RU2297414C2 - Derivatives of pyrazine or their salts, pharmaceutical composition containing these compounds and intermediate compounds for their preparing - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

and their salts wherein R¹ represents hydrogen atom or halogen atom; R² represents hydrogen atom or protected or unprotected group of monophosphoric, diphosphoric or triphosphoric acid; R³, R⁴, R⁵ and R⁶ can be similar or different and represent hydrogen atom, halogen atom, substituted or unsubstituted, protected or unprotected hydroxyl group or amino-group; or R⁴ and R⁶ taken in common form a simple bond; A represents oxygen atom or methylene group; n = 0 or 1; Y represents oxygen atom pr NH-group. Compounds elicit the excellent antiviral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and derivatives of fluoropyrazine carboxamide as intermediate compounds used in synthesis of compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 6 tbl, 57 ex

Description

Technical field

The present invention relates to new pyrazine derivatives or their salts, pharmaceutical compositions containing these compounds, and intermediate compounds for their preparation.

BACKGROUND OF THE INVENTION

Antiviral agents currently used in clinical practice include acyclovir and vidarabine directed against herpes viruses, ganciclovir and foscarnet, directed against cytomegaly viruses, and interferon, etc., directed against hepatitis viruses. In addition, vaccines are widely prevented against the influenza virus, and low molecular weight compounds such as amantadine hydrochloride and ribavirin are also used for this purpose. In addition, zanamivir has also been used recently.

On the other hand, with regard to the antiviral activity of nucleoside and nucleotide analogs based on a pyrazine ring, for example, it was previously reported that compounds of the general formula:

where R ⁷ represents a hydrogen atom, a methyl group or C ₁₀ H ₂₁ , have antiviral activity. However, this type of compound does not exhibit “activity against the Visnas virus” [Nucleosides & Nucleotides, Vol.15, Nos.11 and 12, Pages 1849-1861 (1996)]. In addition, analogues of nucleoside and nucleotide having a pyrazine ring substituted by a carbamoyl group have not yet been reported.

The problems associated with the use of amantadine are that it does not show activity against type B influenza virus, although it is effective against type A influenza virus, due to its mechanism of action, which may result in the virus becoming resistant to this compound, which leads to a nervous breakdown, etc. On the other hand, although ribavirin has an inhibitory effect on polymerase and is effective against influenza virus type A and type B, it does not show a sufficient clinical effect when used orally.

It follows that it is necessary to develop an antiviral agent that has a prophylactic effect against various viruses and especially against the influenza virus and exhibits a therapeutic effect.

PCT / JP99 / 04429 (WO 00/10569) describes nitrogen-containing heterocyclic carbamoyl derivatives represented by the following general formula [22]:

where ring A represents a substituted or unsubstituted pyrazine, pyrimidine, pyridazine or triazine ring, R ²³ represents O or OH, R ²⁴ represents a hydrogen atom, an acyl group or a carbamoylalkyl group, and the broken line represents a single bond or double bond, or their salts, which are used as an antiviral agent. Although the authors of the aforementioned patent application mention a method for preparing compounds represented by the general formula [22] and intermediates used for their synthesis, it does not describe the use of fluoropyrazine derivatives of the present patent application as intermediates for the synthesis of compounds represented by the general formula [22]. Along with the compounds represented by the general formula [22], compounds are described in which the substituent on the pyrazine ring is a fluorine atom, namely, compounds represented by the following general formula [23]:

where ring A ′ is a pyrazine ring and R ²³ , R ²⁴ and the dashed line have the same meanings as above, which have significant activity against the influenza virus and are excellent antiviral agents.

Description of the invention

In order to solve the above problems, comprehensive studies have been conducted. As a result, it was found that the pyrazine derivative represented by the following general formula [1]:

where R ¹ represents a hydrogen atom or a halogen atom; R ² represents a hydrogen atom or a protected or unprotected group of monophosphoric, diphosphoric or triphosphoric acid; R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, represent a hydrogen atom, a halogen atom, an azido group, a substituted or unsubstituted, protected or unprotected hydroxyl or amino group, or R ⁴ and R ⁶ taken together represent a simple connection; A represents an oxygen atom or a methylene group; n is 0 or 1; and Y represents an oxygen atom, a sulfur atom or an NH group, or a salt thereof, provided that the compounds in which R ¹ is hydrogen or a halogen atom; R ² represents hydrogen; R ³ and R ⁵ represent hydrogen; R ⁴ and R ⁶ represent a substituted or unsubstituted, protected or unprotected hydroxyl group; A represents an oxygen atom; n is 0; and Y represents an oxygen atom, are excluded; exhibit excellent antiviral activity. Based on the obtained data, the present invention has been completed.

In addition, it was also found that the fluoropyrazine derivative represented by the following general formula [21]:

where R ²¹ represents a hydrogen atom, a methyl group, a halogenated methyl group, a methyl group substituted by 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 group or an amino group, a nitro group, an azido group or a substituted or unsubstituted phenylsulfanyl, phenylsulfinyl or phenylsulfonyl group; with the proviso that a compound where R ²¹ represents a carbamoyl group or a carbamoyl group substituted with an acyl group and R ²² represents a hydroxyl group, and also a compound where R ²¹ represents a hydrogen atom and R ²² represents a hydrogen atom, are excluded, or its salt is an excellent intermediate for the industrial production of a fluoropyrazine carboxamide derivative, which is an intermediate for the synthesis of a compound represented by the general formula [1] in which R ¹ is It is a fluorine atom. Based on the obtained data, the present invention has been completed.

In addition, it was found that the fluoropyrazine derivative represented by the general formula [21] or its salt is an excellent intermediate for the industrial production of the fluoropyrazine carboxamide derivative represented by the general formula [23] having antiviral activity. Based on the obtained data, the present invention has been completed.

The present invention is described in detail below.

The terms used in this description have the following meanings, unless otherwise indicated. The term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; “halogenated methyl group” means a mono-, di- or trisubstituted halogenated methyl group such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl, dichloromethyl, trifluoromethyl, trichloromethyl and the like; "halogenated carbonyl group" means a fluorocarbonyl, chlorocarbonyl, bromocarbonyl or iodocarbonyl group; "lower alkyl group" means a C _1-5 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; “lower alkoxy group” means a C _1-5 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; "lower alkoxycarbonyl group" means a C _1-5 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like; “lower alkylamino group” means a mono- or di-C _1-5 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino and the like; “lower alkyl group containing a halogen” means a C _1-5 alkyl group containing a halogen such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl and the like; “lower alkenyl group” means a C _2-5 alkenyl group such as vinyl, allyl and the like; “cycloalkyl group” means a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; “aryl group” means a phenyl group, a naphthyl group or the like; and "heterocyclic group" means a 4-6 membered or fused heterocyclic group containing at least one heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom, such as azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanil, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimide Inyl, pyridazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenyl, indolisinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthylazinyl vinyl, vinylphyninyl, phthalidinyl, isochromanil, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolpyridazinyl, thiadiazolopyridazinyl, benzimidazolidazole, 1,2imidazole-1,2-tetrazolazole , 4] -triazinyl, quinuclide Neil and the like.

In those cases where the compound of the present invention and the intermediate compound contain a hydroxyl group, a mercapto group, an amino group, a carbamoyl group or a carboxy group, these substituents may be protected by known protecting groups.

The terms “monophosphoric acid group”, “diphosphoric acid group” and “triphosphoric acid group” mean groups of the following general formula:

where k is 1, 2 and 3, respectively.

The protecting groups for the monophosphoric acid, diphosphoric acid and triphosphoric acid groups include all groups commonly used to protect the phosphoric acid groups. Examples of such groups include lower alkyl groups such as methyl, cyclopropylmethyl, tert-butyl, ethane-1,2-diyl and the like; lower alkyl groups containing halogen, such as 2,2,2-trichloroethyl, 2,2,2-trichloro-1,1-dimethylethyl, 2,2,2-tribromethyl and the like; acyl lower alkyl groups such as 1-acetyl ethyl and the like; cyano lower alkyl groups such as 2-cyanoethyl and the like; lower alkylsulfonyl lower alkyl groups such as 2-methylsulfonylethyl and the like; arylsulfonyl lower alkyl groups such as 2-phenylsulfonylethyl and the like; alkenyl groups such as allyl and the like; aryl groups such as phenyl, o-hydroxyphenyl, o-chlorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, p-nitrophenyl, 2-dimethylamino-4-nitrophenyl, 2-tert-butylphenyl, 2-chloromethyl-4-nitrophenyl , o-phenylene and the like; aryl lower alkyl groups such as benzyl, o-nitrobenzyl, p-nitrophenylethyl and the like; heterocyclic groups such as 8-quinolyl, 5-chloro-8-quinolyl and the like, etc. For protection, one or more kinds of the aforementioned protecting groups may be used.

Protective groups for a carboxyl group may include all groups commonly used to protect a carboxyl group. Examples of such groups include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; aryl lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl and the like; acyl lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; lower alkyl groups containing halogen, such as 2,2,2-trichloroethyl and the like; lower alkyl silyl alkyl groups such as 2- (trimethylsilyl) ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocycle lower alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; lower alkoxy lower alkyl groups such as methoxymethyl, methoxyethoxyethyl, 2- (trimethylsilyl) ethoxymethyl and the like; aryl lower alkoxy lower alkyl groups such as benzyloxymethyl and the like; lower alkylthio lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl, allyl and the like, and lower alkyl substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyl diphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

Protecting groups for amino groups and lower alkylamino groups may include all groups commonly used to protect amino groups. Examples of such groups include acyl groups such as trichloroethoxycarbonyl, tribromethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di- and tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoylcarbon, tert-amyl β-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, 1-succinyl sikarbonil, 8-quinolyloxycarbonyl and the like; aryl lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkane and allensulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di-lower alkylamino lower alkylidene groups such as N, N-dimethylaminomethylene and the like; aryl lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-hydroxycyclohexylidene and the like; di-aryl or di-aryl lower alkylphosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl and the like; and lower alkyl substituted silyl groups such as trimethylsilyl group and the like.

The protecting groups for the hydroxyl group and mercapto group may include all groups commonly used to protect the hydroxyl group. Examples of such groups include acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, 1,2-dimethylphenoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-alkoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl, 2-methoxycarbonyl and 2-methoxycarbonyl. , 2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxy rbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl; lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; lower alkenyl groups such as allyl and the like; aryl lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy and lower alkylthio lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and the like; alkane and allensulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like; substituted aryl groups such as hydroquinone, p-methoxyphenol and the like; enol- (ether) ether groups such as (2-methyl-3-oxo-1-cyclopenten-1-yl) and the like.

The protecting groups for a carbamoyl group may include all groups commonly used to protect a carbamoyl group. Examples of such groups include aryl lower alkyl groups such as benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and the like; lower alkoxyalkyl groups such as methoxymethyl and the like; aryl lower alkoxy groups such as benzyloxymethyl and the like; substituted silyl lower alkoxy lower alkyl groups such as tert-butyldimethylsiloxymethyl and the like; lower alkoxy groups such as methoxy and the like; aryl lower alkoxy groups such as benzyloxy and the like; lower alkylthio groups such as methylthio, triphenylmethylthio and the like; aryl lower alkylthio groups such as benzylthio and the like; substituted silyl groups such as tert-butyldimethylsilyl and the like; aryl groups such as 4-methoxyphenyl, 4-methoxymethylphenyl, 2-methoxy-1-naphthyl and the like; acyl groups such as trichloroethoxycarbonyl, trifluoroacetyl, tert-butoxycarbonyl and the like, etc.

Substituents 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 may include a protected or unprotected carboxyl group, a lower alkyl group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a lower alkyl group containing a halogen, and a heterocyclic group. For substitution, one or more types of substituents selected from the above substituents may be used.

Substituents 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 may include substituted, protected or unprotected carboxyl, hydroxyl, amino and lower alkylamino groups, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a lower alkyl group containing a halogen, and a heterocyclic group. For substitution, one or more substituents selected from the above groups may be used.

Substituents phenylsulfanyl group fenilsulfinilnoy group and phenylsulfonyl group represented by R ²² may include lower alkyl groups such as methyl, ethyl and the like.

Salts of the compounds of general formulas [1] and [21] can usually include known salts formed by a basic group, such as an amino group, etc., and salts formed by an acid group, such as a hydroxyl group, a phosphoryl group, a carboxyl group, etc. d. Salts formed by the main group include, for example, salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; organic acid salts such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like, and sulfonic acid salts such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylene sulfonic acid, naphthalene sulfonic acid and the like. Salts formed by the acid group include salts with an alkali metal such as sodium, potassium and the like; salts with an alkaline earth metal such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dmethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, , N, N'-dibenzylethylenediamine and the like.

Of the salts mentioned above, pharmacologically acceptable salts are preferred.

In some cases, compounds of the general formulas [1] and [21] and their salts have isomers such as optical isomers, geometric isomers and tautomers. In such cases, the present invention includes these isomers and, in addition, includes solvated products, hydrates, as well as various crystalline forms.

Of the pharmaceutical compositions of the present invention, the preferred pharmaceutical compositions are antiviral agents, and furthermore, the preferred antiviral compositions are agents against influenza virus, RS virus (Raus sarcoma), AIDS virus, papilloma virus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, polio virus, ECHO virus, Coxsackie virus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus. Even more preferred antiviral agents are those directed against rotavirus, RS virus and influenza virus. The most preferred antiviral agent is an anti-influenza agent.

Of the compounds of the present invention, preferred compounds are those in which R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, are a hydrogen atom, a halogen atom or a substituted or unsubstituted, protected or unprotected hydroxyl group, or R ⁴ and R ⁶ taken together form a single bond, and the salts of such compounds, and furthermore, preferred compounds are those compounds wherein R ² represents a hydrogen atom or a protected or unprotected group mo ofosfornoy acid or triphosphoric acid; and most preferred compounds are those compounds in which R ² represents a hydrogen atom or a protected or unprotected monophosphoric acid group R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, represent a hydrogen atom or a protected or unprotected a hydroxyl group, A is an oxygen atom, and n is 0, as well as salts of the compounds; and in addition, more preferred compounds are those compounds in which R ² represents a hydrogen atom, as well as salts of these compounds.

Even more preferred compounds include compounds in which R ¹ means a hydrogen atom, a chlorine atom or a fluorine atom, as well as salts of these compounds; and preferred compounds also include those compounds wherein R ¹ is a hydrogen atom or a fluorine atom, as well as salts of said compounds.

Of the intermediate compounds of the present invention, preferred are those compounds in which R ²¹ represents 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, carbamoyl or carboxyl group, and salts thereof compounds; and further preferred are those compounds in which R ²² is a protected or unprotected hydroxyl group or amino group, a halogen atom, a nitro group or an azido group, as well as salts of said compounds; and further preferred are those compounds in which 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 or carboxyl group, as well as salts of these compounds; and more preferred are those compounds wherein R ²¹ is a halogenated methyl group, a formyl group, a carbamoyl group, a nitrile group, a halogenated carbonyl group or a protected or unprotected hydroxymethyl or carboxyl group, as well as salts of these compounds; and even more preferred are those compounds in which R ²¹ is a carbamoyl group, a protected or unprotected carboxyl group, a nitrile group or a halogenated carbonyl group, as well as salts of these compounds. However, among the above compounds, those compounds are excluded where R ²¹ is a carbamoyl group or a carbamoyl group substituted by an acyl group and R ²² is a hydroxyl group, as well as those compounds where R ²¹ is a hydrogen atom and R ²² is a hydrogen atom.

Among the compounds of the present invention, typical compounds are, for example, those shown in Table I-1, where “Bn” represents a benzyl group and “-” represents a single bond.

Table I-1 R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ A n Y H H H OH H OH O 0 NH H H H OH H OH O 0 S 6-f H H OH H OH O 0 NH 6-f H H OH H H O 0 O H H H OH H H O 0 O H H H OH H F O 0 O 6-f H H OH H NH ₂ O 0 O 6-f H H NH ₂ H OH O 0 O 6-f H H OH OH H O 0 O H H H OH H NH ₂ O 0 O H H H NH ₂ H OH O 0 O H H H OH OH H O 0 O H H H OH F H O 0 O H H H OH N ₃ H O 0 O 6-f H H N ₃ H H O 0 O 6-f H H H H H O 0 O 6-f (HO) ₂ PO H OH H OH O 0 O H H H N ₃ H H O 0 O H H H H H H O 0 O H (HO) ₂ PO H OH H OH O 0 O H (BnO) ₂ PO H OH H OH O 0 O 6-f H H OH H OH CH ₂ 0 O H H H OH H OH CH ₂ 0 O H H H OH OH H CH ₂ 0 O H H H H H H CH ₂ 0 O H H H - H - CH ₂ 0 O H H H OH H H O one O H H H OH H OH O one O 6-f H [OP (O) OH] ₃ H OH H OH O 0 O H H [OP (O) OH] ₃ H OH H OH O 0 O 6-f [CH ₂ = CHCH ₂ O] P (O) H OH H OH O 0 O H [CH ₂ = CHCH ₂ O] P (O) H OH H OH O 0 O

Typical intermediates for the compounds of the present invention are shown in the following Tables II-1 to II-5, where “Et” is an ethyl group, “Ac” is an acetyl group, “Ph” is a phenyl group, “Bz” is a benzoyl group, “tBu” represents a tert-butyl group, “OPh (p-OH)” represents a parahydroxyphenyloxy group, and “C ₆ H ₇ O” represents a 2-methyl-3-oxo-1-cyclopenten-1-yl group .

Table II-1 R ²¹ R ²² H Och ₃ H NH ₂ CH ₃ H CH ₃ OH CH ₃ Och ₃ CH ₃ NH ₂ CH ₃ F CH ₂ OH H CH ₂ OH OH CH ₂ OH Och ₃ CH ₂ OH NH ₂ CH ₂ OH F CH ₂ Cl H CH ₂ Cl OH CH ₂ Cl Och ₃ CH ₂ Cl NH ₂ CH ₂ Cl F CH ₂ Br H CH ₂ Br OH CH ₂ Br NH ₂

Table II-2 R ²¹ R ²² Cho H Cho OH Cho Och ₃ Cho NH ₂ Cho F CONH ₂ H CONH ₂ Och ₃ CONH ₂ NH ₂ CONH ₂ Cl CONH ₂ F CONH ₂ NO ₂ CONH ₂ N ₃ Cool H Cool OH Cool Och ₃ Cool NH ₂ Cool F Cool NO ₂ Cool N ₃

Table II-3 R ²¹ R ²² Couch ₃ H Couch ₃ OH Couch ₃ Och ₃ Couch ₃ NH ₂ Couch ₃ F Couch ₃ NO ₂ Cool H Cool OH Cool Och ₃ CN H CN OH CN Och ₃ CN NH ₂ CN F CN NO ₂ CN N ₃ CN OCH ₂ Ph CN OCH ₂ CH = CH ₂ CN OPh (p-OH) CN SPh CN Soph CN SO ₂ Ph CN OSO ₂ CH ₃ CN OC ₆ H ₇ O COCl OH COCl Och ₃ COCl NH ₂ COCl F COF Och ₃ COF NH ₂ COF F

Table II-4 R ²¹ R ²² CONHAc H CONHAc Och ₃ CONHAc NH ₂ CONHAc Cl CONHAc F CONHAc NO ₂ CONHAc N ₃ CONHBz Och ₃ CONHBz NH ₂ CONHBz Cl CONHBz F CONHBz NO ₂ CONHBz N ₃ CONHC (O) tBu Och ₃ CONHC (O) tBu NH ₂ CONHC (O) tBu Cl CONHC (O) tBu F CONHC (O) tBu NO ₂ CONHC (O) tBu N ₃ Table II-5 R ²¹ R ²² CONHCH ₂ Ph Och ₃ CONHCH ₂ Ph NH ₂ CONHCH ₂ Ph Cl CONHCH ₂ Ph F CONHCH ₂ Ph NO ₂ CONHCH ₂ Ph N ₃ CONHCH ₂ OCH ₂ Ph Och ₃ CONHCH ₂ OCH ₂ Ph NH ₂ CONHCH ₂ OCH ₂ Ph Cl CONHCH ₂ OCH ₂ Ph F CONHCH ₂ OCH ₂ Ph NO ₂ CONHCH ₂ OCH ₂ Ph N ₃

The following describes a method for producing compounds of the present invention.

Compounds according to the present invention can be obtained according to the schemes of the synthesis method from I-1 to I-4, below.

wherein R ^1, R ^3, R ^4, R ^5, R ^6, A, Y and n are as defined above; R ⁸ represents a lower alkyl group; Z ¹ represents a hydrogen atom or a protective group for a hydroxyl group; Z ² , Z ³ , Z ⁴ and Z ⁵ , which may be the same or different, represent a hydrogen atom, a halogen atom, an azido group, a protected hydroxy group or an amino group; or Z ³ and Z ⁵ taken together form a single bond.

(a) A compound of general formula [1a] or a salt thereof can be prepared by deprotecting a compound of general formula [2a] or a salt thereof.

The solvent used in this reaction is not limited, unless the solvent has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As a reagent for deprotection, reagents that are commonly used to deprotect a hydroxyl group, an amino group and a phosphoric acid group can be used. However, bases such as sodium methoxide, hydrogen gas, ammonia gas, aqueous ammonia, butylamine and the like are preferred; acids such as formic acid, an aqueous solution of acetic acid, an aqueous solution of trifluoroacetic acid, hydrochloric acid and the like; palladium catalysts such as tetrakis-triphenylphosphine palladium (0) and the like; and phosphines, such as triphenylphosphine and the like. These deprotecting reagents may be used in combination or may be prepared in a reaction system. The deprotecting reagent is used in an amount of at least 0.01 mol per mol of the compound of general formula [2a] or its salt. If desired, a deprotecting reagent can be used as a solvent.

The deprotection reaction is usually carried out at a temperature of from -50 to 170 ° C and preferably from -20 to 100 ° C, for a time of 1 minute to 100 hours, and preferably for a time of 5 minutes to 50 hours.

(b) A compound of general formula [1a] in which Y is an oxygen atom or a salt thereof can be prepared by ammonolysis of a carboxylic acid ester of a compound of general formula [2b] or a salt thereof in the presence or absence of a catalyst.

The solvent used in this reaction is not limited, unless it has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water, etc. The listed solvents may be used as such or as a mixture of two or more solvents. The reaction can be carried out in the presence of reagents and under conditions that are usually used in the ammonolysis reaction of aromatic carboxylic acid esters. However, it is preferable to use gaseous ammonia, liquid ammonia or aqueous ammonia. These reagents are used in an amount of at least 0.5 mol per mol of the compound of formula [2b] or its salt. You can also use these solvents as a solvent, if desired. Catalysts that can be used if necessary in the reaction include acidic ammonium salts such as ammonium chloride; bases such as sodium methoxide, butyl lithium and the like; and alkali metal amides such as sodium amide and the like. The catalyst is used in an amount of from 0.01 mol to 100 mol and preferably from 0.01 to 20 mol per mol of the compound of formula [2b] or its salt.

The reaction is usually carried out at a temperature of from -100 to 250 ° C and preferably from -78 to 100 ° C for a time from 1 minute to 72 hours and preferably from 30 minutes to 50 hours.

where 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 as defined above; R ⁹ represents a protected or unprotected monophosphoric acid group or monophosphoric acid chloride; and R ¹² represents a protected or unprotected group of diphosphoric acid or triphosphoric acid.

(a) A compound of the general formula [2 c] or its salt can be prepared by protecting a compound of the general formula [2b] or its salt with a reagent in the presence or absence of an acid catalyst or base.

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; ketones such as acetone and the like; water, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

The reagent used is those which are usually used to protect the hydroxyl group and amino group, and preferably 2,2-dimethoxypropane, acetyl chloride and benzoyl chloride. If desired, these reagents can be obtained in the reaction system. The amount of reagent is at least an equimolar amount and preferably 1.0-10 mol per mol of the compound of formula [2b] or its salt.

The acid catalyst or base used in this reaction includes, for example, p-toluenesulfonic acid, triethylamine and the like. The amount of these compounds may be for both 0.01-10 mol and preferably 0.05-10 mol per mol of the compound of formula [2b] or its salt.

The specified reaction is usually carried out at a temperature of from -50 to 170 ° C and preferably from 0 to 150 ° C for a time of from one minute to 24 hours and preferably from 5 minutes to 10 hours.

(b) A compound of general formula [2d] or its salt can be obtained (1) by reacting a compound of general formula [2c] or its salt with a phosphorylating reagent in the presence or absence of an additive according to the method described in Jikken Kadaku Koza, 4 ^th Edition, Vol, 22, Pages 313-438 (edited by the Chemical Society of Japan (corporate juridical person), 1992) or by (2) reacting said compound with a phosphitizing agent and then with an oxidizing agent.

In the method (1), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As the phosphorylating reagent, reagents that are commonly used to phosphorylate a hydroxyl group can be used. Examples of such a phosphorylating agent include phosphoric acid diesters such as dibenzyl phosphate and the like; phosphoric acid dithioesters such as S, S'-diphenylphosphorodithioate monocyclohexylammonium and the like; phosphoric acid chlorides such as phosphoryl chloride, diallyl chlorophosphonate and the like, etc. The phosphorylating reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or its salt. Additives include, for example, azo compounds such as diethyl ether azodicarboxylic acid, diisopropyl ether azodicarboxylic acid and the like; phosphines such as triphenylphosphine and the like; allensulfonic acid chlorides such as 2,4,6-triisopropylbenzenesulfonic acid chlorides and the like, etc .; bases such as pyridine, magnesium tert-butylate chloride and the like; etc. If desired, these additives may be used in combination. The additive is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or its salt.

