml of acetonitrile and 15 ml of water. After addition of 8.5 g of diammonium cerium nitrate, the resulting mixture was heated at reflux for 3 hours. After the reaction mixture was returned to room temperature, a mixture consisting of 50 ml of ethyl acetate, 5 ml of water, and 5 ml of an aqueous 5% thiosulfate solution was added to separate the organic layer. The obtained organic layer was washed with saturated aqueous sodium chloride solution, treated with activated carbon, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile which is a yellow solid.
[693] (f) 0.45 g of 6-fluoro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile was dissolved in a mixture of 7.5 ml of acetonitrile and 3 ml of water. Thereafter, 1.17 g of diammonium cerium nitrate was added at room temperature, and stirred for 15 minutes at the same temperature as above. A mixture of 10 ml of ethyl acetate and 5 ml of 5% aqueous sodium thiosulfate solution was added to the reaction mixture to separate an organic layer. The obtained organic layer was washed with saturated aqueous sodium chloride solution, treated with activated carbon, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile which is a yellow solid.
[694] (g) 6-Fluoro-3-[(2-methyl-3-oxo-1-cyclopenten-l-yl) oxy] -2-pyrazine in a mixture of 5 ml of 6 mol / l hydrochloric acid and 1 ml of dioxane. Carbonitrile was suspended. The suspension was heated at 50 ° C. for 15 minutes, returned to room temperature, and 10 ml of acetone was added to separate the organic layer. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 0.25 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile which is a yellow solid.
[695] The physical properties of the compound were consistent with that of the compound obtained in Example II-5.
[696] (Example II-6)
[697] 0.20 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 2.0 ml of N, N-dimethylformamide. At 5 ° C., 0.11 g of sodium azide was added and stirred for 10 minutes at the same temperature as above. The reaction mixture was added to a mixture of 20 mL ether and 20 mL water to separate the organic layer. The organic layer obtained was washed successively with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. This obtained 0.25 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile which is a yellow oil.
[698] IR (neat) cm ^-1 : 2140
[699] ¹ H-NMR (CDCl ₃ ) δ: 8.40 (1H, d, J = 8.2 Hz)
[700] (Example II-7)
[701] (a) 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in a mixture of 1.5 ml of 25% aqueous ammonia and 5.0 ml of dioxane. The resulting solution was stirred at room temperature for 6 hours, then 20 ml of water was added and stirred for 20 minutes while cooling under ice cooling. The precipitate was taken by filtration, washed successively with 5 ml of cold water and 5 ml of ethanol, and then 0.84 g of 3-amino-6-fluoro-2-pyrazine-carbonitrile was obtained as a pale yellow solid.
[702] IR (KBr) cm ^-1 : 3405, 2230
[703] ¹ H-NMR (DMSO-d ₆ ) δ: 7.34 (2H, brs), 8.42 (1H, d, J = 7.8 Hz)
[704] (b) 0.24 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile was dissolved in 5.0 ml of methanol. 0.075 g of lead-poisoned palladium-calcium carbonate was added at room temperature, and then hydrogen gas was injected at 1 atmosphere and room temperature until the absorption of hydrogen was no longer seen in the mixture. After insoluble material was filtered off from the mixture, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; Chloroform] to give 0.078 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid.
[705] The physical properties of the compound were consistent with that of the compound obtained in Example II-7 (a).
[706] (c) 0.35 g of t-butyl 5-bromo-3-cyano-2-pyrazinylcarbamate was dissolved in 10.5 ml of dimethyl succioxide. After addition of 0.17 g of potassium fluoride, the mixture was first stirred at 70 ° C. for 30 minutes and again at 90 ° C. for 30 minutes to afford t-butyl-3-cyano-5-fluor-2 in the reaction system. Pyrazinylcarbamate was formed. 0.17 g of potassium fluoride was then added and stirred at 90 ° C. for 40 minutes. The reaction mixture was returned to room temperature, a mixture of 30 ml of ethyl acetate and 60 ml of water was added, and then the organic layer was separated by adjusting the pH to 8 with saturated aqueous sodium hydrogen carbonate solution. The organic layer obtained was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to obtain 30 mg of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid.
[707] The physical properties of the compound were consistent with that of the compound obtained in Example II-7 (a).
[708] (d) 60 mg of N '-(3-cyano-5-fluoro-2-pyrazinyl) -N, N-dimethyliminoformamide was suspended in 2 ml of 6 mol / L hydrochloric acid. The formed suspension was stirred at 80-90 ° C. for 5.5 hours. The reaction mixture was returned to room temperature, 5 ml of water was added, and the pH was adjusted to 9 with 2 mol / L aqueous sodium hydroxide solution. Thereafter, 5 ml of ethyl acetate was added to separate the organic layer, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. This obtained 20 mg of 3-amino-6-fluoro-2-pyrazinecarbonitrile which is a yellow solid.
