JPS6218550B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is based on the general formula [In the formula, R ¹ _a is an amino group or a protected amino group, R ¹ _b and R ¹ _c are each a hydrogen atom, a halogen atom, a lower alkoxy group, or an arylthio group, and R ¹⁴ is a carboxy group or a protected carboxy group. , X is the expression

[Formula] (wherein R ⁶ is a hydrogen atom, a lower alkyl group, a mono-, di-, or trihalo-(lower) alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an alkyl group, or a halo-(lower) alkyl group) a group represented by (meaning an alkanoyl group),
Z means N or CH, respectively] and their production methods. In the object compound of this invention () and the cephalosporanic acid derivative () described below, the formula in the structural formula of each molecule is

It includes syn isomers, anti isomers, and mixtures of these isomers, which are geometric isomers derived from the partial structure represented by the formula. Here, the syn isomer is the formula (In the formula, R ¹ _a , R ¹ _b , R ¹ _c , R ⁶ and Z have the same meanings as above) (wherein R ¹ _a , R ¹ _b , R ¹ _c , R ⁶ and Z have the same meanings as above). Preferred examples of salts of the object compound () of this invention include salts with inorganic bases such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts;
Examples include salts with organic bases such as trimethylammonium salts and triethylammonium salts, and acid salts such as hydrochloric acid. The object compound () of this invention is a new compound, for example, the following known compounds (A-1), (B
-1), (C-1a) and (D-1a) according to Manufacturing Methods A to Q shown below. Here, the above-mentioned known compounds (A-1), (B-
1), (C-1a) and (D-1a) are described, for example, in the following literature. Compound (A-1) (Journal of Organic Chemistry, Volume 27, Page 3608) Compound (B-1) (Journal of the American Chemical Society, Vol. 69, p. 2657) Compound (C-1a) (Chemical Abstracts Vol. 54, p. 6709) (Chemical Abstracts Vol. 52, No. 7313g
page) (Chemical Abstracts Vol. 53, p. 7162c) (Universal Future Practitioners Chemie, Reich 4, Volume 13, Page 58) Compound (D-1a) (Proceedings of the 9th Heterocyclic Chemistry Conference, p. 146) (A) Production method A: (B) Manufacturing method B: (C) Manufacturing method C: (D) Manufacturing method D: (E) Manufacturing method E: (F) Manufacturing method F: (G) Manufacturing method G: (H) Manufacturing method H: (I) Manufacturing method I: (J) Manufacturing method J: (K) Manufacturing method K: (L) Manufacturing method L: (M) Manufacturing method M: (N) Manufacturing method N: (O) Manufacturing method O: (P) Manufacturing method P: (Q) Manufacturing method Q: [In the formula, R ¹ _a , R ¹ _b , R ¹ _c , R ⁶ , R ¹⁴ and Z
each has the same meaning as above, R ¹ ′ _a is a protected amino group, R ⁶ ′ is a lower alkyl group, a mono-, di- or trihalo (lower) alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an alkyl group, a (lower) alkyl group or halo (lower) alkanoyl group, R ⁸ is a halogen atom, R ⁹ is a protected carboxy group, R ¹⁰ is a lower alkyl group, R ¹¹ is a lower alkoxy group or arylthio group, R ¹² is a hydrogen atom or lower alkyl group, R ¹³ is a protected carboxy group or formula −X ₄ −R ¹⁴ or formula

[Formula] (wherein, X ₄ is a lower alkylene group, R ⁶ and R ¹⁴ have the same meanings as above), R ¹⁵ is a hydrogen atom or a halogen atom, and X ₁ is a lower alkylene group or the formula

[Formula] (wherein R ⁶ has the same meaning as above), X ₂ is a lower alkylene group or a group -
CO− or formula

A group represented by [Formula] (in which R ⁶ has the same meaning as above), X ₃ is a group -CO- or the formula

[Formula] (In the formula, R ⁶ has the same meaning as above) respectively] The object compound () of the present invention is, for example, a group represented by the general formula (In the formula, R ¹ _a , R ¹ _b , R ¹ _c , X and Z each have the same meaning as above, R ² is a hydrogen atom or a lower alkoxy group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is hydrogen atom, a halogen atom, a carbamoyloxymethyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxymethyl group, a lower alkanoylthiomethyl group, or a heterocyclic thiomethyl group that may have an appropriate substituent, R ⁵ is carboxy or a derivative thereof] is useful as a raw material for synthesizing a cephalosporanic acid derivative or its salts useful as a preventive/therapeutic agent for bacterial infections.The salt in this cephalosporanic acid derivative () is For example, alkali metal salts of alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts,
Salts with inorganic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pididine salts, picoline salts, dicyclohexylamine salts, N,
Salts with organic amines such as N'-benzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts, right salts, acetates, maleates, tartaric acid Salts, salts with organic carboxylic acids or sulfonic acids such as methanesulfonates, benzenesulfonates, and toluenesulfonates; salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, and phosphates; , salts with basic or acidic amino acids such as arginine salt, aspartate, glutamate, and the like. This cephalosporanic acid derivative () and its salts can be produced by the process shown below.

[Table] If
is that
salts
Or that
Salts of (wherein R ¹ _a , R ¹ _b , R ¹ _c , R ² , R ³ , R ⁴ , R ⁵ ,
X
and Z have the same meanings as above) Next, the definition of the above general formula will be explained. In this specification, unless otherwise specified, the term "lower" means carbon atoms of 1 to 6. Protected amino groups and protected amino-substituted (lower) alkyl groups include acyl groups, al(lower) alkyls such as benzyl, trityl and diphenylmethyl, substituted phenylthio such as 2-nitrophenylthio, Protecting groups for amino groups other than acyl groups such as substituted aralkylidenes such as 4-nitrobenzylidene, substituted alkylidenes such as 1-methoxycarbonyl-2-propylidene, substituted (lower) cycloalkylidenes such as 2-ethoxycarbonylcyclohexylidene, etc. Examples include groups used as Here, the acyl group is an acyl group derived from carboxylic acid, sulfonic acid, or carbamic acid, and more specifically includes an acyl group containing a substituted or unsubstituted carbamoyl group, an aliphatic acyl, an aromatic ring, or a heterocycle. Specific examples of the acyl group defined in this way are as follows. Examples of aliphatic acyl include formyl, acetyl, propionyl, butyryl, isobutyryl,
Lower alkanoyl groups such as isovaleryl, oxalyl, succinyl, pivaloyl, lower cycloalkanecarbonyl groups such as cyclopentanecarbonyl, cyclohexanecarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyl Lower alkoxycarbonyl groups such as oxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, lower cycloalkyl (lower) alkoxycarbonyl groups such as 1-cyclopropylethoxycarbonyl, lower alkoxy such as methoxyacetyl, ethoxyacetyl, methoxypropionyl, etc. Examples include alkanoyl groups, and lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, and butanesulfonyl groups. Examples of the acyl containing an aromatic ring include alkanoyl groups such as phenylacetyl and phenylpropionyl, alkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl, benzenesulfonyl, tosyl, and the like. Examples include arenesulfonyl groups, benzoyl, toluoyl, naphthoyl, phthaloyl, aroyl groups such as indancarbonyl, and the like. Examples of acyls containing heterocycles include thienylacetyl, furylacetyl, prolylacetyl,
Heterocyclic substituted (lower) alkanoyl groups such as thiadiazolyl acetyl, tetrazolylacetyl, piperazinyl acetyl, heterocyclic oxycarbonyl groups such as 8-quinolyloxycarbonyl, thenoyl,
Examples include heterocyclic carbonyl groups such as furoyl, nicotinoyl, isonicotinoyl, pyrrole carbonyl, pyrrolidine carbonyl, and tetrahydropyran carbonyl, and heterocyclic substituted (lower) alkoxycarbonyl groups such as 2-pyridylmethoxycarbonyl. Examples of substituted or unsubstituted carbamoyl groups include carbamoyl groups, lower alkylcarbamoyl groups such as methylcarbamoyl and ethylcarbamoyl, arylcarbamoyl groups such as phenylcarbamoyl, alk(lower)alkylcarbamoyl groups such as benzylcarbamoyl and tritylcarbamoyl, and formyl. Examples include lower alkanoylcarbamoyl groups such as carbamoyl and acetylcarbamoyl, and mono-, di-, or trihalo(lower) alkanoylcarbamoyl groups such as chloroacetylcarbamoyl and trichloroacetylcarbamoyl. The above acyl group may have 1 to 3 suitable substituents at any position, such as chromium, bromo, iodo,
Acyls such as halogen atoms such as fluoro, hydroxy groups, cyano groups, nitro groups, lower alkoxy groups, lower alkyl groups, lower alkenyl groups, mono-, di-, or trihalo (lower) alkanoyls such as chloroacetyl, dichloroacetyl, trichloroacetyl, etc. and aryl groups such as phenyl and tolyl. Preferred examples of the amino protecting group include acyl groups, and more preferred examples include lower alkanoyl groups, mono-, di-, or trihalo(lower) alkanoyl groups, and lower alkoxycarbonyl groups. A lower alkyl group is a linear or branched saturated aliphatic hydrocarbon residue, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, Examples include tertiary pentyl and hexyl, and more preferably an alkyl group having 1 to 4 carbon atoms. a lower alkyl group, a mono- or di- or trihalo(lower) alkyl group in R ⁶ and R ⁶ ′;
Specific examples of the lower alkenyl group, lower alkynyl group, aryl group, a(lower) alkyl group, and halo(lower) alkanoyl group are as follows. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc. Mono-, di-, or trihalo(lower) alkyl groups include For example, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl,
Dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc. are mentioned, and lower alkenyl groups include, for example, vinyl, 1-propenyl, allyl, 1-methylallyl, 1-, 2- or 3-butenyl, 1-, 2 -, 3- or 4-pentenyl, 1-, 2-, 3-, 4- or 5-hexenyl, etc., and lower alkynyl groups include, for example, ethynyl, 1-propynyl,
propargyl, 1-methylpropargyl, 1-,
2- or 3-butynyl, 1-, 2-, 3- or 4-pentynyl, 1-, 2-, 3-, 4-
or 5-hexynyl, etc.; examples of the aryl group include phenyl, tolyl, xylyl, cumenyl, naphthyl, etc.; examples of the alkyl group include phenyl (lower) such as benzyl, phenethyl, phenylpropyl, etc. (low grade)
Examples of the halo(lower)alkanoyl group include chloroacetyl, dichloroacetyl, and the like. Lower alkoxy groups include linear or branched groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, neopentyloxy, hexyloxy. etc., and more preferably an alkoxy group having 1 to 4 carbon atoms. Examples of the halogen atom include chromium, bromine, iodine, and fluoro. Examples of the lower alkanoyloxymethyl group include acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, etc. Can be mentioned. Examples of the lower alkanoylthiomethyl group include acetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, isobutyrylthiomethyl, valerylthiomethyl, isovalerylthiomethyl, pivaloylthiomethyl, hexanoylthiomethyl, and the like. The heterocyclic moiety in the heterocyclic thiomethyl group which may have an appropriate substituent is a saturated or unsaturated monocyclic or polycyclic ring containing at least one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. A ring heterocyclic group, such as a pyrrolyl group, pyrrolinyl group, imidazolyl group, pyrazolyl group, pyridine group and its N-oxide, pyrimidinyl group, pyrazinyl group, pyridazinyl group, 4H -1,2,4-
3 containing 1 to 4 nitrogen atoms, such as triazolyl groups such as triazolyl, 1H-1,2,3-triazolyl, and 2H-1,2,3-triazolyl, and tetrazolyl groups such as 1H-tetrazolyl and 2H-tetrazolyl; ~6-membered unsaturated monocyclic heterocyclic group, 3 to 6 containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperazino, piperazinyl, etc.
Member saturated monocyclic heterocyclic group, indolyl group, isoindolyl group, indolizinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, indazolyl group, benzotriazolyl group, tetrazolo[1,
5-b] Unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms such as tetrazolopyridazinyl group such as pyridazinyl, oxazolyl group, isoxazolyl group, 1,2,4-oxadiazolyl, 1, 3,
3- to 4-oxadiazolyl groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxadiazolyl groups such as 4-oxadiazolyl and 1,2,5-oxadiazolyl
1 of 6-membered unsaturated monocyclic heterocyclic group, morpholinyl, etc.