The specified reaction is usually carried out at a temperature of from -50 to 170 ° C. And preferably from 0 to 100 ° C for a time from 1 minute to 72 hours and preferably from 5 minutes to 24 hours.

In the method (2), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As the phosphitizing reagents, those reagents that are commonly used in the phosphitization reaction of the hydroxyl group can be used. Examples include phosphoramidites, such as diallyldiisopropylphosphoramidite and the like, and phosphoric acid chlorides, such as diallyl phosphorochloridite and the like. The phosphitizing reagent is used at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per mol of the compound of formula [2c] or its salt. As an additive, for example, tetrazole compounds, such as 1H-tetrazole and the like, and bases, such as pyridine, collidine and the like, and these additives can be used in combination, if desired. The additive is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or its salt.

The oxidizing agents used in this reaction include, for example, peroxides such as m-chloroperbenzoic acid, tert-butyl hydroperoxide and the like, and halogen compounds such as iodine and the like. The oxidizing agent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or its salt.

The specified reaction is usually carried out at a temperature of from -78 to 100 ° C and preferably at a temperature of from -50 to 50 ° C for a time of from 1 minute to 24 hours and preferably from 5 minutes to 6 hours.

(c) A compound of general formula [1b] or a salt thereof can be prepared by the reaction according to method I-1 (b) using a compound of general formula [2d] or a salt thereof.

(d) A compound of general formula [1c] or a salt thereof can be prepared by the reaction according to method I-1 (a) using a compound of general formula [1b] or a salt thereof.

(e) A compound of general formula [1b] or a salt thereof can be prepared by a reaction according to method I-2 (b) using a compound of general formula [1d] or a salt thereof.

(f) A compound of general formula [1e] or a salt thereof can be prepared by reacting a compound of general formula [1c] or its salt with a phosphorylating agent in the presence or absence of a condensing reagent according to the method described, for example, in Chem. Rev., Vol. 100, Pages 2047-2059 (2000).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine etc. The listed solvents may be used as a single solvent or as a mixture of two or more solvents.

As the phosphorylating reagent, those reagents that are commonly used to phosphorylate the monophosphoric acid group can be used. Examples of such a phosphorylating agent include phosphoric acid salts such as tri-n-butylammonium phosphate, n-butylammonium pyrophosphate and the like, and said phosphorylating reagents can be synthesized in the reaction system, if desired. The phosphorylating reagent is used at least in an equimolar amount and preferably in an amount of 1.0-10 mol per mol of the compound of formula [1c] or its salt. As a condensing reagent, for example, imidazoles such as N, N-carbonyldiimidazole, N-methylimidazole and the like, and amines such as morpholine, diisopropylamine and the like, and such amines can be used in combination, if desired. The condensing reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of the formula [1 s] or its salt.

The specified reaction is carried out at a temperature of from -50 to 100 ° C. And preferably at a temperature of from 0 to 50 ° C for a time from 1 minute to 72 hours and preferably from 5 minutes to 24 hours.

where R ¹ , R ⁸ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are as defined above; Y ¹ represents an oxygen atom or an NH group, and R ¹⁰ represents a halogen atom, a carbonyloxy group or a sulfonyloxy group.

(a) A compound of general formula [2a] or its salt can be obtained by (1) converting a compound of general formula [3a] or its salt into a compound of general formula [3b] or its salt according to a conventional silylation method in the presence or absence of an additive, and followed by (2) reacting the obtained compound with a compound of the general formula [4a] or a salt thereof in the presence or absence of a Lewis acid.

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like. The listed solvents may be used as a single solvent or as a mixture of two or more solvents.

The silylating reagent used in reaction (1) can be any silylating reagent that is commonly used to convert a carbonyl group to a silyl enol ether. Examples of such reagents include 1,1,1,3,3,3-hexamethyldisilazane, N, O-bis (trimethylsilyl) acetamide, trimethylsilyl chloride and the like. The silylating reagent is used at least in an equimolar amount and preferably in an amount of 1.0-10.0 mol per mol of the compound of formula [3a] or its salt.

An additive which, if necessary, can be used in said reaction includes, for example, ammonium sulfate and the like. The specified additive is used in an amount of 0.01-10.0 mol and preferably 0.05-5.0 mol per mol of the compound of formula [3a] or its salt.

This reaction is usually carried out at a temperature of 0-200 ° C and preferably at a temperature of 0-150 ° C for a time from 5 minutes to 24 hours and preferably from 5 minutes to 12 hours.

In the reaction (2), the compound of the formula [4a] or its salt is used in an amount of 0.5-10 mol and preferably 0.5-5 mol per mol of the compound of the formula [3a] or its salt.

Lewis acid, which, if necessary, can be used in this reaction, includes, for example, trimethylsilyl trifluoromethanesulfonic acid, tin (IV) chloride, titanium (IV) chloride, zinc chloride and the like. Lewis acid is used at least in an amount of 0.5 mol and preferably in an amount of 0.5-10 mol per mol of the compound of formula [3a] or its salt.

This reaction is usually carried out at a temperature of 0-100 ° C. And preferably at a temperature of 0-50 ° C for a time from 1 minute to 72 hours and preferably from 5 minutes to 24 hours.

(b) A compound of the general formula [2a] or its salt can be prepared by reacting a compound of the general formula [3a] or its salt with a compound of the general formula [4b] or its salt in the presence or absence of an additive using a base as an acid-removing reagent .

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. The listed solvents may be used as a single solvent or as a mixture of two or more solvents.

The bases used in this reaction include, for example, inorganic and organic bases such as triethylamine, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and the like. In carrying out this reaction, the compound of the formula [4b] or its salt is used in an amount of 0.1-5 mol and preferably 0.2-2 mol per mol of the compound of the general formula [3a] or its salt. In carrying out this reaction, the base is used in an amount of 0.1-10 mol and preferably 0.2-10 mol per mol of the compound of general formula [3a] or its salt.

An additive which, if necessary, can be used in said reaction includes, for example, palladium catalysts such as tetrakis-triphenylphosphine palladium and the like; phosphines such as triphenylphosphine and the like; and polyethers such as 18-crown-6- (ether) ether and the like. The specified additive is used in an amount of 0.01-10.0 mol and preferably 0.03-5.0 mol per mol of the compound of formula [3a] or its salt.

This reaction is usually carried out at a temperature of from -50 to 170 ° C and preferably at a temperature of from 0 to 120 ° C for a time of from 1 minute to 72 hours and preferably from 5 minutes to 24 hours.

where R ¹ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are as defined above.

A compound of the general formula [2g] or its salt can be prepared by reacting a compound of the general formula [2f] or its salt with a thionation reagent in the presence or absence of a base as described, for example, Shin Jikken Kagaku Koza, Vol, 14, Pages 1819-1831 ( edited by the Chemical Society of Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As a thionation reagent, such reagents as are commonly used for thionation of acid amides can be used. Examples of such reagents include hydrogen sulfide gas, diphosphorus pentasulfide, Lauson reagent, etc. The thionation reagent is used in this reaction in an amount of 0.1-10 mol and preferably 0.2-5.0 mol per mol of the compound of general formula [2f] or its salt.

The base used in this reaction, for example, includes bases such as ammonia, triethylamine, morpholine, pyridine, 4-dimethylaminopyridine and the like. In carrying out this reaction, the base is used at least in an amount of 0.01 mol per mol of the compound of formula [2f] or its salt. If desired, the base can be used as a solvent.

The specified reaction is usually carried out at a temperature of from -50 to 170 ° C and preferably from 0 to 120 ° C for a time from 1 minute to 24 hours and preferably from 5 minutes to 6 hours.

Next, a method for producing compounds of the general formulas [2a], [2b], [3a '] and [3j] and their salts, which are the starting materials for preparing the compound according to the present invention, will be described.

Compounds of the general formulas [2a], [2b], [3a '] and [3j] can be prepared by well known methods or an appropriate combination of methods. For example, these compounds can be obtained according to the following method I-A.

where 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 R ¹⁰ are as defined above.

(a) A compound of the general formula [2e] or a salt thereof can be prepared by reacting a compound of the general formula [3c] or its salt with a compound of the general formula [4a] or its salt according to the synthesis method I-3 (a).

(b) A compound of general formula [2e] or its salt can be prepared by reacting a compound of general formula [3c] or its salt with a compound of general formula [4b] or its salt according to the synthesis method I-3 (b).

(c) A compound of general formula [2b] or a salt thereof can be prepared by reacting a compound of general formula [2e] or a salt thereof according to synthesis method I-1 (a).

Among the starting materials for carrying out the aforementioned reactions, a compound of the general formula [3c] or its salt can be obtained by the method, for example, 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 General formula [4A] or its salt can be obtained by the method, for example, described in J. Med. Chem., Vol. 28, No. 7, Pages 904-910 (1985); and a compound of general formula [4b] or a salt thereof can be prepared by the method 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).

where R ⁸ is as defined above; R ^1a represents a halogen atom; R ¹¹ represents a protective group for a hydroxyl group and X represents a halogen atom other than a fluorine atom.

(a) A compound of general formula [3f] or a salt thereof can be prepared by reacting a compound of general formula [3e] or a salt thereof using a diazotizing reagent and an alcohol.

The solvents used in this reaction may be any solvents, provided that they do not adversely affect the reaction. Examples of the solvent include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amino oxides such as triethylamine, N, N-dimethylaniline, pyridine-N-oxide and the like; ketones such as acetone and the like; alcohols such as methanol, ethanol and the like; water, etc. If desired, these solvents may be used as a mixture. The diazotizing reagents used in this invention are practically unlimited, if they are usually used for diazotization of aromatic amino compounds. However, it is preferred that alkali metal nitrites such as sodium nitrite and the like are used. The diazotizing reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [3e] or its salt.

The alcohol used in this reaction includes, for example, methanol and the like. Alcohol is used at least in an equimolar amount with respect to the compound of formula [3e] or its salt. Alcohol can also be used as a solvent, if desired.

The specified reaction is usually carried out at a temperature of from -70 to 200 ° C. And preferably at a temperature of from -50 to 100 ° C for a time from 1 minute to 24 hours and preferably from 30 minutes to 10 hours.

(b) A compound of the general formula [3g] or its salt can be obtained (1) by reacting a compound of the general formula [3f] or its salt with an imine in the presence of a catalyst and a base as a reagent for eliminating acidity, according to the method described in the literature [ Tetrahedron Letters, Vol. 38, No. 36, Pages 6367-6370 (1997)], and (2) by its hydrolysis in the presence of an additive.

(1) When carrying out the reaction (1), the solvents used are not strictly limited, unless they have a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

To carry out this reaction, the catalyst may be selected from combinations of a palladium catalyst such as palladium (II) acetate, tris (dibenzylidene-acetone) dipalladium and the like, a nickel catalyst such as bis (1,5-cyclooctadiene) nickel (0) and the like and a phosphine ligand such as 1,1'-bis (diphenylphosphino) ferrocene, (s) - (-) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and the like. The catalyst is used in an amount of 0.001-1.0 mol and preferably 0.002-0.5 mol per mol of the compound of formula [3f] or its salt.

The base used in this reaction includes alkali metal salts such as sodium tert-butoxide, cesium carbonate and the like. The base is used at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per mol of the compound of formula [3f] or its salt.

The imine used in this reaction includes, for example, benzophenonyminine and the like. The imine is used at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per mol of the compound of formula [3f] or its salt.

The specified reaction is usually carried out at a temperature of 0-120 ° C and preferably at a temperature of 5-100 ° C for a time from 1 minute to 48 hours and preferably from 5 minutes to 24 hours.

(2) When carrying out the reaction (2), the solvents used are not strictly limited, unless they have a detrimental effect on the reaction. Solvents used are, for example, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; water, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

The additive used in this reaction includes, for example, salts of organic and inorganic acids, such as sodium acetate, hydroxylamine hydrochloride, ammonium formate and the like; inorganic acids such as hydrochloric acid and the like; and palladium catalysts such as palladium on carbon and the like. These additives can be used in combination, if desired. The additive is used in an amount of 0.01-50 mol and preferably 0.1-20 mol per mol of the compound of general formula [3f] or its salt.

The specified reaction is usually carried out at a temperature of 0-120 ° C and preferably at a temperature of 5-100 ° C for a time from 1 minute to 48 hours and preferably from 3 minutes to 24 hours.

(c) A compound of general formula [3h] or a salt thereof can be prepared by reacting a compound of general formula [3g] or a salt thereof according to synthesis method I-1 (b).

(d) A compound of general formula [3i] or its salt can be obtained by deamination of the amino group of a compound of general formula [3h] or its salt using a diazotizing reagent in the presence of acid, in the presence or absence of an additive according to the method described, for example, in Fusso Kagaku Nyumon, Pages 219-230 (edited by Nippon Gakujutsu Shinkokai, 155 Fluorine Chemistry Committee, 1997), followed by a fluorination reaction.

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of solvents include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amino oxides such as triethylamine, N, N-dimethylaniline, pyridine, pyridine-N-oxide and the like; ketones such as acetone and the like; water etc. The listed solvents may be used as a mixture, if desired.

The diazotizing reagents used in this reaction can be any reagents, if they are usually used for diazotization of aromatic amino compounds. Preferred diazotizing agents are, for example, alkali metal salts of nitrous acid such as sodium nitrite and the like. The diazotizing reagent is used at least in an equimolar amount, preferably in an amount of 1.0-5.0 mol, and in addition, preferably 1.0-1.5 mol per mol of the compound of formula [3h] or its salt.

The acid used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of acids include acids such as hydrochloric acid, hydrofluoric acid, hydrogen fluoride and the like; solutions of hydrogen fluoride in bases, such as a solution of hydrogen fluoride in pyridine, etc. These acids may be used as a mixture, if desired.

To carry out this reaction, the acid is used in at least 1 ml and preferably 1-50 ml per g of the compound of general formula [3h] or its salt, which is determined based on the volume / weight ratio.

The additive used in this reaction includes hydrofluoric acid, sodium tetrafluoride, ammonium fluoroborate and the like. The acid is used at least in an equimolar amount and preferably 1.0 to 20.0 mol per mol of the compound of formula [3h] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 100 ° C. And preferably at a temperature of from -60 to 30 ° C for a time from 50 minutes to 24 hours and preferably from 1 hour to 10 hours.

(e) A compound of general formula [3i] or a salt thereof can be prepared by reacting a compound of general formula [3f] or a salt thereof according to synthesis method I-1 (b).

(f) A compound of general formula [3a '] or a salt thereof can be prepared by reacting a compound of general formula [3i] or a salt thereof with a reagent to remove a protective group.

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of solvents include alcohols such as methanol, ethanol, propanol and the like; thioalcohols such as ethanethiol, thiophenol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; thioethers such as dimethyl sulfide and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, trifluoroacetic acid and the like; sulfonic acids such as trifluoromethanesulfonic acid and the like; organic bases such as pyridine, triethylamine and the like; water etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As a reagent that promotes the removal of the protective group, reagents that are usually used to remove the protection of the aromatic alcohol can be used. Preferably, trimethylsilyl iodide and the like can be used. It is also acceptable to obtain a reagent that promotes the removal of the protective group in the reaction system. The deprotecting reagent is used in an amount of 0.01-50 mol and preferably 0.1-30 mol per mol of the compound of formula [3i] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 200 ° C. And preferably at a temperature of from 0 to 160 ° C for a time of from one minute to 48 hours and preferably from 5 minutes to 20 hours.

A compound of the general formula [3e] or a salt thereof, which are the starting material for the aforementioned reaction, can be prepared, for example, by the method described in J. Am. Chem. Soc., Vol. 71, Pages 2798-2800 (1949).

where R ¹ is as defined above, and R ¹³ represents a lower alkoxy group or an aryloxy group.

(a) A compound of the general formula [3k] or its salt can be prepared by reacting a compound of the general formula [3l] or its salt with an alcohol in the presence or absence of an acid catalyst or base according to the procedure described, for example, in Shin Jikken Kagaku Koza, Vol .14, Pages 1599-1602 (edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

The alcohol used in this reaction includes, for example, methanol, ethanol, phenol and the like. Alcohol is used at least in an equimolar amount with respect to the compound of formula [3l] or its salt. The use of alcohol as a solvent is permissible, if desired.

As the acid catalyst used in this reaction, reagents are used that are commonly used to imitate nitriles. For these purposes, for example, hydrogen chloride and the like can be used. The acid catalyst is used in an amount of at least 0.1 mol per mol of the compound of formula [3l] or its salt.

The base used in this reaction may include, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, sodium phenoxide and the like. It is permissible to obtain these bases in the reaction system, if desired. To carry out this reaction, the base is used in an amount of at least 0.01 mol and preferably 1.0-5.0 mol per mol of the compound of formula [3l] or its salt.

The specified reaction is usually carried out at a temperature of from -78 to 170 ° C. And preferably at a temperature of from -40 to 120 ° C for a time of from one minute to 72 hours and preferably from 5 minutes to 24 hours.

(b) A compound of the general formula [3j] or its salt can be prepared by reacting a compound of the general formula [3k] or its salt with a reagent according to the procedure described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 1614-1617 (edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. The listed solvents may be used as such or as a mixture of two or more solvents.

As the aforementioned reagent used in this reaction, such reagents are used that are commonly used for amidination of imidates. Examples of the above reagent include gaseous ammonia, alcoholic ammonia solution, aqueous ammonia solution and ammonium acid salts such as ammonium chloride and the like. The reagent is used at least in an equimolar amount with respect to the compound of formula [3k] or its salt. The use of a reagent as a solvent is permissible, if desired.

The specified reaction is usually carried out at a temperature of from -78 to 170 ° C and preferably at a temperature of from 0 to 120 ° C for a time of from one minute to 72 hours and preferably from 5 minutes to 24 hours.

where R ^1A is as defined above.

(a) A compound of the general formula [3m] or its salt can be prepared by reacting a compound of the general formula [3n] or its salt with a diazotizing agent and a hydroxylating agent in the presence or absence of an additive according to the procedure described for example in Shin Jikken Kagaku Koza, Vol.14, Pages 537-538 (edited by the Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of solvents include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amino acids such as triethylamine, N, N-dimethylaniline, pyridine-N-oxide and the like; ketones such as acetone and the like; water etc. The listed solvents may be used as such or as a mixture.

The diazotizing reagent used in this reaction is not strictly limited, if it is usually used for deaminohydroxylation of aromatic amino compounds. Preferably, alkali metal nitrites such as sodium nitrite and the like are used. The diazotizing reagent is used at least in an equimolar amount, preferably in an amount of 1.0-5.0 mol, and, in addition, preferably 1.0-2.0 mol per mol of the compound of the formula [3n].

The hydroxylating reagent used in this reaction may include, for example, water and the like. The hydroxylating reagent is used at least in an equimolar amount with respect to the compound of formula [3n], although the hydroxylating reagent can also be used as a solvent, if desired.

The additive used in this reaction may include, for example, copper salts such as copper sulfate and the like; and inorganic bases such as sodium hydroxide, sodium carbonate and the like. The additive is used in an amount of 0.01-100 mol and preferably 0.1-50 mol per mol of the compound of the formula [3n].

The above reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -50 to 100 ° C for a time of from one minute to 24 hours and preferably from 30 minutes to 10 hours.

(b) A compound of the general formula [3n] or its salt can be obtained (1) by reacting a compound of the general formula [3o] or its salt with an electrophilic fluorinating agent in the presence or absence of an additive and, in more detail, according to the procedure described in Fusso no Kagaku, Pages 28-37 (edited by Kodansha Scientific, 1993) or (2) by reacting a compound of the formula [3o] or its salt with a halogenating reagent in the presence or absence of an additive according to the procedure described, for example, in Shin Jikken Kagaku Koza, Vol .14, Pages 354-360 (edited by the Chemical Society Japan (corporate juridical person), 1977).

(1) In the method (1), the solvents used are not strictly limited, unless they have a detrimental effect on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane, 1,1,2-trichlorotrifluoroethane and the like; ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol and the like; nitriles such as acetonitrile and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid and the like; inorganic acids such as hydrofluoric acid, sulfuric acid and the like; water etc. These solvents may be used as such or in the form of two or more solvents.

The electrophilic fluorinating reagents that are used in this reaction are not strictly limited if they are usually used for the reaction of attachment of fluorine atoms to carbon-carbon multiple bonds. Preferred examples of such reagents include fluorine gas, trifluoromethylhypofluorite, acetyl hypofluorite, difluoroxenone, perchloric acid fluoride, cesium sulfate fluorite, N-fluoropyridinium triflate, N-fluoro-N-alkyl-alkylene sulfonamide (N-fluorosaccharino-fluorosulfonamide), benzenesulfone) imide and N-fluoro-O-benzenedisulfonimide. Of these electrophilic fluorinating reagents, gaseous fluorine is preferred. The electrophilic fluorinating reagent is used in an amount of 0.05-50 mol and preferably 0.1-20 mol per mol of the compound of formula [3o] or its salt.

The additive, which if necessary can be used in this reaction, is not strictly limited, if it is usually used in electrophilic fluorination reactions. Preferred examples of such additives include acid catalysts such as boron trifluoride, hydrofluoric acid and the like; organic and inorganic bases such as triethylamine, sodium fluoride and the like; and halogens such as chlorine, bromine, iodine and the like. These additives can be used as such or as a mixture of two or more additives. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1-10 mol per mol of the compound of formula [3o] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 170 ° C. And preferably at a temperature of from -80 to 100 ° C for a time of from one minute 72 hours and preferably from 5 minutes to 48 hours.

(2) In the method (2), the solvents used are not strictly limited, unless they have a detrimental effect on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane, 1,1,2-trichlorotrifluoroethane and the like; ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol and the like; nitriles such as acetonitrile and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid and the like; inorganic acids such as sulfuric acid and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The halogenating reagents that are used in this reaction are not strictly limited if they are usually used to halogenate aromatic compounds. Preferred examples of such reagents include bromine, chlorine, sulfuryl chloride, N-bromosuccinimide, N-chlorosuccinimide and the like. The halogenating reagent is used in an amount of 0.05-50 mol and preferably 0.1-20 mol per mol of the compound of formula [3o] or its salt.

Additives that are used if necessary in this reaction are not strictly limited, if they are usually used for halogenation of aromatic compounds. Preferred examples of additives include sodium bromide, lead tetraacetate, titanium (IV) chloride, aluminum chloride, silver sulfate and the like. These additives can be used as such or as a mixture of two or more additives. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1-10 mol per mol of the compound of formula [3o] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 170 ° C. And preferably at a temperature of from -80 to 100 ° C for a time of from one minute 72 hours and preferably from 5 minutes to 48 hours.

In the above methods for producing compounds, all compounds can be used in the form of their salts. As the indicated salt, the same salts may be used as described in the paragraph on the salt of the compound of the general formula [1]. If desired, these reactions can be carried out in an atmosphere of inert gas, such as nitrogen. The compound of the general formula [1] or its salt, which were obtained by the aforementioned method, can be converted into other compounds of the general formula [1] or their salts by carrying out known reactions such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration, hydrolysis and similar, or the implementation of an appropriate combination of these reactions.

Some compounds referenced in the above preparation methods may have isomers, such as optical isomers, geometric isomers, tautomers, etc. In such cases, these isomers are also used in the present invention, and solvated products, hydrates and various crystalline forms are also used. After completion of the reaction, the target compound can be used in the next reaction step without isolation, if desired.

Some compounds referred to in the above methods for their preparation may have an amino group, a hydroxyl group or a carboxyl group. If desired, it is possible to pre-protect said groups with a conventional protecting group and, after the reaction has ended, remove the protecting group in a manner well known per se.

A compound of the general formula [1] or a salt thereof can be isolated, purified or recrystallized by conventional methods such as extraction, crystallization and / or column chromatography, etc.

The compound of the present invention is formulated with various pharmaceutical additives, such as an inert filler, a binding agent, a disintegrant, an anti-disintegrating agent, a release agent and a non-sticking agent, a lubricating agent, an absorption adsorption carrier, a solvent, a filler, an isotonic agent, an dissolution promoting agent , emulsifier, suspending agent, thickener, coating agent, absorption promoter, gelation-coagulation promoter, light stabilizer , preservative, moisture insulating agent, emulsion-suspension-dispersion stabilizer, color protector, deoxygenation-oxidation inhibiting agent, sweetening-flavoring agent, colorant, blowing agent, anti-foaming agent, painkiller, antistatic, buffering agent, pH adjusting agent, etc. ., and form in a pharmaceutical composition, such as an oral composition (tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, solution, syrup, etc.), injection, suppository, external composition (ointment , adhesive, etc.), aerosol, etc.

Based on the above compositions, pharmaceutical formulations are prepared according to conventional methods.

Solid preparations for oral administration, such as a tablet, powder, granule and the like, are prepared according to the usual method together with pharmaceutical additives intended for solid preparations, including excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin crystalline cellulose, anhydrous secondary acidic calcium phosphate, partially pregelatinized starch, corn starch, alginic acid and the like; binding agents such as syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, sodium alginate, gum arabic, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, ethanol, cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, ethanol, cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, ethanol; disintegrants such as dry starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, starch glycolic acid sodium salt and the like; disintegration inhibitors such as stearyl alcohol, stearic acid, cocoa butter, hydrogenated oil and the like; anti-adhesive and anti-sticking agents such as aluminum silicate, calcium hydrogen phosphate secondary, magnesium oxide, talc, silicic anhydride and the like; lubricating agents such as carnauba wax, volatile silicic anhydride, aluminum silicate, magnesium silicate, hydrogenated oil, derivatives of hydrogenated vegetable oil, sesame oil, white wax, titanium oxide, dry aluminum hydroxide gel, stearic acid, calcium stearate, magnesium stearate, talc , secondary acidic calcium phosphate, sodium lauryl sulfate, polyethylene glycol and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, urea, enzymes and the like; absorption-adsorption carriers such as starch, lactose, kaolin, bentonite, silicic anhydride, hydrated silicon dioxide, magnesium metasilicate-aluminate, colloidal silicic acid and the like, etc.