[709] (e) 0.3 g of 3-amino-2-pyrazinecarbonitrile was dissolved in 15 ml of acetonitrile. While cooling the solution under ice cooling, 10% fluorine gas was injected at a rate of 45 ml / min per 20 minutes. Thereafter, nitrogen gas was injected for 1 hour while the temperature was raised to room temperature under ice cooling. The reaction mixture was concentrated under reduced pressure, and the obtained oily substance was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to obtain 0.01 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid.
[710] (Example II-8)
[711] (a) 17.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate was dissolved in 140 ml of a 70% hydrogen fluoride solution of pyridine under ice-cooling temperature. Then, 7.8 g of sodium nitrite was added three times at -50 ° C. After molding stopped, the temperature was raised slowly and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 300 ml of ice and 200 ml of chloroform, the precipitated insoluble material was filtered off, and the organic layer was separated. The remaining aqueous layer was extracted with 10 chloroform so that the total amount was 500 ml. The obtained organic layer was combined and the pH was adjusted to 7 with saturated aqueous sodium hydrogen carbonate solution, and then the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 4: 1] to obtain 14.3 g of methyl 6-fluoro-3-methoxy-2-pyrazinecarboxylate as a solid.
[712] IR (KBr) cm ^-1 : 1734
[713] ¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 4.08 (3H, s), 8.17 (1H, d, J = 8.5 Hz)
[714] (b) 0.2 g of methyl 3,6-difluoro-2-pyrazinecarboxylate was dissolved in 4 ml of methanol. Thereafter, an aqueous 28% methanol solution of sodium methoxide was added at -25 ° C, and the obtained mixture was stirred at 0 ° C for 10 minutes. The reaction mixture was poured into a mixture of 30 ml of ethyl acetate and 30 ml of water to separate an organic layer. The organic layer obtained was washed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to obtain 0.09 g of methyl 6-fluoro-3-methoxy-2-pyrazinecarboxylate as a colorless solid.
[715] The physical properties of the compound were consistent with that of the compound obtained in Example II-8 (a).
[716] (Example II-9)
[717] 0.1 g of methyl 6-chloro-3-nitro-2-pyrazinecarboxylate was dissolved in 2.0 ml of acetonitrile. After successively adding 40 mg of potassium chloride and 61 mg of 18-crown-6-ether, the obtained mixture was stirred at room temperature for 1.5 hours. Thereafter, a mixture of 10 ml of ethyl acetate and 10 ml of water was added, and the pH was adjusted to 7.0 with saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer obtained was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel chromatography [eluent; n-hexane: ethyl acetate = 7: 1] to obtain 0.03 g of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate as a pale yellow oil.
[718] IR (KBr) cm ^-1 : 1752, 1560
[719] ¹ H-NMR (CDCl ₃ ) δ: 4.60 (3H, s), 8.50 (1H, d, J = 8.3 Hz)
[720] (Example II-10)
[721] (a) 20 mg of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate was dissolved in 1.0 ml of acetic acid. After addition of 6 mg of lead- poisoned palladium-calcium carbonate, hydrogen gas was injected at atmospheric pressure of 1 at room temperature until no more hydrogen gas was absorbed into the mixture. Insoluble matter was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to obtain 2 mg of 3-amino-6-fluoro-2-pyrazinecarboxylate as a pale yellow solid.
[722] IR (KBr) cm ^-1 : 1700
[723] ¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 6.29 (2H, brs), 8.15 (1H, d, J = 8.3 Hz)
[724] (b) 0.5 g of methyl 3-amino-2-pyrazinecarboxylate was dissolved in 10 ml of acetic acid. At room temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected at a rate of 23 ml / min for 32 minutes. After stirring the solution for 30 minutes at room temperature, a mixture of 50 ml of saturated aqueous sodium hydrogen carbonate solution and 50 ml of ethyl acetate was added to separate an organic layer. The organic layer obtained was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to obtain 0.01 g of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a pale yellow solid.
[725] The physical properties of the compound were consistent with that of the compound obtained in Example II-10 (a).
[726] (Example II-11)
[727] (a) 10 ml of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate was dissolved in 1 ml of methanol. After addition of 1 ml of 25% aqueous ammonia solution at room temperature, the resulting mixture was stirred for 4.5 hours. After removing the solvent under reduced pressure, diethyl ether was added to the residue and the precipitate was filtered off. This obtained 4 mg of 3-amino-6-fluoro-2-pyrazinecarboxamide which is a pale yellow solid.
[728] IR (KBr) cm ^-1 : 1685
[729] ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 3.85 (4H, b4s). 8.10 (1H, d, J = 7.3 Hz)
[730] (b) 0.2 g of 3,6-dichloro-2-pyrazinecarboxylic acid was suspended in 2.0 ml of methylene chloride. To this, 0.01 ml of N, N-dimethylformamide and 0.14 ml of oxalyl chloride were successively added under ice-cooling temperature, and the obtained mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness, the residue was dissolved in 3.0 ml of acetonitrile, 0.35 g of potassium fluoride and 0.054 g of 18-crown-6-ether were added, and the obtained mixture was then heated at 60 ° C. Stir for hours. Thereafter, 3.0 ml of 25% aqueous ammonia solution was added to the reaction solution at room temperature, and the obtained solution was stirred at 50 ° C for 2.5 hours. The reaction mixture was poured into a mixture of 30 ml of ethyl acetate and 30 ml of water to separate an organic layer. The obtained organic layer was washed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, and the solvent was removed under reduced pressure. The precipitate was washed with diethyl ether to obtain 0.12 g of 3-amino-6-fluoro-2-pyrazinecarboxamide as a yellow solid.