A 3- to 6-membered saturated monocyclic heterocyclic group containing ~2 oxygen atoms and 1 to 3 nitrogen atoms, 1 to 2 oxygen atoms, such as benzoxazolyl, benzoxadiazolyl, etc. unsaturated fused heterocyclic group containing 3 nitrogen atoms, thiazolyl group, 1,2,
3- to 6-membered unsaturated monomers containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiadiazolyl groups such as 4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,5-thiadiazolyl; 3- to 6-membered saturated monocyclic heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a ring heterocyclic group, thiazolidinyl, 1 to 2 rings, such as benzothiazolyl, benzothiadiazolyl, etc. Examples include unsaturated fused heterocyclic groups containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms, and such heterocyclic groups have 1 to 4 substituents at arbitrary positions. Examples of such substituents include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl,
Lower alkyl or lower cycloalkyl groups such as pentyl, cyclopentyl, hexyl, cyclohexyl, vinyl, allyl, 1-, 2- or 3-propenyl, 1-, 2-, 3- or 4-
Butenyl, 1-, 2-, 3-, 4- or 5-
Lower alkenyl groups such as pentenyl, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3
-Amino(lower)alkyl groups such as aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, lower alkoxy groups such as tertiary-butoxycarbonylaminomethyl, 2-(tertiary-butoxycarbonylamino)ethyl, etc. Protected amino(lower)alkyl groups such as carbonylamino(lower)alkyl, carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxy Carboxy (lower) alkyl groups such as hexyl, sulfomethyl,
Sulfo (lower) such as 2-sulfoethyl, 2-sulfopropyl, 3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl, 6-sulfohexyl, etc.
Alkyl group, phenyl, 2-, 3- or 4-
1 to 3 halogen atom substituted or unsubstituted phenyl groups such as chlorophenyl, 2-, 3- or 4-bromophenyl, N-methylaminomethyl,
N,N-dimethylaminomethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl, 3-(N-methyl amino)propyl, 3-(N,N-dimethylamino)propyl,
3-(N,N-diethylamino)propyl, 4-
(N-methyl-N-ethylamino)butyl, 5-
Lower alkylamino (lower) such as (N-methylamino)pentyl, 5-(N,N-dimethylamino)pentyl, 6-(N,N-diethylamino)hexyl, 6-(N,N-dimethylamino)hexyl, etc.
Examples include alkyl groups. Preferred examples of the heterocyclic group thus defined include a thiadiazolyl group substituted with a group selected from lower alkyl, amino (lower) alkyl and lower alkoxycarbonylamino (lower) alkyl, Substituted with a group selected from oxadiazolyl, lower alkyl, carboxy (lower) alkyl, lower alkenyl, amino (lower) alkyl, and lower alkoxycarbonylamino (lower) alkyl, which may have a halogen atom substituted or unsubstituted phenyl Examples include a tetrazolyl group, a pyrazinyl group, a tetrazolopyrazinyl group, and the like. Examples of lower alkylene groups include methylene,
Ethylene, trimethylene, 1-methylethylene, etc., preferably groups consisting of 1 to 2 carbon atoms,
More preferred is methylene. Derivatives of carboxy groups include protected carboxy groups such as esterified carboxy groups, examples of such esters include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, Lower alkyl esters such as tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, and 1-cyclopropyl ester; lower alkenyl esters such as vinyl ester and allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; Methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester,
Lower alkoxyalkyl esters such as 1-methoxyethyl ester and 1-ethoxyethyl ester, lower alkylthioalkyl esters such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, 2-iodoethyl ester,
Mono-, di- or trihalo (lower) alkyl esters such as 2,2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, lower alkanoyloxy (lower) alkyl ester such as hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, lower alkanesulfonyl (lower) alkyl ester such as mesyl methyl ester, mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5 - Al (lower) alkyl esters such as phenyl (lower) alkyl esters which may have one or more substituents such as di-tertiary butyl benzyl esters;
Substituted or unsubstituted phenyl esters such as phenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, tri( Examples include lower alkylthioesters such as lower) alkylsilyl esters, methylthioesters, and ethylthioesters. As the protected carboxy group, specific examples of the esterified carboxy group exemplified in the above-mentioned carboxy group derivatives can be mentioned. Next, manufacturing methods A to Q of the object compound () of this invention
I will explain in detail. (A) Manufacturing method A: Compound (A-3) or its salt is prepared by adding compound (A-2) to compound (A-1) or its salt.
It can be produced by reacting. This reaction is usually carried out in the presence of a base in a solvent that does not adversely affect the reaction. Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide;
Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, magnesium carbonate,
Alkaline earth metal carbonates such as calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, disodium hydrogen phosphate, and dihydrogen phosphate. Inorganic bases such as alkali metal hydrogen phosphates such as potassium, alkali metal acetates such as sodium acetate and potassium acetate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and sodium propoxide, trialkylamines such as trimethylamine and triethylamine. , picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-nonene, 1,
4-diazabicyclo[2,2,2]octane,
Examples include organic bases such as 1,5-diazabicyclo[5,4,0]-5-undecene. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. (B) Manufacturing method B: Compound (A-3) or a salt thereof is obtained by adding compound (B-1) to compound (A-1) or a salt thereof.
Alternatively, it can be produced by reacting its salts. This reaction is substantially the same as Production Process A, and therefore, the description of Production Process A above can be applied as is to the reaction conditions such as use of a base, reaction temperature, and solvent. (C) Production method C: Compound (C-2) or a salt thereof can be produced by reacting compound (C-1) or a salt thereof with carbon dioxide. This reaction is usually carried out in the presence of a base such as an alkyllithium such as butyllithium in a solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. (D) Production method D: Compound (D-2) or its salts can be produced by reacting compound (D-1) or its salts with a halogenating agent. As the halogenating agent used in this reaction, a halogenating agent commonly used for halogenating a hydroxy group can be used, and examples of such halogenating agents include phosphorus oxychloride, phosphorus trichloride, and phosphorus trichloride.
Examples include phosphorus compounds such as phosphorus bromide and phosphorus pentachloride. This reaction is usually carried out in a solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, the reaction is often carried out at or under heating. (E) Production method E: Compound (E-2) can be produced by subjecting compound (E-1) to a reductive dehalogenation reaction. The reductive dehalogenation reaction used in this method is carried out by catalytic reduction using a conventional catalyst such as palladium on carbon, palladium black, or palladium sponge. This reaction is usually carried out in a solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, it is often carried out at room temperature. (F) Production method F: Compound (F-2) or a salt thereof can be produced by reacting compound (F-1) or a salt thereof with a nucleophilic compound selected from alkanols and frenethiol or a salt thereof. This reaction is usually carried out in the presence of a base as exemplified in Production Method A in a solvent that does not adversely affect the reaction. Although the reaction temperature is not particularly limited, it is often carried out under cooling or at room temperature. (G) Production method G: Compound (G-2) or a salt thereof can be produced by reacting compound (G-1) or a salt thereof with an agent for introducing a carboxy protecting group. Examples of carboxy-protecting group introducing agents used in this production method include alkyl halides such as methyl iodide, di(lower) alkyl sulfates such as dimethyl sulfate, diazo(lower) alkanes such as diazomethane, and lower alkanes such as methanol and ethanol. Examples include alkanol. This reaction is usually carried out in the presence of an acid in a solvent that does not adversely affect the reaction. Examples of the acids used include inorganic or organic acids such as dinic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or heating. (H) Production method H: Compound (H-2) is produced by reacting compound (H-1) with a compound represented by the general formula R ¹⁰ SCH ₂ SOR ¹⁰ (wherein R ¹⁰ has the same meaning as above). can. This reaction is usually carried out in the presence of a base as exemplified in Production Method A in a solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or heating. (I) Production method I: Compound (I-1) can be produced by reacting compound (H-2) with an acid and/or acid anhydride such as acetic acid and/or acetic anhydride. This reaction takes place in the coexistence of alkali metal perchlorates such as sodium perchlorate and potassium perchlorate, alkaline earth metal perchlorates such as magnesium perchlorate and calcium perchlorate, and organic carboxylic acids such as diic acid. It is preferable to do so. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction at or under heating. (J) Production method J: Compound (J-2) or a salt thereof can be produced by subjecting compound (J-1) to an elimination reaction of the carboxy protecting group. For this reaction, methods used for the usual elimination reactions of carboxy protecting groups, such as hydrolysis and reduction, are applied, and the methods of hydrolysis and reduction, as well as reaction conditions such as reaction temperature and solvent, are explained in Production Method N below. This is substantially the same as the method for removing the amino protecting group, and therefore the explanation for Production Method N can be applied as is. (K) Production method K: Compound (K-2) or a salt thereof can be produced by reacting compound (K-1) or a salt thereof with an agent for introducing an amino protecting group. When the amino-protecting group-introducing agent used in this reaction is an acylating agent, the reaction is substantially the same as the method explained in the process below, and therefore the explanation can be applied as is. (L) Production method L: Compound (L-2) can be produced by oxidizing compound (L-1). For the oxidation of this reaction, a conventional method for converting an active methylene group into a carbonyl group can be applied, and such oxidation is carried out using an oxidizing agent such as gelene dioxide. This reaction is usually carried out in a solvent that does not adversely affect the reaction, and although the reaction temperature is not particularly limited, it is often carried out with or under heating. (M) Production method M: Compound (M-2) or a salt thereof is a compound (M-1) or a hydrate thereof or a salt thereof having the general formula R ⁶ -ONH ₂ (wherein R ⁶ has the same meaning as above).