In addition, if desired, the tablet can be made in the form of conventional coated tablets, such as a sugar-coated tablet, a gelatin-coated tablet, a stomach-soluble tablet, an enteric-coated tablet, or a water-soluble film-coated tablet.

A capsule is prepared by mixing together the aforementioned pharmaceutical ingredients and filling the resulting mixture with a hard gelatin capsule, soft capsule, etc.

In addition, an aqueous or oily suspension, solution, syrup and elixir can be prepared by forming a pharmaceutical composition together with the aforementioned additives for the preparation of a liquid preparation, such as a solvent, excipient, isotonic agent, emulsifier, suspension stabilizer, thickener, etc. ., in the form of a liquid preparation according to the usual method.

A suppository can be prepared by adding an appropriate absorption promoter to polyethylene glycol, cocoa butter, lanolin, higher alcohol, higher hydroxy acid ester, gelatin, semi-synthetic glyceride, Witepsol or the like, and mixing these ingredients together with the pharmaceutical composition to form a suppository.

An injection form is prepared by mixing the pharmaceutical composition with pharmaceutical additives for the manufacture of a liquid preparation, including diluents such as water, ethyl alcohol, Macrogol, polyethylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, sodium hydroxide and the like; pH adjusting agents and buffering agents such as sodium citrate, sodium acetate, sodium phosphate and the like; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like; isotonic agents such as sodium chloride, glucose, mannitol, glycerin and the like; dissolution promoting agents such as sodium carboxymethyl cellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin and the like; a painkiller such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol and the like; local anesthetics; etc., with the formation of a mixture in the form of an injection solution according to the usual method.

An ointment in the form of a paste, cream or gel can be prepared by forming a pharmaceutical composition with a base, such as white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like; preservatives such as paraoxybenzoic acid methyl ester, paraoxybenzoic acid ethyl ester, paraoxybenzoic acid propyl ester and the like; stabilizers; wetting agents, etc., to form a mixture in the form of an ointment according to the usual method.

The patch can be made using the aforementioned ointment, cream, gel, or paste applied to a conventional substrate according to a conventional method. As the substrate, you can use textile and non-textile fabrics and films or foam plates made of soft vinyl chloride, polyethylene, polyurethane and the like.

The method of administration of the aforementioned pharmaceutical composition is not limited to any particular one and can, in fact, be determined in accordance with the form of the drug, age, gender and other conditions of the patient, as well as according to the severity of the symptoms of the patient.

The dose of the active ingredient of the pharmaceutical composition according to the present invention is essentially determined based on the method of application of the composition, the age and sex of the patient, the type of disease and other conditions. Typically, a dose based on the active ingredient of 0.1-100 mg / kg / day for an adult individual can be administered in the composition, either as a single dose or as several parts of a dose.

Next will be described a method of obtaining derivatives of fluoropyrazine or its salts, which are intermediate compounds according to the present invention.

wherein R ²¹ is as defined above; R ^22a represents a hydrogen atom, a halogen atom, a nitro group, a protected amino group, a protected hydroxyl group or a substituted or unsubstituted phenylsulfanyl, phenylsulfinyl or phenylsulfonyl group; and X represents a halogen atom other than a fluorine atom; with the proviso that a compound wherein R ²¹ is a hydrogen atom and R ^22a is a hydrogen atom is excluded.

A compound of the general formula [24] or its salt can be prepared by reacting a compound of the general formula [25] or its salt with a fluorinating agent in the presence or absence of an additive according to the method described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 321 -322 (edited by the Chemical Society of Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfones such as sulfolane, dimethyl sulfone and the like; nitrogen-containing heterocyclic compounds such as challidine and the like, etc. The listed solvents may be used as a mixture, if desired.

As the fluorinating reagent used in this reaction, alkali metal fluorides such as cesium fluoride, rubidium fluoride, potassium fluoride, sodium fluoride, lithium fluoride and the like are used; alkaline earth metal fluorides such as calcium fluoride and the like; other metal fluorides such as zinc fluoride, silver fluoride and the like; hydrogen fluoride; ammonium salts such as fluorinated tetrabutylammonium fluoride and the like; phosphonium salts; and their hydrogen fluoride complexes. The listed reagents can be used as a mixture, if desired. Although the amount of fluorinating reagent used in this reaction varies depending on the type of such reagent, however, the amount of fluorinating reagent may be at least an equimolar amount with respect to the compound of general formula [25] or its salt, and preferably 1.0-20 mol and also preferably 1.0-10 mol per mol of the compound of formula [25] or its salt.

An additive which can be used if necessary in the above reaction can include, for example, quaternary ammonium salts such as tetra-n-butylammonium bromide, tetramethylammonium chloride, tetramethylammonium fluoride and the like; phosphonium quaternary salts such as tetraphenylphosphonium bromide and the like; polyethers such as 18-crown-6- (simple) ether, polyethylene glycol and the like, etc. These additives can be used as a mixture, if desired. Although the amount of the additive varies depending on the type of additive, the amount of such an additive is 0.01-2.0 mol and preferably 0.1-1.0 mol per mol of the compound of formula [25] or its salt.

The specified reaction is carried out in an atmosphere of nitrogen, if desired. This reaction is usually carried out at a temperature of 0-300 ° C. And preferably at a temperature of 20-200 ° C for a time from 10 minutes to 24 hours.

A compound of the general formula [25] or a salt thereof used as a starting compound for the above reaction can be prepared by a well-known method, namely as described in the literature [J. Med. Chem., Vol. 27, Pages 1634-1639 (1984); or Acta Poloniae Pharmaceutica, Vol. 33, Pages 153-161 (1976)].

where R ^21a represents a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl, aminomethyl, carbamoyl or carboxyl group, a methyl group substituted by a protected or unprotected mercapto group, a halogenmethyl group, a formyl group or a nitrile group, and R ^22b represents a protected hydroxy group or or a halogen atom.

A compound of general formula [26] or its salt can be obtained by deamination of the amino group of a compound of general formula [27] or its salt with a diazotizing agent in the presence of acid, in the presence or absence of an additive, and then fluorinating the product according to the method described in Fusso no Kagaku Nyumon, Pages 219-230 (edited by Nippon Gakujutsu Shinkokai, Fluorine Chemistry No. 155 Committee, 1997).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine, pyridine-N-oxide and the like; ketones such as acetone and the like; water etc. The listed solvents may be used as a mixture, if desired.

The diazotizing agent used in this reaction may be any diazotizing agent that is commonly used to diazotize aromatic amino compounds. Preferred examples of such agents include alkali metal nitrites such as sodium nitrite and the like. The diazotizing agent is used at least in an equimolar amount, preferably 1.0-5.0 mol, and, in addition, preferably 1.0-1.5 mol per mol of the compound of the general formula [27] or its salt.

The acid used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of the acid include acids such as hydrochloric acid, hydrofluoric acid, hydrogen fluoride and the like; as well as a mixed solution of hydrogen fluoride in a basic substance, such as a solution of hydrogen fluoride in pyridine; etc. These acids and solutions may be used as a mixture, if desired. Acids can be used as a solvent as they are.

The amount of acid used in this reaction, which is determined based on the volume / weight ratio (ml / g), is at least 1 ml and preferably 1-50 ml per gram of the compound of the general formula [27] or its salt.

The additive used in this reaction may include hydrofluoric acid, sodium tetrafluoride, ammonium borofluoride and the like. The amount of the additive is at least an equimolar amount and preferably 1.0 to 20.0 mol per mol of the compound of formula [27] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 100 ° C and preferably from -60 to 30 ° C for a time from 30 minutes to 24 hours and preferably from 1 hour to 10 hours.

wherein R ^21e represents a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl, aminomethyl, carbamoyl or carboxyl group, a methyl group substituted by a protected or unprotected mercapto group, a halogenomethyl group, a formyl group or a nitrile group or a halogenated carbonyl group, and R ^22e represents a protected or unprotected hydroxyl group or amino group, a halogen atom, a nitro group or an azido group.

A compound of general formula [21] or a salt thereof can be prepared by reacting a compound of general formula [28] or its salt with an electrophilic fluorinating agent in the presence or absence of an additive, and in more detail, as described, for example, Fusso no Kagaku, Pages 28-37 (edited by Kodansha Scientific, 1993).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane, 1,1,2-trichlorotrifluoroethane and the like; ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol and the like; nitriles such as acetonitrile and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid and the like; inorganic acids such as hydrogen fluoride, sulfuric acid and the like; water etc. The listed solvents may be used as such or as a mixture of two or more solvents.

The electrophilic fluorinating reagent that is used in this reaction is not strictly limited, if it is usually used to attach fluorine atoms to carbon-carbon multiple bonds. Preferred examples of such agents include fluorine gas, trifluoromethylhypofluorite, acetyl hypofluorite, difluoroxenone, perchloric acid fluoride, cesium sulfate fluorite, N-fluoropyridinium triflate, N-fluoro-N-alkylalkylene sulfonamide (N-fluorosaccharinsulfonodisulfonamide (N-fluorosaccharinsulfonodisulfonamide (NF) benzenesulfone) imide and N-fluoro-O-benzenedisulfonimide, and fluorine gas is also a preferred example. The electrophilic fluorinating reagent is used in an amount of 0.05-50 mol and preferably 0.1-20 mol per mol of the compound of the general formula [28] or its salt.

The additive, which, if necessary, can be used in this invention, is not strictly limited, if it is an agent that is usually used in electrophilic fluorination reactions. Preferred examples of such additives include acid catalysts such as boron trifluoride, hydrogen fluoride and the like; organic and inorganic bases such as triethylamine, sodium fluoride and the like; and halogens such as chlorine, bromine, iodine and the like. These additives can be used as such or as a mixture of two or more additives. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1-10 mol per mol of the compound of general formula [28] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 170 ° C. And preferably at a temperature of from -80 to 100 ° C for a time of from one minute 72 hours and preferably from 5 minutes to 48 hours.

A compound of the general formula [28] or a salt thereof, used as starting material for the above reaction, can be prepared by a well-known method, namely, according to the method described in JP-A-53-119882.

where R ²¹ is as defined above, R ^22c represents a halogen atom and R ^22f represents a protected amino group.

(4-1)

A compound of general formula [21d] or a salt thereof can be prepared by reacting a compound of general formula [21a] or a salt thereof with a reducing agent in the presence or absence of a catalyst as described, for example, by Shin Jikken Kagaku Koza, Vol.14, Pages 1333-1335 ( edited by the Chemical Society of Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; organic acids such as acetic acid and the like; amines such as hydrazine and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The reducing reagent that is used in this invention is not strictly limited if it is an agent that is usually used to reduce the nitro group of aromatic nitro compounds. Preferred examples of such agents include sodium amide, lithium amide, zinc, aluminum-nickel, tin, tin (II) chloride, iron, sodium borohydride, cyclohexane, hydrogen gas, etc. The reducing reagent is used in an amount of 0.01-100 mol and preferably 0.01-30 mol per mol of the compound of formula [21a] or its salt.

As a catalyst, which can be used if necessary in said reaction, for example, inorganic acids such as hydrochloric acid, sulfuric acid and the like are used; Lewis acids such as nickel (II) chloride, tin (II) chloride and the like; metal salts such as copper (II) bis (acetylacetonate) and the like; palladium catalysts such as palladium on carbon, lead etched palladium calcium carbonate and the like; rhodium; Raney nickel; platinum (IV) oxide, etc. Palladium catalysts and Raney nickel are used in an amount of 0.01-100 parts by weight and preferably 0.1-10 parts by weight per part by weight of a compound of formula [21a] or a salt thereof. Other catalysts other than the palladium catalyst and Raney nickel are used in an amount of 0.01-10 mol and preferably 0.01-5.0 mol per mol of the compound of formula [21a] or its salt.

The specified reaction is usually carried out at a temperature of from -78 to 250 ° C. And preferably at a temperature of from -50 to 150 ° C for a time of from one minute 72 hours and preferably from 30 minutes to 24 hours.

(4-2)

A compound of general formula [21d] or its salt can be prepared by reacting a compound of general formula [21b] or its salt with a reducing agent in the presence or absence of a catalyst by the method described in Shin Jikken Kagaku Koza, Vol.14, edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; organic acids such as acetic acid and the like; amines such as hydrazine and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The reducing reagent that is used in this invention is not strictly limited if it is a reagent that is usually used to reduce the azido group in aromatic azide-containing compounds. Preferred examples of such reagents include zinc, chromium (II) chloride, tributyltin hydride, lithium aluminum hydride, hydrogen gas and the like. The reducing reagent is used in an amount of 0.01-100 mol and preferably 0.01-30 mol per mol of the compound of general formula [21b] or its salt.

The catalyst used in this reaction may include, for example, inorganic acids such as hydrochloric acid, sulfuric acid and the like; palladium on carbon, lead etched with palladium-calcium carbonate, platinum oxide (IV) and the like. The catalyst is used in an amount of 0.01-10 mol and preferably 0.01-5.0 mol per mol of the compound of formula [21b] or its salt. For example, when a palladium catalyst or Raney nickel is used, the amount of catalyst may be 0.01-10 parts by weight and preferably 0.1-5.0 parts by weight per part by weight of a compound of formula [21b] or a salt thereof.

The specified reaction is usually carried out at a temperature of from -78 to 250 ° C. And preferably at a temperature of from -50 to 150 ° C for a time of from one minute 72 hours and preferably from 30 minutes to 24 hours.

(4-3)

A compound of general formula [21d] or a salt thereof can be prepared by reacting a compound of general formula [21c] or its salt with an aminating agent in the presence or absence of a copper catalyst by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 1342-1351 ( edited by the Chemical Society of Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; esters such as ethyl acetate and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The amination reagent used in this reaction is not strictly limited if it is a reagent that is usually used for amination by nucleophilic substitution of aromatic halogen compounds. Preferred examples of such reagents include gaseous ammonia; aqueous ammonia; alkali metal amides such as sodium amide and the like; and ammonium salts such as ammonium carbonate and the like. The amination reagent is used at least in an equimolar amount and preferably in an amount of 2.0-30 mol per mol of the compound of the formula [21 s] or its salt.

The copper catalyst used in this reaction may include, for example, copper powder, copper (I) chloride and the like. The copper catalyst is used in an amount of 0.01-30 mol and preferably 0.05-2 mol per mol of the compound of formula [21c] or its salt.

The specified reaction is usually carried out at a temperature of 0-250 ° C. And preferably at a temperature of 0-40 ° C for a period of from one minute to 96 hours and preferably from 30 minutes to 7 hours.

(4-4)

A compound of the general formula [21b] or its salt can be prepared by reacting a compound of the general formula [21c] or its salt with an azide reagent by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 1659-1666 (edited by Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; esters such as ethyl acetate and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The reagent used in this reaction, which promotes the formation of azide, is not strictly limited, if it is an agent that is usually used in reactions with the formation of azide by nucleophilic substitution of aromatic halogen compounds. Preferred examples of such reagents include sodium azide and the like. The azide forming reagent is used at least in an equimolar amount, and preferably in an amount of 1.0-30 mol, and also preferably 1.0-1.5 mol per mol of the compound of formula [21c] or its salt.

The specified reaction is usually carried out at a temperature of 0-250 ° C. And preferably at a temperature of 0-40 ° C for a time from one minute to 96 hours and preferably from 5 minutes to 6 hours.

(4-5)

A compound of the general formula [21d] or its salt can be prepared by reacting a compound of the general formula [21t] or its salt with a reagent to remove a protective group in the presence or absence of a catalyst in the usual manner, namely, according to the method described in Theodora W. Greene : PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Third Edition, Pages 494-653 (edited by John Wiley & Sons, Inc., 1999).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include water; alcohols such as methanol, ethanol, propanol and the like; thioalcohols such as ethanethiol, thiophenol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; thioethers such as dimethyl sulfide and the like; ketones such as acetone and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, trifluoroacetic acid and the like; sulfonic acids such as trifluoromethanesulfonic acid and the like; nitroalkanes such as nitromethane and the like; organic bases such as pyridine, triethylamine and the like, etc. These solvents may be used as such or as a mixture of two or more solvents.

The deprotecting reagent that is used in this reaction is not strictly limited if it is the reagent that is usually used to deprotect the protected amino groups. Preferred examples of such reagents include hydrogen gas; ammonium formate; zinc; sodium; acid chlorides such as vinyl chloroformate, acetic acid chloride and the like; organosilicon compounds such as triethylsilane, trimethylsilyl iodide and the like; tributyltin hydride; alkali metal alkoxides such as potassium tert-butoxide and the like; alkali metal thioalkoxides such as sodium thiomethoxide and the like; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; sodium borohydride; alkali metal salts such as potassium fluoride, sodium iodide and the like; Lewis acids such as boron trifluoride, aluminum chloride, ruthenium chloride, zinc chloride and the like; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; organic acids such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like; inorganic bases such as potassium carbonate, sodium bicarbonate, sodium hydroxide and the like; organic bases such as piperidine and the like; amines such as ammonia, hydrazine and the like; lithium-containing organic compounds such as methyl lithium and the like; cerium diammonium nitrate; peroxides such as hydrogen peroxide, ozone, manganese acid and the like; etc. The deprotecting agent is used in an amount of 0.01-1000 mol and preferably 0.1-100 mol per mol of the compound of formula [21t] or its salt.

The catalyst, which is used if necessary in this reaction, is not strictly limited, if it is usually used to deprotect protected amino groups. Preferred examples of such catalysts include palladium catalysts such as palladium on carbon and the like; rhodium, Raney nickel, platinum (IV) oxide and the like. For example, palladium on carbon and Raney nickel are used in an amount of 0.01-10 parts by weight and preferably 0.01-5 parts by weight per part by weight of a compound of formula [21t] or a salt thereof. Other catalysts other than palladium on carbon and Raney nickel are used in an amount of 0.01-10 mol and preferably 0.01-5 mol per mol of the compound of formula [21t] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 200 ° C and preferably at a temperature of from 0 to 160 ° C for a time of from one minute to 48 hours and preferably from 5 minutes to 12 hours.

where R ^22c is as defined above; R ^21b represents a hydrogen atom, a methyl group, a protected or unprotected hydroxymethyl, aminomethyl or carboxyl group, a methyl group substituted by a protected or unprotected mercapto group, a halogenated methyl group, a formyl group, a protected carbamoyl group, a nitrile group or a halogenated R ²⁵ carbonyl group represents a protective group for a hydroxyl group; with the proviso that a compound wherein R ^21b is a carbamoyl group protected by an acyl group is excluded.

(5-1)

A compound of the general formula [21h] or its salt can be prepared by reacting a compound of the general formula [21e] or its salt with a diazotizing agent and a hydroxylating agent in the presence or absence of an additive by the method described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 537-538 (edited by Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of such a solvent include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine-N-oxide and the like; ketones such as acetone and the like; water etc. These solvents may be used as a mixture, if desired.

The diazotizing reagent used in this reaction is not strictly limited if it is usually used for deamination hydroxylation of aromatic amino compounds. Preferred examples of such reagents include alkali metal nitrites such as sodium nitrite and the like. The diazotizing agent is used at least in an equimolar amount, preferably in an amount of 1.0-5.0 mol, and also preferably 1.0-2.0 mol per mol of the compound of formula [21e] or its salt.

The hydroxylating agent used in this reaction may include, for example, water and the like. The hydroxylating agent is used at least in an equimolar amount with respect to the compound of formula [21e] or its salt. You can also use a hydroxylating agent as a solvent.

The additive used in this reaction may include, for example, copper salts such as copper sulfate and the like, and inorganic bases such as sodium hydroxide, sodium carbonate and the like. The additive is used in an amount of 0.01-100 mol and preferably 0.1-50 mol per mol of the compound of the formula [21e] or its salt.

The above reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -50 to 100 ° C for a time of from one minute to 24 hours and preferably from 30 minutes to 10 hours.

(5-2)

A compound of general formula [21h] or its salt can be obtained by hydroxylation of a compound of general formula [21f] or its salt by the method described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 535-536 (edited by Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water etc. Solvents are used as such or as a mixture of two or more solvents.

The hydroxylating reagent that is used in this reaction is not strictly limited if it is a reagent that is usually used for hydroxylation by nucleophilic substitution of aromatic halogen compounds. Preferred examples of such reagents include inorganic and organic bases such as sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate and the like; and inorganic and organic acids, such as hydrochloric acid, phosphoric acid, an aqueous solution of formic acid, and the like. The hydroxylating reagent is used in an amount of at least 0.01 mol and preferably 0.05-20 mol per mol of the compound of formula [21f] or its salt.

The specified reaction is usually carried out at a temperature of from -78 to 180 ° C and preferably at a temperature of from -20 to 100 ° C for a time of from one minute to 96 hours and preferably from 10 minutes to 72 hours.

(5-3)

A compound of the general formula [21g] or its salt can be obtained (1) by reacting a compound of the general formula [21f] or its salt with a nucleophilic substitution reagent in the presence or absence of a copper catalyst by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 570-571 (edited by the Chemical Society of Japan (corporate juridical person), 1977), or (2) reacting a compound of general formula [21f] or a salt thereof with a nucleophilic substitution reagent in the presence of a base.

In the method (1), the solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents can be used as such or as a mixture of two or more solvents.

The nucleophilic substitution reagent that is used in this reaction is not strictly limited if it is used for nucleophilic substitution of aromatic halogen compounds. Preferred examples include C _1-6 lower alkali metal alkoxides such as sodium methoxide and the like; aryl-C _1-6 lower alkoxides of alkali metals such as potassium benzyl oxide and the like; and salts of organic carboxylic acids and alkali metals such as sodium acetate and the like. If desired, said nucleophilic substitution reagents can be synthesized in the reaction system. The nucleophilic substitution reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [21f] or its salt. A copper catalyst, which can be used if necessary, is not strictly limited if it is an agent that is usually used for nucleophilic substitution of aromatic halogen compounds. Preferred examples of such catalysts include copper catalysts such as powdered copper, copper (I) iodide and the like. The copper catalyst is used in an amount of 0.01-30 mol and preferably 0.05-2 mol per mol of the compound of formula [21f] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 200 ° C. And preferably at a temperature of from -20 to 50 ° C for a time of from one minute to 24 hours and preferably from 5 minutes to 6 hours.

In the method (2), the solvents used in this reaction are not strictly limited, unless they have a detrimental effect on the reaction. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like, etc. These solvents can be used as such or as a mixture of two or more solvents.

The nucleophilic substitution reagent that is used in this reaction is not strictly limited if it is used for nucleophilic substitution of aromatic halogen compounds. Preferred examples of such a reagent include C _1-6 lower alcohols, such as methanol, ethanol, isopropyl alcohol, allyl alcohol and the like; aryl-C _1-6 lower alcohols such as benzyl alcohol and the like; substituted phenols such as hydroquinone, p-methoxyphenol and the like; alpha diketones such as 3-methyl-1,2-cyclopentadione and the like; beta diketones such as 2-methyl-1,3-cyclopentanedione and the like; etc. The nucleophilic substitution agent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [21f] or its salt. The base used in this reaction is not strictly limited if it is usually used for nucleophilic substitution of aromatic halogen compounds. Preferred examples of such a base include organic bases such as triethylamine, pyridine and the like; and inorganic bases such as sodium carbonate, potassium carbonate and the like. The base is used in an amount of 0.01-30 mol and preferably 0.5-2 mol per mol of the compound of the general formula [21f] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -20 to 100 ° C for a time of from one minute to 24 hours and preferably from 5 minutes to 6 hours.

(5-4)

A compound of general formula [21h] or its salt can be prepared by reacting a compound of general formula [21g] or its salt with an agent to remove a protective group, in the presence or absence of a catalyst, by the method described, for example, in Theodora W. Greene: PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Third Edition, Pages 75 and 249-287 (edited by John Wiley & Sons, Inc., 1999).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of solvents include alcohols such as methanol, ethanol, propanol and the like; thioalcohols such as ethanethiol, thiophenol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; thioethers such as dimethyl sulfide and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, trifluoroacetic acid and the like; sulfonic acids such as trifluoromethanesulfonic acid and the like; organic bases such as pyridine, triethylamine and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The deprotecting reagent that is used in this reaction is not strictly limited if it is usually used to deprotect protected aromatic alcohols. Preferred examples of such reagents include hydrogen gas; Lewis acids such as aluminum trichloride, boron tribromide, iodine and magnesium complex and the like; inorganic acids such as hydrobromic acid and the like; salts with acids such as pyridine hydrochloride and the like; inorganic bases such as potassium carbonate, sodium bicarbonate, sodium hydroxide and the like, and oxidizing agents such as cerium diammonium nitrate, iron trichloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; etc. The deprotecting agent is used in an amount of 0.01-50 mol and preferably 0.1-30 mol per mol of the compound of formula [21g] or its salt.

The catalyst, which if necessary can be used in this reaction, is not strictly limited, if it is usually used to remove protection from protected aromatic alcohols. Preferred examples of such a catalyst include palladium catalysts such as palladium on carbon and the like; rhodium; Raney nickel; platinum (IV) oxide and the like. Palladium on carbon and Raney nickel are used in an amount of 0.001-10 parts by weight and preferably 0.01-5 parts by weight per part by weight of a compound of the formula [21g] or a salt thereof. Catalysts other than palladium on carbon and Raney nickel are used in an amount of from 0.001-10 mol and preferably 0.01-5 mol per mol of the compound of formula [21g] or its salt.

