JPH0357912B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [] "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is a hydrogen atom or an alkyl, cycloalkyl, aralkyl or dialkylamino group which may be substituted with an acyloxy group; R ³ is a hydrogen atom or a carboxyl protecting group; Atom or alkoxy group; R ⁴
represents an amino group; Z is S or S→O
and the dotted line in the ring mean that the 2nd to 3rd or 3rd to 4th positions are double bonds, respectively. ” and a method for producing them. That is, the present invention provides 7-amino-3-{[1-(4-substituted or unsubstituted)-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl )] Methyl}-cephem-4-
This invention relates to carboxylic acids, their salts, and their production methods. Therefore, an object of the present invention is to provide a novel compound useful as an intermediate in producing various novel cephalosporin antibiotics useful as antibacterial agents. Another object of the present invention is to provide a method for producing novel cephalosporanic acids. The cephalosporanic acids of the present invention have a formula at the 3-position exomethylene group of the cefem ring.

[Formula] (In the formula, R ² has the same meaning as above.)
2,3-dioxo-1,2,3,4 represented by
This is a novel compound that is characterized by the fact that -tetrahydropyrazinyl group is bonded thereto. Hereinafter, the present invention will be explained in further detail. In this specification, unless otherwise specified, alkyl refers to straight-chain or branched _C1-14 alkyl, such as methyl, ethyl, n _- propyl,
iso-propyl, n-butyl, iso-butyl, sec
-butyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, dodecyl or lauryl; alkoxy refers to -O-alkyl having an alkyl group as defined above; lower alkyl refers to
Straight-chain or branched _{C 1-5 alkyl} , e.g.
Methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-
such as butyl or pentyl; lower alkoxy refers to -O- having a lower alkyl group as defined above;
lower alkyl; anyl refers to _C1-12 acyl, such as acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl, _{cyclohexanecarbonyl} , furoyl or thenoyl; acyloxy refers to C1-12 acyl having an acyl group as defined above; -O-acyl; alkylthio refers to -S _- alkyl having an alkyl group as defined above; alkenyl refers to _C2-10 alkenyl, such as vinyl, allyl, iso-propenyl, 2
-pentenyl or butenyl; alkynyl refers to _C2-10 alkynyl, such as ethynyl or ₂ -propynyl; cycloalkyl refers to _C3-7 cycloalkyl, such as cyclopropyl _, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc.; cycloalkenyl refers to _C5-7 cycloalkenyl, such as cyclopentenyl or _cyclohexenyl ; aryl refers to phenyl, naphthyl or indanyl; aralkyl refers to benzyl, phenethyl, 4-methyl benzyl or naphthylmethyl; heterocyclic group refers to a heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
Isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, 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; and halogen atom means fluorine, chlorine, bromine or iodine atom , respectively. R ¹ in each general formula herein is a hydrogen atom or a carboxyl protecting group, and 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, organic tin groups, etc., which have the property of being easily eliminated by treatment with; and various other known ester-forming groups. Among these types of carboxyl protecting groups, preferable carboxyl protecting groups include the following. (a) Alkyl group. (b) At least one of the substituents is halogen, nitro, acyl, alkoxy, oxo, cyano, 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, thiomorpholino, 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, cycloalkyloxy, cycloalkenyloxy, heterocyclic alkyloxy,
Alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclicalkyloxycarbonyloxy,
alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
Substituted lower alkyl groups which are cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocycloalkyloxycarbonyl, alkylanilino or alkylanilino 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 or substituted derivatives thereof whose substituent is a halogen or lower alkyl group. Furthermore, anhydrides of a 4-position carboxyl group and N-hydroxysuccinimide, N-hydroxyphthalimide, dimethylhydroxyamine, diethylhydroxyamine, 1-hydroxypiperidine, oxime, etc. can also be mentioned as carboxyl protecting groups. The carboxyl protecting groups exemplified above are representative examples, and carboxyl protecting groups described in the following documents can also be arbitrarily selected. U.S. Patents 3499909, 3573296 and 3641018
