JPH0527637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel cephalosporins, specifically, the general formula "In the formula, R ¹ is a hydrogen atom or a carboxy protecting group; R ² is a phthalidyl group or a carboxyl group or

[Formula] (In the formula, R ⁶ represents a lower alkyl group.) An alkyl group substituted with a group represented by; R ³ is a hydrogen atom; R ⁴ is
a hydrogen atom; R ⁵ is an optionally protected amino group; and A is a formula

[Formula] [wherein R ⁷ represents an alkyl group optionally substituted with a group represented by the formula -COOR ¹ (wherein R ¹ has the same meaning as above), ~ indicates that it may be the syn or anti isomer or a mixture thereof. ] The groups represented by are shown below. ” Concerning cephalosporin and its salts. Therefore, the object of the present invention is to provide a drug that has a broad antibacterial spectrum, exhibits excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is also stable against β-lactamases produced by bacteria. The object of the present invention is to provide novel cephalosphorins or novel intermediates thereof, which have the following properties and exhibit excellent therapeutic effects on human and animal diseases. The cephalosporins of the present invention have the formula

[Formula] (In the formula, R ² has the same meaning as above.)
2,3-dioxo-1,2,3,4 represented by
-It is characterized by the fact that it has a tetrahydropyrazinyl group attached to it. Hereinafter, the present invention will be explained in further detail. In the present specification, unless otherwise specified, an alkyl group refers to a straight chain or branched C _1-14 alkyl,
For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl or lauryl;
Alkoxy group refers to -O-alkyl having an alkyl group as defined above; lower alkyl group refers to straight-chain or branched C _1-5 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl, sec-butyl, tert-butyl or pentyl, etc.; lower alkoxy group means -O- with a lower alkyl group as defined above.
Lower alkyl; acyl group refers to C _1-12 acyl,
For example, formyl, acetyl, propionyl,
Butyryl, pivaloyl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl or thenoyl, etc.; acyloxy group means -O having an acyl group as defined above.
-acyl; alkylthio group refers to -S-alkyl having an alkyl group as defined above; alkenyl group refers to _C2-10 alkenyl, e.g. vinyl,
Allyl, isopropenyl, 2-pentenyl or butenyl, etc.; alkynyl group refers to C _2-10 alkynyl, such as ethynyl or 2-propynyl; cycloalkyl group refers to C _3-7 cycloalkyl, such as cyclo propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; alkadienyl group is
_C4-10 alkadienyl, such as 1,3-butadienyl or 1,4-hexadienyl;
Cycloalkenyl group refers to _C5-7 cycloalkenyl, such as cyclopentenyl or cyclohexenyl; cycloalkadienyl group refers to
C _5-7 cycloalkadienyl, such as cyclopentadienyl or cyclohexadienyl; aryl group refers to phenyl, naphthyl or indanyl; aralkyl group refers to benzyl,
phenethyl, 4-methylbenzyl or naphthylmethyl; heterocyclic groups are heterocyclic groups containing at least one heteroatom selected from oxygen, nitrogen and sulfur, such as furyl, thienyl,
Pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazyl, oxaazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4-(5-methyl-2-pyrrolinyl), 4-(2-pyrrolinyl) , N
- methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl or coumarinyl; heterocyclic alkyl group means a heterocyclic group as defined above; and a group consisting of an alkyl group; and a halogen atom means a fluorine, chlorine, bromine or iodine atom, respectively. R ¹ in each general formula herein means a hydrogen atom or a carboxyl protecting group. Examples of the carboxyl protecting group include protecting groups conventionally used in the field of penicillin and cephalosporin compounds. These carboxyl-protecting groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction, or other mild conditions; ester-forming groups that are easily eliminated in vivo; water or alcohol; Examples include organic silyl groups, organic phosphorus groups, and organic tin groups, which have the property of being easily eliminated by treatment with; and various other known ester-forming groups. Among these types of protecting groups, suitable protecting groups include:
Specifically, the following can be mentioned. (a) Alkyl group. (b) At least one of the substituents is halogen, nitro, acyl, alkoxy, oxo, cyano, hydroxyl, di-C _1-4 alkylamino, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-
1,3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4
-imidazolyl, phthalimide, succinimide, azetidino, aziridino, pyrrolidino, piperidino, morpholino, theomorpholino, N-
Lower alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl , 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, 4-(5-methyl-2-pyrrolidino), 4-(2- pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cyclo Alkyloxy, cycloalkenyloxy, heterocyclicoxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclicoxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, Substituted lower alkyl groups which are cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclic oxycarbonyl, alkylanilino or an alkylanilino group substituted with halogen, lower alkyl or lower alkoxy. (c) Cycloalkyl group; lower alkyl-substituted cycloalkyl or (2,2-di-lower alkyl-
1,3-dioxol-4-yl)methyl group. (d) Alkenyl group. (e) Alkynyl group. (f) A substituted phenyl group or a substituent in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituted phenyl group of the formula "In the formula, -Y ¹ - is -CH=CH-O-, -CH=
CH−S−, −CH ₂ CH ₂ S−, −CH=N−CH=
N-, -CH=CH-CH=CH-, -CO-CH=
CH-CO- or -CO-CO-CH=CH-. ” or a substituted derivative thereof [the substituents are arbitrarily selected from those exemplified in (b) above], or a group represented by the formula “In the formula, −Y ² − is −(CH ₂ ) ₃ − or −(CH ₂ ) ₄
It is a lower alkylene group such as -. '' or a substituted derivative thereof [substituents are arbitrarily selected from those exemplified in (b) above]. (g) An aralkyl group such as benzyl or a substituted benzyl in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (h) A substituted heterocyclic group in which the heterocyclic group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (li) Alicyclic indanyl or phthalidyl and their substituted derivatives whose substituent is methyl or halogen, alicyclic tetrahydronaphthyl and their substituted derivatives whose substituent is methyl or halogen, or trityl, cholesteryl or bicyclo[4.4.0]decyl Such. (v) Alicyclic phthalidylidene lower alkyl group and substituted derivatives thereof in which the substituent is a halogen or a lower alkyl group. The carboxyl protecting groups exemplified above are representative examples, and in addition to these, protecting groups described in the following documents can be arbitrarily selected. U.S. Patents 3499909, 3573296 and 3641018
No.; and West German Patent Publication No. 2301014, 2253287
No. 2337105. Among them, preferred carboxyl protecting groups include, for example, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl group, acyloxyalkyl group, acylthioalkyl group, phthalidyl group, indanyl group. , a phenyl group, a phthalidylidene lower alkyl group with or without a substituent, or a group that is easily eliminated in vivo, such as a group represented by the following formula.