Alternatively, it can be produced by reacting its salts. This reaction is usually carried out in a solvent that does not adversely affect the reaction, and the compound R ⁶ −
When salts of ONH ₂ are used, the reaction is preferably carried out in the presence of a base such as those listed in Preparation A above. Although the reaction temperature is not particularly limited, it is often carried out at a heating room temperature. (N) Production method N: Compound (N-2) or a salt thereof can be produced by subjecting compound (N-1) or a salt thereof to an amino-protecting group elimination reaction. This elimination reaction is carried out by conventional methods such as hydrolysis and reduction, and such methods are appropriately selected depending on the type of protecting group to be eliminated. Hydrolysis here includes acid hydrolysis, base hydrolysis, hydrazine decomposition, etc. Among these, acid hydrolysis involves substitution of tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, trichloroethoxycarbonyl, etc. or unsubstituted alkoxycarbonyl group, substituted or unsubstituted alkanoyl group such as formyl, lower cycloalkoxycarbonyl group, benzyloxycarbonyl group,
Substituted or unsubstituted alkoxycarbonyl groups such as substituted benzyloxycarbonyl, alkyl groups such as benzyl and trityl,
It is applied to the removal of protecting groups such as substituted phenylthio groups, substituted aralkylidene groups, substituted alkylidene groups, and substituted (lower) cycloalkylidene groups. Examples of the acid used for hydrolysis with this acid include inorganic or organic acids such as syllic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid, and preferably syllic acid, trifluoroacetic acid, Examples include solvents that can be easily distilled off from the reaction mixture, such as hydrochloric acid, by operations such as vacuum distillation. The acid used in this hydrolysis is appropriately selected depending on the type of protecting group to be removed, and the hydrolysis can be carried out in the presence or absence of a solvent. Here, as the solvent used for this hydrolysis, a usual organic solvent, water, a mixed solvent thereof, etc. are used. When this acid hydrolysis is carried out in the presence of trifluoroacetic acid, the reaction is preferably carried out in the presence of anisole. In addition, hydrolysis with a base can be applied to remove the protective group of a haloalkanoyl group such as trifluoroacetyl, and the bases used include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, magnesium hydroxide, Alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate,
Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, and alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, etc. Inorganic bases, alkali metal acetates such as sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide,
Alkali metal alkoxides such as sodium propoxide, trialkylamines such as trimethylamine and triethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-
diazabicyclo[4,3,0]-5-nonene,
1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-5
-Organic bases such as undecene. This hydrolysis with a base is often carried out in water, a hydrophilic solvent, an organic solvent containing a small amount of water, or a mixed solvent thereof. In addition, decomposition with hydrazine usually results in succinyl,
Applicable to removal of protecting groups such as phthaloyl. The amino protecting group is eliminated by the above hydrolysis to generate a free amino group, but methods of elimination other than hydrolysis will be described in detail below. The elimination reaction of the amino protecting group by reduction is a halo (lower) alkoxycarbonyl group such as trichloroethoxycarbonyl, a substituted or unsubstituted aralkoxycarbonyl group such as benzyloxycarbonyl, substituted benzyloxycarbonyl, 2-pyridylmethoxycarbonyl group, It can be applied to the elimination reaction of protecting groups such as benzyl groups, and as reducing agents, for example,
Examples include alkali metal borohydrides such as sodium borohydride. Further, when the protecting group is a halo(lower) alkoxycarbonyl group or an 8-quinolyloxycarbonyl group, this may be achieved by treatment with a heavy metal such as copper or zinc. The reaction temperature for the above elimination reaction is not particularly limited and is appropriately selected depending on the type of protecting group to be eliminated and the elimination method to be applied, but it is usually carried out under mild conditions such as cooling, room temperature, or heating. There are many things. (O) Production method O: Compound (O-2) or a salt thereof can be produced by reacting compound (O-1) or a salt thereof with a nitrosating agent. Examples of nitrosating agents include alkali metal nitrites such as sodium nitrite and potassium nitrite. This reaction is usually carried out in a solvent that does not adversely affect the reaction, and the reaction temperature is not particularly limited, but it is usually carried out under cooling or at room temperature. (P) Production method P: Compound (P-2) or its salts are added to compound (P-1) or its salts by adding a hydrogen atom of the hydroxy group to the group R ⁶ ' (in the group, R ⁶ ' is the same as above). It can be produced by reacting a substituent that can be substituted with (meaning). This reaction is usually carried out in a solvent that does not adversely affect the reaction, and although the reaction temperature is not particularly limited, it is often carried out under cooling or at room temperature. (Q) Production method Q: Compound (Q-2) or its salts can be produced by reacting compound (Q-1) or its salts with a halogenating agent. The halogenating agent used in this reaction can be any conventional halogenating agent used for halogenating aromatic rings, and examples of such halogenating agents include halogens such as chlorine and bromine. This reaction is usually carried out in a solvent that does not adversely affect the reaction, and although the reaction temperature is not particularly limited, it is often carried out at room temperature. Next, the method for producing the cephalosporanic acid derivative () will be described in detail. Process: A cephalosporanic acid derivative () or a salt thereof is added to a 7-aminocephalosporanic acid derivative () or a reactive derivative at its amino group or a salt thereof to a carboxylic acid (a) or a reactive derivative at its carboxy group or a salt thereof. It can be produced by reacting. The starting material for this method, the 7-aminocephalosporanic acid derivative (), is a known compound and can be easily prepared by one skilled in the cephalosporin art. In this process, reactive derivatives used in normal amidation reactions can be used as reactive derivatives at the amino group of the compound (), and such reactive derivatives include, for example,
Silyl derivatives produced by silyl compounds such as bis(trimethylsilyl)acetamide and trimethylsilylacetamide and compounds (); isocyanates or isothiocyanates; With aldehyde compounds such as nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, and thiophenecarbaldehyde, or ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, and acetoacetic acid ethyl ester. Schiff's base formed or its enamine type tautomer; and the like. Specific examples of the carboxy group derivatives and salts in compound () include the specific examples of the carboxy group derivatives and salts exemplified in compound () above. Examples of reactive derivatives at the carboxy group of compound (a) include acid halides, acid anhydrides,
Active amides, active esters, etc., preferably acid halides such as acid chlorides and acid bromides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acids; , alkyl carbonates such as sulfite, methyl carbonate, ethyl carbonate, propyl carbonate, aliphatic carboxylic acids such as pivalic acid, valeric acid, isovaleric acid, 2-ethylbutanoic acid, trichloroacetic acid, and aromatic carboxylic acids such as benzoic acid. Acid anhydride or symmetric acid anhydride; active amide with imino group-containing heterocyclic group such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propargyl ester, p
-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
Pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidinyl ester, 8-quino Lythioester or N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc. Examples include active esters such as esters with N-hydroxy compounds, and such reactive derivatives are appropriately selected depending on the type of compound (a) used. This reaction typically involves water, acetone, dioxane,
The reaction is carried out in acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, or an organic solvent that does not have an adverse effect on the reaction. It can also be used in combination with This reaction is usually carried out under cooling. When carboxylic acid (a) is used in this reaction in the free or salt form, N,N'-
Dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,
N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl)carbodiimide; Ketenimine compounds such as N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; ethoxyacetylene, β- Olefinic or acetylenic ether compounds such as chlorovinylethyl ether; sulfonic acid esters of N-hydroxybenzotriazole derivatives such as 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; trialkyl phosphites; Ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride,
Phosphorus compounds such as triphenylphosphine; thionyl chloride; oxalyl chloride; N-ethylbenzisoxazolium salt; N-ethyl-5-phenylisoxazolium-3-sulfonic acid; dimethylformamide, diethylformamide, N
- It is preferable to carry out the reaction in the presence of a condensing agent such as the so-called Vils-Meyer reagent obtained by the reaction of an amide compound such as methylformamide with thionyl chloride, phosphorus oxychloride, phosgene, etc. In each of the above production methods and processes, the syn or anti isomer may be converted into an anti or syn isomer, respectively, during the reaction or post-treatment of the reaction, and such cases are also included in this production method and process. Next, examples of the present invention will be described. Example 1 (1) A 15% n-hexane solution (636 g) of n-butyllithium was added to a solution of 6-amino-2-methylpyridine (64.8 g) in tetrahydrofuran (500 ml) at -20 to -30°C. It took a while to add, -8~
Stirred at -10°C for 30 minutes. −15 to − in this solution
Trimethylsilyl chloride (161.7 g) was added over 40 minutes at 5°C and the product mixture was stirred at room temperature for 1 hour.
Stirred overnight. This solution was mixed with silica gel (180
g) After filtering through a packed column and washing with tetrahydrofuran, the liquid was concentrated under reduced pressure. Purification of the residue by fractional distillation yields 6-
[N,N-bis(trimethylsilyl)amino]-
2-methylpyridine (117.6g), bp95-97℃/
5-6 mmHg was obtained. NMRδppm (CCl ₄ ): 0.13 (18H, s). 2.35
(3H.s). 6.43 (1H.dJ=8Hz). 6.60 (1H.d.
J=8Hz). 7.25 (1H.tJ = 8Hz) (2) A 15% n-hexane solution (338.6g) of n-butyllithium was added to 6-[N,N-bis(trimethylsilyl)amino]-2-methylpyridine (100g).
g) in anhydrous tetrahydrofuran (300 ml) at -20 to -30°C over 1 hour, and the solution was stirred at 20 to 23°C for 1 hour. The resulting liquid was added little by little to crushed dry ice (1 kg) with stirring, and stirring was continued until the temperature reached room temperature. Tetrahydrofuran was distilled off under reduced pressure, and anhydrous ethanol (1) was added to the residue. of hydrochloric acid
Add 30% ethanol solution (660ml) to this solution.
It was added dropwise at 5 to -10°C, hydrogen chloride gas was further blown in at 0 to 5°C for 30 minutes, and the reaction solution was stirred at 10°C overnight. After distilling off ethanol from the reaction solution,
The residue was dissolved in water and washed three times with ethyl acetate. Add this solution to pH 7-8 with sodium hydrogen carbonate.
and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to obtain the crude target substance (54 g). The product was developed on a silica gel (1Kg) column chromatograph and purified using an eluent consisting of ethyl acetate and benzene, resulting in 2-
Ethyl (6-aminopyridin-2-yl)acetate (30.2g), mp 66-68°C was obtained. _{IRνnujiolnax} : 3430, 3340, 3200, 1730,
1645, 1480, 1190 cm ^-1 NMRδppm (CDCl ₃ ): 1.25 (3H.tJ=6
Hz). 3.67 (2H.s). 4.20 (2H.qJ=6Hz).
5.33 (2H.broad s). 6.43 (1H.dJ=8
Hz). 6.62 (1H.dJ=8Hz). 7.40 (1H.tJ=
(8Hz) (3) Acetic anhydride (16.6ml) and 98% sulfuric acid (7.32ml) were mixed at room temperature and stirred at 50-66°C for 30 minutes. This solution was mixed with 2-(6-aminopyridin-2-yl)ethyl acetate (26.5 g) and ethyl acetate (250 g).
ml) solution over a period of 30 minutes at 20-23℃,
The mixture was stirred at the same temperature for 1 hour. Cold water was added to the reaction solution, and the mixture was thoroughly shaken. Separate the ethyl acetate layer;
It was washed with water, an aqueous sodium bicarbonate solution, and water in this order. This was dried and concentrated under reduced pressure to obtain ethyl 2-(6-formamidopyridin-2-yl)acetate (28 g), mp 35-38°C. _{IRνnujiolnax} : 3250, 3100, 1738, 1690,
1580, 1460, 1305, 1277 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.17 (3H.tJ=
8Hz). 3.75 (2H.s). 4.08 (2H.qJ=8
Hz). 6.85 (0.5H.broad dJ=8Hz). 7.95
(0.5H.broad s). 7.08 (1H.dJ=8Hz).
7.73 (1H.tJ=8Hz). 8.33 (0.5H.broad
s). 9.25 (0.5H.broad d). 10.58 (1H.
(4) To a solution of 2-(6-formamidopyridin-2-yl)acetic acid (26 g) in dioxane (260 ml) at 85-90°C, add gelene dioxide little by little over 1 hour, and at the same temperature. The mixture was further stirred for 1 hour.
After cooling the reaction solution, the dioxane layer was separated, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate, treated with activated carbon, and then concentrated under reduced pressure. When diethyl ether is added to the residue to make it powder, ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3
g), mp 124-126°C was obtained. IRνnujiol _nax : 3220, 3100, 1737, 1720,
1690, 1273, 1233 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.34 (3H.tJ=
8Hz). 4.44 (2H.qJ=8Hz). 7.33 (0.65H.
broad s). 7.8~8.2 (0.35H). 7.84 (1H.d.
J=8Hz). 8.09 (1H.tJ=8Hz). 8.44
(0.35H.broad s). 9.22 (0.65H.broad
s). 10.85 (1H.broad s) (5) 2N aqueous sodium hydroxide solution [solvent: water (1 part) + ethanol (4 parts), 14.87ml]
The mixture was added to a solution of ethyl -(6-formamidopyridin-2-yl)glyoxylate (6.00 g) in ethanol (180 ml) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. Methoxyamine hydrochloride (2.71g)
was added to this reaction solution, stirred at room temperature for 1.5 hours, and then concentrated under reduced pressure to a small volume. The precipitate was collected, washed with ethyl acetate and water, then dissolved in methanol and treated with activated carbon. The solution was concentrated under reduced pressure and the precipitate was removed to give 2-(6-
Formamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g), mp 170-171°C (decomposition) was obtained. _{IRνnujiolnax} : 3230, 3132, 1745, 1680,
1575, 1450, 1320, 1208, 1032 cm ^-1 NMRδppm (DMSO−d ₆ ): 3.70 (3H.s).
6.90 (0.6H.broad d). 7.9 (0.4H.broad
s). 7.10 (1H.dJ=8Hz). 7.75 (1H.tJ=
8Hz). 8.38 (0.4H.broad s). 9.25 (0.6H.
broad d). 10.58 (1H.broad d) (6) Ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g) in ethanol (44
ml) solution, add 2N aqueous sodium hydroxide solution [solvent: water (1 part) + ethanol (4 parts), 15.9
ml] was added over 30 minutes at 18-20°C, and the reaction solution was stirred at room temperature for 1 hour. After adding 1N hydrochloric acid (31.7 ml) to the reaction solution, it was concentrated under reduced pressure.