No.: West German Patent Publications No. 2301014, No. 2253287 and 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 ⁵ is a straight-chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without known substituents; R ⁶ is a hydrogen atom or a straight-chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without known substituents; R ⁷ 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 -(CH ₂ ) _o CO
a group represented by OR ⁶ (wherein R ⁶ 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-ethyl-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, butyryloxymethyl, isobutyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-
Acyloxyalkyl groups such as n-propyl, 1-pivaloyloxyethyl and 1-pivaloyloxy-n-propyl groups; acetylthiomethyl,
pivaloylthiomethyl, benzoylthiomethyl,
Acylthioalkyl groups such as p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl and 1-(p-chlorobenzoylthio)ethyl groups; methoxymethyl, ethoxymethyl, Alkoxymethyl groups such as propoxymethyl, isopropoxymethyl and n-butyloxymethyl groups; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butyloxycarbonyloxymethyl,
tert-butyloxycarbonyloxymethyl, 1
- alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl and 1-butyloxycarbonyloxyethyl groups; methoxycarbonylmethyl and ethoxycarbonyl Alkoxycarbonylmethyl groups such as methyl groups; phthalidyl groups; indanyl groups; phenyl groups; and 2-(phthalidylidene)
Examples include phthalidylidene alkyl groups such as ethyl, 2-(5-fluorophthalidylidene)ethyl, 2-(6-chlorophthalidylidene)ethyl and 2-(6-methoxyphthalidylidene)ethyl groups. In addition, as salts of the compound of general formula [],
Mention may be made of the salts with basic or acidic groups commonly known in the field of penicillins and cephalosporins. 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,
Mesitylene sulfonic 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,
Salts with sulfonic acids, such as benzene-1,2,4-trisulfonic acid or naphthalene-1,3,5-trisulfonic acid, and salts with acidic groups, for example with alkali metals such as sodium or potassium, are used. salts with alkaline earth metals such as calcium or magnesium; ammonium salts; procaine, dibenzylamine,
N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine or dicyclohexylamine Examples include salts with nitrogen-containing organic bases such as. Also, in the general formula [],

When R ² of the group represented by [Formula] is a hydrogen atom, the following balanced formula: Tautomers exist as shown in , and these tautomers are also included. Next, the method of the present invention will be explained. The method of the present invention is as follows. "In the formula, R ¹ , R ² , R ³ , R ⁴ , Z and the dotted line in the ring have the same meanings as described above; X is acyloxy or carbamoyloxy which may have a substituent. That is, in the method of the present invention, a 1-substituted or unsubstituted-2,3 group of the general formula [] is added to a cephalosporanic acid of the general formula [ ] or a salt thereof in the presence of an acid or an acid complex compound. -dioxo-1,2,
7-Amino-3-{[1 -(4-substituted or unsubstituted -2,3-
Dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids or salts thereof can be produced with high yield and high purity. The method of the present invention will be further explained in detail below. The acyloxy and carbamoyloxy groups of X in the general formula [] include, for example, alkanoyloxy groups such as acetoxy, propionyloxy and butyryloxy; alkenoyloxy groups such as acryloyloxy; aroyloxy groups such as benzoyloxy and naphthoyloxy; and carbamoyloxy groups, which include halogen atoms, nitro groups, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl groups, amino groups, carboxyl groups, sulfamoyl groups, carbamoyl groups, and alkoxycarbonylcarbamoyl groups. may be substituted with one or more substituents such as aroylcarbamoyl group, aroylcarbamoyl group, alkoxycarbonylsulfamoyl group, aryl group, and carbamoyloxy group. Among the substituents for X mentioned above, the hydroxyl group, amino group, carboxyl group, etc. may be protected with a commonly used protecting group. Here, the hydroxyl-protecting group includes all groups that can normally be used as a hydroxyl-protecting group, 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