【formula】

【formula】

[Formula] "In the formula, R ¹⁰ is a straight-chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without known substituents; R ¹¹ is a hydrogen atom or a straight-chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without known substituents; R ¹² is a hydrogen atom, a halogen atom or a known substituent; an alkyl, cycloalkyl, aryl or heterocyclic group with or without substituents or of the formula -( _CH2 ) _o
A group represented by COOR ¹¹ (wherein R ¹¹ has the same meaning as above, and n represents 0, 1 or 2, respectively); and m is 0, 1 or 2.
, respectively. ” Furthermore, specifically, for example, 5-methyl-
2-oxo-1,3-dioxol-4-yl-
5-lower alkyl-2 such as methyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl and 5-propyl-2-oxo-1,3-dioxol-4-yl-methyl groups -oxo-1,3-dioxol-4-yl-methyl group;
Acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy Acyloxyalkyl groups such as ethyl and 1-pivaloyloxy-n-propyl groups; acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1
- acylthioalkyl groups such as benzoylthioethyl and 1-(p-chlorobenzoylthio)ethyl groups; methoxyethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl and n-
Alkoxymethyl groups such as butyloxymethyl group; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butyloxycarbonyloxymethyl, tert-butyloxycarbonyloxymethyl, 1-methoxy carbonyloxyethyl, 1-
Alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl and 1-n-butyloxycarbonyloxyethyl groups; alkoxycarbonyl groups such as methoxycarbonylmethyl and ethoxycarbonylmethyl groups Alkyl group; phthalidyl group; indanyl group; phenyl group; Examples include phthalidylidene alkyl groups such as phthalidylidene) ethyl group. In addition, R ² is a phthalidyl group or carboxyl group or

It means an alkyl group substituted with a group represented by the formula: (wherein R ⁶ represents a lower alkyl group). Here, the expression

Examples of the group represented by the formula include 5-methyl-2-oxo-1,3-dioxol-4-yl, 5-ethyl-2-oxo-1,
Examples include 3-dioxol-4-yl and 5-propyl-2-oxo-1,3-dioxol-4-yl groups. Among the substituents on the alkyl groups mentioned above, carboxyl groups and the like may be protected with suitable protecting groups commonly used in the field. Here, the carboxyl group-protecting group includes all groups that can be used as ordinary carboxyl group-protecting groups, such as methyl, ethyl, n-
Propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl,
p-nitrobenzyl, p-methoxybenzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2,2-trichloroethyl, 1,1-dimethyl -2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3
-butynyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxid-2-yl-methyl, pyridin-1-oxid-2-yl-methyl or when it is protected with a group such as bis(p-methoxyphenyl)methyl or when it is protected with a nonmetallic compound such as titanium tetrachloride;
-7073 and Dutch Publication No. 7105259, for example, when protected with a silyl compound such as dimethylchlorosilane. Moreover, R ⁵ means an optionally protected amino group. Examples of the protecting group for the amino group include protecting groups conventionally used in the field of penicillin and cephalosporin compounds.
Specifically, these amino protecting groups include:
2,2,2-trichloroethoxycarbonyl,
2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-
Bromobenzyloxycarbonyl, o-nitrophenylsulfinyl, (mono-, di-, tri-)
Chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4- methoxyphenylazo)
Benzyloxycarbonyl, pyridin-1-oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl , 1-adamantyloxycarbonyl or 8-quinolyloxycarbonyl, which are easily eliminated, and trityl, 2-
Nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-
Pyridylmethylene, 1-methoxycarbonyl-2
-propylidene, 1-ethoxycarbonyl-2-
Propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1
-benzoyl-2-propylidene, 1-[N-(2
-methoxyphenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetyl Cyclohexylidene or 3,3-dimethyl-5-
Examples thereof include easily leaving groups such as oxocyclohexylidene; and silyl groups such as di- or trialkylsilyl. next,

The oxime represented by the formula (wherein R ⁷ and ~ each have the same meanings as defined above) includes syn and anti isomers and mixtures thereof. Formula for each general formula

The group represented by [Formula] (wherein R ⁴ and R ⁵ each have the same meaning as above) has the following balanced formula: "In the above balanced formula, R ⁴ and R ⁵ each have the same meaning as described above, and R ^5a represents an optionally protected imino group." exists, but its tautomers are also included. Examples of the protecting group for the imino group of R ^5a in the above formula include protecting groups conventionally used in the field of penicillin and cephalosporin compounds. These imino protecting groups include:
Specifically, among the same amino protecting groups as explained for R ⁵ , the same groups as monovalent groups can be mentioned. Examples of the salts of the compound of general formula [] include salts with basic groups or acidic groups well known in the field of penicillin and cephalosporin compounds. Salts on basic groups include, for example, salts with mineral acids such as hydrochloric acid, nitric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; or methanesulfonic acid. , ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid),
naphthalene-1-sulfonic acid, naphthalene-2-
Sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-
Disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,
3,5-trisulfonic acid, benzene-1,2,4
-trisulfonic acid or naphthalene-1,3,
Salts with sulfonic acids such as 5-trisulfonic acid,
Salts of acidic groups include, for example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; or procaine, dibenzylamine, N-benzyl-
β-phenethylamine, 1-phenamine, N,
Examples include salts with nitrogen-containing organic bases such as N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, or dicyclohexylamine. Furthermore, the present invention encompasses all optical isomers and racemates, as well as all crystal forms and hydrates of cephalosporin of general formula [] or its salts. Furthermore, among the compounds of the general formula [ ], as a preferable example, A is of the formula