The specified reaction is usually carried out at a temperature of from -80 to 200 ° C and preferably at a temperature of from 0 to 160 ° C for a time of from one minute to 48 hours and preferably from 5 minutes to 12 hours.

(5-5)

A compound of the general formula [21g] or its salt can be prepared by reacting a compound of the general formula [21e] or its salt with a diazotizing agent and an alcohol or sulfonic acid.

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of such a solvent include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine-N-oxide and the like; ketones such as acetone and the like; alcohols such as methanol, ethanol and the like; water etc. These solvents may be used as a mixture, if desired.

The diazotizing reagent used in this reaction is not strictly limited if it is usually used for diazotization of aromatic amino compounds. Preferred examples of such reagents include alkali metal nitrites such as sodium nitrite and the like. The diazotizing reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [21e] or its salt.

The alcohol used in this reaction may include, for example, methanol and the like. Alcohol is used at least in an equimolar amount with respect to the compound of formula [21e] or its salt. Alcohol can also be used as a solvent, if desired.

Sulfonic acids used in this reaction include methanesulfonic acid, p-toluenesulfonic acid and the like. Sulfonic acid is used, at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [21e] or its salt. Sulfonic acid can also be used as a solvent, if desired.

The above reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -50 to 100 ° C for a time of from one minute to 24 hours and preferably from 30 minutes to 10 hours.

where R ²² is as defined above; R ^21c represents a methyl group, a protected or unprotected hydroxymethyl or aminomethyl group, a methyl group substituted by a protected or unprotected mercapto group, a halogenated methyl group or formyl group; R ²⁶ represents a protective group for a carboxyl group, and R ²⁷ represents a halogen atom.

(6-1)

A compound of the general formula [21j] or its salt can be prepared by reacting a compound of the formula [21i] or its salt with an oxidizing agent in the manner described in Shin Jikken Kagaku Koza, Vol.15, Pages 922-926 (edited by Chemical Society Japan (corporate juridical person ), 1977) or ibid Vol. 14, Pages 1051-1053 (edited by Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not very strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol, propanol and the like; ketones such as acetone and the like; organic bases such as pyridine and the like; organic acids such as acetic acid and the like; inorganic acids such as nitric acid, sulfuric acid and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The oxidizing agent used in this reaction is not very strictly limited if it is usually used as an oxidizing agent for aromatic carboxylic acids. Preferred examples of the oxidizing agent include potassium permanganate, chromium (VI) oxide, sodium dichromate, selenium dioxide, silver oxide, molybdenum (VI) oxide and the like. The oxidizing agent is used in an amount of 0.1-20 mol and preferably 0.5-10 mol per mol of the compound of formula [21i] or its salt.

The specified reaction is usually carried out at a temperature of from -50 to 170 ° C. And preferably at a temperature of 0-150 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 24 hours.

(6-2)

A compound of the general formula [21m] or its salt can be obtained by esterification of a compound of the general formula [21j] or its salt by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 1002-1016 and 1106-1119 (edited by Chemical Society Japan ( corporate juridical person), 1977).

In more detail, acceptable methods are (1) condensation with dehydration with alcohol in the presence or absence of a catalyst or dehydrating reagent, (2) treatment with an alkylating agent, (3) a method comprising reacting an alkali metal salt or an ammonium salt of a compound of the general formula [21j ] with dialkyl sulfate or haloalkyl, (4) a method comprising reacting a compound of general formula [21j] or a salt thereof with a halogenating reagent or the like in the presence or absence of a catalyst to form actively of intermediate such as acid halide [21l] or the like, followed by reaction with an alcohol in the presence or absence of a base, etc.

In the method (1), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; alcohols such as methanol, ethanol, propanol and the like; etc. Solvents can be used as such or as a mixture of two or more solvents.

The catalyst, which if necessary can be used in this reaction, can include, for example, inorganic acids such as hydrochloric acid, sulfuric acid and the like; organic acids such as aromatic sulfonic acids and the like; and Lewis acids such as boron trifluoride etherate and the like. The catalyst is used in an amount of 0.01-20 mol and preferably 0.01-10 mol per mol of the compound of formula [21j] or its salt.

A dehydrating reagent, which may be used if necessary in this reaction, may include, for example, carbodiimides, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide and the like. The dehydrating reagent is used at least in an equimolar amount and preferably in an amount of 1-20 mol per mol of the compound of formula [21j] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C. And preferably at a temperature of 0-180 ° C for a time from 5 minutes to 10 days and preferably from 30 minutes to 6 days.

In the method (2), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene and the like; orthoesters such as triethoxymethane and the like, etc. These solvents may be used as such or as a mixture of two or more solvents.

The alkylating agent used in this reaction may include, for example, diazo compounds such as diazomethane and the like, orthoesters such as triethoxymethane and the like, etc. The alkylating agent is used at least in an equimolar amount and preferably in an amount of 1-20 mol per mol of the compound of formula [21j] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C and preferably at a temperature of 0-180 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 48 hours.

In the method (3), the solvent used in this reaction is not strictly limited, unless the solvent has a harmful effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol, propanol and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide and the like; etc. These solvents may be used as such or as a mixture of two or more solvents.

The alkali metal salts used in this reaction include, for example, sodium salts and potassium salts. Ammonium salts include, for example, organic basic salts such as tetramethylammonium salts and the like. These salts can be obtained in the reaction system, if desired.

The dialkyl sulfate used in this reaction includes, for example, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate and the like. The haloalkyl used in this reaction include, for example, haloalkyls such as methyl iodide, ethyl iodide and the like. Dialkyl sulfate and haloalkyl are used at least in an equimolar amount and preferably in an amount of 1-20 mol per mol of the compound of the general formula [21j] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 250 ° C. And preferably at a temperature of 0-180 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 48 hours.

In the method (4), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone and the like; etc. Solvents can be used as such or as a mixture of two or more solvents. The halogenating agent used in this reaction includes, for example, inorganic halogen compounds such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and the like; oxalic acid halides such as oxalyl chloride, oxalyl bromide and the like; etc. The halogenating reagent is used in the reaction at least in an equimolar amount and preferably in an amount of 1-10 mol per mol of the compound of formula [21j] or its salt.

Catalysts which, if necessary, can be used in the reaction include organic bases such as triethylamine, pyridine and the like; Lewis acids such as zinc chloride and the like; iodine; N, N-dimethylformamide; etc. The catalyst can be used in an amount of 0.001-10 mol and preferably 0.001-0.5 mol per mol of the compound of formula [21j] or its salt.

The base used in this reaction includes organic and inorganic bases, such as pyridine, dimethylaniline, magnesium metal and the like. The base is used at least in an equimolar amount and preferably in an amount of 1-10 mol per mol of the compound of formula [21j] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C and preferably at a temperature of from -10 to 120 ° C for a time of from one minute to 72 hours and preferably from 10 minutes to 24 hours.

(6-3)

A compound of the general formula [21m] or its salt can be prepared by reacting a compound of the general formula [21k] or its salt with an ester in the presence or absence of a catalyst by the method described, for example, in Collect. Czech Chem. Commun., Vol. 54, No. 5, Pages 1306-1310 (1989).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include sulfuric acid, water and the like. These solvents may be used as such or as a mixture of two or more solvents.

The ester used in this reaction may include, for example, esters such as methyl pyruvic acid, ethyl pyruvic acid and the like. The ester is used in an amount of 0.1-10 mol and preferably 0.2-5 mol per mol of the compound of formula [21k] or its salt.

The catalyst, which is optionally used in this reaction, can include, for example, copper sulfate, an aqueous solution of hydrogen peroxide and the like. The catalyst is used in an amount of 0.01-10 mol and preferably 0.1-5 mol per mol of the compound of the formula [21k] or its salt.

The specified reaction is usually carried out at a temperature of from -50 to 150 ° C. And preferably at a temperature of from -20 to 100 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 24 hours.

where R ²⁶ and R ²⁷ are as defined above; and R ^22d represents a protected hydroxyl group, a protected or unprotected amino group, a halogen atom, a nitro group or an azido group.

(7-1)

A compound of the general formula [21q] or its salt can be obtained by amidation of a compound of the general formula [21n] or its salt by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 1106-1119 and 1136-1147 (edited by Chemical Society Japan ( corporate juridical person), 1977).

In more detail, suitable methods include: (1) dehydrating the compound [21n] or its salt with ammonia in the presence or absence of a catalyst or dehydrating reagent, (2) a method comprising reacting a compound of the formula [21n] or its salt with an amidating agent, (3 ) a method comprising reacting a compound of the formula [21n] or a salt thereof with a halogen compound to form an active intermediate, such as an acid halide [21o] or the like, followed by reaction with ammonia, etc.

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide and the like; water etc. Solvents can be used as such or as a mixture of two or more solvents. The catalyst, which is optionally used in reaction (1), can include, for example, activated aluminum, organic acids, such as aromatic sulfonic acids, etc. The catalyst is used in an amount of 0.01-20 mol and preferably 0.1-10 mol per mol of the compound of formula [21n] or its salt. The dehydrating agent used in the reaction (1) may include, for example, carbodiimides, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide and the like. The amidating agent used in reaction (2) may include amidating agents such as, for example, urea and the like. The halogen compound used in reaction (3) may include, for example, halogenating agents such as oxalyl chloride, thionyl chloride and the like. In these reactions, the dehydrating agent, amidating agent and halogen compound are used in at least an equimolar amount and preferably in an amount of 1-20 mol per mol of the compound of the formula [21n] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C and preferably at a temperature of 0-180 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 48 hours.

(7-2)

A compound of the general formula [21q] or its salt can be obtained by ammonolysis of a carboxylic acid ester of a compound of the general formula [21p] or its salt in the presence or absence of a catalyst by the method described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 1147 -1151 (edited by Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water etc. Solvents can be used as such or as a mixture of two or more solvents. Although this reaction can be carried out under standard conditions used for the ammonolysis of aromatic carboxylic acid esters, a method comprising using gaseous ammonia, liquid ammonia or aqueous ammonia is preferred. Ammonium salts of acids such as ammonium chloride and the like can be referred to the catalyst, which is optionally used in this reaction; bases such as sodium methoxide, butyl lithium and the like; alkali metal amides such as sodium amide and the like; etc. The catalyst is used in an amount of 0.01-100 mol and preferably 0.01-20 mol per mol of the compound of formula [21p] or its salt.

The specified reaction is usually carried out at a temperature of from -100 to 250 ° C. And preferably at a temperature of from -78 to 100 ° C for a time of from one minute to 72 hours and preferably from 30 minutes to 50 hours.

(7-3)

A compound of the general formula [21q] or its salt can be obtained by amidation of a compound of the general formula [21r] or its salt either (1) under acidic conditions, (2) under basic conditions in the presence or absence of acid, or (3) under neutral conditions by the method described in Shin Jikken Kagaku Koza, Vol. 14, Pages 1151-1154 (edited by Chemical Society of Japan (corporate juridical person), 1977).

In the method (1), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; inorganic acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid and the like; organic acids such as acetic acid, formic acid and the like; water etc. Solvents can be used as such or as a mixture of two or more solvents.

The acid that is used in this reaction may include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid and the like; Lewis acid saturated organic acids such as hydrogen chloride, hydrogen bromide, boron trifluoride and the like; etc. The acid is used in an amount of 0.1-100 ml and preferably 0.5-50 ml per gram of a compound of the formula [21r] or its salt, expressed in terms of volume / weight (ml / g). If desired, these acids may be used as a solvent.

The specified reaction is usually carried out at a temperature of 0-200 ° C. And preferably at a temperature of 0-160 ° C for a time from one minute to 72 hours and preferably from 5 minutes to 48 hours.

In the method (2), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; esters such as ethyl acetate and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The base used in this reaction is not strictly limited if it is used for carbamoylation of aromatic nitriles. Preferred examples of such a base include alkali metal bases, such as sodium hydroxide and the like, and aqueous amine solutions, such as aqueous ammonia and the like. The base is used in an amount of 0.1-20 mol and preferably 0.5-10 mol per mol of the compound of formula [21r] or its salt.

The peroxy acid that is used in this reaction includes hydrogen peroxide and the like. Peracid is used in an amount of 0.1-20 mol, and preferably 0.5-10 mol, per mol of the compound of formula [21r] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 170 ° C. And preferably at a temperature of 0-160 ° C for a time from one minute to 72 hours and preferably from 5 minutes to 48 hours.

In the method (3), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The reagent used in this reaction is not strictly limited if it is a reagent that is commonly used for carbamoylation of aromatic nitriles. Preferred examples of such a reagent include manganese dioxide and the like. The reagent is used at least in an equimolar amount and preferably in an amount of 1-100 mol per mol of the compound of formula [21r] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 170 ° C. And preferably at a temperature of 0-160 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 48 hours.

(7-4)

A compound of the general formula [21q] or its salt can be prepared by reacting a compound of the general formula [21s] or its salt with an amide in the presence or absence of a catalyst by the method described, for example, in Collect. Czech Chem. Commun., Vol. 54, No. 5, Pages 1306-1310 (1989).

The solvent used in this reaction is not strictly limited, unless it has a detrimental effect on the reaction. Examples of the solvent include sulfuric acid, water, etc. These solvents may be used as such or as a mixture of two or more solvents.

The amide that is used in this reaction may include, for example, formamides and the like. Amide is used in an amount of 0.1-100 mol and preferably 0.2-50 mol per mol of the compound of the general formula [21s] or its salt.

The catalyst, which, if necessary, can be used in this reaction, can include, for example, copper sulfate, an aqueous solution of hydrogen peroxide and the like. The catalyst is used in an amount of 0.01-10 mol and preferably 0.1-5 mol per mol of the compound of the formula [21s] or its salt.

The specified reaction is usually carried out at a temperature of from -50 to 150 ° C. And preferably at a temperature of from -20 to 100 ° C for a time from 5 minutes to 72 hours and preferably from 30 minutes to 24 hours.

где R^22c является таким, как определено выше, и R^21d представляет собой метильную группу, защищенную или незащищенную гидроксиметильную, аминометильную, карбамоильную или карбоксильную группу, метильную группу, замещенную защищенной или незащищенной меркаптогруппой, галогенметильную группу, формильную группу, нитрильную группу или галогенированную карбонильную группу.

where R ^22c is as defined above and R ^21d is 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 halogenmethyl group, a formyl group, a nitrile group or a halogenated group.

(8-1)

A compound of the general formula [21v] or its salt can be prepared by reacting a compound of the general formula [21u] or its salt with an oxidizing agent in the presence or absence of a catalyst by the method described, for example, in Jikken Kagaku Koza, Fourth Edition, Vol.23, (edited by Chemical Society Japan (corporate juridical person), 1991).

The solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; nitriles such as acetonitrile, benzonitrile and the like; organic acids such as acetic acid, trifluoroacetic acid and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The oxidizing agent used in this reaction is not strictly limited, if it is usually used for the oxidation of tertiary amines. Preferred examples of such an oxidizing agent include inorganic peracids such as hydrogen peroxide and the like; organic peracids such as m-chloroperbenzoic acid, peracetic acid, super trifluoroacetic acid and the like; dioxisilanes such as dimethyldioxisilane and the like; peroxides such as potassium peroxodisulfate, sodium peroxoborate and the like; ozone; gaseous oxygen, etc. These oxidizing agents may be synthesized in the reaction system, if desired. The oxidizing agent is used in an amount of 0.01-10 mol and preferably 1.0-5.0 mol per mol of the compound of the formula [21u] or its salt.

The catalyst, which if necessary can be used in this reaction, may include, for example, molybdenum oxide, iron oxide (III) and the like. The catalyst is used in an amount of 0.01-100 parts by weight and preferably 0.1-10 parts by weight per part by weight of a compound of the formula [21u] or a salt thereof.

The specified reaction is usually carried out at a temperature of from -78 to 200 ° C. And preferably at a temperature of 0-150 ° C for a period of time from one minute to 24 hours and preferably from 30 minutes to 8 hours.

(8-2)

A compound of general formula [21w] or a salt thereof can be prepared by reacting a compound of general formula [21v] or a salt thereof with a halogenating agent in the manner described in Heterokan Kagoubutsu no Kagaku, Pages 177-201 (edited by Kodansha Scientific, 1988).

The solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; etc. These solvents may be used as such or as a mixture of two or more solvents.

The reagent used in this reaction is not strictly limited if it is a halogenating agent. Preferred examples of the halogenating reagent include phosphorus oxychloride, thionyl chloride and the like. The halogenating agent is used in an amount of 0.3-100 mol and preferably 1-30 mol per mol of the compound of general formula [21v] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C. And preferably at a temperature of 0-120 ° C for a time from one minute to 24 hours and preferably from 30 minutes to 6 hours.

where R ^21c is as defined above; R ²⁶ represents a substituted or unsubstituted phenyl group, and n is 1 or 2.

A compound of the general formula [21y] or its salt can be prepared by reacting a compound of the general formula [21x] or its salt with an oxidizing agent according to the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 1749-1756 and 1759-1763 (edited by Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ketones such as acetone and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; nitriles such as acetonitrile, benzonitrile and the like; organic acids such as acetic acid, trifluoroacetic acid and the like; organic bases such as pyridine, quinoline and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The oxidizing agent used in this reaction is not strictly limited if it is a reagent that is commonly used for the oxidation of sulfides. Preferred examples of such an oxidizing agent include peroxyacids such as hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like; sodium salt of metaiodic acid, hydroperoxides, ozone, selenium dioxide, chromic acid, nitrogen tetroxide, acyl nitrate, iodine, bromine, N-bromosuccinimide, iodosilbenzene, sulfuryl chloride plus hydrated silica gel, tert-butyl hypochlorite, ruthenium oxide, (ruthenium oxide, . These oxidizing agents may be synthesized in the reaction system, if desired. These oxidizing agents are used in an amount of 0.01-10 mol and preferably 1.0-5.0 mol per mol of the compound of the general formula [21x] or its salt. The specified reaction is usually carried out at a temperature of from -78 to 200 ° C. And preferably at a temperature of 0-150 ° C for a time from one minute to 24 hours and preferably from 30 minutes to 8 hours.

The following describes methods for the synthesis of compounds of General formula [25] and [27] or their salts, which are used in the methods for producing II-1 and II-2.

where R ²¹ , R ^22a , R ^22c and X are as defined above.

(A-1)

A compound of the general formula [25] or its salt can be obtained (1) by deamination of the amino group of a compound of the general formula [29] or its salt with a diazotizing agent in the presence of an additive by the method described in Shin Jikken Kagaku Koza, Vol.14, Pages 383-387 (edited by Chemical Society of Japan (corporate juridical person), 1977), subsequent halogenation of the deamination product, or (2) by reacting a compound of the general formula [29] or its salt with a protective reagent in the presence or absence of an additive by the method described in Theodora W. Greene: PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Third Edition, Pages 503-615 (1999).

In the method (1), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of such a solvent include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine-N-oxide and the like; ketones such as acetone and the like; water etc. These solvents may be used as a mixture, if desired.

The diazotizing reagent used in this reaction is not strictly limited if it is a reagent used for diazotizing aromatic amino compounds. Preferred examples of such a reagent include alkali metal nitrites such as sodium nitrite and the like. The diazotizing agent is used at least in an equimolar amount, preferably in an amount of 1.0-5.0 mol, and also preferably 1.0-2.0 mol per mol of the compound of formula [29] or its salt.

The additive used in this reaction may include, for example, copper salts such as copper chloride, copper bromide and the like; iron salts such as iron chloride, iron bromide and the like, etc. The additive is used in an amount of 0.01-100 mol and preferably 1-50 mol per mol of the compound of the formula [29] or its salt.

The above reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -50 to 100 ° C for a time of from one minute to 24 hours and preferably from 30 minutes to 10 hours.

In the method (2), the solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of such a solvent include alcohols such as methanol, ethanol, propanol and the like; aliphatic hydrocarbons such as n-hexane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; thioethers such as dimethyl sulfide and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; acetals such as N dimethyl acetal, N-dimethylformamide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, trifluoroacetic acid and the like; organic bases such as pyridine, triethylamine and the like; water etc. These solvents may be used as such or as a mixture of two or more solvents.

The protective reagent that is used in this reaction is not strictly limited if it is a reagent commonly used to protect aromatic amino compounds. Preferred examples of such a reagent include organic halogen compounds such as benzoyl chloride, benzyl chloroformate, trityl chloride and the like; organic acid anhydrides such as acetic anhydride, di-tert-butyl dicarbonate and the like; aldehydes such as benzaldehyde and the like; acetals such as N dimethyl acetal, N-dimethylformamide and the like; etc. The protective reagent is used at least in an equimolar amount, and preferably in an amount of 1.0-5.0 mol, and also preferably 1.0-3.0 mol per mol of the compound of formula [29] or its salt, unless the protective the reagent is used as a solvent, as is the case with N, N-dimethylformamide dimethyl acetal.

The additive used in this reaction may include, for example, inorganic bases such as sodium bicarbonate, sodium hydride, sodium hydroxide and the like; carboxylic acid salts such as sodium acetate and the like; organic bases such as pyridine, triethylamine and the like; lithium-containing organic compounds such as n-butyllithium and the like; organosilicon compounds such as trimethylsilyl chloride and the like; alkali metal salts such as sodium sulfate and the like; ortho acids such as ethyl orthoformate and the like; organic acids such as acetic acid, p-toluenesulfonic acid, N-hydroxysuccinimide and the like; inorganic acids such as hydrochloric acid, hydrofluoric acid and the like; alkali metals such as sodium and the like; carbodiimides, such as N, N'-dicyclohexylcarbodiimide and the like; N, N'-carbonyldiimidazole and the like; crown (ether) ethers such as 18-crown-6 and the like; ammonium salts such as tetra-n-butylammonium iodide and the like; copper salts such as copper chloride and the like; palladium salts such as palladium chloride and the like; etc. The additive is used in an amount of 0.01-100 mol and preferably 1-50 mol per mol of the compound of the formula [29] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 200 ° C and preferably at a temperature of from -50 to 160 ° C for a time of from one minute to 24 hours and preferably from 10 minutes to 10 hours.

The compound of the general formula [29] or its salt, which are the starting material for the above reaction, can be obtained by the method described, for example, in J. Med. Chem., Vol. 8, Pages 638-642 (1965).

(A-2)

A compound of general formula [25] or a salt thereof can be prepared by halogenating a compound of general formula [30] in the presence or absence of an additive.

The solvent used in this reaction is not strictly limited, unless the solvent has a deleterious effect on the reaction. Examples of such a solvent include aromatic hydrocarbons such as toluene and the like; ethers such as tetrahydrofuran and the like; etc. These solvents may be used as a mixture, if desired.

The halogenating reagent that is used in this reaction is not strictly limited if it is a conventional halogenating agent. Examples of such a reagent include phosphorus halides such as phosphorus oxychloride, phosphorus bromide, phosphorus pentachloride, dichlorotriphenylphosphorane and the like; compounds having a halide ion such as phosgene, thioniochloride, benzenesulfonyl chloride and the like; etc. If desired, these agents may be used as a mixture. Although the amount of halogenating reagent varies depending on the type of halogenating reagent, it is used at least in an equimolar amount with respect to the compound of general formula [30] or its salt. If desired, a halogenating reagent can be used as a solvent. For example, when phosphorus oxychloride is used, it can be used as a solvent and its amount can be 2.0-100 mol and preferably 2.0-30 mol per mol of the compound of formula [30] or its salt.

The additive, which, if necessary, is used in this reaction, may include, for example, bases such as pyridine, N, N-diethylaniline and the like. Although the amount of the additive varies depending on the type of additive, it can be used in an amount of 0.1-30 mol and preferably 1.0-10 mol per mol of the compound of formula [30] or its salt.

The specified reaction is carried out at a temperature of 0-300 ° C. And preferably at a temperature of 20-120 ° C for a time from 30 minutes to 48 hours and preferably from one hour to 24 hours.

A compound of the general formula [30] or its salt can be prepared by reacting a compound of the general formula [3l] or its salt with a nitrating agent according to the method described, for example, in Shin Jikken Kagaku Koza, Vol.14 (III), Pages 1266-1277 (edited by Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of such a solvent include inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid and the like; aliphatic carboxylic acids such as acetic acid and the like and acid anhydrides; ethers such as diethyl ether and the like; halogenated hydrocarbons such as methylene chloride and the like; water etc. These solvents may be used as a mixture, if desired. The nitrating agent used in this reaction may include, for example, inorganic acids such as nitric acid; alkali metal nitrates such as potassium nitrate and the like; nitronium salts such as nitronium tetrafluoroborate, nitronium trifluoromethanesulfonate and the like; etc. These agents may be used as a mixture, if desired.

Although the amount of nitrating reagent used in this reaction varies depending on the type of nitrating reagent, it can be used in at least an equimolar amount with respect to the compound of the general formula [3l] or its salt, and preferably in an amount of 1.0- 10 mol and also preferably 1.0 to 3.0 mol per mol of the compound of the formula [3l] or a salt thereof.

The specified reaction is usually carried out at a temperature of from -60 to 200 ° C. And preferably at a temperature of 0-100 ° C for a time from 10 minutes to 48 hours and preferably from one hour to 24 hours.

(A-3)

A compound of general formula [25] or a salt thereof can be prepared by reacting a compound of general formula [34] or a salt thereof with a halogenating agent in the presence or absence of a catalyst in the manner described, for example, in Shin Jikken Kagaku Koza, Vol.14, Pages 1106- 1119 (edited by Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone and the like; etc. These solvents may be used as such or as a mixture of two or more solvents.