[731] The physical properties of the compound were consistent with that of the compound obtained in Examples II-11 (a).
[732] (c) 0.3 g of 3-amino-2-pyrazinecarboxamide was dissolved in 9 ml of trifluoroacetic acid. At an ice cooling temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected at a rate of 45 ml / min for 22 minutes. The mixture was stirred at ice cold for 17 minutes and then the temperature was raised to room temperature. The reaction mixture was added to a mixture of 30 ml of saturated aqueous sodium hydrogen carbonate solution and 30 ml of ethyl acetate to separate the organic layer. The remaining aqueous layer was acidified with 6 mol / l hydrochloric acid and extracted with 20 ml of ethyl acetate. The obtained organic layers were combined, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 0.015 g of 3-amino-6-fluoro-2-pyrazinecarboxamide as a pale yellow solid.
[733] The physical properties of the compound were consistent with that of the compound obtained in Examples II-11 (a).
[734] (d) 100 mg of 3-amino-2-pyrazinecarboxamide was dissolved in 5 ml of trifluoroacetic acid. Under ice-cooling temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected at a rate of 45 ml / min for 36 minutes. Then, nitrogen gas was inject | poured for 1 hour, heating up from ice-cooling temperature to room temperature. The reaction mixture was concentrated under reduced pressure to give 305 mg of an oil. In the oil obtained, the 251 mg portion was dissolved in 9.3 ml of water and heated at reflux for 4 hours. The liquid reaction mixture was raised to room temperature and the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the obtained solid was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 9 mg of 3-amino-6-fluoro-2-pyrazinecarboxamide as a solid.
[735] The physical properties of the compound were consistent with that of the compound obtained in Examples II-11 (a).
[736] (Example II-12)
[737] 1.0 g of 3-hydroxy-2-pyrazinecarmoxamide was suspended in 200 ml of water. At room temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected at a rate of 45 ml / min for 25 minutes. Thereafter, nitrogen gas was injected for 45 minutes, the liquid reaction mixture was neutralized with calcium carbonate, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to give 0.008 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white solid.
[738] The physical properties of the compound were consistent with that of the compound obtained in Preparation Example 1.
[739] (Example II-13)
[740] In 5 ml of toluene, 0.5 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved. After successively adding 0.41 ml of benzyl alcohol and 0.74 ml of triethylamine, the obtained mixture was stirred at 80 ° C. for 1 hour. After cooling the reaction mixture to room temperature, silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 0.58 g of 3- (benzyloxy) -6-fluoro-2-pyrazinecarnitrile as a white solid.
[741] IR (KBr) cm ^-1 : 2236
[742] ¹ H-NMR (CDCl ₃ ) δ: 5.53 (2H, s), 7.3 to 7.6 (5H, m), 8.20 (1H, d, J = 8.1 Hz)
[743] (Example II-14)
[744] 10.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 30 ml of dimethyl sulfoxide. After 50 ml of allyl alcohol and 14.8 ml of triethylamine were added successively, the obtained mixture was stirred at 60 ° C. for 40 minutes. The reaction mixture was cooled to room temperature, and then poured into a mixture of 50 ml of toluene and 50 ml of water to separate an organic layer. The obtained organic layer was washed with 50 ml of water ten times, and successively washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 11.5 g of 3- (allyloxy) -6-fluoro-2-pyrazinecarbonitrile as a pale yellow oil.
[745] IR (neat) cm ^-1 : 2238
[746] ¹ H-NMR (CDCl ₃ ) δ: 4.98 (2H, d, J = 5.6 Hz), 5.33 (1H, dd, J = 1.5, 7.1 Hz), 5.48 (1H, dd, J = 1.5, 13.9 Hz), 5.9 to 6.2 (1H, m), 8.20 (1H, d, J = 8.1 Hz)
[747] (Example II-15)
[748] 2.5 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 25 ml of methanol. To this was added 2.4 g of a 28% metaol solution of sodium methoxide dropwise at 5 to 15 ° C., and then the resulting mixture was stirred for 2 hours under ice-cooling temperature. The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The obtained organic layer was successively washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to obtain 0.45 g of 6-fluoro-3-methoxy-2-pyrazinecarbonitrile as a colorless oil.
[749] IR (KBr) cm ^-1 : 2237
[750] ¹ H-NMR (CDCl ₃ ) δ: 4.12 (3H, s), 8.22 (1H, d, J = 8.1 Hz)
[751] (Example II-16)