The oxime represented by [Formula] (in which R ⁷ and ~ each have the same meaning as defined above) is a syn isomer, more preferably a syn isomer, and more preferably R ⁷ is an alkyl group. , in particular a methyl group or an ethyl group, or each group in which R ⁷ is represented by the formula -CH ₂ COOR ¹ (wherein R ¹ has the same meaning as defined above). Next, the pharmacological effects obtained from some representative compounds among the compounds of the general formula [] will be shown. The compounds shown below were used as test compounds. (A) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-{[1-(4-phthalidyl-2,3-dioxo-1,2) ,3,4-tetrahydropyrazinyl)]methyl}-△ ³ -cephem-4-carboxylic acid trifluoroacetate (B) 7-[2-(2-aminothiazol-4-yl)-2-( Syn)-methoxyiminoacetamide]-3-<{1-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3, 4-tetrahydropyrazinyl]}methyl>-△ ³ -cephem-4-carboxylic acid trifluoroacetate (1) Antibacterial action Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY, Vol. 23, Nos. 1-2 (1975)], the bacterial solution was cultured at 37°C for 20 hours in Heart Infusion broth [manufactured by Eiken Kagaku Co., Ltd.].
Heart Infusion Agar medium [manufactured by Eiken Kagaku Co., Ltd.] containing various concentrations of drugs was inoculated, and after culturing at 37℃ for 20 hours, the presence or absence of bacterial growth was observed. The minimum concentration at which inhibition was observed was defined as MIC (μg/ml). However, the amount of inoculated bacteria is 10 ⁴ per plate (10 ⁶
pieces/ml). The antibacterial effect test results are shown in Table-1.

【table】

[Table] Next, the method for producing the compound of the present invention will be explained. The compound of the present invention can be obtained by appropriately combining known methods or methods similar thereto, and can be produced, for example, according to the production route shown below. “In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and ~ each have the same meaning as described above; R ¹⁶ is an amino group or

[Formula] (In the formula, R ¹⁹ , R ²⁰ , and R ²¹ are the same or different and each represents a hydrogen atom or an organic residue that does not participate in the reaction.) or the formula

[Formula] (wherein, R ²² and R ²³ are the same or different and each represents a hydrogen atom or an organic residue that does not participate in the reaction); R ¹⁷ has a substituent or or no acyloxy or carbamoyloxy group; X is a halogen atom; Z is S or S→O; and the dotted line in the ring indicates a double bond between the 2-3 or 3-4 positions ;R ¹⁸ is
benzyl, phenoxymethyl or formula

[Formula] (In the formula, R ⁴ , R ⁵ and A each have the same meaning as defined above.) ” Hereinafter, to explain in detail, R ¹⁶ is an amino group or an amino group of the formula