The halogenating reagent that is used in this reaction is not strictly limited if it is a common halogenating reagent. Examples of such a reagent include inorganic halogen compounds such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and the like; oxalic acid halides such as oxalyl chloride, oxalyl bromide and the like; etc. The halogenating reagent is used at least in an equimolar amount and preferably in an amount of 1-10 mol per mol of the compound of formula [34] or its salt.

The catalyst used in this reaction may include, for example, organic bases such as triethylamine, pyridine and the like; Lewis acids such as zinc chloride and the like; iodine; N, N-dimethylformamide; etc. The catalyst is used in an amount of 0.001-10 mol and preferably 0.001-0.5 mol per mol of the compound of formula [34] or its salt.

The specified reaction is usually carried out at a temperature of from -20 to 200 ° C and preferably at a temperature of from -10 to 120 ° C for a time of from one minute to 72 hours and preferably from 10 minutes to 24 hours.

(A-4)

A compound of general formula [25] or a salt thereof can be prepared by reacting a compound of general formula [35] or a salt thereof with a nucleophilic substitution agent in the presence of a base.

The solvent used in this reaction is not strictly limited, unless the solvent has a detrimental effect on the reaction. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used as such or as a mixture of two or more solvents.

The nucleophilic substitution reagent that is used in this reaction is not strictly limited if it is a reagent commonly used for nucleophilic substitution of aromatic halogen compounds. Preferred examples of such a reagent include substituted phenols such as hydroquinone, p-methoxyphenol and the like; aryl mercaptans such as thiophenol and the like, etc. The nucleophilic substitution reagent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [35] or its salt. The base used in this reaction is not strictly limited if it is a reagent that is usually used in nucleophilic substitution reactions of aromatic halogen compounds. Examples of such a base include organic bases such as triethylamine, pyridine and the like; and inorganic bases such as sodium carbonate, potassium carbonate and the like. The base is used in an amount of 0.01-30 mol and preferably 0.5-2 mol per mol of the compound of the formula [35] or its salt.

The specified reaction is usually carried out at a temperature of from -70 to 200 ° C. And preferably at a temperature of from -20 to 50 ° C for a time of from one minute to 24 hours and preferably from 5 minutes to 6 hours.

where R ^21a and R ^22b are as defined above.

(IN 1)

A compound of general formula [27] or a salt thereof can be prepared by a reaction using a compound of general formula [32] or a salt thereof, the same as the reaction mentioned in method II-4-1.

(IN 2)

A compound of general formula [32] or a salt thereof can be prepared by a reaction using a compound of general formula [33] or a salt thereof, the same as the reaction mentioned in method II-A-2.

The following describes a process for preparing a compound of general formula [23] using a compound of general formula [21] or a salt thereof as a starting compound.

where A ', R ²¹ , R ²² , R ²³ , R ²⁴ and the broken line are as defined above; with the proviso that a compound wherein R ²¹ is a carbamoyl group or a carbamoyl group substituted with an acyl group and R ²² is a hydroxyl group is excluded.

A compound of the general formula [23] or its salt can be prepared by a hydroxylation reaction and / or a carbamoylation reaction of a compound of the general formula [21] or its salt.

With regard to this synthesis scheme, the hydroxylation of a compound of the formula [21] or its salt can be carried out in a well-known manner, such as reduction, substitution, Sandmeyer reaction, hydrolysis and / or deprotection reaction, etc. mentioned in synthesis methods II -4-1, II-4-2, II-4-3, II-4-4, II-5-1, II-5-1, II-5-3, II-5-4, etc. d. or using an appropriate combination of these methods.

With regard to this synthesis scheme, the carbamoylation of a compound of the formula [21] or its salt can be carried out in a well-known manner, such as oxidation, reduction, substitution, addition, halogenation, dehydration and / or hydrolysis, etc. mentioned in the synthesis methods II-6-1, II-6-2, II-6-3, II-7-1, II-7-2, II-7-3, II-7-4, etc. or using an appropriate combination of these methods.

In cases where both hydroxylation and carbamoylation take place in the indicated synthesis schemes, either hydroxylation or carbamoylation is performed earlier.

The salts of the compounds of general formulas [21] to [35] in the aforementioned methods for the preparation of intermediates include known salts formed by a basic group such as an amino group and salts formed by an acid group such as a hydroxyl group, a carboxyl group and the like. The salts formed by the main group include, for example, salts formed with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts formed with an organic carboxylic acid such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like, and salts formed with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenes. The salts formed by the acid group include, for example, salts formed with an alkali metal such as sodium, potassium and the like; alkaline earth metal salts such as calcium, magnesium and the like; ammonium salts; and salts formed with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethyl -ephenamine, N, N'-dibenzylethylenediamine and the like.

In addition, in the above methods for preparing salts of compounds of general formulas [21] to [35], they can be used instead of compounds of formulas [21] to [35] and the same salts as mentioned above can be used as salts.

In some cases, compounds of the general formulas [21] - [35] and their salts may have isomers, such as tautomers, optical isomers, positional isomers, etc. and solvated products. In such cases, all of these isomers and solvated products may be used in the present invention. After completion of the reaction, the target compound of this reaction can be used in the next step of the method as it is, that is, without isolation.

In particular, for a compound of general formula [21], where R ²² is OH, the following ketoforms and enol forms of tautomers exist, and these tautomers are essentially the same compound.

In the above methods for producing a compound of general formulas [21] to [35] or their salts, they may have an amino group, a carbamoyl group, a hydroxyl group, a mercapto group or a carboxyl group. In such cases, it is possible to pre-protect said groups with a conventional protecting group and, after completion of the reaction, remove the protecting group in a well-known manner.

The following describes the antiviral and cytotoxic activity of pyrazine derivatives represented by the general formula [1] according to the present invention, or their salts.

Sample: a pyrazine derivative represented by the general formula [1] or a salt thereof was dissolved in dimethyl sulfoxide to give a solution with a concentration of 10 mg / ml. At the time of use, the solution was diluted to the desired concentration with the culture medium and used.

Culture medium: minimum maintenance culture medium (E'-MEM) with 10% fetal bovine serum added was used for the growth of MDCK cells (obtained from a dog’s kidney), MA-104 (obtained from a monkey’s kidney) and HEp-2 (obtained from a tumor with human pharyngeal cancer) and to test cytotoxicity.

MDCK cells were used as influenza virus host cells and to check for cytotoxicity. MA-104 cells were used as rotavirus host cells, and HEP-2 cells were used as Rous sarcoma virus host cells.

Test Example 1 [Activity against influenza virus]

MDCK cells were placed in a 6-well plate (manufactured by CORNING) with a density of 5 × 10 ⁵ cells / well and cultured overnight at 35 ° C. under 5% carbon dioxide. The influenza virus (strain A / PR / 8/34) was diluted to 200 PFU / ml with a serum-free culture medium and the cells were infected, the virus was adsorbed at a rate of 0.5 ml / well for one hour. At the end of infection and adsorption, an E'-MEM culture medium was added to the wells containing the test compound at a predetermined concentration along with 0.6% purified agar, 1% bovine serum albumin and 3 μg / ml acetylated trypsin. Upon achieving sufficient coagulation, the plate was turned upside down and cultured for 3 days. At the end of the cultivation, living cells were stained with 1% neutral red, cells were fixed with 10% formalin, the agar medium was removed with running water, and the number of spots was counted. The stain inhibition rate was expressed as a percentage with respect to a control sample containing no test compound.

The results are shown in table I-2, where the presented series of test compounds is the same as in the examples.

Table I-2 Example No. The concentration of the added test compound (μg / ml) Inhibition Rate (%) I-4 one hundred 80 I-8 one hundred 42 I-9 one hundred 31 I-10 one hundred 26 I-12 one hundred 28 I-13 one hundred 39

In addition, the activity against the influenza virus exhibited by nitrogen-containing heterocyclic carbamoyl derivatives represented by the general formula [23], which are derivatives of the compounds of the present invention, or salts of these derivatives, was determined in the same manner as in Test Example 1. As the test compound, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide dissolved in dimethyl sulfoxide to form a solution with a concentration of 10 mg / ml, which was diluted with a culture solution to a certain concentration before use. The results showed that the activity against influenza virus was 100% in the form of the degree of inhibition at a concentration of the test compound of 1 μg / ml, which indicates that this test compound is an excellent antiviral drug.

Test Example 2 [Activity against rotavirus]

MA-104 cells were placed in a 6-well plate (manufactured by CORNING) with a density of 5 × 10 ⁵ cells / well and cultured overnight at 37 ° C. under 5% carbon dioxide. Rotavirus (Ku strain), activated with acetylated trypsin at a concentration of 10 μg / ml for 30 minutes, was diluted to 140 PFU / ml with a serum-free culture medium and the cells were infected, the virus was adsorbed at a rate of 0.5 ml / well for one hour. After completion of infection and adsorption, the infectious medium was removed and an E'-MEM culture medium containing 30 μg / ml of the test compound, 5 μg / ml of trypsin and 1.4% agarose was added. MA-104 cells infected with rotavirus were cultured for 3 days at 37 ° C under 5% carbon dioxide, after which a 0.7% agarose solution containing 0.005% neutral red was layered and continued to be cultured for one day in the same conditions as described above. At the end of the cultivation, the plate was fixed with a 3% formaldehyde solution, the culture medium hardened with agar was removed, and then the number of spots was counted. The rate of inhibition against rotavirus was calculated based on the number of spots in the group of cells treated with the compound and in the untreated group of cells.

Test Example 3 [Activity against RS virus (Routh sarcoma) (respiratory syncytial virus)]

HEP-2 cells were scattered on a 6-well plate (manufactured by CORNING) with a density of 5 × 10 ⁵ cells / well and cultured overnight at 37 ° C. under 5% carbon dioxide. The RS virus (strain A-2) was diluted to 140 PFU / ml with a serum-free culture medium and the cells were infected; the virus was adsorbed at a rate of 0.5 ml / well for one hour. At the end of infection and adsorption, the infectious medium was removed and an E'-MEM culture medium containing 30 μg / ml of the test compound, 0.12% glutamine, 2% fetal bovine serum and 1% methylcellulose was added to the wells. Hep-2 cells infected with the RS virus were cultured for 3 days at 35 ° C. under 5% carbon dioxide. At the end of the cultivation, the plate was fixed with a 3% formaldehyde solution and the culture medium containing methyl cellulose was removed. After this, the plate was stained with 5% Giemza solution and the number of spots was counted. The inhibition rate against RS virus was calculated based on the number of spots in the group of cells treated with the compound and in the untreated group of cells.

As a result, the compound of Example I-14 was shown to be active against the RS virus.

Test Example 4 (Cytotoxic Activity)

A culture medium containing the test compound at a predetermined concentration was added to a 96-well plate (manufactured by CORNING CO.) At a volume of 100 μl / well. Then, a dispersion of MDCK cells having a concentration of 2 × 10 ⁴ cells / ml in a culture medium was prepared, dispersed at a rate of 100 μl / well and cultured for 3 days at 37 ° C under 5% carbon dioxide. At the end of the cultivation, the number of living cells was calculated by the XTT method [for example, CANCER RESEARCH, Vol. 48, Pages 4827-4833 (1988), etc.].

The results showed that the concentration of all compounds listed in table I-2, at which growth inhibition of 50% of the cells (IC ₅₀ ) is observed, is 100 μg / ml or higher.

PREFERRED EMBODIMENTS FOR CARRYING OUT THE INVENTION

The compounds of the present invention and the intermediates of the present invention are described below using reference examples and examples according to the invention. The present invention is in no way limited to these examples.

In the reference examples and examples below, mixed relationships that relate to eluents, all variants in “volumetric relationships”. Silica gel BW-127ZH (manufactured by Fuji Silysia Chemical Co.) was used as a carrier for column chromatography; YMC • GEL ODS-AM 120-S50 (YMC CO., LTD.) was used as a carrier for reverse phase chromatography and DEAE cellulose (manufactured by Wako Pure Chemical Industries) was used as a carrier for ion exchange column chromatography.

The abbreviation used in the reference examples and examples according to the invention has the following meaning:

DMSO-d ₆ : deuterated dimethyl sulfoxide.

Reference Example I-1

17.0 g of methyl 3-amino-6-bromo-2-pyrazinecarboxylate were dissolved in 100 ml of concentrated sulfuric acid. Then, 10.1 g of sodium nitrite was added to the ice-cooled solution and stirred for 30 minutes. The reaction mixture was poured into 920 ml of methanol and heated under reflux for 5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the obtained residue was added to the mixture with 500 ml of ice water and 600 ml of chloroform, and the resulting mixture was separated into layers. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 6.30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was obtained as a pale yellow oily product.

IR (KBr) cm ^-1 : 1735

¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 4.06 (3H, s), 8.37 (1H, s).

Reference Example I-2

In 227 ml of toluene, 11.4 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was dissolved in a stream of nitrogen gas, and 10.3 g of benzophenonimine, 0.42 g of tris (dibenzylideneacetone) dipalladium, 0.86 g (s) were successively added. ) - (-) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and 6.20 g of sodium tert-butoxide. The mixture was stirred at 80 ° C for one hour. After cooling the reaction mixture, it was filtered. The filtrate was purified by column chromatography [eluent - toluene: ethyl acetate = 20: 1]. The resulting oily product was dissolved in 140 ml of tetrahydrofuran, 7 ml of a 2 mol / L hydrochloric acid solution was added, and the mixture was stirred at room temperature for 15 minutes. Then, a mixture of 200 ml of chloroform and 50 ml of water was added to the reaction mixture, and then 1 mol / l of a solution of sodium hydroxide to alkalize the mixture, and the organic layer was separated. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent, toluene: ethyl acetate = 1: 1] to obtain 3.64 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a yellow oily product.

IR (KBr) cm ^-1 : 1716, 1670

¹ H-NMR (DMSO-d ₆ ) δ: 3.80 (3H, s), 3.82 (3H, s), 7.20 (2H, br s), 7.77 (1H, s).

Reference Example I-3

3.5 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate was dissolved in 70 ml of methanol. After feeding ammonia gas into the solution to prepare a saturated solution, the solution was stirred at room temperature for 14 hours. Removal of the solvent from the reaction mixture under reduced pressure afforded 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide as a solid.

IR (KBr) cm ^-1 : 1684

¹ H-NMR (DMSO-d ₆ ) δ: 3.79 (3H, s), 5.87 (2H, br s), 7.30-7.75 (3H, m).

Reference Example I-4

1.50 g of 6-amino-3-methoxy-2-pyrazinecarboxamide was dissolved in 12 ml of a 70% solution of hydrogen fluoride-pyridine in a nitrogen gas atmosphere, while cooling the solution with ice. Then, 0.71 g of sodium nitrite was added at -50 ° C and the resulting mixture was stirred at 10 ° C for one hour. After stirring the reaction mixture for another hour, a mixture of 50 ml of ice water and 100 ml of chloroform was added, and the resulting mixture was separated into layers. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was obtained as a solid.

IR (KBr) cm ^-1 : 1707

¹ H-NMR (DMSO-d ₆ ) δ: 3.95 (3H, s), 7.55-8.15 (2H, m), 8.39 (1H, d, J = 8.3 Hz).

Reference Example I-5

1.51 g of sodium iodide was dissolved in 22 ml of acetonitrile in a nitrogen gas atmosphere. After adding 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 resulting mixture was stirred at the same temperature as described above for 18 hours. The reaction mixture was added to the mixture of 10 ml of water and 200 ml of chloroform, and the resulting mixture was separated into layers. The organic layer was washed successively with a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and 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.

IR (KBr) cm ^-1 : 1685, 1658

¹ H-NMR (CDCl ₃ ) δ: 5.40-7.80 (2H, m), 8.31 (1H, d, J = 7.8 Hz), 12.33 (1H, s).

Reference Example I-6

1.0 g of methyl 6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 40 ml of dichloroethane. Then, 1.0 ml of 1,1,1,3,3,3-hexamethyldisilazane and 0.54 ml of chlorotrimethylsilane in a nitrogen gas atmosphere were successively added to the solution and heated at 90 ° C for 2 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of dichloroethane, then 2.68 g of β-D-ribofuranose-1-acetate-2,3,5-tribenzoate and 1.24 ml of tin (IV) chloride were successively added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was added to 30 ml of ice water and adjusted to pH 8 with saturated aqueous sodium bicarbonate and separated into layers. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography [eluent - hexane: ethyl acetate = 4: 1] to obtain 1.76 g of methyl 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5 - [(benzoyloxy ) methyl] tetrahydro-2-furanyl} -6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a yellow oily product.

IR (neat) cm ^-1 : 1728

¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.5-4.9 (3H, m), 5.6-6.0 (2H, m), 6.3-6 5 (1H, m), 7.1-8.2 (16H, m).

Reference Example I-7

0.80 g of methyl 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5 - [(benzoyloxy) methyl] tetrahydro-2-furanyl} -6-chloro was suspended in 16 ml of methanol -3-oxo-3,4-dihydro-2-pyrazinecarboxylate. The suspension was ice-cooled, and 0.73 g of a 28% methanol solution of sodium methoxide was added at the same time, and the resulting mixture was stirred at the same temperature as described above for one hour. After the mixture was stirred at room temperature for an additional 3 hours, the mixture was adjusted to pH 7 with a solution of 6 mol / L hydrochloric acid, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent - chloroform: methanol = 10: 1] to obtain 0.29 g of methyl 6-chloro-4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a yellow oily product.

IR (neat) cm ^-1 : 1728

¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 3.6-5.6 (11H, m), 5.99 (1H, s), 8.67 (1H, s).

Reference Example I-8

0.39 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 4.0 ml of N, N-dimethylformamide. Then, 90 mg of sodium hydride was added to the solution under a nitrogen gas atmosphere and stirred at room temperature for 2 hours. Then a suspension of 0.50 g of 4 - [(trityloxy) methyl] -2-cyclopenten-1-yl acetate, 0.62 g of tetrakis-triphenylphosphine palladium and 50 mg of triphenylphosphine in 4 ml of tetrahydrofuran was added and the resulting mixture was stirred at room temperature for one hours and then at 60 ° C for 4 hours. The reaction mixture was cooled, diluted with 30 ml of ethyl acetate and 20 ml of water, adjusted to pH 4 with a solution of 1 mol / L hydrochloric acid, and separated into layers. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and 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 obtain 0.23 g of methyl 3-oxo-4- {4 - [(trityloxy) methyl] -2-cyclopenten-1-yl} -3,4 -dihydro-2-pyrazinecarboxylate in the form of an oily product of a light yellow color.

IR (neat) cm ^-1 : 1735

¹ H-NMR (CDCl ₃ ) δ: 1.2-1.6 (2H, m), 2.8-3.4 (3H, m), 3.98 (3H, s), 5.6-5 8 (1H, m), 5.8-6.1 (1H, m), 6.2-6.4 (1H, m), 7.0-7.6 (17H, m).

Reference Example I-9

0.20 g of methyl 3-oxo-4- {4 - [(trityloxy) methyl] -2-cyclopenten-1-yl} -3,4-dihydro-2- was dissolved in 2.0 ml of an 80% aqueous solution of acetic acid. pyrazinecarboxylate and the resulting solution was heated at 80 ° C for one hour. The reaction mixture was cooled and diluted with 10 ml of water, the precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [eluent-ethyl acetate] to obtain 77 mg of methyl 4- [4- (hydroxymethyl) -2-cyclopenten-1-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a light oily product -yellow color.

IR (neat) cm ^-1 : 1738

¹ H-NMR (CDCl ₃ ) δ: 1.4-1.7 (1H, m), 2.2-3.2 (3H, m), 3.5-3.9 (2H, m), 3 96 (3H, s), 5.6-5.8 (1H, m), 5.8-6.1 (1H, m), 6.2-6.5 (1H, m), 7.43 (1H, d, J = 4.2 Hz), 7.70 (1H, d, J = 4.2 Hz).

Reference Example I-10

0.24 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 6.0 ml of N, N-dimethylformamide. After adding 82 mg of 18-crown-6-ether and 62 mg of sodium hydride, the resulting mixture was heated at 80 ° C for one hour. Then, a solution of 0.30 g (4aR, 7R, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl 4-methylbenzenesulfonate in 3.0 ml of N, N-dimethylformamide was added dropwise. and the resulting mixture was heated for 4 hours at 100 ° C. The reaction mixture was cooled, diluted with 50 ml of ethyl acetate and 25 ml of water and separated into layers. Then the aqueous layer was extracted with three portions of 25 ml of ethyl acetate. All organic layers were combined and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography [eluent, toluene: ethyl acetate = 3: 1]. Isopropyl ether and diethyl ether were added to the purified product, and the solid product was collected by filtration. Thus, 84 mg of methyl 4 - [(4aR, 7S, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3-oxo-3,4-dihydro- 2-pyrazinecarboxylate as a white solid.

IR (KBr) cm ^-1 : 1732

¹ H-NMR (DMSO-d ₆ ) δ: 1.97-2.37 (2H, m), 3.22-4.36 (6H, m), 3.95 (3H, s), 5.4 -5.6 (1H, m), 5.67 (1H, s), 7.3-7.5 (5H, m), 8.35 (1H, d, J = 10 Hz), 8.37 ( 1H, d, J = 10 Hz).

Reference Example I-11

0.38 g 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 resulting mixture was heated at 80 ° C for 30 minutes. Then, 0.19 g of (1aS, 3aR, 7aR, 7bS) -6-phenylhexahydro-1,3,5,7-tetraoxacycloprop [a] naphthalene was added and heated at 100 ° C. for an additional 4.5 hours. The reaction mixture was cooled and diluted with 30 ml of ethyl acetate and 20 ml of water, and the resulting mixture was separated into layers. Then the aqueous layer was extracted with 30 ml of ethyl acetate. All organic layers were combined and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography [eluent-toluene: ethyl acetate = 2: 1], isopropyl ether and diethyl ether were added, and the solid product was collected by filtration. Thus, 65 mg of methyl 4 - [[(4aR, 7R, 8S, 8aS) -8-hydroxy-2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3-oxo was obtained -3,4-dihydro-2-pyrazinecarboxylate as a yellow solid.

IR (KBr) cm ^-1 : 3447, 1740

¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, d, J = 2.2 Hz), 3.98 (3H, s), 3.52-4.62 (7H, m), 4, 6-5.0 (1H, m), 5.59 (1H, s), 7.2-7.6 (5H, m), 7.52 (1H, d, J = 4.0 Hz), 8 17 (1H, d, J = 4.0 Hz).

Reference Example I-12

1.52 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate was suspended in 12.2 ml of 1,1,1,3,3,3-hexamethyldisilazane. The resulting suspension was heated under reflux for one hour. The mixture was cooled and the solvent was removed under reduced pressure. The resulting residue was redissolved in 30 ml of dichloroethane in a nitrogen gas atmosphere, 4.98 g of β-D-ribofuranoso-1-acetate-2,3,5-tribenzoate and 1.73 ml of tin (IV) chloride were successively added and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with 30 ml of chloroform and 30 ml of a saturated aqueous solution of sodium bicarbonate, the precipitate was filtered off and the organic layer was taken. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography [eluent, n-hexane: ethyl acetate = 1: 1] to obtain 3.4 g of methyl 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5- [ (benzoyloxy) methyl] tetrahydro-2-furanyl} -3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a white solid.

IR (KBr) cm ^-1 : 1728

¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 4.55-5.00 (3H, m), 5.75-6.00 (2H, m), 6.42 (1H d, J = 3.0 Hz), 7.20-8.20 (17H, m).

Reference Example I-13

Methyl 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5 - [(benzoyloxy) 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- (hydroxymethyl) tetrahydro-2-furanyl] -3- oxo-3,4-dihydro-2-pyrazinecarboxylate.

IR (KBr) cm ^-1 : 1740

¹ H-NMR (DMSO-d ₆ ) δ: 3.60-4.20 (5H, m), 3.83 (3H, s), 5.00-5.40 (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).

Reference Example I-14

0.50 g of methyl 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4-dihydro was suspended in 5 ml of acetone -2-pyrazinecarboxylate. Then, 1 ml of trimethylorthoformate and 33 mg of p-toluenesulfonic acid monohydrate were successively added, the resulting mixture was heated under reflux for one hour, and the solvent was removed under reduced pressure. Purification of the residue by column chromatography [eluent - ethyl acetate] gives 0.49 g of 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 as a white solid.

IR (KBr) cm ^-1 : 1728

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, s), 1.59 (3H, s), 3.10 (1H, br s), 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).

Reference Example I-15

0.22 g of methyl 4 - [(3aR, 4R, 6R, 6aR) -6- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4- was dissolved in 4 ml of pyridine yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, 0.17 g of dibenzyl phosphate, 0.40 g of triphenylphosphine and 0.30 ml of diisopropylazodicarboxylate were successively added and stirred at room temperature for 15 hours, and the solvent was removed under reduced pressure. Purification of the residue by column chromatography [eluent-ethyl acetate] afforded 0.37 g of methyl 4 - [(3aR, 4R, 6R, 6aR) -6 - ({[bis (benzyloxy) phosphoryl] oxy} methyl) -2,2- dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate as an orange solid.

IR (KBr) cm ^-1 : 1734

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, s), 1.56 (3H, s), 3.96 (3H, s), 4.10-4.30 (2H, m), 4.30-4.55 (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).

Reference Example I-16

1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile, synthesized according to the procedure described in J. Heterocycl, was dissolved in 33 ml of methanol. Chem., Vol.19, Pages 1397-1402 (1982). While cooling the solution with ice, gaseous hydrogen chloride was supplied until saturation, after which the solution was stirred at the same temperature as described above for 8 hours. The solvent was removed under reduced pressure, the obtained residue was dissolved in 55 ml of a solution of 7 mol / L ammonia in methanol, cooling the solution with ice, and the resulting solution was stirred at the same temperature as above for 5 minutes. The resulting solid was collected by filtration to give 1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide as a pale yellow solid.