- Easily eliminated such as tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl or trifluoroacetyl an acyl group; an alkylsulfonyl group such as methanesulfonyl or ethanesulfonyl; an arylsulfonyl group such as phenylsulfonyl or toluenesulfonyl; or benzyl, trityl, methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-nitrophenylthio or 2,
Examples include 4-dinitrophenylthio group. In addition, protecting groups for amino groups include all groups that can be normally used as amino protecting groups, such as trichloroethoxycarbonyl, 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-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-
Easily eliminated acyl groups such as dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl or 8-quinolyloxycarbonyl; 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-
Easily leaving groups such as ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene or 3,3-dimethyl-5-oxocyclohexylidene; or silyl groups such as di- or tri-alkylsilyl Examples include. Furthermore, the carboxyl group-protecting group includes all groups that can normally be used as carboxyl-protecting groups, such as methyl, ethyl, n-propyl, iso-propyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p
-Nitrobenzyl, p-methoxybenzyl, benzoylmethyl, 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-butenyl, succinimidomethyl,
1-cyclopropylethyl, methylsulfinylmethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-yl-methyl, pyridin-1-oxide-2-yl-methyl or bis(p-methoxy phenyl)methyl, or with a non-metallic compound such as titanium tetrachloride, as further described in JP-A-46-7073 and Dutch Publication No. 7105259. For example,
For example, it is protected with a silyl compound such as dimethylchlorosilane. Further, as the salts of the compound of the general formula [] and the salts of the compound of the general formula [], the same salts as explained for the salts of the compound of the general formula [] can be mentioned. First, 1-substituted or unsubstituted-2,3-dioxo-1,2,
3,4-tetrahydropyrazine or its salt is
Journal of the Chemical Society Parkin I
Society Perkin I), pp. 1888-1890 (1975). Although tautomers may exist in this raw material, any of the isomers or a mixture thereof can be used in this reaction. Furthermore, 1-substituted-2,3-dioxo-1,
In 2,3,4-tetrahydropyrazine, 1
When the substituent at the position has a basic group or an acidic group, it may be subjected to the reaction in each form as required. In this case, the salt of the basic group and the salt of the acidic group are of the general formula [ Examples include salts with basic groups and acidic groups similar to those described for the salts of cephalosporin. In addition, the salts of the compound of the general formula [] may be used after being isolated in advance, 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. Examples of protonic acids include sulfuric acids, sulfonic acids, and super strong acids (super strong acids mean acids stronger than 100% sulfuric acid, and include some of the aforementioned sulfuric acids and sulfonic acids). , 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 aryl (mono, di) sulfonic acids such as p-toluenesulfonic acid; Sulfonic acids such as di- or tri-sulfonic acid; as well as perchloric acid, magicic acid (FSO ₃ H−SbF ₅ ),
Examples include superacids such as _FSO3H - _AsF5 , _CF3SO3H - _SbF5 , _HF - _BF3 and _{H2SO4 - SO3} . Furthermore, examples of the Lewis acid include boron trifluoride. Further, as complex compounds of Lewis acids, for example, dialkyl ether complex salts of boron trifluoride and diethyl ether, di-n-propyl ale or di-n-butyl ether; ethylamine;
Amine complexes with n-propylamine, n-butylamine or triethanolamine; carboxylic acid ester complexes with ethyl formate or ethyl acetate; fatty acid complexes with acetic acid or propionic acid; or acetonitrile or propionitrile. Examples include nitrile complex salts. 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; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole and dimethyl cellosolve; ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate and esters such as butyl acetate; nitriles such as acetonitrile and butyronitrile; and sulfolanes such as sulfolane.