[752] In a mixture of 140 ml of acetonitrile and 280 ml of toluene were suspended 58 g of potassium fluoride (spray-dried, spray dried) and 8.7 g of 18-crown-6-ether. After the suspension was heated under reflux for 1 hour under a nitrogen gas atmosphere, acetonitrile and toluene were distilled off under reduced pressure. The obtained residue was suspended in 280 ml of acetonitrile, and then Acta Poloniae Pharmaceutica, Vol. 23 g of 6-chloro-2-pyrazinecarbonitrile synthesized according to the method described in Pages 153-161 (1976) was added, and the resulting mixture was heated under reflux for 1 hour under nitrogen gas. The reaction mixture was cooled to room temperature, 280 ml of ethyl acetate and 280 ml of water were added to separate an organic layer. The obtained organic layer was successively washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 10 g of 6-fluoro-2-pyrazinecarbonitrile as a white solid.
[753] IR (KBr) cm ^-1 : 2244
[754] ¹ H-NMR (CDCl ₃ ) δ: 8.72 (1H, d, J = 8.1 Hz), 8.88 (1H, d, J = 3.7 Hz)
[755] (Example II-17)
[756] 1.6 g of 6-fluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of concentrated hydrochloric acid. The resulting solution was stirred at 40 ° C. for 2 hours. The reaction mixture was cooled to room temperature, and a mixture of 25 ml of ethyl acetate and 10 ml of water was added to separate an organic layer. The aqueous layer was extracted with ethyl acetate. The oily layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 1: 1] to give 0.75 g of 6-fluoro-2-pyrazinecarboxamide as a light brown solid.
[757] IR (KBr) cm ^-1 : 1713
[758] ¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, brs), 8.22 (1H, brs), 8.92 (1H, d, J = 8.0), 9.14 (1H, d, J = 4.4)
[759] (Example II-18)
[760] (a) 0.50 g of 6-fluoro-2-pyrazinecarboxamide was dissolved in 1.5 ml of trifluoroacetic acid. After addition of 0.40 ml of 30% hydrogen peroxide, the resulting mixture was stirred at 50-60 ° C. for 1 hour. After cooling the reaction mixture to 5 ° C., 5 ml of isopropyl alcohol was added. The precipitate was taken through filtration and washed with 5 ml of isopropyl alcohol and 5 ml of diethyl ether to obtain 0.35 g of 3- (aminocarbonyl) -5-fluoropyrazine-1-ium-1-oleate as a white solid.
[761] IR (KBr) cm ^-1 : 1708
[762] ¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, brs), 8.25 (1H, brs), 8.53 (1H, brs), 8.70 (1H, dd, J = 1.2, 3.9Hz)
[763] (b) 0.39 g of 3- (aminocarbonyl) -5-fluoropyrazine-1-ium-1-oleate was suspended in 1.95 ml of phosphorus oxychloride. The mixture was stirred at 100 ° C. for 1.5 h. After concentrating the reaction mixture under reduced pressure to dryness, the residue was suspended in 20 ml of ethyl acetate, and poured into 20 ml of ice water, and the organic layer was separated. 20 ml of water was added to the obtained organic layer, the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; Toluene: n-hexane = 3: 1] to give 3-chloro-6-fluoro-2-pyrazinecarbonitrile as an oil.
[764] (c) 0.3 g of 3-chloro-2-pyrazinecarbonitrile was dissolved in 15 ml of acetonitrile. Under ice-cooling temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected into the solution at a rate of 45 ml / min for 20 minutes. Then, nitrogen gas was inject | poured for 1 hour or more, heating up from an ice-cooling temperature to room temperature. The reaction mixture was concentrated under reduced pressure, and the oily substance obtained was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 0.12 g of 3-chloro-6-fluoro-2-pyrazinecarbonitrile as a colorless oil.
[765] IR (KBr) cm ^-1 : 2232
[766] ¹ H-NMR (CDCl ₃ ) δ: 8.50 (1H, d, J = 8.1 Hz)
[767] (Example II-19)
[768] 1.30 g of N '-(5-bromo-3-cyano-2-pyrazinyl) -N, N-dimethyliminoformamide was dissolved in 26 ml of dimethyl sulfoxide. After adding 2.97 g of potassium fluoride, the obtained mixture was stirred at 145 to 150 ° C. for 1.5 hours, and a mixture of 30 ml of ethyl acetate and 100 ml of water was added to separate an organic layer. The organic layer obtained was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; Toluene: ethyl acetate = 5: 1] gave 0.75 g of N '-(3-cyano-5-fluoro-2-pyrazinyl) -N, N-dimethyliminoformamide as a yellow solid.
[769] IR (KBr) cm ^-1 : 2230
[770] ¹ H-NMR (CDCl ₃ ) δ: 3.19 (6H, s), 8.18 (1H, d, J = 8.1 Hz), 8.54 (1H, s)
[771] (Example II-20)
[772] 4.3 g of N- (5-bromo-3-cyano-2-pyrazinyl) benzamide was dissolved in 86 ml of dimethyl sulfoxide. After addition of 8.3 g of potassium fluoride, the resulting solution was stirred at a temperature of 100-115 ° C. for 1 hour. The reaction mixture was returned to room temperature, and a mixture of 100 ml of ethyl acetate and 200 ml of water was added to separate an organic layer. The separated organic layer was successively washed with water and saturated aqueous sodium chloride solution, treated with activated carbon, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; Toluene: ethyl acetate = 5: 1] gave 0.47 g of N- (3-cyano-5-fluoro-2-pyrazinyl) benzamide as a white solid.
[773] IR (KBr) cm ^-1 : 2238, 1670
[774] ¹ H-NMR (CDCl ₃ ) δ: 7.48 to 7.80 (3H, m), 8.08 to 8.21 (2H, m), 9.01 (1H, d, J = 8.1 Hz), 11.67 (1H, s)
[775] (Example II-21)
[776] 1.95 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile was dissolved in 39 ml of dimethyl sulfoxide. After adding 2.16 g of potassium fluoride, the obtained mixture was stirred at 100 to 110 ° C for 3 hours. The reaction mass was returned to room temperature and the organic layer was separated by addition of a mixture of 40 mL of ethyl acetate and 200 mL of water. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to obtain 1.45 g of 6-fluoro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.
[777] IR (KBr) cm ^-1 : 2238