IR (KBr) cm ^-1 : 3379, 3000, 1698

¹ H-NMR (DMSO-d ₆ ) δ: 7.50 (1H, d, J = 2.0 Hz), 8.33 (1H, br s), 8.18 (1H, d, J = 2 , 0 Hz), 8.33 (2H, br s).

Reference Example I-17

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 cooling the solution with ice, hydrogen chloride gas was supplied until saturation, and then the solution was stirred for 5 hours. The reaction mixture was mixed with 5.0 ml of diethyl ether, the precipitated solid was collected by filtration and washed successively with 10 ml of diethyl ether, a mixture of 2.5 ml of ethanol and 2.5 ml of diethyl ether and 5 ml of diethyl ether. Thus, 0.28 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidoate was obtained as a yellow solid.

IR (KBr) cm ^-1 : 3041, 1670

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).

Reference Example I-18

Ammonia gas was added to 2.0 ml of ice-cooled ethanol to prepare a saturated solution, and then 0.10 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidoate and 2.0 ml of ethanol were added. After raising the temperature to room temperature, the mixture was left for 17 hours. The precipitated solid was collected by filtration and washed with ethanol. The resulting residue was purified by silica gel column chromatography [eluent, chloroform: methanol = 10: 1], ethanol was added to the purified product, and the solid product was collected by filtration. Thus, 20 mg of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidamide was obtained.

IR (KBr) cm ^-1 : 3445, 3030, 1684

¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 8.26 (1H, d, J = 8.5 Hz).

Reference Example I-19

1.0 g of 3-hydroxy-2-pyrazinecarboxamide was suspended in 5.0 ml of 1,1,1,3,3,3-hexamethyldisilazane. The suspension was refluxed for 30 minutes and allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in 5.0 ml of dichloroethane in a nitrogen gas atmosphere, then 3.11 g of β-D-ribofuranoso-1-acetate-2,3,5-tribenzoate and 0.50 ml of tin (IV) were successively added and the resulting mixture stirred at room temperature for 22 hours. The reaction mixture was diluted with 30 ml of ethyl acetate and 20 ml of water, adjusted to pH 8 with saturated aqueous sodium bicarbonate, the precipitate was filtered off, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [developing solution: ethyl acetate: methanol = 10: 1], then isopropyl ether was added and the solid material was collected by filtration. Thus, 0.41 g of [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2 was obtained -furanyl] methylbenzoate as a white solid.

IR (KBr) cm ^-1 : 1734, 1685

¹ H-NMR (CDCl ₃ ) δ: 4.6-5.1 (3H, m), 5.8-6.2 (3H, m), 6.39 (1H, d, J = 2.5 Hz ), 7.2-8.2 (17H, m), 8.95 (1H, br s).

Reference Example I-20

0.37 g was dissolved in 4 ml of methanol

[(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2-furanyl] methylbenzoate. While cooling the solution with ice, gaseous ammonia was supplied to saturation. The reaction mixture was stirred at room temperature for 15 hours and the solvent was removed under reduced pressure. Methanol was added to the residue and the precipitate was collected by filtration to obtain 0.12 g of 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3 , 4-dihydro-2-pyrazinecarboxamide as a light brown solid.

IR (KBr) cm ^-1 : 1654

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 broad s), 5.24 (1H, t, J = 5.4 Hz), 5.61 (1H, broad s), 5.92 (1H, s), 7.54 (1H, d, J = 4.2 Hz), 7.71 (1H, br s), 8.27 (1H, d, J = 4.2 Hz), 8.30 (1H, br s).

Reference Example I-21

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide was treated in the same manner as in Reference Example I-19 to obtain [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro- 2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2-furanyl] methylbenzoate.

IR (KBr) cm ^-1 : 1726, 1690

¹ H-NMR (DMSO-d ₆ ) δ: 4.6-5.0 (3H, m), 5.9-6.1 (2H, m), 6.33 (1H, s), 7.3 -8.2 (17H, m), 8.53 (1H, br s).

Reference Example I-22

0.15 g of [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3.4 was dissolved in 2.0 ml of methanol bis (benzoyloxy) tetrahydro-2-furanyl] methylbenzoate. Then, 0.14 g of a 28% methanol solution of sodium methoxide was added to the ice-cooled solution, and stirred at this temperature for 20 minutes and then at room temperature for 30 minutes. The reaction mixture was acidified with 0.75 ml of a 1 mol solution / L hydrochloric acid and the solvent was removed under reduced pressure. After purification of the residue by column chromatography [eluent - chloroform: methanol = 5: 1], isopropanol and diethyl ether were added, and the solid product was collected by filtration to obtain 40 mg 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5 - (hydroxymethyl) tetrahydro-2-furanyl] -6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.

IR (KBr) cm ^-1 : 1686

Reference Example I-23

0.26 g of methyl 6-chloro-4 - [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3 was dissolved in 4 ml of methanol , 4-dihydro-2-pyrazinecarboxylate. Ammonia gas was supplied to the solution cooled by ice until saturation. The reaction mixture was stirred under ice cooling for one hour, and then the solvent was removed under reduced pressure. Purification by column chromatography [eluent - chloroform: methanol = 7: 1] of the residue gave 0.06 g of 6-chloro-4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro -2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a pale yellow solid.

IR (KBr) cm ^-1 : 1693

Example I-3

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 under reflux for one hour. The reaction mixture was allowed to cool, the solvent was removed under reduced pressure, and the residue was dissolved in 2.0 ml of dichloroethane in a nitrogen gas atmosphere, then a solution of dichloroethane (3.0 ml) containing a mixture of (2R, 3S) -5- (acetyloxy) was added. ) -2 - [(acetyloxy) methyl] tetrahydro-3-furanyl acetate and (3R, 4S) -4,6-bis (acetyloxy) tetrahydro-2H-pyran-3-yl, obtained in advance by the method described in J. Med. Chem., Vol. 28, No. 7, pp. 904-910 (1985), together with 0.32 ml of titanium (IV) chloride. After adding an additional 5.0 ml of dichloroethane to the reaction mixture, the resulting mixture was stirred for 17 hours. The reaction mixture was diluted with 100 ml of chloroform and 25 ml of a saturated aqueous solution of sodium bicarbonate, the precipitate was filtered off and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography [eluent, ethyl acetate: methanol = 10: 1] to obtain 0.43 g of {(2R, 3S) -3- (acetyloxy) -5- [3- (aminocarbonyl) -2-oxo-1 ( 2H) -pyrazinyl] tetrahydro-2-furanyl} methyl acetate as a light brown oily product.

IR (KBr) cm ^-1 : 1735, 1685

¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H, s), 2.14 (3H, s), 1.8-2.6 (2H, m), 4.0-4.6 (2H , m), 5.0-5.4 (2H, m), 6.33 (1H, d, J = 5.9 Hz), 6.64 (1H, br s), 7.76 (1H, d, J = 4.2 Hz), 7.83 (1H, d, J = 4.2 Hz), 9.06 (1H, br s).

Example I-4

0.20 g of {(2R, 3S) -3- (acetyloxy) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) pyrazinyl] tetrahydro-2-furanyl} methyl acetate was dissolved in 2 ml of methanol . While cooling the resulting solution with ice, 0.23 g of a 28% methanol solution of sodium methoxide was added and stirred for 20 minutes. Then, 1.2 ml of hydrochloric acid (1 mol / L) was added to the reaction mixture, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography [eluent - chloroform: methanol = 10: 1] to obtain 90 mg of 4 - [(4S, 5R) -4-hydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3 , 4-dihydro-2-pyrazinecarboxamide as a yellow oily product.

IR (KBr) cm ^-1 : 1684

¹ H-NMR (DMSO-d ₆ ) δ: 1.8-2.2 (2H, m), 3.0-4.4 (4H, m), 4.50-5.20 (2H, m) 6.13 (1H, d, J = 5.9 Hz), 7.59 (1H, d, J = 4.2 Hz), 7.70 (1H, broad s), 7.92 (1H, d, J = 4.2 Hz), 8.45 (1H, br s).

Example I-8

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. Then a 25% aqueous ammonia solution was added at room temperature and stirred for 13 hours, and then the solvent was removed under reduced pressure. Isopropanol was added to the residue and the resulting solid was collected by filtration to obtain 20 mg of 4- [4- (hydroxymethyl) -2-cyclopenten-1-yl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a white solid colors.

IR (KBr) cm ^-1 : 1668

¹ H-NMR (DMSO-d ₆ ) δ: 1.2-3.8 (5H, m), 4.92 (1H, br s), 5.8-6.1 (2H, m), 6 2-6.4 (1H, m), 7.4-8.1 (3H, m), 8.20 (1H, br s).

Example I-9

80 mg of methyl 4 - [(4aR, 7S, 8aS) -2-phenylhexahydropyrano [3,2-d] [1,3] dioxin-7-yl] -3- was dissolved in 5.0 ml of an 80% aqueous solution of acetic acid. oxo-3,4-dihydro-2-pyrazinecarboxylate. The solution was heated at 80 ° C. for 2 hours and then allowed to cool and the solvent was removed under reduced pressure. The residue was diluted with 20 ml of water and washed with diethyl ether, and water was distilled off from the aqueous layer. The resulting residue was dissolved in 4.0 ml of methanol and gaseous ammonia was fed to saturation in an ice-cooled solution. After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent - chloroform: methanol = 10: 1] to obtain 24 mg of 4 - [(3S, 5S, 6R) -5-hydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] - 3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a solid.

IR (KBr) cm ^-1 : 3451, 1676

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.85 (1H, m), 2.10-2.30 (1H, m), 2.95-4.05 (6H, m) 4.47 (1H, t, J = 5.6 Hz), 4.83 (1H, d, J = 5.4 Hz), 5.20-5.30 (1H, m), 7.68 ( 1H, br.s.), 7.80 (1H, br.s), 8.24 (1H, d, J = 7.0 Hz), 8.27 (1H, d, J = 7.0 Hz) .

Example I-10

Methyl 4 - [(4aR, 7R, 8S, 8aS) -8-hydroxy-2-phenylhexahydro-pyrano [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 give 4 - [(3R, 4S, 5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl ] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide.

IR (KBr) cm ^-1 : 3404, 1670

¹ H-NMR (DMSO-d ₆ ) δ: 3.42-3.67 (4H, m), 3.95 (1H, dd, J = 3.1, 13 Hz), 3.90-3.95 (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 (1H, d, J = 4, 3 Hz), 7.66 (1H, br s), 8.21 (1H, d, J = 4.3 Hz), 8.34 (1H, br s).

Example I-11

Methyl 4 - [(3aR, 4R, 6R, 6aR) -6 - ({[bis (benzyloxy) phosphoryl] oxy} methyl) -2,2-dimethyltetrahydrofuro [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 give {(3aR, 4R, 6R, 6aR) -6- [3- (aminocarbonyl ) -2-oxo-1 (2H) -pyrazinyl] -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl} methyldibenzylphosphate.

IR (KBr) cm ^-1 : 1685, 1654

¹ H-NMR (CDCl ₃₎ δ: 1,35 (3H, c), 1,59 (3H, c), 4,00-4,65 (5H, m), 4,80-5,40 (4H , m), 5.93 (1H, d, J = 2.2 Hz), 6.15 (1H, br s), 7.10-7.80 (10H, m), 7.59 (1H, d, J = 4.3 Hz), 7.67 (1H, d, J = 4.3 Hz), 9.15 (1H, br s).

Example I-12

60 mg of {(3aR, 4R, 6R, 6aR) -6- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2,2-dimethyltetrahydrofuro [3] were dissolved in 3 ml of a 90% aqueous solution of trifluoroacetic acid 3,4-d] [1,3] dioxol-4-yl} methyldibenzylphosphate, cooling the solution with ice. After stirring the ice-cooled solution for 30 minutes and then after moving at room temperature for 2 hours, the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and washed with methanol. Thus, 15 mg of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl diphosphate was obtained in the form solid product light red.

IR (KBr) cm ^-1 : 1654

¹ H-NMR (DMSO-d ₆ ) δ: 2.80-4.80 (9H, m), 5.90-6.00 (1H, m), 7.47 (1H, d, J = 4, 5 Hz), 7.68 (1H, br s), 7.97 (1H, d, J = 4.5 Hz), 8.30 (1H, br s).

Example I-13

In a mixture of 2 ml of tetrahydrofuran and 1 ml of water, 100 mg of {(3aR, 4R, 6R, 6aR) -6- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2,2-dimethyltetrahydrofuro [ 3,4-d] [1,3] dioxol-4-yl} methyldibenzylphosphate. After adjusting the pH to 0.5 with a solution of 6 mol / L hydrochloric acid, the mixture was left at room temperature for 2 days. The precipitated solid was collected by filtration and washed with ethanol to obtain 40 mg of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro 2-furanyl} methyl dibenzyl phosphate as a solid.

IR (KBr) cm ^-1 : 1676, 1660

¹ H-NMR (DMSO-d ₆ ) δ: 3.70-4.60 (5H, m), 5.04 (2H, s), 5.12 (2H, s), 5.30-5.45 (1H, m), 5.71 (1H, d, J = 4.6 Hz), 5.85-6.00 (1H, m), 7.10-7.60 (11H, m), 7, 76 (1H, br s), 7.78 (1H, d, J = 3.9 Hz), 8.30 (1H, br s).

Example I-14

In 2.0 ml of 1,1,1,3,3,3-hexamethyldisilazane, 0.20 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide and 10 mg of ammonium sulfate were suspended. The suspension was heated under reflux for 10 minutes in a stream of nitrogen gas. After adding 9.0 mg of ammonium sulfate, the mixture was refluxed for another 2 hours. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in 4.0 ml of acetonitrile, then 0.46 g of β-D-ribofuranoso-1,2,3,5-tetraacetate and 0.34 ml of tin (IV) chloride were successively added, the resulting mixture was stirred at room temperature for 3 hours. Then, 10 μl of trifluoroacetic acid and 1.0 ml of water were added to the reaction mixture, and the solvent was removed under reduced pressure. Then, the same reaction was carried out as described above, using 0.05 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide.

The reaction mixture was combined with the reaction mixture obtained above, and the product was purified by reverse phase column chromatography on silica gel [eluent - acetonitrile: water = 1: 4] to obtain 0.34 g (2R, 3R, 4R, 5R) -4- ( acetyloxy) -2 - [(acetyloxy) methyl] -5- [3- [amino (imino) methyl] -2-oxo-1 (2H) pyrazinyl] tetrahydro-3-furanyl acetate as a pale yellow solid.

IR (KBr) cm ^-1 : 3392, 1750, 1685

¹ H-NMR (DMSO-d ₆ ) δ: 2.11 (3H, s), 2.16 (6H, s), 4.4-4.7 (3H, m), 5.31 (1H, t , J = 5.0 Hz), 5.5-5.6 (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, br s), 10.45 (2H, br s).

Example I-15

To 5.0 ml of a 25% aqueous ammonia solution was added 0.10 g of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2 - [(acetyloxy) methyl] -5- [3- [amino (imino) methyl] -2-oxo-1 (2H) -pyrazinyl] tetrahydro-3-furanyl acetate, cooling the solution with ice, and the resulting mixture was stirred while continuing to cool the mixture with ice for 2 hours. After 4.9 ml of acetic acid was added to the reaction mixture, the solvent was removed under reduced pressure. Then, the same reaction was carried out as described above using 20 mg of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2 - [(acetyloxy) methyl] -5- [3- [amino (imino) methyl] -2-oxo-1 (2H) -pyrazinyl] tetrahydro-3-furanyl acetate and the resulting reaction mixture was combined with the reaction mixture prepared above. The combined mixture was purified by reverse phase column chromatography on silica gel [eluent-water]. To the resulting solid product was added 5.0 ml of a 1 mol / L hydrochloric acid solution, and the solvent was removed under reduced pressure. Next, 5.0 ml of a 1 mol / L hydrochloric acid solution was added, and the solvent was removed under reduced pressure. Ethanol was added to the residue and the solid product was collected by filtration to obtain 30 mg of 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3 hydrochloride , 4-dihydro-2-pyrazinecarboximidamide as a pale yellow solid.

IR (KBr) cm ^-1 : 3374, 3281, 1690

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 = 4.0 Hz ), 8.76 (1H, d, J = 4.0 Hz), 9.44 (3H, br s).

Example I-16

0.11 g of 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4- was suspended in 2.0 ml of trimethylphosphate dihydro-2-pyrazinecarboxamide. 0.11 ml of phosphorus oxychloride was added to the suspension, cooling the suspension with ice, and stirred for 2 hours while continuing to cool the suspension with ice. Then, 1.2 ml of a solution of tributylamine and 0.56 g of tributylammonium phosphate in 6.0 ml of dimethylformamide were added to the reaction mixture, and stirred for one hour while continuing to cool the reaction mixture with ice. Then, a solution of 0.1 mol / L triethylammonium bicarbonate was added to the reaction mixture, and the mixture was left at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by ion-exchange column chromatography [eluent is a solution of 0.07 mol / L triethylammonium bicarbonate] to obtain a fraction containing a salt of triethylamine {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl diphosphate, and the fraction containing the triethylamine salt {(2R, 3S, 4R, 5R) -5- [3 - (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl triphosphate, from which respectively 143 mg of the first compound were obtained as a solid and 113 mg of the second compound as a solid. A portion was taken from 143 mg of the triethylamine salt of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl diphosphate 110 mg and dissolved in 3.0 ml of methanol, a solution of 0.28 g of sodium perchlorate in 7.5 ml of acetone was added to the solution. The solid product was collected by centrifugation and washed with acetone to obtain 64 mg of the {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro sodium salt -2-furanyl} methyl diphosphate as a white solid.

IR (KBr) cm ^-1 : 3418, 1682, 1236, 983, 905

¹ H-NMR (D ₂ O) δ: 4,2-4,5 (5H, m), 6,12 (1H, c), 7,83 (1H, d, J = 3,7 Hz), 8 35 (1H, d, J = 3.7 Hz).

Example I-17

From 113 mg of the salt of triethylamine {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyl triphosphate obtained in Example I-16, a 46 mg portion was taken and dissolved in 1.0 ml of methanol, a solution of 92 mg of sodium perchlorate in 5.0 ml of acetone was added to the solution. The solid product was collected by centrifugation and washed with acetone to obtain 21 mg of the sodium salt of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro -2-furanyl} methyl triphosphate.

IR (KBr) cm ^-1 : 3436, 1692, 1284, 1103, 997

¹ H-NMR (D ₂ O) δ: 4.2-4.5 (5H, m), 6.14 (1H, s), 7.85 (1H, d, J = 3.0 Hz), 8 36 (1H, d, J = 3.0 Hz).

Example I-18

5.3 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide were suspended in 53 ml of acetonitrile in a stream of nitrogen gas. Then, 8.4 ml of N, O-bis (trimethylsilyl) acetamide was added to the suspension, cooling the mixture with ice, and the mixture was stirred at room temperature for 1.5 hours. A solution of 9.4 g of (2R, 3R, 4R) -4,5-bis (acetyloxy) -2- (hydroxymethyl) -tetrahydro-3-furanyl acetate, previously synthesized previously by the method mentioned in Carbohydr, was successively added to an ice-cooled reaction mixture. . Res., Vol.203, No. 9, Pages 324-329 (1990), in 53 ml of acetonitrile and 7.2 ml of tin (IV) chloride, the resulting 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 a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with 700 ml of ethyl acetate. All organic layers were combined and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of methanol, 100 ml of an 80% aqueous solution of acetic acid was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [eluent, chloroform: methanol = 40: 1], chloroform and isopropyl ether were added, and the solid product was collected by filtration to obtain 9.3 g (2R, 3R, 4R, 5R) - 4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -5- (hydroxymethyl) tetrahydro-3-furanyl acetate as a pale yellow solid.

IR (KBr) cm ^-1 : 3411, 1752, 1686

2,04 (3H, с), 2,10 (3H, с), 3,64 (1H, ддд, J=2,5, 5,0, 13 Гц), 3,86 (1H, ддд, J=2,5, 5,0, 13 Гц), 4,29 (1H, д, J=6,0 Гц), 5,35 (1H, т, J=6,0 Гц), 5,49 (1H, дд, J=3,0, 5,0 Гц), 5,65 (1H, т, J=5,0 Гц), 6,11 (1H, д, J=3,0 Гц), 7,96 (1H, шир.с), 8,42 (1H, д, J=5,0 Гц), 8,49 (1H, шир.с). ¹ H-NMR (DMSO-d ₆ )

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 = 5.0 Hz), 6.11 (1H, d, J = 3.0 Hz), 7.96 ( 1H, br s), 8.42 (1H, d, J = 5.0 Hz), 8.49 (1H, br s).

Example I-19

1.5 g of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] - was dissolved in 30 ml of acetonitrile 5- (hydroxymethyl) tetrahydro-3-furanyl acetate and 0.84 g of 1H-tetrazole in a stream of nitrogen gas. To a solution cooled by ice was added a solution of 1.4 ml of diallyldiisopropylphosphoramidate in 20 ml of acetonitrile and stirred for 20 minutes. Then, a solution of 1.4 g of m-chloroperbenzoic acid in 10 ml of acetonitrile was added to the reaction mixture and stirred for 10 minutes. Then, 60 ml of ethyl acetate was added to the reaction mixture, the resulting reaction mixture was poured into 60 ml of water, the organic layer was separated, and the aqueous layer 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, and the aqueous layer was discarded. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, chloroform: methanol = 40: 1] to obtain 1.3 g (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5- fluoro-2-oxo-1 (2H) -pyrazinyl] -5 - ({[bis (allyloxy) phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate as a yellow solid.

IR (KBr) cm ^-1 : 3403, 1753, 1694, 1244, 1024

2,11 (3H, с), 2,15 (3H, с), 4,32-4,35 (1H, м), 4,47-4,52 (2H, м), 4,58-4,64 (4H, м), 5,27 (2H, дт, J=1,0, 10,5 Гц), 5,37-5,44 (4H, м), 5,90-6,00 (2H, м), 6,28 (1H, д, J=4,0 Гц), 6,32 (1H, шир.с), 7,99 (1H, д, J=6,0 Гц), 9,02 (1H, шир.с). ¹ H-NMR (CDCl ₃ )

2.11 (3H, s), 2.15 (3H, s), 4.32-4.35 (1H, m), 4.47-4.52 (2H, m), 4.58-4, 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, br s), 7.99 (1H, d, J = 6.0 Hz), 9.02 ( 1H, broad s).

Example I-20

0.23 g was dissolved in 4.0 ml of methanol

(2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -5 - ({[bis (allyloxy) phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate. 0.17 g of a 28% methanol solution of sodium methoxide was added to the ice-cooled solution, and stirred for 5 minutes. Then, 0.15 ml of acetic acid was added and the solvent was removed under reduced pressure. On the other hand, the same reaction was carried out using 1.0 g of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H ) -pyrazinyl] -5 - ({[bis (allyloxy) phosphoryl] oxy} methyl) tetrahydro-3-furanyl acetate. Both reaction mixtures were combined and purified by silica gel column chromatography [eluent, chloroform: methanol = 40: 1]. Thus, 0.35 g of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2 was obtained -furanyl} methyldiallyl phosphate as a yellow solid.

IR (KBr) cm ^-1 : 3417, 1684, 1264, 1025, 1000

3,1-4,7 (10H, м), 5,1-5,5 (4H, м), 5,7-6,2 (2H, м), 7,94 (1H, д, J=6,0 Гц). ¹ H-NMR (DMSO-d ₆ , D ₂ O)

3.1-4.7 (10H, m), 5.1-5.5 (4H, m), 5.7-6.2 (2H, m), 7.94 (1H, d, J = 6 , 0 Hz).

Example I-21

In a mixture of 8.2 ml of methanol and 8.2 ml of tetrahydrofuran, 0.82 g of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) was dissolved -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methyldiallyl phosphate in a stream of nitrogen gas. After successively adding 0.11 g of tetrakistriphenylphosphine-palladium (0) and 0.28 g of triphenylphosphine, the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, cooled by ice, a solution of 0.68 ml of formic acid in 1.9 ml of tetrahydrofuran and a solution of 0.25 ml of n-butylamine in 8.2 ml of tetrahydrofuran were successively added. The mixture was stirred at 30-35 ° C for one hour and then 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 was washed with 20 ml of chloroform and the washings were extracted with 30 ml of water. All aqueous layers were combined and the solvent was removed under reduced pressure. The residue was purified by reversed-phase column chromatography on silica gel [eluent-water]. Thus, 0.29 g of the salt of n-butylamine {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3.4 was obtained -dihydroxytetrahydro-2-furanyl} methylphosphate as a yellow solid.

IR (KBr) cm ^-1 : 3382, 1685, 1183, 1110

0,75-0,90 (3H, м), 1,25-1,40 (2H, м), 1,45-1,70 (2H, м), 2,70-2,80 (2H, м), 3,3-4,7 (9H, m), 5,33 (1H, д, J=10 Гц), 5,42 (1H, д, J=17 Гц), 5,90 (2H, шир.с), 7,95 (1H, шир.с), 8,34 (1H, д, J=5,0 Гц), 8,63 (1H, шир.с). ¹ H-NMR (DMSO-d ₆ )

0.75-0.90 (3H, m), 1.25-1.40 (2H, m), 1.45-1.70 (2H, m), 2.70-2.80 (2H, m) ), 3.3-4.7 (9H, m), 5.33 (1H, d, J = 10 Hz), 5.42 (1H, d, J = 17 Hz), 5.90 (2H, broad s), 7.95 (1H, br s), 8.34 (1H, d, J = 5.0 Hz), 8.63 (1H, br s).