[expression] or expression

Indicates a group represented by [Formula],

The group represented by [Formula] Formulas that are isomers

A group represented by the formula is also included. And R ¹⁹ , R ²⁰ , R ²¹ ,
Organic residues not involved in the reaction in R ²² and R ²³ include organic residues known in the art;
Specific examples include aliphatic residues, alicyclic residues, aromatic residues, araliphatic residues, heterocyclic residues, and acyl groups with or without substituents. can be exemplified by the following groups. (1) Aliphatic residues: for example alkyl groups such as methyl, ethyl, propyl, butyl, isobutyl and pentyl; and alkenyl groups such as vinyl, propenyl and butenyl. (2) Alicyclic residues, such as cycloalkyl groups such as cyclopentyl, cyclohexyl and cycloheptyl; and cycloalkenyl groups such as cyclopentenyl and cyclohexenyl. (3) Aromatic residues: for example, aryl groups such as phenyl and naphthyl. (4) Aroaliphatic residues: for example, aralkyl groups such as benzyl and phenethyl. (5) Heterocyclic residues: For example, heteroatoms (oxygen , nitrogen or sulfur atoms). (6) Acyl group: An acyl group that can be derived from an organic carboxylic acid, such as an aliphatic carboxylic acid, an alicyclic carboxylic acid, an alicyclic aliphatic carboxylic acid, or an aliphatic carboxylic acid. Aromatic substituted aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heterocycles in which an aromatic residue or a heterocyclic group is bonded to an acid with or without an oxygen or sulfur atom. substituted aliphatic carboxylic acids,
Heterocyclic oxyaliphatic carboxylic acid, heterocyclic thioaliphatic carboxylic acid or carbonyl group with oxygen,
Examples include organic carboxylic acids to which an aromatic ring, aliphatic group, or alicyclic group is bonded via a nitrogen or sulfur atom, or organic carboxylic acids such as aromatic carboxylic acids and heterocyclic carboxylic acids. Here, examples of aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, and crotonic acid, and examples of alicyclic carboxylic acids include cyclohexane. Examples of the alicyclic aliphatic carboxylic acids include cyclopentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, and cyclohexadieneacetic acid. In addition, aromatic residues in the organic carboxylic acid in (6) above include phenyl and naphthyl, and further examples of the heterocyclic group in (6) above include furan, thiophene, pyrrole, pyrazole, imidazole, and triazole. , thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, thiatriazole, oxatriazole, tetrazole, benzoxazole and benzofuran. It will be done. The groups constituting these organic carboxylic acids include, for example, a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, a nitro group, an amino group, a protected amino group, and a carboxyl group. It may be further substituted with substituents such as groups and protected carboxyl groups. Examples of the acyloxy and carbamoyloxy groups of R ¹⁷ include alkanoyloxy groups such as acetoxy, propionyloxy and butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy and naphthoyloxy; and carbamoyloxy groups. Oxy groups are mentioned, and these are:
Halogen atom, nitro atom, alkyl group, alkoxy group, alkylthio group, acyloxy group, acylamino group, hydroxyl group, carboxyl group,
Sulfamoyl group, carbamoyl group, alkoxycarbonylcarbamoyl group, aroylcarbamoyl group, alkoxycarbonylsulfamoyl group,
It may be substituted with one or more substituents such as an aryl group and a carbamoyloxy group. Among the substituents for R ¹⁷ described above, the hydroxyl group, amino group, carboxyl group, etc. may be protected with a commonly used protecting group.
Hydroxyl-protecting groups include all groups that can normally be used as hydroxyl-protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4 -dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)
Benzyloxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-fluor furyloxycarbonyl,
Easily eliminated acyl groups such as 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl or trifluoroacetyl; alkylsulfonyl groups such as methanesulfonyl or ethanesulfonyl ; an arylsulfonyl group such as phenylsulfonyl or toluenesulfonyl; or a benzyl, trityl, methoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-nitrophenylthio or 2,4-dinitrophenylthio group. Further, specific examples of the protecting groups for amino groups and carboxyl groups include the protecting groups for amino groups and carboxyl groups explained for R ⁵ and R ² . Next, each method for producing the compound of the present invention will be explained in more detail according to the above-mentioned production route. (a) Three-position conversion reaction 1-substituted-2,3-dioxo- of the general formula [] is added to the cephalosporanic acid of the general formula [] or its salt in the presence of an acid or an acid complex compound.
7-substituted or unsubstituted amino of the general formula -3-Substituted methyl cefem carboxylic acids or salts thereof can be produced with high yield and high purity through industrially easy operations. In addition, 1-substituted-2,3-dioxo-1,2,3,4 of the general formula [ ] which is a raw material compound
- Tetrahydropyrazine or its salts are listed in the Journal of the Chemical Society.
Parkin (Journal of the Chemical
Society Perkin), pp. 1888-1890 (1975
It can be obtained by the method described in 2010). Furthermore, if desired, the substituent on the 7-position amino group can be removed by a conventional method to derive a 7-unsubstituted amino compound. According to this method, △
Favorable results can be obtained with both the ³ -cephem compound and the △ ² -cepheme compound, and △ as the cephalosporanic acid of the general formula [] or its salts.
Even if a ² -cephem compound is used, the △ ² -cepheme compound obtained after the reaction is converted into △ ³ - of the general formula []
Can be converted to cefem compounds. In addition, not only compounds where Z is S,
Compounds in which Z is S→O can also be used as starting compounds, in which case S→O can be converted to S during the reaction or in a post-reaction treatment step. In addition, 1-substituted-2,3-dioxo- of the general formula [], which is a raw material compound in this reaction,
When 1,2,3,4-tetrahydropyrazine has an acidic group in the substituent at the 1-position, it may be subjected to the reaction in the form of each salt, if necessary, and in that case, as a salt of the acidic group. teeth,
Salts with basic groups and acidic groups similar to those described for the salts of cephalosporin of general formula [] can be mentioned. In addition, salts of the compounds of general formulas [] and [] include salts in basic groups or acidic groups, and examples of these salts include the same salts as explained for the salts of compounds of general formula []. It will be done. In addition, the salt of the compound of the general formula [] may be isolated beforehand and used, or may be prepared in-system. The acid or acid complex used in this reaction includes, for example, a protonic acid, a Lewis acid, or a Lewis acid complex. Protonic acids include, for example, sulfuric acids, sulfonic acids, and super strong acids (super strong acids are 100%
% sulfuric acid, and includes some of the aforementioned sulfuric acids and sulfonic acids. ), and more specifically, sulfuric acids such as sulfuric acid, chlorosulfuric acid, and fluorosulfuric acid; alkyl (mono- or di-)sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid, and p-toluenesulfone. sulfonic acids such as aryl (mono-, di- or tri-)sulfonic acids; as well as perchloric acid, magicic acid ( _FSO3H - _SbF5 ), _FSO3H - _AsF5 ,