[778] ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.95 (2H, d, J = 9.2 Hz), 7.12 (2H, d, J = 9.2 Hz), 8.15 (1H, d, J = 8.4 Hz)
[779] (Example II-22)
[780] 3.50 g of 3- [4- (benzyloxy) phenoxy] -6-chloro-2-pyrazinecarbonitrile was dissolved in 70 ml of dimethyl sulfoxide. After addition of 2.16 g of potassium fluoride, the mixture was stirred at 100-110 ° C for 3 hours. The reaction mass was returned to room temperature and the organic layer was separated by addition of a mixture of 70 ml of ethyl acetate and 350 ml of water. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; Purified by n-hexane: ethyl acetate = 5: 1] to obtain 1.88 g of 3- [4- (benzyloxy) phenoxy] -6-fluoro-2-pyrazinecarbonitrile as a white solid.
[781] IR (KBr) cm ^-1 : 2237
[782] ¹ H-NMR (CDCl ₃ ) δ: 5.07 (2H, s), 6.95-7.40 (9H, m), 8.13 (1H, d, J = 8.1Hz)
[783] (Example II-23)
[784] 0.3 g of methyl 3-chloro-2-pyrazinecarboxylate was dissolved in 15 ml of acetonitrile. Under ice-cooling temperature, 10% of fluorine gas (fluorine gas diluted with nitrogen gas) was injected at a rate of 45 ml / min for 18 minutes. Thereafter, nitrogen gas was injected for 1 hour while the temperature was raised from room temperature to room temperature, and the reaction was concentrated under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 10: 1] to give 0.03 g of methyl 3-chloro-6-fluoro-2-pyrazinecarboxylate as a colorless oil.
[785] IR (neat) cm ^-1 : 1736
[786] ¹ H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 8.43 (1H, d, J = 8.3 Hz)
[787] (Example II-24)
[788] 3.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 30 ml of dimethylformamide. Thereafter, 6.5 g of potassium carbonate and 2.6 g of hydroquinone were added under ice-cooling temperature, and the obtained mixture was stirred at room temperature for 15 minutes. A mixture of 30 ml of ethyl acetate and 60 ml of water was added to the reaction mixture, and the pH was adjusted to 5 with 6 mol / L hydrochloric acid to separate the organic layer. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to give 0.75 g of 6-fluoro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.
[789] IR (KBr) cm ^-1 : 3398, 2237
[790] ¹ H-NMR (DMSO-d ₆ ) δ: 6.92 (2H, d, J = 9.2 Hz), 7.05 (2H, d, J = 9.2 Hz), 7.40 (1H, s), 8.68 (1H, d, J = 8.1 Hz)
[791] (Example II-25)
[792] 0.20 g of 6-chloro-3- (phenylsulfanyl) -2-pyrazinecarnitrile was dissolved in 3.6 ml of dimethyl sulfoxide. 0.42 g of potassium fluoride and 0.16 g of tetra-n-butylammonium bromide were added successively, and the resulting reaction was then stirred at 50-60 ° C. for 2.5 hours. The reaction mixture was added to a mixture of 20 ml of ethyl acetate and 20 ml of water to separate the organic layer. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; Toluene: n-hexane = 1: 2] to give 0.10 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile as a pale yellow oil.
[793] IR (KBr) cm ^-1 : 2233
[794] ¹ H-NMR (CDCl ₃ ) δ: 7.10 to 7.70 (5H, m), 8.34 (1H, d, J = 8.1 Hz)
[795] (Example II-26)
[796] 1.00 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile was dissolved in 10 ml of methylene chloride. To this, 1.00 g of m-chlorofebenzoic acid were added under ice-cooling temperature, and the obtained mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a mixture of 20 ml of chloroform and 20 ml of water, and the organic layer was separated by adjusting the pH to 10 with potassium carbonate. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 0.42 g of 6-fluoro-3- (phenylsulfinyl) -2-pyrazinecarbonitrile as a pale yellow oil.
[797] IR (KBr) cm ^-1 : 2237
[798] ¹ H-NMR (CDCl ₃ ) δ: 7.35 to 7.75 (3H, m), 7.75 to 8.10 (2H, m), 8.68 (1H, d, J = 8.1 Hz)
[799] (Example II-27)
[800] 1.00 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile was dissolved in 20 ml of methylene chloride. After addition of 3.70 g of m-chloroperbenzoic acid under ice-cooling temperature, the obtained mixture was stirred at room temperature for 4 hours. Insoluble matter was filtered out of the reaction mixture, and the filtrate was placed in a mixture of 50 ml of methylene chloride and 50 ml of water, and the pH was adjusted to 7.5 with saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue and the solid was taken through filtration to obtain 0.66 g of a colorless solid, 6-fluor-3- (phenylsulfonyl) -2-pyrazinecarbonitrile.
[801] IR (KBr) cm ^-1 : 2243
[802] ¹ H-NMR (CDCl ₃ ) δ: 7.40 to 7.90 (3H, m), 7.95 to 8.30 (2H, m), 8.65 (1H, d, J = 8.3 Hz)
[803] (Example II-28)
[804] 0.50 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile was dissolved in 5.0 ml of methanesulfonic acid. After adding 0.30 g of sodium nitrite at 7-9 ° C., the obtained mixture was stirred under ice-cooling temperature for 2 hours. While maintaining the temperature below 10 ° C, the reaction mixture was added dropwise to a mixture of 15 ml of ice water and 15 ml of ethyl acetate. The resulting mixture was extracted twice with 10 ml of ethyl acetate. The obtained organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was dissolved in a mixture of 100 ml of n-hexane and 50 ml of ethyl acetate, and the obtained solution was washed three times with a saturated aqueous sodium hydrogen carbonate solution, and then the solvent was separated under reduced pressure. As a result, 0.12 g of 3-cyano-5-fluoro-2-pyrazinylmethanesulfonate as a colorless oil was obtained.
[805] IR (neat) cm ^-1 : 2246