The residue was extracted with hot ethyl acetate (500 ml), the extract was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate to give 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g), mp125 ~126
°C (decomposition) was obtained. _{IRνnujiolnax} : 3270, 1720, 1655, 1575,
1460cm ^-1 NMRδppm (DMSO−d ₆ +D ₂ O): 3.70
(2H.s). 6.9and7.9 (1H.m). 7.10 (1H.dJ
=8Hz). 7.75 (1H.tJ=8Hz). 9.25and8.38
(1H.broad s) (7) A suspension of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (1.5 g) and concentrated hydrochloric acid (0.77 g) in methanol (30 ml) was stirred at room temperature for 45 minutes. Stir for a minute. The reaction solution was concentrated under reduced pressure, the resulting residue was washed with diethyl ether,
The precipitate was collected to give 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (1.63 g), mp 100-105°C. IRνnujiol _nax : 3400-3150, 1730, 1670,
1245, 1050, 803cm ^-1 NMRδppm (DMSO−d ₆ ): 4.13 (3H.s).
6.89 (1H.dJ=8Hz). 7.22 (1H.dJ=8.5
Hz). 7.95 (1H.dd.J=8.5Hz.8Hz) (8) 2-(6-aminopyridin-2-yl)-2-
A suspension of methoxyiminoacetic acid hydrochloride (410 mg) in ethyl acetate (5 ml) was stirred, and bis(trimethylsilyl)acetamide (1.61 g) was added all at once, followed by stirring at 40°C for 50 minutes. . To this solution, trifluoroacetic anhydride (1.3 g) was added dropwise at -10 to -5°C over 30 minutes, and the reaction solution was stirred at the same temperature for 3 hours. Ethyl acetate (10 ml) and water (3 ml) were added to this, washed successively with water and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and then concentrated under reduced pressure. -yl)-2-methoxyiminoacetic acid (470 mg), mp 194-195°C was obtained. IRνnujiol _nax : 3350, 1680-1670, 1600,
1380, 1040, 850, 810cm ^-1 (9) 1N sodium hydroxide aqueous solution (27.5ml)
was added to a solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (5.55 g) in ethanol (100 ml) at room temperature with stirring, and stirring was continued at the same temperature for 30 minutes. Hydroxylamine hydrochloride (1.9 g) was added at once to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Ethanol was distilled off from the reaction solution under reduced pressure, ethyl acetate was added to the residue, and the pH was adjusted to 7 with an aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and adjusted to pH 2 with 10% hydrochloric acid. When the precipitate was removed, washed with water, and dried, 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g), mp190-192℃ (decomposition)
was gotten. IRν _Nujiornax : 3120, 1700, 1665, 1620cm
^-1 (10) A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g), dichloroacetic acid chloride (7.6 g) and methylene chloride (100 ml) was stirred at room temperature for 5 hours. . The precipitate was collected, washed with diethyl ether, and dried to give 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (4.6 g), mp 88-90°C. IRv Nudiol _nax : 1800, 1720, 1620 cm ^-1 Example 2 (1) A mixture of acetic anhydride (32.7 g) and formic acid (16.2 g) was stirred at 50 to 60°C for 30 minutes. Add this liquid to 2
The mixture was added to a suspension of methyl -(2-aminopyrimidin-4-yl)acetate (17.93 g) in ethyl acetate (300 ml) at room temperature over 10 minutes, and stirring was continued at room temperature for 3 hours. After removing insoluble materials, water (300 ml) was added to the solution, and the mixture was diluted with an aqueous sodium bicarbonate solution.
Adjusted to PH7. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with activated carbon, and concentrated under reduced pressure. When the residue is triturated with diethyl ether,
Methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g), mp 103-107°C was obtained. IRν _Nujiolnax : 3000-3400 (multiple),
1740, 1703, 1600, 1567 cm ^-1 NMRδppm (DMSO−d ₆ ): 3.70 (3H.s).
3.90 (2H.s). 7.25 (1H.dJ=5Hz). 8.60
(1H.dJ=5Hz). 9.43 (1H.dJ=10Hz).
11.07 (1H.broad dJ=10Hz) (2) Methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.52g) in dioxane (200
ml) solution was added gelene dioxide (9.92 g) over 20 minutes at 90-95°C, and stirring was continued at the same temperature for 1 hour. After cooling the reaction solution, it was filtered through a column packed with silica gel (20 g), washed with dioxane, and then concentrated under reduced pressure. The residue was dissolved in acetone and filtered, and the solution was concentrated again under reduced pressure. Trituration of the residue with chloroform gave the crude product (8.2g). This was dissolved in ethyl acetate and heated to remove insoluble matter. When the mother liquor is cooled and the precipitate is removed, 2
-(2-formamidopyrimidin-4-yl)
Methyl glyoxylate (5.55 g) was obtained.
When this is recrystallized from water-saturated ethyl acetate,
Its monohydrate, mp 143-144°C, was obtained. Elemental analysis: C ₈ H ₇ N ₃ O ₄・H ₂ O C H N Theoretical value 42.30 3.99 18.50 Actual value 42.22 3.95 18.34 _IRnujiolnax : 3270, 3200, 1750, 1710,
1597, 1585, 1416, 1233cm ^-1 NMRδppm (DMSO−d ₆ ): 3.65 (3H.s).
7.30 (2H.s). 7.40 (1H.dJ=5Hz). 8.63
(1H.dJ=5Hz). 9.33 (1H.dJ=10Hz).
10.95 (1H.bd.J=10Hz) (3) 4N sodium hydroxide aqueous solution (10.85ml)
is the monohydrate of methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate (4.55
g) in methanol (60 ml) and stirred for 1 hour. Methoxyamine hydrochloride (1.82 g) was added little by little to this solution, stirred at room temperature for 30 minutes, and further stirred for 30 minutes under ice cooling. The precipitate was collected and dissolved in water to remove insoluble matter. The liquid was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, concentrated, and the precipitate was removed.
(2-formamidopyrimidin-4-yl)-2
-Methoxyiminoacetic acid (0.63g) was obtained.
The methanol solution obtained above was concentrated under reduced pressure,
The residue was dissolved in water. The aqueous solution was treated with activated carbon, brought to pH 1 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure to collect the resulting precipitate. The same target substance as above (0.73 g, total yield: 1.36 g), mp 180-182°C (decomposed) was obtained. It was done. IRν _Nujiolnax : 3300-2400 (multiple),
1750, 1670, 1590, 1573, 1408, 1240, 1048
cm ^-1 NMRδppm (DMSO−d ₆ ): 4.00 (3H.s).
7.47 (1H.dJ=5Hz). 8.60 (1H.dJ=5
Hz). 9.23 (1H.dJ=10Hz). 11.02 (1H.
broad dJ=10Hz) Example 3 (1) 1N sodium hydroxide aqueous solution (8.5ml)
was added to a solution of 2-(6-formamidopyridin-2-yl)glyoxylic acid (1.9 g) in ethanol (30 ml) at room temperature with stirring, and the solution was stirred at the same temperature for 30 min.
Stirring was continued for a minute. Ethoxyamine hydrochloride (912 mg) was added to this, and the mixture was stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, and ethyl acetate and an aqueous sodium hydrogen carbonate solution were added. The aqueous layer was separated, ethyl acetate was added, and the pH was adjusted to 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Trituration of the residue with a mixture of diethyl ether and petroleum ether gives 2-(6-formamidopyridine-2-
yl)-2-ethoxyiminoacetic acid (920 mg),
mp155-156°C (decomposition) was obtained. IRν _Nujiolnax : 3250, 1740, 1650cm ^-1 NMRδppm (DMSO-d ₆ ): 1.3 (3H.tJ=7
Hz). 4.3 (2H.qJ=7Hz). 6.8~8.2 (3H.
m). 9.4 (1H.broad d). 10.5 (1H.broad
d) Example 4 (1) A mixture of formic acid (20 g) and acetic anhydride (41.3 g) was stirred at 50°C for 30 minutes, and methyl 4-amino-2-pyridinecarboxylate (11 g) was added at room temperature. Stirring was continued for an additional 2 hours at 70-75°C. After distilling off the solvent from the reaction mixture, the residue was recrystallized from ethanol to give methyl 4-formamide-2-pyridinecarboxylate (8.3
g), mp185-186.5°C was obtained. IRνnujiol _nax : 3200-3300, 1690, 1675,
1585, 1570, 1495, 1420, 1260, 990, 860,
840cm ^-1 (2) Add 50% sodium hydride (7.92g) to a mixture of methyl 4-formamide-2-pyridinecarboxylate (9.9g), methylthiomethylsulfoxide (6.82g) and N,N-dimethylformamide (200ml). ) was added with stirring at 10°C, followed by continued stirring at 45°C for 10.5 hours. After distilling off the dimethylformamide from the reaction mixture, a cold mixture of ethyl acetate and dilute hydrochloric acid was added to the residue. The ethyl acetate layer was separated, and the remaining aqueous layer was further extracted with ethyl acetate. Combine the extracts,
After washing with an aqueous sodium chloride solution, it was dried over magnesium sulfate, and the solvent was distilled off. Residue (6.0
g) was washed with a mixture of ethyl acetate and diethyl ether, taken to dry, and a yellowish brown powder of 4 was obtained.
-Formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (1.96
g), mp132-132.5°C was obtained. The other liquid was concentrated to remove the precipitate, which was washed with diethyl ether and dried to obtain the same target substance (1.11 g) as above. Total yield: 3.07g IRnujiol _nax : 3200-3225, 1680, 1580,
1290, 1170, 1020, 845 cm ^-1 (3) After stirring a mixture of acetic anhydride (14 ml) and formic acid (136 ml) at 40 to 50°C for 10 minutes, 4-formamide-2-(2-methanesulfuric acid) was added to the mixture. Nil-
2-methylthioacetyl)pyridine (3.7g)
was added, and stirring was continued at 65°C for 30 minutes. Add sodium periodate (0.872g) to this mixture,
Stir for 15 minutes. After distilling off the solvent from the reaction mixture, the residue was dissolved in ethyl acetate. This solution was washed successively with an aqueous sodium bicarbonate solution, an aqueous sodium thiosulfate solution, and water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was washed with diethyl ether and dried to give 2-(4-formamidopyridine-2) as a pale yellow powder.
-yl) S-methyl thioglyoxylate (1.96
g), mp145-148°C was obtained. IRνnujiol _nax : 3150-3300, 1690, 1670,
1585, 1570, 1500, 1420, 1265, 990, 860,
835,745cm ^-1 (4) S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate (1.07
g), methanol (20 ml), and a 1N aqueous sodium hydroxide solution (5.7 ml) were stirred at room temperature for 50 minutes to obtain a 2-(4-formamidopyridin-2-yl)glyoxylic acid-containing solvent. O-methylhydroxylamine hydrochloride (438 mg) was added to this, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent from the reaction mixture, water (5 ml) was added to the residue, and after washing with ethyl acetate, water was distilled off. The water in the residue was removed by azeotropy with ethanol and then benzene, leaving a light brown powder of 2-(4-formamidopyridine-
2-yl)-2-methoxyiminoacetic acid (syn isomer: 960 mg) was obtained.

[Table] Example 5 (1) A mixture of formic acid (559.3 g) and acetic anhydride (1033.4 g) was stirred at 40 to 50°C for 30 minutes, and then heated to 40°C.