_CF3SO3H − _{SbF5 , HF} − _BF3 and _H2SO4−
Examples include super strong acids such as SO ₃ . Furthermore, examples of the Lewis acid include boron trifluoride. Further, as complex compounds of Lewis acids, for example, boron trifluoride and diethyl ether, di-n
-Dialkyl ether complex salts with propyl ether or di-n-butyl ether; amine complex salts with ethylamine, n-propylamine, n-butylamine or triethanolamine; carboxylic acid ester complex salts with ethyl formate or ethyl acetate; acetic acid or fatty acid complex salts with propionic acid, etc.; or nitrile complex salts with acetonitrile, propionitrile, etc., and the like. In addition, it is preferable to use an organic solvent in this reaction, and the organic solvent used here can include all organic solvents that are inert to the reaction, such as nitroalkanes such as nitromethane, nitroethane and nitropropane. organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid and propionic acid; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole and dimethyl Ethers such as cellosolve; ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate,
Examples include esters such as ethyl chloroacetate and butyl acetate; nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane, and these solvents may be used alone or in combination of two or more. Moreover, a complex compound formed by these organic solvents and a Lewis acid can also be used as a solvent. The amount of acid or acid complex compound to be used may be at least equimolar, preferably 2 to 10 mol, based on the compound of general formula [] or its salt, and may vary depending on the raw materials and solvent used. It may be increased or decreased as appropriate. When using an acid complex compound, it can be used itself as a solvent, or a mixture of two or more kinds of complex compounds may be used. In addition, 1-substituted-2,3-dioxo-1,2,
The amount of 3,4-tetrahydropyrazine or its salt to be used may be at least equimolar, preferably 1.0 to 5.0 times the molar amount of the compound of general formula [] or its salt. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and are usually 0 to 80°C and several minutes to several tens of hours. If there is water in the reaction system, it may cause undesirable side reactions such as lactonization of raw materials or products and cleavage of the β-lactam ring, so it is desirable to keep the reaction system in an anhydrous state. . To meet this condition, a suitable dehydrating agent is added to the reaction system, such as a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride; N,O-bis(trimethylsilyl)acetamide. , an organic silylating agent such as trimethylsilylacetamide, trimethylchlorosilane or dimethyldichlorosilane; an organic acid chloride such as acetyl chloride or p-toluenesulfonyl chloride;
An acid anhydride such as acetic anhydride or trifluoroacetic anhydride; or an inorganic desiccant such as anhydrous magnesium sulfate, anhydrous calcium chloride, monocular sieve or calcium carbide, etc. may be added. General formula where R ¹ is a carboxyl protecting group []
When using a compound as a starting material, the corresponding compound of the general formula [] in which R ¹ is a hydrogen atom may be obtained by post-reaction treatment, but if desired, the protecting group may be removed by a conventional method. , R ¹
It is also possible to obtain a compound of the general formula [ ] in which is a hydrogen atom. Next, the three-position conversion reaction described as Production Method Diagram-2 will be explained. The halogen compound of general formula [ ] is shown in Tetrahedron Letters No.
46, pp. 3991-3994 (1974) and Tetrahedron Letters No.
40, pp. 3915-3918 (1981). Then, the halogen compound of general formula [] or its salt is reacted with 1-substituted-2,3-dioxo-1,2,3,4-tetrahydropyrazine of general formula [] or a salt thereof in the presence of a base. Then, a compound of the general formula [] or a salt thereof can be obtained. Bases used here include alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and triethylamine, pyridine. and nitrogen-containing organic bases such as N,N-dimethylaniline. This three-position conversion reaction is generally carried out in a suitable solvent. Solvents used include halogenated hydrocarbons such as chloroform and methylene chloride; ethers such as tetrahydrofuran and dioxane; N,N-dimethylformamide, N,N,-dimethylacetamide, acetone and water, and mixtures thereof. can be mentioned. The amount of the compound of the general formula [] or the salt thereof to be used is preferably about 1.0 to 2.0 mol per 1 mol of the compound of the general formula [] or the salt thereof. The reaction temperature and reaction time are usually
The temperature is 0 to 50°C for 30 minutes to 10 hours. The mixture of the △ ² -cepheme form and the △ ³ -cepheme form obtained as above, that is, the compound of the general formula [], is completely converted into the △ ³ -cephem form (that is, the compound of the general formula []). Then, by performing a deacylation reaction, a compound of the general formula [] can be derived. The conversion reaction to the ^Δ3 -cepheme form and the deacylation reaction are generally carried out by methods known in the field of penicillin and cephalosporin compounds, but specifically, the methods described in the Journal of Organic・Chemistry (Journal of Organic
Chemistry) Volume 35, No. 7 (1970), No.
Pages 2430-2433 and Cephalosporins and Penicillins
penicillins) [Author Flynn, Publisher Academic Press] No.
The method described on pages 56-64 can be applied. In addition, the 1-substituted-2,3-dioxo-1,2,
If the substituent at position 1 in 3,4-tetrahydropyrazine or its salt is substituted with a carboxyl group, etc., protect these groups with the above-mentioned protecting group before carrying out this reaction, and after the completion of the reaction. , the desired compound can be obtained by subjecting it to a conventional elimination reaction. Further, the general formula [] and the compound of the general formula [] can be derived into other compounds of the general formula [] by protecting the carboxyl group or converting it into a salt according to a conventional method, if desired. Furthermore, the general formula [] where R ¹⁶ is an amino group
The compound and the compound of general formula [] can be derived into reactive derivatives at the amino group described below in accordance with conventional methods. (b) Acylation The thus obtained compound of the general formula [] or a salt thereof or a reactive derivative thereof at the amino group is added to the compound of the general formula [], [],
By reacting compounds of [], [] or [] or reactive derivatives thereof, compounds of general formula [], [], [], [XI] or [] or salts thereof can be obtained. . Examples of reactive derivatives at the amino group of the compound of general formula [] or its salt include:
Isocyanates; Compounds of general formula [] are also Schiff's bases (imino type or its enamine type isomer) produced by reacting their salts with carbonyl compounds such as aldehydes or ketones; Compounds of general formula [] or their A silyl derivative produced by reacting a salt with a silyl compound such as N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide or trimethylsilyl chloride; a compound of the general formula [] or a salt thereof and phosphorus trichloride;