[806] ¹ H-NMR (DMSO-d ₆ ) δ: 3.40 (3H, s), 8.95 (1H, d, J = 7.8Hz)
[807] (Example II-29)
[808] 3.0 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 60 ml of dimethyl sulfoxide. After addition of 3.0 g of potassium chloride, the resulting mixture was stirred at 90-100 ° C. for 2 hours. The reaction mixture was returned to room temperature, and successively 2.1 g of 2-methyl-1,3-cyclopentanedione and 7.2 ml of triethylamine were added. The resulting mixture was stirred at rt for 1 h. The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 200 ml of water to separate an organic layer. The separated organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to give the yellow solid 6-fluoro-3-[(2-methyl-3-oxo-1-cyclopenten-l-yl) oxy] -2-pyrazinecarbonitrile 1.7 g were obtained.
[809] IR (KBr) cm ^-1 : 2238, 1707, 1676
[810] ¹ H-NMR (CDCl ₃ ) δ: 1.72 (3H, t, J = 1.8 Hz), 2.58 to 2.68 (2H, m), 2.67 to 2.91 (2H, m), 8.29 (1H, d, J = 8.1 Hz )
[811] (Manufacture example 1)
[812] 0.12 g of methyl 6-fluor-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 3.0 ml of methanol. Here, ammonia gas was injected for 10 minutes under ice-cooling temperature, and the obtained mixture was stood at room temperature for 2 days. The solvent was removed under reduced pressure, and the obtained residue was added to a mixture of 30 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 7.5 with saturated aqueous sodium bicarbonate solution to separate the organic layer. 30 ml of ethyl acetate was added to the remaining aqueous layer, the pH was adjusted to 1.0 with 1 mol / l hydrochloric acid, and the entire mixture was extracted twice with 15 ml of ethyl acetate. The obtained organic layers were combined, washed successively with 15 ml of water and 15 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained solid was washed with diisopropyl ether to obtain 0.015 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a yellow solid.
[813] IR (KBr) cm ^-1 : 1685, 1671, 1655
[814] ¹ H-NMR (DMSO-d ₆ ) δ: 8.46 (1H, brs), 8.50 (1H, d, J = 7.8Hz), 8.70 (1H, brs), 13.39 (1H, s)
[815] (Manufacture example 2)
[816] 0.17 g of 3,6-difluoro-2-pyrazinecarboxamide was suspended in a mixture of 3.44 ml of water and 0.5 ml of dioxane. After adding 0.45 g of sodium hydrogen carbonate, the resulting mixture was stirred at 50 ° C. for 8.5 hours. Thereafter, 0.95 ml of 6 mol / l hydrochloric acid was added to the reaction mixture, the pH was adjusted to 1.0, and the precipitated solid was collected by filtration to obtain 6-fluoro-3-hydroxy-2-pyrazincar as a solid. Radiation mid 89 mg was obtained.
[817] The physical properties of the compound were consistent with that of the compound obtained in Preparation Example 1.
[818] (Manufacture example 3)
[819] 280 ml of 97% sulfuric acid was cooled under ice-cooling and 28.5 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was added while maintaining 5 to 12 ° C to prepare a uniform solution. After adding 18.9 g of sodium nitrite to the solution at 5-12 ° C., the resulting mixture was stirred for 1.5 hours while cooling under ice-cooling. The reaction mixture was added dropwise to 1.4 L of ice water, while maintaining the temperature not more than 10 DEG C, and the obtained mixture was extracted once with 850 mL of ethyl acetate and twice with 200 mL. The obtained organic layers were combined, 400 ml of water was added, and then 16-0 ml of saturated aqueous sodium hydrogen carbonate solution was added, the pH was adjusted to 3.0, and the organic layer was separated. The organic layer obtained was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was washed with a mixture of diisopropyl ether and ethyl acetate to obtain 22.4 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid.
[820] The physical properties of the compound were consistent with that of the compound obtained in Preparation Example 1.
[821] (Manufacture example 4)
[822] Under water cooling, 2.2 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved in an aqueous sodium hydroxide solution prepared from 1.27 g of sodium hydroxide and 24.2 mL of water. After adding 2.75 ml of 30% hydrogen peroxide at the same temperature as above, the resulting mixture was stirred at 40 ° C. for 1.5 hours. While cooling under ice-cooling, 2.77 ° C of concentrated sulfuric acid was added dropwise to the reaction mixture obtained above, followed by cooling the formed mixture to 10 ° C. The precipitated crystals were collected by filtration and washed with 2 ml of cold water to obtain 2.2 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a pale yellow solid.
[823] The physical properties of the compound were consistent with that of the compound obtained in Preparation Example 1.
[824] The pyrazine derivatives of the present invention or salts thereof, that is, the compounds of the present invention have excellent antiviral action and are also useful as pharmaceuticals. In addition, the intermediate of the present invention, that is, the compound represented by the general formula [21], may be used as a pyrazine derivative of the present invention or a salt thereof, that is, as an intermediate of the preparation of the compound of the present invention and as a protective and therapeutic agent for viral infection and in particular influenza virus infection. Useful as intermediates for the preparation of known compounds.