Example I-22

In a mixture of 4.2 ml of acetonitrile and 8.4 ml of N, N-dimethylformamide, 0.21 g of the salt of n-butylamine {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro- was suspended 2-oxo-1 (2H) -pyrazinyl] -3,4-dihydroxytetrahydro-2-furanyl} methylphosphate. Then, 0.15 g of N, N-carbonyldiimidazole was added and stirred at room temperature for 2 hours. Then, 19 μl of methanol was added to the reaction mixture and stirred for 30 minutes. Then, a solution of 0.86 g of tri-n-butylammonium pyrophosphate in 2.0 ml of N, N-dimethylformamide was added and stirred for another 14 hours. The solvent was removed under reduced pressure, and the residue was sequentially purified by ion-exchange column chromatography [developing solution 0.10 mol / L triethylammonium bicarbonate] and reverse phase column chromatography [eluent-water]. To the solid product, 0.90 ml of methanol and a solution of 0.17 g of sodium perchlorate in 4.5 ml of acetone were successively added. The precipitate was collected by centrifugation and then washed with acetone to obtain 60 mg of the sodium salt of {(2R, 3S, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3 , 4-dihydroxytetrahydro-2-furanyl} methyl triphosphate as a pale yellow solid.

IR (KBr) cm ^-1 : 3422, 1686, 1252, 1108

4,3-4,5 (5H, м), 6,09 (1H, с), 8,41 (1H, д, J=5,1 Гц). ¹ H-NMR (D ₂ O)

4.3-4.5 (5H, m), 6.09 (1H, s), 8.41 (1H, d, J = 5.1 Hz).

Example I-23

(2R, 3R, 4R) -5- (Acetyloxy) -2 - [(benzoyloxy) methyl] -4-fluorotetrahydro-3-furanylbenzoate synthesized by the method described in international application WO 93/10137 was treated in the same manner as indicated in Reference Example I-19, to give (2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2 - [(benzoyloxy) methyl] -4 -fluorotetrahydro-3-furanylbenzoate.

IR (KBr) cm ^-1 : 3422, 1718, 1685

4,1-6,2 (6H, м), 7,3-8,2 (12H, м), 8,1-8,3 (1H, м), 8,8-9,1 (2H,м). ¹ H-NMR (CDCl ₃ )

4.1-6.2 (6H, m), 7.3-8.2 (12H, m), 8.1-8.3 (1H, m), 8.8-9.1 (2H, m )

Example I-24

(2R, 3R, 4R, 5R) -5- [3- (Aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -2 - [(benzoyloxy) methyl] -4-fluorotetrahydro-3-furanylbenzoate was treated with the same as in Reference Example I-22, to give 4 - [(2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3 , 4-dihydro-2-pyrazinecarboxamide.

IR (KBr) cm ^-1 : 3376, 1684, 1654

3,7-4,4 (4H, м), 4,96 (1H, дд, J=4,0, 52 Гц), 6,22 (1H, д, J=16 Гц), 7,76 (1H, д, J=4,0 Гц), 8,42 (1H, д, J=4,0 Гц). ¹ H-NMR (CDCl ₃ , CD ₃ OD)

3.7-4.4 (4H, m), 4.96 (1H, dd, J = 4.0, 52 Hz), 6.22 (1H, d, J = 16 Hz), 7.76 (1H d, J = 4.0 Hz), 8.42 (1H, d, J = 4.0 Hz).

Reference Example II-1

In a mixture of a solution of 12 mol / L hydrochloric acid and 14 ml of tetrahydrofuran, 8.0 g of methyl 3-amino-6-chloro-2-pyrazinecarboxylate was suspended. After adding 5.9 g of sodium nitrite to the suspension at a temperature of 5-12 ° C, the mixture was stirred for 50 minutes, cooling it with ice. Then, 8.4 g of copper (I) chloride suspended in a solution of 6 mol / L hydrochloric acid was added, and stirred at the same temperature as described above for 10 minutes. The reaction mixture was poured into the mixture, 100 ml of ethyl acetate and 100 ml of water, and the organic layer was separated. The organic layer was washed successively with 50 ml of water and 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, 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 oily product.

IR (neat) cm ^-1 : 1747

¹ H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 8.54 (1H, s).

Reference Example II-2

2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate was dissolved in 10 ml of methanol. Then, 10.2 ml of a 1 mol / L aqueous sodium hydroxide solution was added to the ice-cooled solution, and stirred at room temperature for one hour. The reaction mixture was poured into a mixture of 200 ml of ethyl acetate and 200 ml of water, and the organic layer was separated. The organic layer was washed successively with 50 ml of water and 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was washed with hexane to obtain 1.6 g of 3,6-dichloro-2-pyrazinecarboxylic acid as a white solid.

IR (KBr) cm ^-1 : 1718

¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (1H, s), 8.84 (1H, s).

Reference Example II-3

In 1.2 L of 97% sulfuric acid, 208.0 g of 3-hydroxy-2-pyrazinecarboxamide was added and dissolved, maintaining the temperature of the solution at 10-25 ° C, cooling with ice. 185.0 g of potassium nitrate was added to the solution at 30-35 ° C and the mixture was stirred at room temperature for 15 hours and then at 40 ° C for 2 hours. After the reaction mixture was cooled to 20 ° C, it was poured into ice water with a volume of 6 L and stirred at room temperature for one hour, the precipitated product was collected by filtration and washed with two 500 ml portions of water. The resulting solid product was suspended in 1 L of water, the pH was adjusted to 1.5 with 5 mol / L aqueous sodium hydroxide solution, then the solid product was collected by filtration. The solid was washed successively 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.

IR (KBr) cm ^-1 : 1707, 1685, 1654

¹ H-NMR (DMSO-d ₆ ) δ: 5.60 (1H, broad s), 8.10 (1H, broad s), 8.35 (1H, broad s), 8.96 (1H , from).

Reference Example II-4

88.7 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide was added to 400 ml of phosphorus oxychloride at a temperature of 55-60 ° C. After carrying out the reaction at the same temperature for 15 minutes, 150 ml of pyridine was added dropwise to the reaction mixture at 40-60 ° C. First, the reaction mixture was stirred at 60 ° C for one hour, then at 80 ° C for one hour and finally at 100 ° C for 4 hours, mixed with 600 ml of toluene and then the temperature was brought to room temperature. After filtering off the precipitate, the filtrate was concentrated to dryness under reduced pressure. 500 ml of toluene and 1 L of water were successively added to the residue, the mixture was stirred at 40 ° C. for 30 minutes, and the organic layer was separated. The organic layer was first washed with two 500 ml portions of water and then with 200 ml of a saturated aqueous solution of sodium chloride in one portion and 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: toluene = 1: 1] to obtain 64.5 g of 3,6-dichloro-2-pyrazinecarbonitrile as a solid.

IR (KBr) cm ^-1 : 2236, 2252

¹ H-NMR (CDCl ₃ ) δ: 8.60 (1H, s).

Reference Example II-5

80.0 g of 3-hydroxy-6-nitro-2-pyrazinecarboxamide and 47.5 g of sodium hydroxide were dissolved in 1.19 L of water. After heating under 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 30 minutes. After adding an additional 400 ml of ethanol at 20 ° C, the mixture was cooled to 10 ° C and the precipitated product was collected by filtration. The collected product was washed with 160 ml of ethanol and dried at 40 ° C for 15 hours to obtain 78.8 g of a solid product. The solid product (78.5 g) was suspended in 1.5 L of methanol, dry gaseous hydrogen chloride was added to the suspension until saturation within one hour. The mixture was heated under reflux for one hour and cooled, the precipitated salt was filtered off, the filtrate was concentrated to dryness under reduced pressure. Ethanol (500 ml) was added to the residue and concentrated to dryness under reduced pressure, the residue was washed with 250 ml of isopropyl alcohol to obtain 48.8 g of methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a solid.

IR (KBr) cm ^-1 : 1736

¹ H-NMR (CDCl ₃ ) δ: 2.45 (1H, br s), 3.87 (3H, s), 8.98 (1H, s).

Reference Example II-6

48.7 g of methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate were suspended in 2.0 L of dioxane, 42.4 ml of N-ethyldiisopropylamine and 9.9 ml of methanol were successively added to the suspension. Then, 122 ml of a solution of 2.0 mol / L trimethylsilyldiazomethane in hexane was added at room temperature, the mixture was stirred at the same temperature as above for 15 hours, and the solvent was removed under reduced pressure. Then, 500 ml of ethyl acetate and 250 ml of water were added to the obtained residue, the pH was adjusted to 1.5 with a solution of 6 mol / L hydrochloric acid, and the organic layer was separated. The remaining aqueous layer was extracted with two 200 ml portions of ethyl acetate. All organic layers were combined, washed successively with 200 ml of water and 200 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by 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.

IR (KBr) cm ^-1 : 1729

¹ H-NMR (DMSO-d ₆₎ δ: 4,03 (3H, s), 4.22 (3H, s), 9.25 (1H, s).

Reference Example II-7

Hydrogen gas was introduced into a mixture of 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate, 480 ml of acetic acid and 1.2 g of lead-etched palladium-calcium carbonate at room temperature and at a pressure of 1 atmosphere until the mixture did not cease to absorb hydrogen. After filtering off the insoluble product from the reaction mixture, the solvent was removed under reduced pressure, and the obtained solid product was washed with ethyl acetate and diethyl ether. Thus, 15.0 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate was obtained as a solid. In addition, the solvent was removed from the filtrate under reduced pressure to give a solid, and the solid was washed with ethyl acetate to obtain 2.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a solid.

IR (KBr) cm ^-1 : 1717

¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 3.99 (3H, s), 4.38 (2H, br s), 7.79 (1H, s).

Reference Example II-8

4.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile synthesized in 80 ml of tetrahydrofuran synthesized by the method described in US patent No. 3341540. To the ice-cooled solution, 1.2 g of 60% sodium hydride and 2.8 ml of benzoyl chloride and 0.8 g of 60% sodium hydride were successively added. The ice-cooled mixture was stirred for one hour and then at room temperature for 30 minutes. Then, 0.4 g of 60% sodium hydride was further added and the mixture was stirred at room temperature for 30 minutes. After cooling the reaction mixture with ice, this mixture was poured into a liquid mixture of 50 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 5 with a solution of 6 mol / L hydrochloric acid. The precipitated product was collected by filtration and the residue was dissolved in a mixture of 50 ml of ethyl acetate and 100 ml of tetrahydrofuran, treated with activated carbon and filtered, after which the solvent was removed under reduced pressure. The 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. In addition, the organic layer was separated from the filtrate obtained above, the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, treated with activated carbon and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give 2.9 g of N- (5-bromo-3-cyano-2-pyrazinyl) benzamide as a yellow solid.

IR (KBr) cm ^-1 : 2238, 1667

¹ H-NMR (CDCl ₃ ) δ: 7.41-7.64 (3H, m), 8.04-8.15 (2H, m), 8.76 (1H, s), 11.31 (1H , s).

Reference Example II-9

0.50 g of 3-amino-6-bromo-2-pyrazinecarbonitrile was dissolved in 10 ml of tetrahydrofuran. After adding 0.15 g of 60% sodium hydride, the mixture was stirred at room temperature for 15 minutes. Then, 0.7 ml of di-tert-butyl dicarbonate and 0.10 g of 60% sodium hydride were successively added to the mixture, and the mixture was stirred at room temperature for one hour. The reaction mixture was added to a liquid mixture of 30 ml of ethyl acetate and 60 ml of water, the pH was adjusted to 5 with 2 mol / L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and 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 = 5: 1] to obtain 0.30 g of tert-butyl 5-bromo-3-cyano-2-pyrazinyl carbamate as a white solid.

IR (KBr) cm ^-1 : 2239, 1708

¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.57 (9H, s), 7.41 (1H, br s), 8.62 (1H, s).

Reference Example II-10

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 resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 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 organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and 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 = 3: 1] to obtain 1.0 g of 6-chloro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.

IR (KBr) cm ^-1 : 3384, 2250

¹ H-NMR (CDCl ₃ ) δ: 6.82-7.05 (4H, m), 8.27 (1H, s), 8.88 (1H, s).

Reference Example II-11

1.5 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 15 ml of dimethylformamide. After adding 1.2 g of 4-methoxyphenol and 1.8 g of potassium carbonate, the resulting 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 organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and 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 = 5: 1] to obtain 2.1 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.

IR (KBr) cm ^-1 : 2236

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).

Reference Example II-12

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 one hour. A mixture of 25 ml of ethyl acetate and 100 ml of water was added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, insoluble material was filtered off, and the filtrate was concentrated. The residue was washed with n-hexane to give 3.84 g of 3 - [(4- (benzyloxy) phenoxy)] - 6-chloro-2-pyrazinecarbonitrile as a light brown solid.

IR (KBr) cm ^-1 : 2238

¹ H-NMR (CDCl ₃ ) δ: 5.12 (2H, s), 7.03-7.48 (9H, m), 8.65 (1H, s).

Reference Example II-13

0.4 g of 6-chloro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile was dissolved in 8 ml of dimethylformamide. After adding 0.5 ml of iodomethane and 0.89 g of potassium carbonate, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 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 a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.43 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile was obtained as a tan solid.

IR (KBr) cm ^-1 : 2236

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).

Reference Example II-14

1.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile was dissolved in 5 ml of dimethylacetal dimethylformamide. The solution was heated under reflux for 3 hours. The temperature of the reaction mixture was brought to room temperature, and a mixture of 5 ml of n-hexane and 5 ml of diisopropyl ether was added and stirred at room temperature for 10 minutes. The precipitate was collected by filtration and washed with a mixture of 5 ml of n-hexane and 5 ml of diisopropyl ether to obtain 1.0 g of N '- (5-bromo-3-cyano-2-pyrazinyl) -N, N-dimethyliminoformamide as a solid yellow-brown color.

IR (KBr) cm ^-1 : 2234

¹ H-NMR (CDCl ₃ ) δ: 3.21 (6H, s), 8.32 (1H, s), 8.60 (1H, s).

Reference Example II-15

10.0 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 50 ml of N, N-dimethylformamide. After successive addition of 6.49 ml of thiophenol and 11.91 g of potassium carbonate, the mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was poured into a mixture of 100 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 2 with a solution of 6 mol / L hydrochloric acid. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, toluene: n-hexane = 1: 3] to obtain 3.80 g of 6-chloro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile as a pale yellow oily product.

IR (neat) cm ^-1 : 2238

¹ H-NMR (CDCl ₃ ) δ: 7.00-7.70 (5H, m), 8.39 (1H, s).

Example II-1

(a) 2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate was dissolved in 20 ml of acetonitrile. After adding 2.8 g of potassium fluoride and 0.51 g of 18-crown-6-ether, the mixture was heated under reflux for 9.5 hours in an atmosphere of nitrogen gas. After cooling, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography [eluent, n-hexane: ethyl acetate = 15: 1] to obtain 1.1 g of methyl 3,6-difluoro-2-pyrazinecarboxylate as a colorless oily product.

IR (neat) cm ^-1 : 1743

¹ H-NMR (CDCl ₃ ) δ: 4.05 (3H, s), 8.28 (1H, dd, J = 1.6 Hz, 8.4 Hz).

(b) 0.2 g of 3,6-dichloro-2-pyrazinecarboxylic acid was suspended in 2.0 ml of methylene chloride. Then, 0.001 ml of N, N-dimethylformamide and 0.14 ml of oxalyl chloride were successively added to an ice-cooled suspension, and the resulting 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. Then, 0.3 g of potassium fluoride and 0.056 g of 18-crown-6-ether were added and the resulting mixture was stirred at 60 ° C for 2.5 hours in a nitrogen gas atmosphere. The reaction mixture was poured into 3.0 ml of methanol, the insoluble product was filtered off, and then the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography [eluent, n-hexane: ethyl acetate = 9: 1] to obtain 0.15 g of methyl 3,6-difluoro-2-pyrazinecarboxylate as a colorless oily product.

The physical properties of this compound coincided with the properties of the compound obtained in example II-1 (a).

Example II-2

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 to an ice-cooled solution, the mixture was stirred at 50 ° C. for 2.5 hours. The reaction mixture was poured into a mixture of 50 ml of ethyl acetate and 30 ml of water, and the organic layer was separated. The residual aqueous phase was adjusted to pH 1.5 with 1 mol / L hydrochloric acid and extracted with three 25 ml portions of ethyl acetate. The organic layers were combined, washed successively with 15 ml of water and 15 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, 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-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a colorless solid.

IR (KBr) cm ^-1 : 1677

¹ H-NMR (CDCl ₃ ) δ: 4.09 (3H, s), 8.35 (1H, d, J = 8.3 Hz), 11.1 (1H, br s).

Example II-3

(a) 90.1 g of 3,6-dichloro-2-pyrazinecarbonitrile was suspended in 1.1 L of dimethyl sulfoxide. After adding 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 temperature of the reaction mixture was brought to room temperature, and 1.1 L of ethyl acetate and 2.2 L of water were added to the mixture, and the organic layer was separated. Water (1 L) was added to the organic layer, the pH was adjusted to 2.5 with 1 mol / L hydrochloric acid, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography [eluent, n-hexane: ethyl acetate = 10: 1] to obtain 58.3 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid.

IR (KBr) cm ^-1 : 2250

¹ H-NMR (CDCl ₃ ) δ: 8.34 (1H, dd, J = 1.3, 7.9 Hz).

(b) 0.40 g of 6-fluoro-3- (phenylsulfonyl) -2-pyrazinecarbonitrile was dissolved in 4 ml of dimethyl sulfoxide. After successive addition of 0.44 g of potassium fluoride and 0.10 g of tetra-n-butylammonium bromide, the 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 a saturated aqueous solution of sodium chloride and 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 obtain 0.06 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid.

Example II-4

In a mixture of 570 ml of a solution of 12 mol / L hydrochloric acid and 57 ml of tetrahydrofuran, 57.3 g of 3,6-difluoro-2-pyrazinecarbonitrile were suspended. 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 residue was washed with ethanol and diisopropyl ether to obtain 53.7 g of 3,6-difluoro-2-pyrazinecarboxamide as a colorless solid.

IR (KBr) cm ^-1 : 1708, 1692

¹ H-NMR (DMSO-d ₆ ) δ: 8.00 (1H, br s), 8.25 (1H, br s), 8.57 (1H, dd, J = 1.7, 8, 1 Hz).

Example II-5

(a) 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of N, N-dimethylformamide. To the ice-cooled solution, 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, the pH was adjusted to 1.5 with a solution of 6 mol / L hydrochloric acid, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by 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.

IR (KBr) cm ^-1 : 2238, 1655

¹ H-NMR (DMSO-d ₆ ) δ: 8.52 (1H, d, J = 7.6 Hz), 12.70 (1H, br s).

(b) 1.0 g of 3- (benzyloxy) -6-fluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of toluene. Then, 0.64 g of aluminum chloride was added to the ice-cooled solution, and the resulting mixture was stirred at room temperature for 2 hours. Then, 10 ml of water was added to the reaction mixture, and the aqueous layer was separated, and the organic layer was extracted with two 2 ml portions of water. The aqueous layers were combined and extracted with two 5 ml portions of ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.51 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

The physical properties of this compound coincided with the properties of the compound obtained in example II-5 (a).

(c) 1.0 g of 3- (allyloxy) -6-fluoro-2-pyrazinecarbonitrile was dissolved in 5 ml of toluene. After adding 0.82 g of aluminum chloride, the mixture was stirred at room temperature for 1.5 hours. Water (5 ml) was added to the reaction mixture, the aqueous layer was separated, and the organic layer was extracted first with 3 ml of water and then 2 ml of water. The aqueous layers were combined and washed with 5 ml of toluene and extracted with 15 ml of ethyl acetate. The resulting organic layer was washed with 3 ml of water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

The physical properties of this compound coincided with the properties of the compound obtained in example II-5 (a).

(d) In a mixture of 30 ml of acetonitrile and 20 ml of water, 1.0 g of 6-fluoro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile was dissolved. After adding 11.2 g of cerium-diammonium nitrate, the mixture was refluxed for 3 hours. The temperature of the reaction mixture was brought to room temperature, a mixture of 50 ml of toluene, 50 ml of water and 10 ml of a 5% aqueous solution of sodium thiosulfate was added to the reaction mixture, and the aqueous layer was separated. Ethyl acetate (50 ml) was added to the aqueous layer and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride, treated with activated carbon and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

(e) In a mixture of 30 ml of acetonitrile and 15 ml of water, 1.0 g of 3- [4- (benzyloxy) phenoxy] -6-fluoro-2-pyrazinecarbonitrile was dissolved. After adding 8.5 g of diammonium-cerium nitrate, the mixture was heated under reflux for 3 hours. The temperature of the reaction mixture was brought to room temperature, a mixture of 50 ml of ethyl acetate, 5 ml of water and 5 ml of a 5% aqueous solution of sodium thiosulfate was added and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride, treated with activated carbon, and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

(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. Then, 1.17 g of diammonium cerium nitrate was added at room temperature and stirred at the same temperature for 15 minutes. A mixture of 10 ml of ethyl acetate and 5 ml of a 5% aqueous solution of sodium thiosulfate was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride, treated with activated carbon, and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

(g) In a mixture of 5 ml of a solution of 6 mol / L hydrochloric acid and 1 ml of dioxane, 0.5 g of 6-fluoro-3 - [(2-methyl-3-oxo-1-cyclopenten-1-yl) oxy] is suspended 2-pyrazinecarbonitrile. The suspension was stirred at 50 ° C for 15 minutes. The temperature of the reaction mixture was brought to room temperature, 10 ml of ethyl acetate was added and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.25 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-5 (a).

Example II-6

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 at the same temperature for 10 minutes. The reaction mixture was added to a mixture consisting of 20 ml of ether and 20 ml of water, and the organic layer was separated. The organic layer was washed successively with 20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.25 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile was obtained as a yellow oily product.

IR (neat) cm ^-1 : 2140

¹ H-NMR (CDCl ₃ ) δ: 8.40 (1H, d, J = 8.2 Hz).

Example II-7

(a) In a mixture of 1.5 ml of a 25% aqueous solution of ammonia and 5.0 ml of dioxane, 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved. The solution was stirred at room temperature for 6 hours. Then, 20 ml of water was added to the reaction mixture, and the ice-cooled mixture was stirred for 20 minutes. The precipitated product was collected by filtration, washed successively with 5 ml of cold water and 5 ml of ethanol to obtain 0.84 g of 3-amino-6-fluoro -2-pyrazinecarbonitrile as a pale yellow solid.

IR (KBr) cm ^-1 : 3405, 2230

¹ H-NMR (DMSO-d ₆ ) δ: 7.34 (2H, br s), 8.42 (1H, d, J = 7.8 Hz).

(b) 0.24 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile was dissolved in 5.0 ml of methanol. After adding 0.075 g of lead-etched lead palladium-calcium carbonate at room temperature, hydrogen gas was introduced into the mixture at room temperature under a pressure of 1 atmosphere until hydrogen ceased to adsorb. After filtering off the insoluble product from the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent - chloroform] to obtain 0.078 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-7 (a).

(c) 0.35 g of tert-butyl 5-bromo-3-cyano-2-pyrazinylcarbamate was dissolved in 10.5 ml of dimethyl sulfoxide. After adding 0.17 g of potassium fluoride, the mixture was first stirred at 70 ° C for 30 minutes and then at 90 ° C for 30 minutes to form tert-butyl 3-cyano-5-fluoro-2-pyrazinylcarbamate in the reaction system. Then, 0.17 g of potassium fluoride was added and stirred at 90 ° C. for 40 minutes. The temperature of the reaction mixture was brought to room temperature, and 30 ml of ethyl acetate and 60 ml of water were added to the mixture, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 3: 1] to obtain 20 mg of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-7 (a).

(d) 60 mg of N ′ - (3-cyano-5-fluoro-2-pyrazinyl) -N, N-dimethyliminoformide were suspended in a 2 ml solution of 6 mol / L hydrochloric acid. The resulting suspension was stirred at 80-90 ° C for 5.5 hours. The temperature of the reaction mixture was brought to room temperature, 5 ml of water was added, and the pH was adjusted to 9 with an aqueous solution of 2 mol / L sodium hydroxide. Then 5 ml of ethyl acetate was added, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Thus, 20 mg of 3-amino-6-fluoro-2-pyrazinecarbonitrile was obtained as a yellow solid.

(e) 0.3 g of 3-amino-2-pyrazinecarbonitrile was dissolved in 15 ml of acetonitrile. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to an ice-cooled solution at a rate of 45 ml per minute over a period of 20 minutes. Then, at a time when the temperature of the ice-cooled mixture was raised to room temperature, nitrogen gas was supplied to the mixture for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting oily product was purified by silica gel column chromatography [developing solution, n-hexane: ethyl acetate = 3: 1] to obtain 0.01 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow solid. colors.

Example II-8

(a) 17.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate was dissolved in 140 ml of a 70% solution of hydrogen fluoride in pyridine, while cooling the solution with ice. Then, 7.8 g of sodium nitrite was added at -50 ° C in three portions. After foaming stopped, the temperature was slowly raised and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of 300 ml of ice-cold water and 200 ml of chloroform, the precipitated insoluble product was filtered off, and then the organic layer was separated. The residual aqueous layer was extracted with ten portions of chloroform, provided that the total amount of liquid reached 500 ml. The organic layers were combined, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by 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.

IR (KBr) cm ^-1 : 1734

¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 4.08 (3H, s), 8.17 (1H, d, J = 8.5 Hz).