【formula】

【formula】

[Formula] A phosphorus derivative produced by reacting a phosphorus compound such as (CH ₃ CH ₂ O) ₂ PCl or (CH ₃ CH ₂ ) ₂ PCl; or a compound of the general formula [] or a salt thereof and (C ₄ H ₉ ) All compounds frequently used in acylation, such as tin derivatives produced by reacting tin compounds such as ₃ SnCl, are included. General formula [], [], [], [] or [
] Examples of reactive derivatives of compounds of the formulas include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and compounds of the general formula [], [], [], [] or [ ] Reactive derivatives of compounds with Vilsmeier's reagent, etc. Examples of mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester; and lower alkanoic acids which may be substituted with halogens such as pivalic acid and trichloroacetic acid. Examples include mixed acid anhydrides with Examples of the active acid amide include N-acyl saccharin, N-acylimidazole, N-
Examples include acylbenzoylamide, N,N'-dicyclohexyl-N-acylurea, and N-acylsulfonamide. Examples of the active ester include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thienyl ester. In addition, examples of derivatives reactive with the Vilsmeier reagent include acid amides such as N,N-dimethylformamide or N,N-dimethylacetamide, phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, and oxychloride. Examples include derivatives reactive with Vilsmeier's reagent obtained by the action of a halogenating agent such as phosphorus, phosphorus pentachloride, trichloromethyl chloroformate, or oxalyl chloride. General formula [], [], [], [] or [
] When using each compound in the form of a free acid or salt, a suitable condensing agent is used. Such condensing agents include, for example, N,
N,N'-disubstituted carbodiimides such as N'-dicyclohexylcarbodiimide;N,N'-
azolide compounds such as thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene; and 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl Examples include 2-halogenopyridinium salts such as iodide. This acylation is usually carried out in a suitable solvent in the presence or absence of a base. Any solvent may be used as long as it does not inhibit this reaction; for example, halogenated hydrocarbons such as chloroform and methylene chloride; ethers such as tetrahydrofuran and dioxane; N,N-dimethylformamide; N,N- Examples include dimethylacetamide; acetone; and water, and these solvents may be used alone or in combination of two or more. Examples of bases used as necessary include inorganic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, alkali metal carbonates, and alkali metal acetates; trimethylamine, triethylamine, tributylamine, pyridine, N- Tertiary amines such as methylpiperidine, N-methylmorpholine, lutidine and collidine; and secondary amines such as dicyclohexylamine and diethylamine. In addition, the compound of general formula [] or its salt which can be derived|derived into the compound of this invention or its salt can also be manufactured as follows. To obtain a compound of general formula [] or a salt thereof from a compound of general formula [] or a salt thereof,
Reaction of diketene with halogens such as chlorine or bromine [Journal of the Chemical Society]
Society), Vol. 97, p. 1987 (1910)] and a compound of the general formula [] or a salt thereof are reacted according to a conventional method. Just let it happen. The reaction conditions and operations are well known in the art and can be applied. Further, the salt of the compound of the general formula [] can be easily obtained according to a conventional method, and examples of the salt include the same salts as explained above for the salt of the compound of the general formula []. . The obtained compound of general formula [] or a salt thereof may be isolated and purified by a conventional method, but it can also be used as it is in the next reaction without isolation. Further, the amount of the compound of general formula [] or a salt thereof to be used is usually about 1~
It is about several moles. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and are usually -50 to 40°C and 10 minutes to 48 hours. Furthermore, the general formulas [], [], [], [XI] and [] where R ¹ is a carboxyl protecting group
into the compounds of the general formulas [], [], [], [XI] and [], where R ¹ is a hydrogen atom; or their salts, where R ¹ is a hydrogen atom; , [], [XI] and [
] to compounds of general formulas [], [], [], [XI] and [] or salts thereof, wherein R ¹ is a carboxyl protecting group; and also to compounds of general formulas [], [], [], [XI] and []
The salts of the compounds can be respectively converted into the corresponding free compounds according to conventional methods. In addition, in this acylation, R ¹ and R ² in the formula
If there is a group active in this acylation in the group R ⁵ , it can be optionally protected with a common protecting group during the reaction, and after the reaction, the protecting group can be used in a conventional manner. can also be removed. The compound of the general formula [] or a salt thereof of the present invention obtained as described above can be isolated by a conventional method. (c) Nitrosation Next, the compound of the general formula [] or a salt thereof can be obtained by reacting the compound of the general formula [] or a salt thereof with a nitrosating agent. This nitrosation is usually carried out in a suitable solvent, the solvents used being any that do not inhibit the reaction, such as water, acetic acid, benzene, methanol, ethanol and tetrahydrofuran. . Preferred examples of nitrosating agents include nitric acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; and butyl nitrite and nitrous acid. Examples include alkyl nitrite esters such as pentyl ester. When using an alkali metal nitrite as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid or formic acid, or an organic acid such as acetic acid. When using an alkyl nitrite ester as a nitrosating agent, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and are usually -15 to 30°C and 10 minutes to 10 hours. Further, the salt of the compound of general formula [] can be easily obtained according to a conventional method, and examples of the salt include the same salts as explained for the salt of the compound of general formula []. The compound of the general formula [] or a salt thereof thus obtained may be isolated and purified by a conventional method, but it can also be used as it is in the next reaction without isolation. (d) Alkylation Next, the compound of general formula [XI] or a salt thereof can be obtained by reacting the compound of general formula [] or a salt thereof with an alkylating agent. This alkylation can be carried out according to conventional methods. Any solvent may be used as long as it does not inhibit this reaction, such as tetrahydrofuran, dioxane, methanol,
Examples include ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide and water, and these solvents may be used alone or in combination of two or more. good. Examples of the alkylating agent include alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide; dimethyl sulfate; diethyl sulfate; diazomethane; diazoethane; and methyl p-toluenesulfonate. . When alkylating agents other than diazomethane and diazoethane are used, they are typically alkali metal carbonates such as sodium or potassium carbonate; alkali metal hydroxides such as sodium or potassium hydroxide; triethylamine; pyridine; or N,N - carried out in the presence of a base such as dimethylaniline. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and are usually -20 to 60°C and 5 minutes to 10 hours. Further, the salt of the compound of general formula [XI] can be easily obtained according to a conventional method, and examples of the salt include the same salts as explained for the salt of the compound of general formula []. The compound of general formula [XI] or a salt thereof thus obtained may be isolated and purified by a conventional method, but it can also be used as it is in the next reaction without isolation. (e) Ring-closing reaction Next, by reacting the compound of general formula [XI] or a salt thereof with thioformamide or thiourea of general formula [XII], the compound of general formula [] or a salt thereof of the present invention is prepared. can be obtained. This ring-closing reaction is usually carried out in a suitable solvent, and any solvent may be used as long as it does not inhibit this reaction. For example,