Then, methyl 6-amino-2-pyridinecarboxylate (616 g) was added thereto, and the mixture was stirred at 80°C for 1 hour. After distilling off the solvent from the reaction mixture, benzene and n-
The residue was dissolved in a mixture of hexanes and then filtered. When the obtained precipitate was recrystallized from benzene (2), methyl 6-formamido-2-pyridinecarboxylate (647.8g), mp134-136℃
was gotten. Elemental analysis C N H Theoretical value 53.33 4.48 15.55 Actual value 53.37 4.40 15.58 IRν Nudiol _nax : 3200, 1740, 1700 cm ^-1 (2) Methyl 6-formamide-2-pyridinecarboxylate (435.7 g), Methyl methylthiomethyl sulfoxide (300 g ) and N,N-dimethylformamide (2.2), 50
% sodium hydride (348 g) was added under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture,
Benzene (4.4) was added under ice cooling, and the precipitate was collected. This was mixed with methylene chloride (3) and ice (2
Kg) and concentrated hydrochloric acid (730 ml), the pH was adjusted to 7 with sodium hydrogen carbonate, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from diethyl ether and dried to give 6-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (430 g), mp 130-132°C. _{IRνnujiolnax} : 3250, 3150, 3050, 1710,
1690, 1600, 1510 cm ^-1 NMRδppm (d _{6 −} acetone + D ₂ O): 2.30
(3H.s). 2.88 (3H.s). 6.00 (1H.s). 7.7〜
8.2 (3 H.m) (3) A mixture of 6-formamide-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (424 g) and sodium periodate (100 g) with acetic acid (2.1) Stirred at ℃ for 30 minutes. After distilling off the solvent from the reaction mixture, water (5) and sodium thiosulfonate (116 g) were added to the residue, and then the mixture was diluted with sodium hydrogen carbonate.
Adjusted to PH7. The precipitate was collected, washed with water, and dried to give 2-(6-formamidopyridine-2
-yl) thioglyoxylate (246.4 g), mp 163-165°C was obtained. Furthermore, the same substance (12 g) was recovered by extracting the aqueous layer with ethyl acetate. IRν _Nujiolnax : 3250, 3150, 3080, 1700,
1670, 1595, 1580, 1510 cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 2.57
(3H.s). 7.77-8.27 (3H.m) (4)-a 2-(6-formamidopyridine-2-
S-methyl thioglyoxylate (4.48
g), methanol (20 ml), and a 1N aqueous sodium hydroxide solution were stirred at room temperature for 50 minutes to obtain a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid. To this was added O-propylhydroxylamine hydrochloride (2.23g), and at the same temperature
Stir for a minute. Add hydrochloric acid to bring the reaction mixture to pH7
and methanol was distilled off. The remaining aqueous layer is washed with ethyl acetate, more ethyl acetate is added, and the pH is adjusted to 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, and dried over magnesium sulfate.
After further treatment with activated carbon, the solvent was distilled off. The product thus obtained is washed with a mixture of diethyl ether and diisopropyl ether and finally dried to give 2-(6-formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer: 1.76 g). mp140-142°C (decomposition) was obtained. _{IRνnujiolnax} : 3250, 3100, 2600, 1755,
1670, 1620, 1580 cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 0.96
(3H.tJ=7Hz). 1.56-1.84 (2H.m). 4.2
(2H.tJ=7Hz). 7.0-8.32 (3H.m) The following compound was obtained in the same manner. (4)-b 2-(6-formamidopyridine-2-
yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer), mp183-184℃
(Decomposition) _{IRνnudjolnax} : 3220, 1760, 1680cm ^-1 NMRδppm (DMSO-d ₆ ): 4.78.5.07 (2H.
ABq.J=9Hz). 7.0~8.2 (3H.m). 9.0~9.3
(1H.m). 10.76 (1H.m) (4)-c 2-(6-formamidopyridine-2-
yl)-2-isopropoxyiminoacetic acid (syn isomer), mp140-150°C (decomposition) IRνnudiol _nax : 3300, 2600, 1750, 1670,
1620, 1580, 1510 cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 1.3
(6H.dJ=6Hz). 4.36-4.64 (1H.m). 6.92
~8.28 (3H.m) (4)-d 2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer), mp140℃ (decomposition) IRνnudiol _nax : 3250, 3100, 2600, 1760,
1670, 1620, 1580cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 4.67 ~
4.9 (2H.m). 5.17-5.6 (2H.m). 5.8~6.52
(1H.m). 7.0-8.33 (3H.m) (4)-e 2-(6-formamidopyridine-2-
yl)-2-propargyloxyiminoacetic acid (syn isomer) mp145-150℃ (decomposition) IRν Nudiol _nax : 3350, 3250, 3100, 2600,
1755, 1685, 1620, 1580, 1510 cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 3.04
(1H.tJ=2Hz). 4.88 (2H.dJ=2Hz). 7.0
~8.28 (3H.m) (4)-f 2-butoxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer), mp129~131°C (decomposition) IRν Nudiol _nax : 3150, 1755 , 1670cm ^-1 NMRδppm (DMSO−d ₆ ): 0.7 to 1.9 (7H.
m). 4.20 (2H.tJ=6Hz). 7.0~8.1 (3H.
m). 10.7 (1H.broad d) (4)-g 2-isobutoxyimino-2-(6-formamidopyridin-2-yl)acetic acid, (syn isomer), mp153-155℃ (decomposition) IRνnudiol _nax : 3250 , 3150, 1750, 1680,
1620, 1580cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 0.96
(6H.dJ=6Hz). 1.88～2.16 (1H.m). 4.0
(2H.dJ=6Hz). 7.0-8.28 (3H.m) (4)-h 2-(6-formamidopyridine-2-
yl)-2-phenoxyiminoacetic acid (syn isomer), mp148-150℃ (decomposed) IRν Nudiol _nax : 1730, 1660, 1560 cm ^-1 NMRδppm (DMSO-d ₆ ): 6.80-8.2 (8H.
m). 10.80 (1H.dJ=8Hz) Example 6 (1) Methyl 6-formamido-3-pyridinecarboxylate,
Obtained mp218-220℃. IRν _Nujiolnax : 3100, 3020, 1710, 1605,
1540cm ^-1 NMRδppm (DMSO−d ₆ +D ₂ O): 3.84
(3H.s). 8.12-8.84 (3H.m) (2) 2-formamide-5-(2-methanesulfinyl-2-
Methylthioacetyl)pyridine, mp125-127
℃ was obtained. IRνnujiol _nax : 3200, 1710, 1660, 1600,
1545cm ^-1 (3) According to the method of Example 4-(3), by using acetic acid instead of acetic anhydride and formic acid, 2-
S-methyl (6-formamidopyridin-3-yl)thioglyoxylate was produced. _{IRνnujiolnax} : 3250, 3150, 3050, 1730,
1680, 1600, 1590, 1510 cm ^-1 NMRδppm (acetone−d ₆ + D ₂ O): 2.47
(3H.s). 8.35-9.17 (3H.m) (4) S-methyl 2-(6-formamidopyridin-3-yl)thioglyoxylate (13g),
A mixture of methanol (50 ml), 1N aqueous sodium hydroxide solution (58 ml) and water (150 ml) was stirred at room temperature for 30 minutes. Add O-methylhydroxylamine hydrochloride (4.85 g) to this mixture,
The mixture was further stirred for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 7, and methanol was distilled off under reduced pressure. The remaining aqueous solution was washed with ethyl acetate, and then more ethyl acetate was added.
The resulting reaction mixture was adjusted to pH 2 with 10% hydrochloric acid, sodium chloride was added, and the mixture was stirred for a while. The precipitate was collected, washed with diisopropyl ether, and then dried to obtain 2-(2-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer: 2.0 g), mp 159-161°C (decomposed). It was done. _{IRνnujiornax} : 1735, 1665, 1590, 1550cm
^-1 NMRδppm (DMSO−d ₆ ): 4.00 (3H.s).
7.8~8.5 (3H.m). 10.87 (1H.dJ=6Hz) On the other hand, the ethyl acetate layer was separated from the liquid, and the remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined and dried over magnesium sulfate, and the solvent was distilled off to give powdered 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (a mixture of syn and anti isomers). )was gotten. This powder was dissolved in an aqueous sodium hydrogen carbonate solution, and the pH was adjusted to 2 to 3 with 10% hydrochloric acid.
When the precipitate was dried, 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (anti-isomer: 1.45 g), mp168-170
°C (decomposition) was obtained. _{IRνnudjolnax} : 1705, 1605, 1535cm ^-1 NMRδppm (DMSO-d ₆ ): 4.00 (3H.s).
7.8~8.5 (3H.m). 10.80 (1H.dJ = 7Hz) Furthermore, an aqueous sodium bicarbonate solution was added to the mother liquor to adjust the pH to 3 to 4, which was washed with ethyl acetate, then adjusted to pH 2 again with 10% hydrochloric acid, and extracted with ethyl acetate. . The extract was dried over magnesium sulfate and the solvent was distilled off to obtain 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer: 2.5 g). Example 7 (1) According to the method of Example 4-(1), methyl 2-formamido-4-pyridinecarboxylate, mp196
~197°C was obtained. _{IRνnujiolnax} : 3100, 1740, 1710, 1580,
1540cm ^-1 NMRδppm (DMSO−d ₆ ): 3.92 (3H.s).
7.48-8.6 (3H.m) (2) According to the method of Example 4-(2), 2-formamide-4-(2-methanesulfinyl-2-methylthioacetyl)pyridine, mp123-125℃
I got it. _{IRνnujiolnax} : 3150, 3050, 1690, 1610,
1565cm ^-1 (3) According to the method of Example 4-(3), using acetic acid instead of acetic anhydride and formic acid, S-methyl 2-(2-formamidopyridin-4-yl)thioglyoxylate, mp165-167°C was obtained. _{IRνnujiolnax} : 3250, 3100, 1710, 1680,
1610, 1565, 1520 cm ^-1 NMRδppm (CDCl ₃ + D ₂ O): 2.48 (3H.
s). 7.5-8.6 (3H.m) (4) According to the method of Example 4-(4), 2-(2- Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer), mp170-172℃ (decomposed)
I got it. IRνnujiol _nax : 2500, 1710, 1640, 1615,
1600, 1520cm ^-1 NMRδppm (DMSO−d ₆ + D ₂ O): 4.02
(3H.s). 7.0-8.6 (3H.m) Example 8 (1) A mixture of 2-(4-amino-6-hydroxypyrimidin-2-yl)ethyl acetate (15.8 g) and phosphoryl chloride (75 ml) was heated to 80-90°C. The mixture was stirred for 4 hours while heating to . Let this solution cool,
Phosphoryl chloride was distilled off. The remaining oil was poured into a mixture of ice water (200ml) and ethyl acetate (200ml), neutralized with aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. The residue was washed with diisopropyl ether and dried to give light brown crystals of 2-(4-amino-6-
Ethyl chloropyrimidin-2-yl)acetate (8.1 g), mp 127-128°C was obtained. IRνnujiol _nax : 3250-3400, 1700, 1650,
1520~1580, 1320, 1160~1210, 860, 840cm
^-1 (2) 2-(6-chloro-4-formamidopyrimidin-2-yl) according to the method of Example 4-(1)
Ethyl acetate (oil) was obtained. IRν liquid film _nax : 2800-3600, 1680-1730, 1560,
1140～1190, 1020cm ^-1 NMRδppm (CDCl ₃ ): 1.30 (3H.tJ=8
Hz). 3.92 (2H.s). 4.23 (2H.qJ=8Hz).
8.3-9.3 (1H.broad). 9.4~10.4 (2H.
(3) A solution of 2-(6-chloro-4-formamidopyrimidin-2-yl)ethyl acetate (2.3 g) and sodium acetate (0.93 g) in 80% aqueous ethanol (50 ml) was added with 10% palladium on carbon. (0.2
g) was added, and the mixture was stirred at room temperature for 8 hours in a hydrogen gas atmosphere. The reaction mixture was filtered and the liquid was concentrated. Ethyl acetate and a small amount of water were added to the residue, the ethyl acetate layer was separated, and the remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate, and then the solvent was distilled off. The oily substance thus obtained (2.2g)
was purified by column chromatography on silica gel (40 g), and from the mixed eluate of benzene and ethyl acetate, 2-(4-formamidopyrimidin-2-yl)ethyl acetate (1.3
g), mp 80-93°C was obtained. _{IRνnujiolnax} : 1710, 1670, 1530, 1310,
1170, 840cm ^-1 NMRδppm (CDCl ₃ ): 1.23 (3H.tJ = 8
Hz). 3.78 (2H.s). 4.33 (2H.qJ=8Hz).