Two or more of these solvents may be used in combination. Moreover, a complex compound formed by these organic solvents and a Lewis acid can also be used as a solvent. The amount of the acid or acid complex compound to be used may be at least the same molar amount, preferably 2 to 10 times the molar amount, relative to the compound of general formula [] or its salt, and should be used in accordance with 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, the amount of 1-substituted or unsubstituted-2,3-dioxo-1,2,3,4-tetrahydropyrazine or its salt of general formula [] to be used, which is the raw material compound of this reaction, is The amount may be at least equimolar, preferably 1.0 to 5.5.0 times the molar amount of the compound or its salt. The reaction temperature and reaction time may be changed as appropriate depending on the raw materials and solvent used, and usually,
The temperature is 0 to 80°C for 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. , trimethylsilylacetamide, trimethylchlorosilane or dimethyldichlorosilane; organic acid chlorides such as acetyl chloride or p-toluenesulfonyl chloride; acid anhydrides such as acetic anhydride or trifluoroacetic anhydride; or acids such as sulfuric anhydride. Anhydrous; or an inorganic desiccant such as anhydrous magnesium sulfate, anhydrous calcium chloride, monocular sieve or calcium carbide may be added. According to the method of the present invention, favorable results can be obtained with both the Δ ³ -cephem compound and the Δ ² -cepheme compound, and even when the Δ ² -cepheme compound is used as the cephalosporanic acid of the general formula [ The obtained Δ ² -cephem compound can be converted into a Δ ³ -cepheme compound of the general formula [] by a conventional method. 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 the post-treatment stage by conventional methods. Furthermore, when a compound of the general formula [] in which R ¹ is a carboxyl protecting group is used as a raw material, the corresponding compound of the general formula [] in which R ¹ is a hydrogen atom may be obtained by post-reaction treatment. However, if desired, the protecting group can be removed by a conventional method to obtain a compound of the general formula [] in which R ¹ is a hydrogen atom. General formula of the present invention thus obtained []
The compound has an acyl group at the 7-position, for example,
2-(2-aminothiazol-4-yl)acetyl, 2-(2-aminothiazol-4-yl)-2
-(syn)-methoxyiminoacetyl, 2-(2-
aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetyl or 2-(2-aminothiazol- By introducing 4-yl)-2-(syn)-(2-carboxyprop-2-oxoimino)acetyl and the like, various useful cephalosporin compounds can be derived. Next, the present invention will be explained by giving examples and reference examples, but the present invention is not limited to these. Example 1 10 ml of ethyl acetate solution containing 2.71 g of boron trifluoride
7-aminocephalosporanic acid (hereinafter referred to as 7-
Abbreviated as ACA. ) 2.72g and 4-ethyl-
Add 1.54 g of 2,3-dioxo-1,2,3,4-tetrahydropyrazine and react at room temperature for 16 hours. After the reaction was completed, the reaction mixture was introduced into 50 ml of methanol under ice cooling, and then 3.16 g of pyridine was added dropwise. The precipitated crystals are collected, thoroughly washed with 30 ml of methanol, and dried to give 7-amino-3-{[1-(4-ethyl-2,3
-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-Δ ³ -cephem-4-carboxylic acid (3.10 g, yield 88.1%). IR (KBr) cm ^-1 ; ν _C=O 1795, 1670, 1620 NMR (CF ₃ COOD) δ value; 1.44 (3H, t, J=7Hz, NCH ₂ CH ₃ ), 3.69 (2H, bs, C ₂ −H), 4.08 (2H, q, J=7Hz, NCH ₂ CH ₃ ), 5.14, 5.51 (2H, ABq, J=15Hz,

[Formula]), 5.48 (2H, s, C ₆ -H, C ₇ -H), 6.74, 7.00 (2H, ABq, J = 6Hz,

[Formula]) Example 2 10 ml of ethyl acetate solution containing 2.72 g of boron trifluoride
, 2.72 g of 7-ACA and 4-n-pentyl-
Add 2.0 g of 2,3-dioxo-1,2,3,4-tetrahydropyrazine and react at room temperature for 16 hours. After the reaction is completed, the reaction mixture is introduced into 15 ml of ice water, and the pH is adjusted to 3.5 with 28% aqueous ammonia under ice cooling. Take the precipitated crystals and add 5 ml of water and 5 ml of acetone.
7-amino-3-{[1-(4-n-pentyl-2,3-dioxo-1,2,3,4- 3.22 g (yield: 81.7%) of methyl-Δ ³ -cephem-4-carboxylic acid (tetrahydropyrazinyl)] are obtained. IR (KBr) cm ^-1 ; ν _C=O 1800 _, 1678, 1630 NMR ( _d6 -DMSO+ _CF3COOD ) δ value; 0.91 (3H, t, J=7Hz, N( _CH2 ) _4CH3 ), 1.10 ~1.95 (6H, m, NCH ₂ (CH ₂ ) ₃ CH ₃ ), 3.63 (2H, bs, C ₂ −H), 3.77 (2H, t, J=7Hz, NCH ₂
(CH ₂ ) ₃ CH ₃ ), 4.34, 4.82 (2H, ABq, J=15Hz,

[Formula] 5.32 (2H, bs, C ₆ -H, C ₇ -H) 6.76 (2H, bs,

[Formula]) Compounds shown in Table 1 were obtained in the same manner. Note that R ² in Table 1 represents a substituent of the following formula.