Examples include water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyridone, and these solvents may be used alone or in combination of two or more. It's okay. Although the addition of a deoxidizing agent is not particularly necessary, the reaction may proceed smoothly by adding a deoxidizing agent as long as the cephalosporin skeleton is not changed. Deoxidizers used for this purpose include alkali metal hydroxides; alkali metal bicarbonates; or inorganic or organic bases such as triethylamine, pyridine or N,N-dimethylaniline. The amount of thioformamide or thiourea of general formula [XII] to be used is usually 1 to 1, respectively, per the compound of general formula [XI] or a salt thereof.
It is several times the mole. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and are usually 0 to 100°C for 1 to 48 hours, preferably,
1 to 10 hours. Furthermore, in the compound of the general formula [ ] or its salt, protection of the carboxyl group, removal of the protecting group, and further conversion to a salt are carried out according to conventional methods, and the corresponding other compounds within the same general formula are protected. It can be converted into the compound of the present invention. Also, in the formula
If a group active in this ring-closing reaction exists in R ¹ , R ² and R ⁵ , it can be optionally protected with a conventional protecting group during the reaction, and after the reaction, it can be protected by a conventional method. The protecting group can then be removed. The target compound of the general formula [] or a salt thereof thus obtained can be isolated by a conventional method. (f) Oxime formation A compound of general formula [] or a salt thereof can be obtained by reacting a compound of general formula [] or a salt thereof with a compound of general formula [] or a salt thereof. Examples of the salt of the compound of general formula [] include hydrochloride, hydrobromide, and sulfate. Any solvent may be used as long as it does not inhibit this reaction, for example,
Examples include water, alcohol, and N,N-dimethylacetamide, and these solvents may be used alone or in combination of two or more. The amount of the compound of general formula [] or its salt to be used is usually one to several times the amount of the compound of general formula [] or its salt. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvents used, and are usually 0 to 100°C, preferably 10 to 50°C, and 10 to 50°C.
Minutes to 48 hours. When using salts of the compound of general formula [] in this reaction, for example, alkali metal hydroxide salts such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxide salts such as magnesium hydroxide and 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 bicarbonates such as sodium bicarbonate and potassium bicarbonate; phosphoric acids such as magnesium phosphate and calcium phosphate alkaline earth metal salts; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; and inorganic bases such as alkali metal acetates such as sodium acetate and potassium acetate or trialkyls such as trimethylamine and triethylamine. Amine; Picoline; N-methylpyrrolidine; N-methylmorpholine; 1,5
-diazabicyclo[4.3.0]-5-nonene; 1,
Preferably, the reaction is carried out in the presence of a base such as 4-diazabicyclo[2.2.2]octane; and an organic base such as 1,5-diazabicyclo[5.4.0]-7-undecene. In the thus obtained compound of the general formula [] of the present invention or its salts, R ¹ can be converted in the same manner as explained above for (b)acylation, and also in a conventional manner. can be isolated. The compound of the general formula [ ] or a salt thereof obtained as above can be used in the form of free acid, non-toxic salt or physiologically acceptable ester for the treatment and prevention of bacterial infections. It can be administered to humans and animals, but especially for the compounds of the general formula [] of the present invention, by parenteral administration in the form of the free acid or in the form of non-toxic salts or in the form of physiologically acceptable esters. Therefore, it is preferable to apply an oral administration method. When administered to humans and animals, the dosage forms usually applied to cephalosporin drugs, such as tablets, capsules, powders,
It may be prepared in the form of granules, fine granules, syrups, injections (including drips), suppositories, or the like. When preparing a drug of the present invention of the compound of general formula [] or its salts, excipients such as starch, lactose, sugar, calcium phosphate and calcium carbonate; gum arabic, starch, crystalline cellulose, carboxylic Diluents and/or additives such as binders such as methylcellulose and hydroxypropylcellulose; lubricants such as talc and magnesium stearate; and disintegrants such as carboxymethylcalcium and talc may be used as appropriate. The administration method, dosage and frequency of administration of the compound of general formula [ ] or its salt of the present invention can be selected as appropriate depending on the age, weight and symptoms of the patient.
The usual dosage for adults is 50 to 5000 mg per day, 1 to 4 times a day.
It may be administered orally or parenterally in divided doses. Next, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Note that Wako Gel C-200 was used as a column packing material in column chromatography. Also,
All mixing ratios in the eluent are volume ratios. Reference example 1 (1) 2,4-dimethoxybenzylamine hydrochloride
Suspend 61.1 g in 350 ml of methanol, add and dissolve 31.8 g of triethylamine. Add ethyl = N-(2,2-diethoxyethyl) to this solution.
Add 69.9g of oxalate, react at room temperature for 2 hours, remove the precipitated crystals, and the melting point is 128~
84.4 g (yield 79.5%) of N-(2,4-dimethoxybenzyl)-N'-(2,2-diethoxyethyl)oxamide having a temperature of 120 DEG C. is obtained. IR (KBr) cm ^-1 ; C=0 1655 (2) To 50.0 g of N-(2,4-dimethoxybenzyl)-N'-(2,2-diethoxyethyl)oxamide obtained in (1) Acetic acid 250 containing 0.5g hydrogen chloride
ml and heat under reflux for 1.5 hours. Then, acetic acid is distilled off under reduced pressure, 150 ml of acetone is added to the resulting residue, and the precipitated crystals are collected.
4-(2,4-dimethoxybenzyl)-2,3-dioxo-1,2,3, having a melting point of 175-176°C
4-tetrahydropyrazine 34.4g (yield 93.0
%). IR (KBr) cm ^-1 ; C=0 1740-1620 (3) 4-(2,4-dimethoxybenzyl)-2,3-dioxo-1,2,3,4- obtained in (2)
Suspend 5.2 g of tetrahydropyrazine in 26 ml of N,N-dimethylformamide and add potassium carbonate.
Add 4.1g and stir at room temperature for 30 minutes. Then,
Add 5.8 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one and react at 50-60°C for 3 hours. Ethyl acetate reaction mixture
Introduce into a mixed solvent of 200 ml and 200 ml of water. Next, the organic layer was separated and washed with 100 ml of water,
Dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (eluent: chloroform) to give 1-(2,4-
dimethoxybenzyl)-4-(5-methyl-2-
4.9 g (yield: 66.0%) of oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine are obtained. IR (KBr) cm ^-1 ; C=0 1820, 1675, 1630 Compounds shown in Table 2 were obtained in the same manner. Note that R ² in Table 2 represents a substituent of the following formula.