(b) 0.2 g of methyl 3,6-difluoro-2-pyrazinecarboxylate was dissolved in 4 ml of methanol. Then, a 28% methanol solution of sodium methoxide was added at −25 ° C. and the mixture was stirred at 0 ° C. for 10 minutes. The reaction mixture was poured into 30 ml of ethyl acetate and 30 ml of water, and the organic layer was separated. The organic layer was washed successively with 15 ml of water and 15 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by 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.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-8 (a).

Example II-9

0.1 g of methyl 6-chloro-3-nitro-2-pyrazinecarboxylate was dissolved in 2.0 ml of acetonitrile. After successive addition of 40 mg of potassium fluoride and 61 mg of 18-crown-6-ether, the mixture was stirred at room temperature for 1.5 hours. Then a mixture of 10 ml of ethyl acetate and 10 ml of water was added, the pH was adjusted to 7.0 with saturated aqueous sodium bicarbonate and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by 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 oily product.

IR (KBr) cm ^-1 : 1752, 1560

¹ H-NMR (CDCl ₃ ) δ: 4.06 (3H, s), 8.50 (1H, d, J = 8.3 Hz).

Example II-10

(a) 20 mg of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate was dissolved in 1.0 ml of acetic acid. After adding 6 mg of lead-etched lead palladium-calcium carbonate, hydrogen gas was supplied to the mixture at room temperature under a pressure of 1 atmosphere until the mixture ceased to absorb hydrogen gas. The insoluble product was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 5: 1] to obtain 2 mg of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a pale yellow solid.

IR (KBr) cm ^-1 : 1700

¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 6.29 (2H, br s), 8.15 (1H, d, J = 8.3 Hz).

(b) 0.5 g of methyl 3-amino-2-pyrazinecarboxylate was dissolved in 10 ml of acetic acid. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to the solution at room temperature at a rate of 23 ml per minute for 32 minutes. After the solution was stirred at room temperature for 30 minutes, the reaction mixture was added to a mixture consisting of 50 ml of a saturated aqueous sodium bicarbonate solution and 50 ml of ethyl acetate, and the organic layer was separated. The organic layer was washed successively with 10 ml of water and 10 ml of a saturated aqueous solution of sodium chloride and 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 = 3: 1] to obtain 0.01 g of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a pale yellow solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-10 (a).

Example II-11

(a) 10 mg of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate was dissolved in 1 ml of methanol. After adding 1 ml of a 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 precipitated product was filtered off. Thus, 4 mg of 3-amino-6-fluoro-2-pyrazinecarboxamide was obtained as a pale yellow solid.

IR (KBr) cm ^-1 : 1685

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 3.85 (4H, br s), 8.10 (1H, d, J = 7.3 Hz).

(b) 0.2 g of 3,6-dichloro-2-pyrazinecarboxylic acid was suspended in 2.0 ml of methylene chloride. Then, 0.001 ml of N, N-dimethylformamide and 0.14 ml of oxalyl chloride were successively added, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to dryness under reduced pressure, 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 mixture was stirred at 60 ° C. for 3 hours. Then, 3.0 ml of a 25% aqueous ammonia solution was added to the reaction mixture at room temperature, and the mixture 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, and the organic layer was separated. The organic layer was washed successively with 15 ml of water and 15 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The precipitated product was washed with diethyl ether and 0.12 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was obtained as a yellow solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-11 (a).

(c) 0.3 g of 3-amino-2-pyrazinecarboxamide was dissolved in 9 ml of trifluoroacetic acid. 10% fluorine gas (fluorine gas was diluted with nitrogen gas) was supplied to an ice-cooled solution at a rate of 45 ml per minute for 22 minutes. After stirring the mixture, which was cooled with ice, for 17 minutes the temperature of the mixture was raised to room temperature. The reaction mixture was added to a mixture consisting of 30 ml of a saturated aqueous solution of sodium bicarbonate and 30 ml of ethyl acetate, and the organic layer was separated. The remaining aqueous layer was acidified with a solution of 6 mol / L hydrochloric acid and then extracted with 20 ml of ethyl acetate. The organic layers were combined, washed successively with 10 ml of water and 10 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The 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.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-11 (a).

(d) 100 mg of 3-amino-2-pyrazinecarboxamide was dissolved in 5 ml of trifluoroacetic acid. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to an ice-cooled solution at a rate of 45 ml per minute for 36 minutes. While raising the temperature of the ice-cooled mixture to room temperature, nitrogen gas was supplied to the mixture for one hour. The reaction mixture was concentrated under reduced pressure to obtain 305 mg of an oily product. A portion of 251 mg was taken from the oily product and dissolved in 9.3 ml of water and heated under reflux for 4 hours. The liquid reaction mixture was cooled to room temperature and the precipitated product was filtered off. The filtrate was concentrated under reduced pressure, and the obtained solid product 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 product.

The physical properties of this compound coincided with the properties of the compound synthesized in example II-11 (a).

Example II-12

1.0 g of 3-hydroxy-2-pyrazinecarboxamide was suspended in 200 ml of water. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to the suspension at room temperature at a rate of 45 ml per minute over a period of 25 minutes. Then, nitrogen gas was introduced into the mixture for 45 minutes and the liquid reaction mixture was neutralized with calcium carbonate, the precipitated substance was filtered off, the filtrate was concentrated under reduced pressure, and the solid product was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 5: 1] to obtain 0.008 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white solid.

The physical properties of this compound coincided with the properties of the compound synthesized in example 1.

Example II-13

0.5 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 5 ml of toluene. After successively adding 0.41 ml of benzyl alcohol and 0.74 ml of triethylamine, the mixture was stirred at 80 ° C. for one hour. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 10: 1] to obtain 0.58 g of 3- (benzyloxy) -6-fluoro-2-pyrazinecarbonitrile as a white solid colors.

IR (KBr) cm ^-1 : 2236

¹ H-NMR (CDCl ₃ ) δ: 5.53 (2H, s), 7.3-7.6 (5H, m), 8.20 (1H, d, J = 8.1 Hz).

Example II-14

10.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 30 ml of dimethyl sulfoxide. After successively adding 50 ml of allyl alcohol and 14.8 ml of triethylamine to the solution, the mixture was stirred at 60 ° C. for 40 minutes. The reaction mixture was cooled to room temperature and 50 ml of toluene and 50 ml of water were poured into the mixture, and the organic layer was separated. The organic layer was washed successively with ten portions of 50 ml water each and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 10: 1] to obtain 11.5 g of 3- (allyloxy) -6-fluoro-2-pyrazinecarbonitrile as a pale yellow oily product.

IR (neat) cm ^-1 : 2238

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), 5.9-6.2 (1H, m), 8.20 (1H, d, J = 8.1 Hz).

Example II-15

2.5 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 25 ml of methanol. Then, 2.4 g of a 28% methanol solution of sodium methoxide was added dropwise to the solution at a temperature of 5-15 ° C., and the resulting ice-cooled mixture was stirred for 2 hours. The reaction mixture was poured into a mixture of 50 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by 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 oily product.

IR (neat) cm ^-1 : 2237

¹ H-NMR (CDCl ₃ ) δ: 4.12 (3H, s), 8.22 (1H, d, J = 8.1 Hz).

Example II-16

In a mixture of 140 ml of acetonitrile and 280 ml of toluene, 58 g of potassium fluoride (spray dried) and 8.7 g of 18-crown-6-ether were suspended. After heating the suspension under reflux for one hour in a nitrogen gas atmosphere, acetonitrile and toluene were distilled off at atmospheric pressure. The residue was suspended in 280 ml of acetonitrile, 23 g of 6-chloro-2-pyrazinecarbonitrile synthesized by the method described in Acta Poloniae Pharmaceutica, Vol. 33, Pages 153-161 (1976) were added, and the mixture was heated under reflux for one hour. nitrogen atmosphere. The reaction mixture was cooled to room temperature, 280 ml of ethyl acetate and 280 ml of water were added, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 10: 1] to obtain 10 g of 6-fluoro-2-pyrazinecarbonitrile as a white solid.

IR (KBr) cm ^-1 : 2244

¹ H-NMR (CDCl ₃ ) δ: 8.72 (1H, d, J = 8.1 Hz), 8.88 (1H, d, J = 3.7 Hz).

Example II-17

1.6 g of 6-fluoro-2-pyrazinecarbonitrile was dissolved in 10 ml of concentrated hydrochloric acid. The solution was stirred at 40 ° C for 2 hours. The reaction mixture was cooled to room temperature, a mixture of 25 ml of ethyl acetate and 10 ml of water was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 1: 1] to obtain 0.75 g of 6-fluoro-2-pyrazinecarboxamide as a light brown solid.

IR (KBr) cm ^-1 : 1713

¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, br s), 8.22 (1H, br s), 8.92 (1H, d, J = 8.0), 9 14 (1H, d, J = 4.4).

Example II-18

(a) 0.50 g of 6-fluoro-2-pyrazinecarboxamide was dissolved in 1.5 ml of trifluoroacetic acid. After adding 0.40 ml of 30% hydrogen peroxide, the mixture was stirred at 50-60 ° C for one hour. After the reaction mixture was cooled to 5 ° C, 5 ml of isopropyl alcohol was added. The precipitated product was collected by filtration and washed with 5 ml of isopropyl alcohol and 5 ml of diethyl ether to obtain 0.35 g of 3- (aminocarbonyl) -5-fluoropyrazin-1-ium-1-oleate as a white solid.

IR (KBr) cm ^-1 : 1708

¹ H-NMR (DMSO-d ₆ ) δ: 8.03 (1H, broad s), 8.25 (1H, broad s), 8.53 (1H, broad s), 8.70 (1H , dd, J = 1.2, 3.9 Hz).

(b) 0.39 g of 3- (aminocarbonyl) -5-fluoropyrazin-1-yum-1-oleate was suspended in 1.95 ml of phosphorus oxychloride. The mixture was stirred at 100 ° C. for 1.5 hours. After the reaction mixture was concentrated to dryness under reduced pressure, 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 organic layer, after which the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, the organic layer was separated and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [developing solution toluene: n-hexane = 3: 1] to obtain 3-chloro-6-fluoro-2-pyrazinecarbonitrile as an oily product.

(c) 0.3 g of 3-chloro-2-pyrazinecarbonitrile was dissolved in 15 ml of acetonitrile. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to an ice-cooled solution at a rate of 45 ml per minute for 20 minutes. Then, while raising the temperature of the ice-cooled mixture to room temperature, nitrogen gas was supplied to the mixture for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting oily product was purified by silica gel column chromatography [developing solution, n-hexane: ethyl acetate = 10: 1] to obtain 0.12 g of 3-chloro-6-fluoro-2-pyrazinecarbonitrile as a colorless oily product .

IR (KBr) cm ^-1 : 2232

¹ H-NMR (CDCl ₃ ) δ: 8.50 (1H, d, J = 8.1 Hz).

Example II-19

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 mixture was stirred at 145-150 ° C for 1.5 hours. The temperature of the reaction mixture was brought to room temperature, a mixture of 30 ml of ethyl acetate and 100 ml of water was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, toluene: ethyl acetate = 5: 1] to obtain 0.75 g of N '- (3-cyano-5-fluoro-2-pyrazinyl) -N, N-dimethyliminoformamide as a yellow solid. colors.

IR (KBr) cm ^-1 : 2230

¹ H-NMR (CDCl ₃ ) δ: 3.19 (6H, s), 8.18 (1H, d, J = 8.1 Hz), 8.54 (1H, s).

Example II-20

4.3 g of N- (5-bromo-3-cyano-2-pyrazinyl) benzamide were dissolved in 86 ml of dimethyl sulfoxide. After adding 8.3 g of potassium fluoride to the solution, the mixture was stirred at 110-115 ° C for one hour. The temperature of the reaction mixture was brought to room temperature, a mixture of 100 ml of ethyl acetate and 200 ml of water was added, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, treated with activated carbon and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, toluene: ethyl acetate = 5: 1] to obtain 0.47 g of N- (3-cyano-5-fluoro-2-pyrazinyl) benzamide as a white solid.

IR (KBr) cm ^-1 : 2238, 1670

¹ H-NMR (CDCl ₃ ) δ: 7.48-7.80 (3H, m), 8.03-8.21 (2H, m), 9.01 (1H, d, J = 8.1 Hz ), 11.67 (1H, s).

Example II-21

1.95 g of 6-chloro-3- (4-methoxyphenoxy) -2-pyrazinecarbonitrile was dissolved in 39 ml of dimethyl sulfoxide. After 2.16 g of potassium fluoride was added to the solution, the mixture was stirred at 100-110 ° C. for 3 hours. The temperature of the reaction mixture was brought to room temperature, a mixture of 40 ml of ethyl acetate and 200 ml of water was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The 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.

IR (KBr) cm ^-1 : 2238

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).

Example II-22

3.50 g of 3- [4- (benzyloxy) phenoxy] -6-chloro-2-pyrazinecarbonitrile was dissolved in 70 ml of dimethyl sulfoxide. After adding 3.01 g of potassium fluoride to the solution, the mixture was stirred at 100-110 ° C. for 3 hours. The temperature of the reaction mixture was brought to room temperature, and a mixture of 70 ml of ethyl acetate and 350 ml of water was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, toluene: ethyl acetate = 5: 1] to obtain 1.88 g of 3- [4- (benzyloxy) phenoxy] -6-fluoro-2-pyrazinecarbonitrile as a white solid.

IR (KBr) cm ^-1 : 2237

¹ H-NMR (CDCl ₃ ) δ: 5.07 (2H, s), 6.95-7.40 (9H, m), 8.13 (1H, d, J = 8.1 Hz).

Example II-23

0.3 g of methyl 3-chloro-2-pyrazinecarboxylate was dissolved in 15 ml of acetonitrile. 10% fluorine gas (fluorine gas diluted with nitrogen gas) was supplied to an ice-cooled solution at a rate of 45 ml per minute for 18 minutes. Then, while raising the temperature of the reaction mixture, cooled by ice, to room temperature, nitrogen gas was introduced into the mixture for one hour, and the reaction product was concentrated under reduced pressure. The oily product was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 10: 1] to obtain 0.03 g of methyl 3-chloro-6-fluoro-2-pyrazinecarboxylate as a colorless oily product.

IR (neat) cm ^-1 : 1736

¹ H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 8.43 (1H, d, J = 8.3 Hz).

Example II-24

3.0 g of 3,6-difluoro-2-pyrazinecarbonitrile was dissolved in 30 ml of dimethylformamide. Then, 2.6 g of hydroquinone was added to the ice-cooled solution, then 6.5 g of potassium carbonate, and the 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, the pH was adjusted to 5 with 6 mol / L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 3: 1] to obtain 0.75 g of 6-fluoro-3- (4-hydroxyphenoxy) -2-pyrazinecarbonitrile as a yellow solid.

IR (KBr) cm ^-1 : 3398, 2237

¹ H-NMR (DMSO-d ₆ ) δ: 6.82 (2H, d, J = 9.2 Hz), 7.05 (2H, d, J = 9.2 Hz), 7.40 (1H, c), 8.68 (1H, d, J = 8.1 Hz).

Example II-25

0.20 g of 6-chloro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile was dissolved in 3.6 ml of dimethyl sulfoxide. After successive addition of 0.42 g of potassium fluoride and 0.16 g of tetra-n-butylammonium bromide, the mixture was stirred at 50-60 ° C for 2.5 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 a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, toluene: n-hexane = 1: 2] to obtain 0.10 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile as a pale yellow oily product.

IR (neat) cm ^-1 : 2233

¹ H-NMR (CDCl ₃ ) δ: 7.10-7.70 (5H, m), 8.34 (1H, d, J = 8.1 Hz).

Example II-26

1.00 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile was dissolved in 10 ml of methylene chloride. Then, 1.00 g of m-chloroperbenzoic acid was added to the ice-cooled solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a mixture, 20 ml of chloroform and 20 ml of water, the pH was adjusted to 10 with potassium carbonate and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 2: 1] to obtain 0.42 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile as a pale yellow oily product.

IR (neat) cm ^-1 : 2237

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.75 (3H, m), 7.75-8.10 (2H, m), 8.68 (1H, d, J = 8.1 Hz )

Example II-27

1.00 g of 6-fluoro-3- (phenylsulfanyl) -2-pyrazinecarbonitrile was dissolved in 20 ml of methylene chloride. After adding to the ice-cooled solution 3.70 g of m-chloroperbenzoic acid, the mixture was stirred at room temperature for 4 hours. The insoluble product was filtered off from the reaction mixture and the filtrate was poured into a mixture of 50 ml of methylene chloride and 50 ml of water, the pH was adjusted to 7.5 with saturated aqueous sodium bicarbonate and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue and the solid product was collected by filtration to obtain 0.66 g of 6-fluoro-3- (phenylsulfonyl) -2-pyrazinecarbonitrile as a colorless solid.

IR (KBr) cm ^-1 : 2243

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.90 (3H, m), 7.95-8.30 (2H, m), 8.65 (1H, d, J = 8.3 Hz )

Example II-28

0.50 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile was dissolved in 5.00 ml of methanesulfonic acid. After adding 0.30 g of sodium nitrite to the solution at 7-9 ° C, the resulting ice-cooled mixture was stirred for 2.0 hours. The reaction mixture, the temperature of which was maintained at 10 ° C. or lower, was added dropwise to a mixture of 15 ml of ice water and 15 ml of ethyl acetate. The mixture was extracted with two 10 ml portions of ethyl acetate. The organic layer was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 100 ml of n-hexane and 50 ml of ethyl acetate, and the solution was washed three times with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. Thus, 0.12 g of 3-cyano-5-fluoro-2-pyrazinylmethanesulfonate was obtained as a colorless oily product.

IR (neat) cm ^-1 : 2246

¹ H-NMR (DMSO-d ₆₎ δ: 3,40 (3H, s), 8.95 (1H, d, J = 7,8 Hz).

Example II-29

3.0 g of 3,6-dichloro-2-pyrazinecarbonitrile was dissolved in 60 ml of dimethyl sulfoxide. After adding 3.0 g of potassium fluoride, the mixture was stirred at 90-100 ° C for 2 hours. The temperature of the reaction mixture was brought to room temperature, after which 2.1 g of 2-methyl-1,3-cyclopentanedione and 7.2 ml of triethylamine were successively added. The mixture was stirred at room temperature for one hour. The reaction mixture was added to a mixture of 50 ml ethyl acetate and 200 ml water, and the organic layer was separated. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent, n-hexane: ethyl acetate = 2: 1] to obtain 1.7 g of 6-fluoro-3 - [(2-methyl-3-oxo-1-cyclopenten-1-yl) oxy ] -2-pyrazinecarbonitrile as a yellow solid.

IR (KBr) cm ^-1 : 2238, 1707, 1676

¹ H-NMR (CDCl ₃ ) δ: 1.72 (3H, t, J = 1.8 Hz), 2.58-2.68 (2H, m), 2.76-2.91 (2H, m ), 8.29 (1H, d, J = 8.1 Hz).

Production Example 1

0.12 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 3.0 ml of methanol. Then, gaseous ammonia was fed into the solution cooled by ice for 10 minutes, after which the mixture was left at room temperature for 2 days. The solvent was removed under reduced pressure, the residue was added to a mixture of 30 ml of ethyl acetate and 30 ml of water, the pH was adjusted to 7.5 with saturated aqueous sodium bicarbonate and the organic layer was separated. After adding 30 ml of ethyl acetate to the residual aqueous layer, the pH was adjusted to 1.0 with 1 mol / L hydrochloric acid and the whole mixture was extracted with two 15 ml portions of ethyl acetate. The organic layers were combined, washed successively with 15 ml of water and 15 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The solid was washed with diisopropyl ether to give 0.015 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a yellow solid.

IR (KBr) cm ^-1 : 1685, 1671, 1655

¹ H-NMR (DMSO-d ₆ ) δ: 8.46 (1H, br s), 8.50 (1H, d, J = 7.8 Hz), 8.70 (1H, br s), 13.39 (1H, s).

Production Example 2

In a mixture of 3.44 ml of water and 0.5 ml of dioxane, 0.17 g of 3,6-difluoro-2-pyrazinecarboxamide was suspended. After adding 0.45 g of sodium bicarbonate, the mixture was stirred at 50 ° C. for 8.5 hours. Then, 0.95 ml of a 6 mol / L hydrochloric acid solution was added to the reaction mixture, the pH was adjusted to 1.0, and the precipitated solid was collected by filtration to obtain 89 mg of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a solid .

The physical properties of this compound coincided with the properties of the compound synthesized in Production Example 1.

Production Example 3

To 285 ml of 97% sulfuric acid at a temperature of 5-12 ° C., achieved by ice cooling, 28.5 g of 3-amino-6-fluoro-2-pyrazinecarboxamide was added to form a homogeneous solution. After adding 18.9 g of sodium nitrite to the solution at 5-12 ° C, the ice-cooled mixture was stirred for 1.5 hours. The reaction mixture, the temperature of which was maintained at not higher than 10 ° C, was added dropwise to 1.4 l of ice water, and the resulting mixture was first extracted with one portion of ethyl acetate 850 ml and then with two portions of ethyl acetate 200 ml each. The organic layers were combined, 400 ml of water was added, then 160 ml of a saturated aqueous solution of sodium bicarbonate was added, the pH was adjusted to 3.0 and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The 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.

The physical properties of this compound coincided with the properties of the compound synthesized in Production Example 1.

Production Example 4

In an aqueous sodium hydroxide solution prepared from 1.27 g of sodium hydroxide and 24.2 ml of water, 2.2 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved, while cooling the solution with water. After adding 2.75 ml of 30% hydrogen peroxide at the same temperature as described above, the resulting mixture was stirred at 40 ° C. for 1.5 hours. After adding 2.77 ml of concentrated sulfuric acid to an ice-cooled reaction mixture, the resulting mixture was cooled to 10 ° C. The precipitated crystalline product was 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.

The physical properties of this compound coincided with the properties of the compound synthesized in Production Example 1.

Industrial application

Derivatives of pyrazine or their salts according to the present invention, namely the compounds according to the present invention, have excellent antiviral activity and are used as a pharmaceutical drug. In addition, intermediates according to the present invention, namely, compounds represented by the general formula [21], are used as intermediates for the synthesis of pyrazine derivatives or their salts according to the present invention, namely, compounds according to the present invention, and also as intermediates for synthesis of known compounds that are used as prophylactic and therapeutic agents in the case of viral infections and especially in the case of influenza virus infections.

Claims (13)

1. Derivatives of pyrazine represented by the following general formula:

where R ¹ represents a hydrogen atom or a halogen atom; R ² represents a hydrogen atom or a protected or unprotected group of monophosphoric, diphosphoric or triphosphoric acid; R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, are a hydrogen atom, a halogen atom, substituted or unsubstituted, protected or unprotected hydroxyl or amino group, or R ⁴ and R ⁶ taken together form a simple communication; A represents an oxygen atom or a methylene group; n is 0 or 1; Y represents an oxygen atom or an NH group, or their salts, provided that compounds in which R ¹ represents hydrogen or a halogen atom, R ² represents hydrogen, R ³ and R ⁵ represent hydrogen, R ⁴ and R ⁶ represent a substituted or unsubstituted, protected or unprotected hydroxyl group, A represents an oxygen atom, n = 0, and Y represents an oxygen atom, are excluded. 2. The pyrazine derivatives or their salts according to claim 1, where R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, represent a hydrogen atom, a halogen atom, a substituted or unsubstituted, protected or unprotected hydroxyl group, or R ⁴ and R ⁶ taken together form a single bond. 3. Derivatives of pyrazine or their salts according to claims 1 and 2, where R ² represents a hydrogen atom or a protected or unprotected group of monophosphoric or triphosphoric acid. 4. Derivatives of pyrazine or their salts according to any one of claims 1 to 3, where R ² represents a hydrogen atom or a protected or unprotected monophosphoric acid group, R ³ , R ⁴ , R ⁵ and R ⁶ , which may be the same or different, represent a hydrogen atom or a protected or unprotected hydroxyl group, A represents an oxygen atom and n = 0. 5. Derivatives of pyrazine or their salts according to any one of claims ^{1 to 4} , where R ² represents a hydrogen atom. 6. Derivatives of pyrazine or their salts according to any one of claims 1 to 5, where Y represents an oxygen atom. 7. A pharmaceutical composition having antiviral activity and containing a compound or its salt according to any one of claims 1 to 6. 8. The pharmaceutical composition according to claim 7, where the specified pharmaceutical composition is an antiviral agent. 9. The pharmaceutical composition of claim 8, where the virus is an influenza virus, RS virus (Routh sarcoma) and rotavirus. 10. The pharmaceutical composition according to claim 9, where the specified virus is an influenza virus. 11. A derivative of fluoropyrazine represented by the following general formula:

Where R ²¹ represents a nitrile group or a protected or unprotected carbamoyl or carboxyl group; R ²² represents a hydrogen atom, a halogen atom, a protected or unprotected hydroxyl group or an amino group, a nitro group, an azido group or a substituted or unsubstituted phenylsulfanyl, phenylsulfinyl or phenylsulfonyl group; with the proviso that a compound wherein R ²¹ is a carbamoyl group or a carbamoyl group substituted with an acyl group and R ²² is a hydroxyl group is excluded, or its salt. 12. The fluoropyrazine derivative or a salt thereof according to claim 11, wherein R ²² represents a protected or unprotected hydroxyl group or amino group, a halogen atom, a nitro group or an azido group. 13. The fluoropyrazine derivative or a salt thereof according to claim 11 or 12, wherein R ²¹ is a carbamoyl group, a nitrile group, or a protected or unprotected carboxyl group.