6.5-8.3 (1H.broad). 8.37 (1H.dJ=5
Hz). 9.15 (1H.broad s). 9.45 (1H.broad)
s) (4) To a solution of 2-(4-formamidopyrimidin-2-yl)ethyl acetate (7.0 g) in acetic acid (34 ml), add sodium nitrite (4.1 g) in water (12 ml).
The solution was added dropwise over 15 minutes while stirring at 10°C, and stirring was continued at the same temperature for 1 hour and at room temperature for 1 hour, respectively. The reaction mixture was cooled in an ice bath and diluted with water (50
ml) was added. The precipitate was collected, washed successively with water and diethyl ether, and then dried to give powdery 2-(4-formamidopyrimidine-2).
-yl)-2-hydroxyiminoacetate,
mp164-168°C (decomposition) was obtained quantitatively. NMRδppm (DMSO−d ₆ ): 1.30 (3H.tJ=
8Hz). 4.40 (2H.qJ=8Hz). 7.5 (1H.
broad）． 8.73 (1H.dJ=6Hz). 9.05 (1H.
(5) 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetic acid (7.0 g) was dissolved in dioxane (200 ml) under heating, and then cooled to room temperature in an ice bath. Furthermore, a solution of diazomethane in diethyl ether was added to this solution until the starting material completely disappeared. The reaction mixtures were mixed to give a brown oil, which was purified by column chromatography on silica gel (140 g). Using benzene as the developing solution and a mixture of benzene and ethyl acetate (3:1) as the eluent, a pale brown semisolid ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.4 g) was obtained. IRν liquid film _nax : 3500~3600 (shoulder), 2900~
3400, 1680〜1740, 1560, 1500, 1250,
1020, 840cm ^-1 NMRδppm (CDCl ₃ ): 1.40 (3H.tJ=8
Hz). 4.17 (3H.s). 4.47 (2H.qJ=8Hz).
7.5-8.6 (1H.broad). 8.73 (1H.dJ=6
Hz). 8.9 (1H.broad) (6) Mixture of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (4.3 g) and 10N aqueous sodium hydroxide solution (6.1 ml) in ethanol (100 ml) was stirred at room temperature for 3 hours. Concentrated base was gradually added to the reaction mixture with stirring to bring the pH to 3. The precipitate was collected, washed successively with ethanol and diethyl ether, and then dried to obtain white crystalline 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid. IRνnujiol _nax : 2500-3300, 1550-1650,
1240, 1000~1040cm ^-1 NMRδppm (D ₂ O−NaHCO ₃ ): 4.05 (3H.
s). 6.67 (1H.dJ=6Hz). 8.18 (1H.dJ=
6Hz) solution and washing solution were combined, and the solvent was distilled off. The same substance was further obtained by adding diethyl ether to the residue, pulverizing it, and drying it. (7) According to the method described in Example 4-(1), 2-
(4-formamidopyrimidin-2-yl)-2
-Methoxyiminoacetic acid brown powder, mp64-70
°C (decomposition) was obtained. NMRδppm (DMSO−d ₆ ): 4.02 (3H.s).
7.1-7.9 (1H.broad). 8.73 (1H.dJ=6
Hz). 8.9 (1H.broad) Example 9 (1) A mixture of 2-(4-formamidopyrimidin-2-yl)ethyl acetate (2.95 g) and gelene dioxide (1.73 g) in dimethylformamide (30 ml) was heated to Stirring was continued for 1 hour while heating to 52°C, and for 0.5 hour while heating to 70-72°C. The reaction mixture was cooled to room temperature, and the collected precipitate was washed with ethyl acetate. The liquid and washing liquid were combined and concentrated under reduced pressure at a temperature below 100°C to a volume of about 5 ml. The residue was poured into water (50ml) and the resulting mixture was stirred for 10 minutes. It was filtered again and the collected precipitate was washed with water. The liquid and washing liquid were combined, and the pH was adjusted to 7 with an aqueous sodium hydrogen carbonate solution. The mixture was washed with ethyl acetate, saturated with sodium chloride, and then extracted with a mixture of ethyl acetate and ethanol (2:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was distilled off, yielding ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e., 2-(4-formamidopyrimidin-2-yl)glyoxylate. A mixture of ethyl-formamidopyrimidin-2-yl)-2,2-dihydroacetate (2.4 g) was obtained as a deep yellow oil. (2) A mixture of 2-(4-formamidopyrimidin-2-yl)ethyl acetate (2.95 g), gelene dichloride (1.87 g) and N,N-dimethylformamide (15 ml) was heated to 70°C for 1 hour. Stirred. The reaction mixture was cooled to room temperature and filtered, and the collected precipitate was washed with a small amount of N,N-dimethylformamide. The solution and washing solution were combined, and the solvent was distilled off. The residue was poured into water (60ml) and the resulting mixture was stirred for 10 minutes. An aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to 6 to 7, and insoluble matter was separated and washed. The liquid and washing liquid were combined and washed successively with diethyl ether and ethyl acetate. The aqueous mixture was saturated with sodium chloride and a mixture of chloroform and ethanol (1:
1) was washed four times (60 ml/time). The extract was dried over magnesium sulfate, and the solvent was distilled off.
The remaining oil (2.2 g) was dissolved in ethyl acetate (10
ml), developed on a column chromatograph using silica gel (15 g), and eluted with ethyl acetate. Fractions of the eluate containing the target substance were collected, and the solvent was distilled off. The residual oil (1.5 g) was dissolved in a small amount of ethyl acetate and recrystallized from diisopropyl ether to give ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e. 2-(4-formamidopyrimidin-2-yl)glyoxylate. -formamidopyrimidin-2-yl)-2,2-dihydroxyethyl acetate mixture as pale yellow crystals (0.6g),
Obtained as mp74-78℃. IRνnujiol _nax : 3200~3400, 1755, 1690~
1710, 1595, 1580, 1280, 1250, 1215,
1135, 1100, 1030, 850 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.16 (1.8 HtJ
=7Hz). 1.26 (1.2HtJ=7Hz). 4.10
(1.2HqJ=7Hz). 4.42 (0.8HqJ=7Hz).
6.97 (1.2H.broad s). 7.0~7.8 (1H.m).
8.64 (0.6HdJ=6Hz). 8.90 (0.4HdJ=6
Hz). 8.8~9.6 (1H.m). 11.15 (1H.broad
s) (3) 2-(4-formamidopyrimidin-2-yl)glyoxylic acid and its monohydrate obtained in Example 6-(1) were dissolved in ethanol (30 ml), and potassium hydroxide was added thereto. 1N ethanol solution (11
ml) was added dropwise under ice-cooling and stirring, and stirring was continued for an additional 2 hours at room temperature. After the reaction was completed, the collected precipitate was washed with a small amount of ethanol and diethyl ether and dried to obtain potassium 2-(4-aminopyrimidin-2-yl)-glyoxylate in the form of a brown powder. (0.4g). The liquid and washing liquid were combined and concentrated to about 15 ml, and diethyl ether (20 ml) was added to the residue. The precipitate was collected and washed successively with a small amount of ethanol and diethyl ether, resulting in potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its 1
A mixture of hydrates (0.8 g) was obtained in the form of a light brown powder. Total yield: 1.2g

[Table] (4) O-methylhydroxylamine hydrochloride (0.25
A methanol (6 ml) solution of 2-(4-
The mixture was added to a mixture of potassium aminopyrimidin-2-yl) glyoxylate and its monohydrate under stirring at room temperature, and stirring was continued for an additional 4 hours. The reaction mixture was left at room temperature overnight and then filtered, and the precipitate collected was washed with ethanol. After combining the liquid and washing liquid, the solvent was distilled off and the resulting oil was pulverized in acetone (15 ml). This was washed with a small amount of acetone and diethyl ether and then dried to obtain 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer: 290 mg) as a light brown powder. IRν _Nujiolnax : 3100-3400, 2500-2900,
1540-1660, 1250, 990-1040 cm ^-1 NMRδppm (D ₂ O + NaHCO ₃ ): 4.05 (3H.
s). 6.63 (1H.dJ=6Hz). 8.13 (1H.dJ=
6Hz) Example 10 (1) 2-(2-
Methyl formamide-6-chloropyrimidin-4-yl)acetate (crystals) was obtained. IRν _Nujiolnax : 3200, 3140, 1730, 1700,
1540〜1580, 1500, 1420, 1380, 1350,
1270, 1240, 1140, 840, 770, 740cm ^-1 (2) 2-(2-
methyl formamido-6-chloropyrimidin-4-yl)-2-hydroxyiminoacetate,
mp110-112°C was obtained. IRνnujiol _nax : 3200, 1740, 1700, 1675,
1570, 1560, 1380, 1270, 1240, 1180,
1045, 860, 810, 750 cm ^-1 NMRδppm (DMSO−d ₆ ): 3.90 (3H.s).
7.57 (1H.s). 9.23 (1H.dJ=9Hz). 11.40
(1H.dJ=9Hz). 13.28 (1H.s) (3) 2-(2-
Methyl formamide-6-chloropyrimidin-4-yl)-2-methoxyiminoacetate (powder),
mp165-172.5℃ was obtained. _{IRνnujiolnax} : 3150, 1750, 1700, 1670,
1645, 1420, 1380, 1270, 1250, 1040,
955, 795, 735 cm ^-1 NMRδppm (DMSO−d ₆ ): 3.93 and 4.14
(6H.s). 7.59 (1H.s). 9.26 (1H.dJ=9
Hz). 11.50 (1H.dJ=9Hz) (4) 2-(2-
amino-6-chloropyrimidin-4-yl)-
2-methoxyiminoacetic acid (powder) was obtained. _{IRνnujiolnax} : 3350, 3200, 1695-1740,
1660, 1365, 1030 cm ^-1 NMRδppm (DMSO−d ₆ + D ₂ O): 3.80
(3H.s). {6.16 (s). 6.77 (s)} (1H) (5) 2-(2-
Formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid (powder), mp138
~142°C (decomposition) was obtained. IRνnujiol _nax : 3400, 3325, 3200, 1740,
1695, 1670, 1550, 1385, 1250, 1040, 820
cm ^-1 NMRδppm (DMSO-d ₆ ): 4.05 (3H.s).
{6.87 (s). 6.93 (s)} (1H). 9.38 (1H.d.
J=9Hz). 11.11 (1H.dJ = 9Hz) Example 11 (1) A 15% solution of n-butyllithium in n-hexane (636g) and 2-amino-6-methylpyridine (64.8g) in tetrahydrofuran (500ml), After adding it for 1 hour at -20 to -30℃, -
Stirred for an additional 30 minutes at 8 to -10°C. Trimethylsilyl chloride (161.7g) was added to this solution.
The mixture was added over 40 minutes at 15--5°C and stirred overnight at room temperature. This solution was filtered through a column packed with silica gel (180 g), washed with tetrahydrofuran, and then concentrated under reduced pressure. The residue was purified by fractional distillation to yield 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (117.6 g), bp 95-97°C/5-6 mmHg. NMRδppm (CCl ₄ ): 0.13 (18H.s). 2.35
(3H.s). 6.43 (1H.dJ=8Hz). 6.60 (1H.d.
J=8Hz). 7.25 (1H.tJ = 8Hz) (2) A 15% n-hexane solution (338.6g) of n-butyllithium was added to 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (100g).
g) in anhydrous tetrahydrofuran (300 ml) at -20 to -30°C over 1 hour.
The mixture was further stirred at 23°C for 1 hour. The reaction mixture was added little by little to crushed dry ice (1Kg) under stirring and stirred until it reached room temperature. After distilling off tetrahydrofuran under reduced pressure, anhydrous ethanol (1) was added to the residue. Add a 30% ethanol solution (660 ml) of hydrogen chloride to this solution from -5 to -
The mixture was added dropwise at 10°C, and hydrogen chloride gas was further blown in at 0 to 5°C for 30 minutes. The reaction solution was stirred overnight at 10° C., and after ethanol was distilled off from the reaction solution, the residue was dissolved in water and washed three times with ethyl acetate. Add sodium hydrogen carbonate to this solution to make the pH 7-8.
and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to obtain the crude target substance (54 g).