权利要求:
Claims (16)
[1" claim-type="Currently amended] Pyrazine derivative or its salt represented by the following general formula.

Wherein R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom or a protected or unprotected monophosphate, diphosphate or triphosphate group; R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different; , A hydrogen atom, a halogen atom, an azido group, a substituted or unsubstituted, protected or unprotected hydroxy group or an amino group, R ⁴ and R ⁶ are bonding units; A is an oxygen atom or a methylene group, n is 0 or 1; Y is an oxygen atom, A sulfur atom or an NH group, R ¹ is a hydrogen atom or a halogen atom; R ² is a hydrogen atom; R ³ and R ⁵ are hydrogen atoms; R ⁴ and R ⁶ are substituted or unsubstituted hydroxyl groups or protected or unprotected hydroxyl groups; A is Oxygen atom; n is 0; and Y is excluded when it is oxygen atom.)
[2" claim-type="Currently amended] The method according to claim 1, wherein R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different, and represent a hydrogen atom, a halogen atom, a substituted or unsubstituted, protected or unprotected hydroxy group, and R ⁴ and R ⁶ A pyrazine derivative or a salt thereof, which represents a bonding unit.
[3" claim-type="Currently amended] The pyrazine derivative or salt thereof according to claim 1 or 2, wherein R ² represents a hydrogen atom or a protected or unprotected monophosphate group or a triphosphate group.
[4" claim-type="Currently amended] The method of claim 1, wherein R ² is a hydrogen atom or a protected or unprotected monophosphate group; R ³ , R ⁴ , R ⁵ and R ⁶ may be the same or different and may represent a hydrogen atom or a protected or unprotected hydroxy group; A is an oxygen atom; And n represents 0. A pyrazine derivative or salt thereof.
[5" claim-type="Currently amended] The pyrazine derivative or salt thereof according to any one of claims 1 to 4, wherein R ² is a hydrogen atom.
[6" claim-type="Currently amended] The pyrazine derivative or salt thereof according to any one of claims 1 to 5, wherein Y is an oxygen atom.
[7" claim-type="Currently amended] A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a salt thereof.
[8" claim-type="Currently amended] 8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is an antiviral agent.
[9" claim-type="Currently amended] The method of claim 8, wherein the virus is influenza virus, RS virus, AIDS virus, papilloma virus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, polio virus, echovirus, cussaki virus, intestine Pharmaceutical composition, characterized in that the virus, rhinovirus, rotor virus, Newcastle disease virus, mumps virus, bullous stomatitis virus or Japanese encephalitis virus.
[10" claim-type="Currently amended] The pharmaceutical composition of claim 9, wherein the virus is an influenza virus.
[11" claim-type="Currently amended] Fluoropyrazine derivatives or salts thereof represented by the following general formula.