【table】

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is a hydrogen atom or an alkyl, cycloalkyl, aralkyl or dialkylamino group which may be substituted with an acyloxy group; R ³ is a hydrogen atom or a carboxyl protecting group; Atom or alkoxy group; R ⁴
represents an amino group; Z is S or S→O
and the dotted line in the ring mean that the 2nd to 3rd or 3rd to 4th positions are double bonds, respectively. 7-amino-3-{[1-(4-substituted or unsubstituted-2,3-dioxo-1,2,3,
4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 2. 7-amino- ³ -{[1-(4-substituted or unsubstituted -2,3-dioxo-1,2,3,
4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 7-Amino-3-{[1-(4-substituted or unsubstituted-2,3-dioxo-1,2,3,
4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 4 Claim 1 in which R ³ is a hydrogen atom
7-amino-3-{[1
-(4-substituted or unsubstituted-2,3-dioxo-
1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 5 Claim 1 in which R ² is a hydrogen atom
7-amino-3-{[1
-(4-substituted or unsubstituted-2,3-dioxo-
1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 7-Amino-3-{[1-( ⁴
-substituted or unsubstituted-2,3-dioxo-1,
2,3,4-tetrahydropyrazinyl)]methyl}
-Cefem-4-carboxylic acids and salts thereof. 7-amino- according to any one of claims 1 to 4, wherein R ² is a cycloalkyl group
3-{[1-(4-Substituted or unsubstituted-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 8 7-Amino-3 according to any one of claims 1 to 4, wherein R ² is an aralkyl group
-{[1-(4-Substituted or unsubstituted-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 9 R ² is a dialkylamino group, 7-amino-3-{[1-(4-substituted or unsubstituted-2,3-
Dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids and salts thereof. 10 General formula "In the formula, R ¹ is a hydrogen atom or a carboxyl protecting group; R ³ is a hydrogen atom or an alkoxy group; R ⁴ is an amino group; X is acyloxy or carbamoyl which may have a substituent. oxy group; Z is S or S→O; and the dotted line in the ring means that the 2-3 or 3-4 position is a double bond, respectively.'' In the presence of an acid or a complex compound of an acid, the general formula 1-Substituted or unsubstituted-2,3-dioxo represented by "In the formula, ^R2 represents an alkyl, cycloalkyl, aralkyl, or dialkylamino group which may be substituted with a hydrogen atom or an acyloxy group." - General formula characterized by reacting 1,2,3,4-tetrahydropyrazine or a salt thereof, and then optionally removing an ester-forming group or converting a carboxyl group into an ester or salt. 7 ^- Amino- ³ -{[ ^{1- (} 4- substituted or unsubstituted-2,3-dioxo-1,2,3,
4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids or salts thereof. 11. 7-Amino- ³ -{[1-(4-
substituted or unsubstituted-2,3-dioxo-1,2,
3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids or salts thereof. 12 Claim 10 in which Z is S
or 7-amino-3-{[1-(4
-substituted or unsubstituted-2,3-dioxo-1,
2,3,4-tetrahydropyrazinyl)]methyl}
- A method for producing cefem-4-carboxylic acids or salts thereof. 13 Claim 10, wherein the acid or acid complex compound is a Lewis acid or a Lewis acid complex compound.
7-amino-3- according to any one of items 12 to 12
{[1-(4-substituted or unsubstituted-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]
A method for producing methyl}-cephem-4-carboxylic acids or salts thereof. 14 7-amino-3-{[1-
(4-substituted or unsubstituted-2,3-dioxo-1,
2,3,4-tetrahydropyrazinyl)]methyl}
- A method for producing cefem-4-carboxylic acids or salts thereof. 7-amino- according to any one of claims 10 to 14, wherein 15 X is an acetoxy group.
Process for producing 3-{[1-(4-substituted or unsubstituted-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids or salts thereof . 16 7-Amino-3-{[1-(4-substituted or unsubstituted-2,3- A method for producing dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-cephem-4-carboxylic acids or salts thereof.