This was purified by column chromatography on silica gel (1Kg), and from the eluate (ethyl acetate + benzene) ethyl 2-(6-aminopyridin-2-yl)acetate (30.2g), mp66-68℃ was obtained. . _{IRνnujiolnax} : 3430, 3340, 3200, 1730,
1645, 1480, 1190 cm ^-1 NMRδppm (CDCl ₃ ): 1.25 (3H.tJ=6
Hz). 3.67 (2H.s). 4.20 (2H.qJ=6Hz).
5.33 (2H.broad s). 6.43 (1H.dJ=8
Hz). 6.62 (1H.dJ=8Hz). 7.40 (1H.tJ=
8 Hz) (3) 2-(6-
Formamidopyridin-2-yl)ethyl acetate, mp 35-38°C was obtained. _{IRνnujiolnax} : 3250, 3100, 1738, 1690,
1580, 1460, 1305, 1277 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.17 (3H.tJ=
8Hz). 3.75 (2H.s). 4.08 (2H.qJ=8
Hz). 6.85 (0.5H.broad dJ=8Hz). 7.95
(0.5H.broad s). 7.08 (1H.dJ=8Hz).
7.73 (1H.tJ=8Hz). 8.33 (0.5H.broad
s). 9.25 (0.5H.broad d). 10.58 (1H.
(4) Ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g) in dioxane (260
ml) solution, add 85~ of gelene dioxide (16.65g)
The mixture was added little by little at 90°C over 1 hour and stirred at the same temperature for 1 hour. After cooling the reaction mixture, the dioxane layer was separated and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed with water, dried over magnesium sulfate, treated with activated carbon, and concentrated under reduced pressure. Trituration of the residue with diethyl ether gave ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3
g), mp 124-126°C was obtained. IRνnujiol _nax : 3220, 3100, 1737, 1720,
1690, 1273, 1233 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.34 (3H.tJ=
8Hz). 4.44 (2H.qJ=8Hz). 7.33 (0.6H.
broad s). 7.8~8.2 (0.35H). 7.48 (1H.d.
J=8Hz). 8.09 (1H.tJ=8Hz). 8.44
(0.35H.broad s). 9.22 (0.65H.broad
s). 10.85 (1H.broad s) (5) By the same method as in Example 4-(4), 2-(6
-formamidopyridin-2-yl)glyoxylic acid to obtain 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer), mp 170-171°C (decomposition). _{IRνnujiolnax} : 3230, 3132, 1745, 1680,
1575, 1450, 1320, 1208, 1032 cm ^-1 NMRδppm (DMSO−d ₆ ): 3.70 (3H.s).
6.90 (0.6H.broad d). 7.9 (0.4H.broad
s). 7.10 (1H.dJ=8Hz). 7.75 (1H.tJ=
8Hz). 8.38 (0.4H.broad s). 9.25 (0.6H.
broad d). 10.58 (1H.broad d) (6) 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer:
methanol (5.0 g) and concentrated hydrochloric acid (2.34 g)
ml) was stirred at room temperature for 40 minutes. After distilling off methanol from the reaction mixture under reduced pressure,
The residue was powdered with diethyl ether and dried to give 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer: 5.2 g) as a light brown powder. . NMRδppm (DMSO− _d6 + _D2O ): 4.10
(3H.s). 6.84 (1H.dJ=7Hz). 7.23 (1H.d.
J=10Hz). 7.99 (1H.dd.J=7Hz.10Hz) (7) 2-(6-aminopyridin-2-yl)-2-
Methoxyiminoacetic acid hydrochloride (syn isomer:
Chlorine gas was introduced into a mixture of 8.0 g), acetic acid (350 ml) and water (10 ml) for 1.5 hours. After releasing excess chlorine by blowing air into the reaction mixture, the solvent was distilled off and the residue was triturated with diethyl ether. After adding water and ethyl acetate to this powder, the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate solution and washing solution were combined and further washed with water. The aqueous layer and this washing liquid were combined and diluted with a 1N aqueous sodium hydroxide solution.
After adjusting the pH to 4, the solvent was distilled off under reduced pressure. The water remaining in the residue was removed using benzene azeotropy three times to obtain a brown powder. By drying this product in a desiccator,
-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer:
3.27g) was obtained. NMRδppm (DMSO− _d6 + _D2O ): 3.81
(3H.s). 6.50 (1H.dJ=9Hz). 7.48 (1H.d.
J=9Hz) Furthermore, the remaining ethyl acetate layer was dried with magnesium sulfate, and the solvent was distilled off. The residue was washed with diethyl ether and dried to give 2-(6-amino-3,5-dichloropyridin-2-yl)-2
-methoxyiminoacetic acid (syn isomer: 2.4 g),
mp139-144°C was obtained. NMRδppm (DMSO−d ₆ ): 9.96 (3H.s).
6.2-7.1 (2H.broad). 7.83 (1H.s) (8)-a 2-a by the same method as Example 4-(1)
(3-chloro-6-formamidopyridine-2
-yl)-2-methoxyiminoacetic acid (syn isomer: powder), mp 151-154°C was obtained. IRνnujiol _nax : 3200, 1740, 1680, 1580,
1290, 1250, 1140, 1050, 840cm ^-1 (8)-b 2-b by the same method as Example 4-(1)
(3,5-dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer: powder), mp 164-165°C was obtained. _{IRνnujiolnax} : 3250, 2300-2600, 1712,
1565, 1410, 1250, 1035cm ^-1 NMRδppm (DMSO): 4.02 (3H.s). 8.29
(1H.s). 9.05 (1H.dJ=10Hz). 10.77 (1H.
dJ=10Hz) Example 12 Ethyl 3-ethoxyacrylimidate hydrochloride (4.0g) and 1-ethoxycarbonylformamidine hydrobromide (4.4g) in methanol (110ml)
A solution of sodium metal (1 g) in methanol (110 ml) was added dropwise to the solution at 0°C. Reaction mixture to 0
Stirring was continued for 1 hour at ~5°C and an additional 4 hours at room temperature.
After evaporating the solvent to dryness, the residue was dissolved in a mixture of ethyl acetate and aqueous sodium chloride solution. The organic layer was separated and the aqueous layer was washed five times with ethyl acetate.
All the organic solvent layers were combined, dried over magnesium sulfate, the solvent was evaporated to dryness, and the residue was triturated with diethyl ether to give 4-aminopyrimidine-
Methyl 2-carboxylate (1.33 g) was obtained and recrystallized from ethyl acetate to obtain the same compound having a melting point of 140-142.5°C. IRνnujiol _nax : 3450, 3300, 3180, 1730,
1630, 1585, 1540cm ^-1 NMRδppm (DMSO−d ₆ ): 3.81 (3H.s).
6.54 (1H.dJ=6Hz). 7.23 (2H.s). 8.16
(1H.dJ=6Hz) Example 13 (1) 2-chloroacrylonitrile (437mg) and 1
- In a solution of ethoxycarbonylformamidine hydrobromide (985 mg) in ethanol (5 ml),
Triethylamine (1.01 g) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours and evaporated to dryness. The residue was added to a mixture of ethyl acetate and water and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was evaporated to dryness. Powdering the residue with diethyl ether gave ethyl 4-aminopyrimidine-2-carboxylate (480 mg), which was recrystallized from a mixture of ethyl acetate and benzene to give a mp of 101-104°C.
The same target substance was obtained. IRνnujiol _nax : 3450, 3300, 3180, 1730,
1630, 1580, 1540 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.30 (3H.tJ=
7Hz). 4.30 (2H.qJ=7Hz). 6.60 (1H.dJ
=6Hz). 7.31 (2H.s). 8.20 (1H.dJ=6
Hz) According to the method of Example 13-(1), the following compound was obtained by using triethylamine or sodium hydrogen carbonate as a base. (2) Methyl 4-aminopyrimidine-2-carboxylate _{IRνnudiolnax} : 3450, 3300, 3180, 1730,
1630, 1585, 1540 cm ^-1 Example 14 (1) A mixture of formic acid (100 g) and acetic anhydride (204 g) was stirred at room temperature for 0.5 hour. Add 4-
Ethyl aminopyrimidine-2-carboxylate (30
g) was added and stirred at 70-75°C for 1.5 hours. The solvent was evaporated to dryness and the residue was triturated with ethanol, collected and washed with ethanol to give ethyl 4-formamidopyrimidine-2-carboxylate (20.0 g), mp 205-206°C. IRνnujiol _nax : 3100, 1720, 1630, 1570,
1520cm ^-1 NMRδppm (DMSO−d ₆ ): 1.37 (3H.tJ=
7Hz). 4.40 (2H.qJ=7Hz). 7.73 (1H.
broad s). 8.83 (1H.dJ=4Hz). 9.00
(1H.broad s). 11.40 (1H.broad s) The following compound was obtained according to the method of Example 14-(1). (2) Methyl 4-formamidopyrimidine-2-carboxylate, mp234-236°C _{IRνnudyolnax} : 3100, 1735, 1710, 1640,
1570, 1530, 1510cm ^-1 NMRδppm (DMSO−d ₆ ): 3.93 (3H.s).
7.73 (1H.broad s). 8.82 (1H.dJ=5
Hz). 9.00 (1H.broad s). 11.40 (1H.broad
s) Example 15 To a solution of methyl 4-formamidopyrimidine-2-carboxylate (1.34 g) and methyl methylthiomethylsulfoxide (0.89 g) in N,N-dimethylformamide (10 ml) was added 50% hydrogen with stirring at 10°C. Sodium chloride (1.0 g) was added and stirring continued at room temperature for 1.5 hours. The mixture was cooled in an ice bath and to this was added methylene chloride (30ml). The precipitated crystals were collected and gradually added to a mixture of methylene chloride (50 ml), ice water and concentrated hydrochloric acid (2.1 ml) with stirring. The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride. The extracts were combined and dried with magnesium sulfate.
The solvent was evaporated to dryness. The residue was triturated with diethyl ether, filtered and washed with diethyl ether to give 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyrimidine (1.2 g).

【table】

[Table] A compound identical to the target substance of Example 15-(1) was produced from the following compound by a similar method. (2) Ethyl 4-formamidopyrimidine-2-carboxylate Example 16 A mixture of formic acid (4.82 g) and acetic anhydride (9.7 g) was stirred at room temperature for 0.5 hour. Add 4-formamide-2-(2-methanesulfinyl-2) to this solution.
-Methylthioacetyl)pyrimidine (2.6 g) was added, and the mixture was stirred at 50°C for 1.5 hours, and sodium periodate (610 mg) was further added and stirred at the same temperature for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (50ml) and aqueous sodium chloride (20ml). The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off. The residue (2.0 g) was developed on a column chromatograph using silica gel (13 g) and eluted with a mixture of ethyl acetate and benzene (volume ratio, 1:1). Fractions containing the target substance were collected, the solvent was evaporated to dryness, and then recrystallized from a small amount of ethyl acetate to obtain pure S-methyl 4-formamidopyrimidine-2-thioglyoxylate (840 mg), mp 112-114℃. Obtained. IRνnujiol _nax : 3480, 3380, 1715, 1680,
1585cm ^-1 NMRδppm (DMSO−d ₆ ): 2.17 (3H.s).