[Table] (4) 1-(2,4-dimethoxybenzyl)-4-(5-methyl-2-oxo-1,3 obtained in (3))
-dioxol-4-yl)methyl-2,3-
Dissolve 3.7 g of dioxo-1,2,3,4-tetrahydropyrazine in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole, and heat at 50 to 60°C.
Let it react for 2 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with diethyl ether 30
ml and remove the precipitated crystals to find the melting point.
2.0 g of 1-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine (yield 90.9%). IR (KBr) cm ^-1 ; 〓C=0 1825, 1805, 1725,
1690, 1670 Compounds shown in Table 3 were obtained in the same manner. Note that R ² in Table 3 represents a substituent of the following formula.

[Table] (5) 1-Carboxymethyl-2,3-dioxo-
1,2,3,4-tetrahydropyrazine 2.6g
was dissolved in 13 ml of N,N-dimethylacetamide, and diphenyldiazomethane was added to this solution at room temperature.
Add 3.9g and stir for 10 minutes. The reaction mixture is introduced into a mixed solvent of 25 ml of ethyl acetate and 25 ml of water and stirred for 15 minutes. Take the precipitated crystals,
After washing successively with 10 ml of ethyl acetate and 10 ml of diethyl ether and drying, 2.9 g of 1-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine has a melting point of 97-98°C. (yield 56.4%). IR (KBr) cm ^-1 ; νC=0 1750, 1675, 1645 Reference example 2 (1) 1-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo -1,2,3,4-tetrahydropyrazine
Dissolve 2.69 g in 27 ml of N,N-dimethylformamide, add 1.52 g of potassium carbonate to this solution, and stir at room temperature for 20 minutes. Then, cool it on ice
tert-butyl=7-phenylacetamide-3
Add 4.67 g of -bromomethyl-Δ ² -cephem-4-carboxylate and allow to react at room temperature for 2 hours. Pour the reaction mixture into 200ml of ethyl acetate and water.
Introduce into 150ml of mixed solvent, separate the organic layer,
After washing with 150 ml of water, dry with anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in 100 ml of chloroform, 2.45 g (70% purity) of m-chloroperbenzoic acid was added, and the mixture was allowed to react at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was added with ethyl acetate.
Add 100ml and 100ml water. The organic layer is separated, washed with 100 ml of water, and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure and the resulting residue is purified by column chromatography (eluent: chloroform), the melting point is 135.
tert-butyl 7-phenylacetamide-3-<{1-[4-(5-
Methyl-2-oxo-1,3-dioxole-
4-yl)methyl-2,3-dioxo-1,
2,3,4-tetrahydropyrazinyl]}methyl>-Δ ³ -cephem-4-carboxylate-1-oxide 2.70 g (yield 43.2%) is obtained. IR (KBr) cm ^-1 ; νC=0 1820, 1790, 1720,
1685, 1650 (2) tert-butyl 7-phenylacetamide
3-<{1-[4-(5-methyl-2-oxo-
1,3-dioxol-4-yl)methyl-
2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]}methyl>-△ ³ -cephem-
Dissolve 3.0 g of 4-carboxylate-1-oxide in a mixed solvent of 12 ml of N,N-dimethylformamide and 6 ml of acetonitrile, and add 1.0 g of stannous chloride and acetyl chloride under ice cooling.
Add 1.58 g in sequence and stir at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water were added to the resulting residue, and the pH was adjusted to 6.0 with sodium hydrogen carbonate. Then, the organic layer is separated, washed with 50 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent, toluene:ethyl acetate = 3:2).
If purified with
tert-butyl=7-phenylacetamide-3
−<{1-[4-(5-methyl-2-oxo-1,
3-Dioxol-4-yl)methyl-2,3
2.12 g (yield: 72.4%) of -dioxo-1,2,3,4-tetrahydropyrazinyl]}methyl>-Δ ³ -cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; 〓C=0 1820, 1775, 1715,
1685, ₁₆₄₅ NMR (CDCl3) δ value; 1.58 (9H, s, -C( _CH3 ) ₃ ), 2.28 (3H, s, _-CH3 ), 3.17, 3.61 (2H, ABq, J=18Hz, C ₂ −H) 3.77 (2H, s,

[Formula]), 4.53, 5.13 (2H, ABq, J=15Hz,

[Formula]), 4.71 (2H, s, NCH ₂ −), 5.03 (1H, d, J=5Hz, C ₆ −H), 5.93 (1H, dd, J=5Hz, J=8Hz, C ₇ −
H), 6.53, 6.89 (2H, ABq, J=6Hz,

【formula】), 7.32~7.51 (5H, m,

[Formula]), 7.57 (1H, d, J=8Hz, -CONH-), Compounds in Table 4 are obtained in the same manner as in (1) and (2). Note that R ² in Table 4 represents a substituent of the following formula.

【table】

【table】

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ is a hydrogen atom or a carboxy protecting group; R ² is a phthalidyl group or a carboxyl group,
or an alkyl group substituted with a group represented by the formula [formula] (wherein R ⁶ represents a lower alkyl group); R ³ is a hydrogen atom; R ⁴ is
a hydrogen atom; R ⁵ represents an optionally protected amino group; and A represents the formula [formula] [wherein R ⁷ represents the formula -COOR ¹ (wherein R ¹ is the same as above represents an alkyl group which may be substituted with a group represented by the following formula, and ~ represents a syn or anti isomer or a mixture thereof. ], respectively. Cephalosporin or its salt represented by 2. Claim 1 in which R ⁵ is an amino group
Cephalosporin or its salt as described in Section 1. 3. The cephalosporin or a salt thereof according to claim 1 or 2, wherein A is a group represented by the formula [Formula] (wherein is a syn isomer). 4. The cephalosporin according to any one of claims 1 to 3, wherein A is a group represented by the formula [Formula] (wherein the syn isomer and R ¹ have the above meanings). Or its salt. 5 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-{[1-(4-phthalidyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]
The compound according to claim 1, which is methyl}-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof. 6 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]
-3-<{1-[4-(5-methyl-2-oxo-
1,3-dioxol-4-yl)methyl-2,
The compound according to claim 1, which is 3-dioxo-1,2,3,4-tetrahydropyrazinyl]}methyl>-Δ ³ -cephem-4-carboxylic acid, an ester thereof, or a salt thereof.