Wherein R ²¹ represents a hydrogen atom, a methyl group, a halogenated methyl group, a methyl group substituted with a protected or unprotected mercapto group, a formyl group, a nitrile group, a halogenated carbonyl group, or a protected or unprotected hydroxymethyl group, aminomethyl group, carbamoyl group or R ²² represents a hydrogen atom, a halogen atom, a protected or unprotected hydroxy group or an amino group, a nitro group, an azido group, or a substituted or unsubstituted phenylsulfanyl group, a phenylsulfinyl group or a phenylsulfonyl group, provided that R ²¹ is carbamo Except where the compound is a carbamoyl group substituted with a diary or acyl group, R ²² is a hydroxy group, and R ²¹ is a hydrogen atom, and R ²² is a hydrogen atom.)
[12" claim-type="Currently amended] 12. The fluoropyrazine derivative according to claim 11, wherein R ²¹ is a hydrogen atom, a methyl group, a halogenated methyl group, a formyl group, a nitrile group, a halogenated carbonyl group, or a protected or unprotected hydroxymethyl group, a carbamoyl group, or a carboxyl group. salt.
[13" claim-type="Currently amended] The fluoropyrazine derivative or salt thereof according to claim 11 or 12, wherein R ²² is a protected or unprotected hydroxy group, an amino group, a halogen atom, a nitro group, or an azido group.
[14" claim-type="Currently amended] The compound according to any one of claims 11 to 13, wherein R ²¹ is a methyl group, a halogenated methyl group, a formyl group, a carbamoyl group, a nitrile group, a halogenated carbonyl group, or a protected or unprotected hydroxymethyl group or a carboxyl group. Fluoropyrazine derivatives or salts thereof.
[15" claim-type="Currently amended] 15. The compound according to any one of claims 11 to 14, wherein R ²¹ is a halogenated methyl group, formyl group, carbamoyl group, nitrile group, halogenated carbamoyl group, or protected or unprotected hydroxymethyl group or carboxyl group. Fluoropyrazine derivatives or salts thereof.
[16" claim-type="Currently amended] The fluoropyrazine derivative or salt thereof according to any one of claims 11 to 15, wherein R ²¹ is a carbamoyl group, a protected or unprotected carboxyl group, a nitrile group, or a halogenated carbonyl 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:
2000-02-16|Priority to JP2000037486

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2000-02-16|Priority to JPJP-P-2000-00037486

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2000-02-18|Priority to JP2000040439

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2000-02-18|Priority to JPJP-P-2000-00040439

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2000-03-29|Priority to JPJP-P-2000-00090071

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2000-03-29|Priority to JP2000090071

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2001-02-14|Application filed by 토야마 케미칼 컴퍼니 리미티드

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2001-02-14|Priority to PCT/JP2001/001038

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2003-06-18|Publication of KR20030048108A

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2006-07-26|Application granted

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2006-07-26|Publication of KR100604955B1

优先权:

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申请号 | 申请日 | 专利标题

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JP2000037486|2000-02-16|

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JPJP-P-2000-00037486|2000-02-16|

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JP2000040439|2000-02-18|

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JPJP-P-2000-00040439|2000-02-18|

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JPJP-P-2000-00090071|2000-03-29|

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JP2000090071|2000-03-29|

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PCT/JP2001/001038|WO2001060834A1|2000-02-16|2001-02-14|Novel pyrazine derivatives or salts thereof, pharmaceutical compositions containing the derivatives or the salts and intermediates for the preparation of both|