7.20 (1H.broad s). 8.12 (1H.dJ=6
Hz). 9.17 (1H.broad s). 11.08 (1H.dJ=
7 Hz) Example 17 (1) S-thiomethyl 4-formamidopyrimidine-2-thioglyoxylate (3.0 g) in water (26
ml) A 1N aqueous sodium hydroxide solution (12 ml) was added dropwise to the suspension at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To this solution was added an aqueous ethoxyamine solution prepared from ethoxyamine hydrochloride (1.3 g), water (10 ml) and sodium hydrogen carbonate (1.12 g), and after stirring at room temperature for 30 minutes, 1N hydrochloric acid (1.5 ml) was added. The pH was set to 4. This solution was stirred for an additional 10 minutes at room temperature, then adjusted to pH 3 with 1N hydrochloric acid, and then washed with ethyl acetate. The aqueous layer was salted out and extracted with ethyl acetate while adjusting the pH to 1 with 10% hydrochloric acid. The extract was dried over magnesium sulfate and the solvent was evaporated to dryness. The resulting crystalline residue was extracted with n-hexane to give 2-ethoxyimino-2-(4-formamidopyrimidine-2-
yl) acetic acid (syn isomer: 2.22g), mp130~
135°C (decomposition) was obtained. _{IRνnujiolnax} : 3250, 1720, 1630, 1605,
1570cm ^-1 NMRδppm (DMSO−d ₆ ): 1.28 (3H.tJ=
7Hz). 4.32 (2H.qJ=7Hz). 7.4~7.7
(1H.m). 8.72 (1H.dJ=6Hz). 8.8~9.1
(1H.m). 11.37 (1H.dJ=6Hz) The following compound was obtained in the same manner as in Example 17-(1). (2) 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer),
mp165-166℃ (decomposition) _{IRνnujiolnax} : 3400, 3250, 3150, 1740,
1700, 1570cm ^-1 NMRδppm (DMSO−d ₆ ): 4.00 (3H.s).
7.53 (1H.broad s). 8.72 (1H.dJ=6
Hz). 8.87 (1H.broad s). 11.23 (1H.dJ=
6Hz) (3) 2-(4-formamidopyrimidin-2-yl)-2-propoxyiminoacetic acid (syn isomer), mp145-148°C (decomposition) IRνnudiol _nax : 3150, 3100, 3050, 1750,
1690, 1615, 1570, 1540cm ^-1 (4) 2-allyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer), mp120-122℃ (decomposition) IRνnudjol _nax : 3250, 3100, 1710, 1630,
1570, 1515cm ^-1 (5) 2-benzyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer), mp75-77℃ IRν Nudiol _nax : 3250, 3050, 1720, 1630,
1570cm ^-1 Example 18 A mixture of a solution of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (24.3g) and gelene dioxide (16.65g) in N,N-dimethylformamide (243ml) was , and stirred at 70-75°C for 1 hour. The precipitate was separated and the liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml), washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated to dryness.
Powdering the residue with diisopropyl ether gives
6-chloro-4-formamidopyrimidine-2-
A powder of ethyl ylglyoxylate (17.74 g) was obtained. This product (1 g) was recrystallized with ethyl acetate (10 ml) to obtain a pure product (570 ml), mp 114-117°C. _{IRνnujiolnax} : 3400, 3230-3100, 1760,
1720-1680, 1580-1550, 1250, 1200,
850,730cm ^-1 Example 19 6-chloro-4-formamidopyrimidine-2
- Ethyl glyoxylate (10.6 g) and methoxyamine hydrochloride (3.34 g) in ethanol (200 g)
ml) in a mixture with sodium bicarbonate (3.36 g)
An aqueous solution (60 ml) of was added thereto, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent, the residue was dissolved in ethyl acetate, washed with water and dried with magnesium sulfate,
The solvent was distilled off again to obtain an oily substance (10.8 g).
This product was developed on a column chromatograph using 118 g of silica gel and eluted with benzene. Fractions containing the target substance were collected and the solvent was evaporated to obtain an oily substance (5.6 g), which was recrystallized from diethyl ether to yield 2.
-(6-chloro-4-formamidopyrimidine-
Ethyl 2-yl)-2-methoxyiminoacetate (syn isomer), mp 116-119°C was obtained. _{IRνnujiolnax} : 3400, 1750, 1725, 1665,
1495, 1270, 1030 cm ^-1 NMRδppm (CDCl ₃ ): 1.35 (3H.tJ=7
Hz). 4.09 (3H.s). 4.40 (2H.qJ=7Hz).
6.5-8.3 (1H.broad). 8.3~9.0 (1H.
broad）． 9.2 (1H.broad s) Example 20 A mixture of 2-(4-formamidopyrimidin-2-yl)ethyl acetate and gelene dioxide (31.87 g) in N,N-dimethylformamide (240 ml) was heated to 70-75°C. The mixture was stirred for 1 hour and then cooled to room temperature. The precipitated solid was removed and the liquid was evaporated under reduced pressure to give an oil. This oil was added to stirring water (750 ml), and the pH was adjusted to 7 with an aqueous sodium bicarbonate solution. The precipitated yellow substance was removed and the liquid was washed. The liquid and washing liquid were combined, and methoxyamine hydrochloride (19.95 g) was added thereto. This mixture was adjusted to pH 4 with an aqueous sodium hydrogen carbonate solution and stirred at room temperature for 3 hours. The aqueous reaction solution was extracted with ethyl acetate, and the extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off. - Ethyl methoxyiminoacetate (syn isomer: 31 g) was obtained. NMRδppm (CDCl ₃ ): 1.36 (3H.tJ=7
Hz). 4.12 (3H.s). 4.42 (2H.qJ=7Hz).
6.5-8.2 (1H.broad). 8.66 (1H.dJ=6
Hz). 8.8-10.0 (2H.broad) Example 21 (1) 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer:
A 1N alcoholic solution of potassium hydroxide (550 g) in ethanol (308 ml) was added
ml) and stirred at room temperature for 3.5 hours. The reaction mixture was cooled in an ice bath and brought to pH 3 with concentrated hydrochloric acid (53ml). Remove the remaining solid matter and add ethanol (60ml), water (100ml), and acetone (100ml).
The crude target substance (28.8g) was washed sequentially with
was gotten. When this product (1 g) is recrystallized from water (10 ml), purified 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate, syn isomer: 0.4 g), mp178~183
°C (decomposition) was obtained. The following compound was obtained in the same manner as in Example 21-(1). (2) 2-(4-amino-6-chloropyrimidine-
2-yl)-2-methoxyiminoacetic acid (syn isomer) IRνnudiol _nax : 3480, 3380, 3200, 1640,
1610-1580, 1530, 1040, 720cm ^-1 NMRδppm (D ₂ O): 4.10 (3H.s). 6.76
(1H.s) Example 22 A solution of ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer: 17 g) in ethanol (255 ml) was added in an ice bath. Phosphoryl chloride (14.7g) under cooling
was dripped. The mixture was stirred at room temperature for 1.5 hours and the solvent was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and the pH was adjusted to 7 with an aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was triturated with n-hexane to give ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer: 9.99 g), mp136~
A temperature of 142°C was obtained. IRν ^KBr _nax : 3500, 3380, 3200, 1735, 1640
，
1575, 1535, 1040 cm ^-1 NMRδppm (DMSO−d ₆ ): 1.30 (3H.tJ=
7Hz). 4.03 (3H.s). 4.30 (2H.qJ=7
Hz). 6.53 (1H.s). 7.5 (2H.broad s) Example 23 (1) 2-(4-amino-6-chloropyrimidine-
To a solution of ethyl 2-yl acetate (21.5 g) in methanol (200 ml) was added a solution of sodium metal (7.25 g) in methanol (130 ml), and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled in an ice bath, saturated with hydrogen chloride gas, and then left overnight at room temperature.
The solvent was evaporated to dryness from the mixture and the residue was taken into a cold aqueous solution of ethyl acetate and sodium bicarbonate. The organic layer was separated, washed with water, and dried over magnesium sulfate. When the solvent is evaporated to dryness,
2-(4-amino-6-methoxypyrimidine-
2-yl) methyl acetate (14.2g), mp91-94℃
was gotten. _{IRνnujiolnax} : 3480, 3390, 3210, 1738,
1660, 1600cm ^-1 NMRδppm (DMSO−d ₆ ): 3.66 (5H.s).
3.82 (3H.s). 5.68 (1H.s). 6.66 (2H.broad
s) (2) A solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was cooled in an ice bath, and 50% sodium hydride was added thereto.
Stirred for 20 minutes at 0-5°C. Add 2-
Ethyl (4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0g)
was added and stirred at room temperature for 6 hours. The reaction mixture was poured into cold water, adjusted to pH 7 with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated to dryness. The residue was applied to a column chromatograph packed with silica gel (50 g) and eluted with a mixture of chloroform and ethyl acetate (volume ratio, 3:1). When fractions containing the target substance are collected and the solvent is evaporated to dryness, 2-
(4-amino-6-phenylthiopyrimidine-
Ethyl 2-yl)-2-methoxyiminoacetate (syn isomer: 460 mg), mp 154-156°C was obtained. _{IRνnujiolnax} : 3450, 3280, 3160, 1720,
1620, 1550, 1520, 1300, 1040, 1025, 700
cm ^-1 NMRδppm (CDCl ₃ ): 1.34 (3H.tJ=7
Hz). 4.05 (3H.s). 4.27 (2H.qJ=7Hz).
5.2 (2H.broad s). 5.84 (1H.s). 7.2~7.7
(5H.m) Example 24 According to the method of Example 14-(1), methyl 2-[4-amino-6-methoxypyrimidin-2-yl)acetate (14 g) was mixed with formic acid (14.7 g) and acetic anhydride. (30.4
By reacting with g), methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)acetate (13.9g), mp61-63°C was obtained. NMRδppm (DMSO−d ₆ ): 3.73 (3H.s).
3.87 (2H.s). 3.96 (3H.s). 6.1~7.8 (1H.
broad）． 8.1-9.8 (1H.broad). 10.87 (1H.
dJ = 6 Hz) Example 25 According to the method of Example 20, methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)acetate (12.24 g) was mixed with gelene dioxide (6.94 g) and methoxyamine hydrochloride ( 4.51 g) to obtain methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer: 12.47 g). IRν liquid film _nax : 3300, 1750, 1720, 1660, 1590,
1565, 1210, 1035 cm ^-1 Example 26 (1) According to the method of Example 21, 2-(4-formamido-6-methoxypyrimidin-2-yl)-
Methyl 2-methoxyiminoacetate (syn isomer:
12.0g) with a 1N ethanol solution of potassium hydroxide (187ml),
(4-amino-6-methoxypyrimidine-2-
yl)-2-methoxyiminoacetic acid (syn isomer: 8.22 g), mp 127-129°C (decomposition) was obtained. _{IRνnujiolnax} : 3420, 3380, 1650, 1615,
1590, 1250, 1050, 1025 cm ^-1 NMRδppm (DMSO−d ₆ + D ₂ O): 3.78
(3H.s). 3.95 (3H.s). 5.78 (1H.s) (2) According to the method of Example 21, 2-(4-amino-
6-phenylthiopyrimidin-2-yl)-2
-ethyl methoxyiminoacetate (syn isomer:
2-(4-
Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer:
130mg), mp136-138℃ (decomposed). _{IRνnujiolnax} : 3300, 1650, 1600, 1560,
1150, 1040, 750cm ^-1

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ _a is an amino group or a protected amino group, R ¹ _b and R ¹ _c are each a hydrogen atom, a halogen atom, a lower alkoxy group, or an arylthio group, and R ¹⁴ is a carboxy group or a protected carboxy group. ^,
a group represented by a lower alkynyl group, an aryl group, an ar(lower) alkyl group, or a halo(lower) alkanoyl group; Z means N or CH, respectively); an acetic acid derivative or a salt thereof; 2 R ¹ _a is an amino group or a protected amino group,
X is the formula [Formula] (where R ⁶ is a hydrogen atom, a lower alkyl group, a halo (lower) alkanoyl group, a trihalo (lower) alkyl group, a lower alkenyl group, a lower alkynyl group, a phenyl group or a phenyl (lower) alkyl group The compound according to claim 1, which is a group represented by the following. 3 General formula [In the formula, R ¹ _a is an amino group or a protected amino group, R ¹ _b and R ¹ _c are each a hydrogen atom, a halogen atom, a lower alkoxy group, or an arylthio group, and R ¹⁴ is a carboxy group or a protected carboxy group. , ^Z means ^N or CH _respectively . , lower alkenyl group, lower alkynyl group, aryl group, al(lower) alkyl group or halo(lower) alkanoyl group) or its salts are reacted with the general formula (In the formula, R ¹ _a , R ¹ _b , R ¹ _c , R ⁶ , R ¹⁴ and Z
has the same meaning as above) or a salt thereof.