JPS60208986A - Novel cephalosporin - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by formula I [R<1> is lower alkyl which may be substituted by (protected) carboxyl group; R<2> is H or a protecting group of the carboxyl group; R<3> is heterocyclic group which is linked through C-N to exomethylene group at the 3-position and may be substituted]. EXAMPLE:Pivaloyloxymethyl=7-[2- ( 2-amino-4-hydroxy-2-thiazolin-4-yl )-2-( syn )- methoxyiminoacetamido]-3-( 5-methyl-1,2,3,4-tetrazol-z-yl )methyl-DELTA<3>-cephem-4-carboxylate. USE:An antimicrobial agent. PREPARATION:For example, a 7-amino-DELTA<3>-cephem-4-carboxylate expressed by formula II is reacted with a 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetyl chloride expressed by formula III (X is halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporins, specifically cephalosporins (syn isomers) and salts thereof.

The present inventors previously discovered that the cephalosporin (syn isomer) represented by the general formula or its salt is an extremely useful compound as an antibacterial agent, and filed a patent application (Japanese Patent Laid-Open No. 57-99592, Japanese Patent Application No. 57-200382, Japanese Patent Application No. 58-67871,
Patent Application No. 1983-113565, Patent Application No. 11431-1982
No. 3).

Subsequently, as a result of intensive research on the method for producing the above compound, it was found that the compound of the present invention is useful as an intermediate for producing the compound represented by the general formula [■], and as an antibacterial agent itself with excellent pharmacological action. They discovered something and completed the present invention.

Therefore, the purpose of the present invention is to provide a useful cephalosporin (syn isomer) represented by the general formula [II] and its salts as a production intermediate, and as an antibacterial agent itself having excellent pharmacological action. An object of the present invention is to provide a useful compound represented by the general formula (I) and a salt thereof.

As described above, the structural characteristics of the cephalosporin (synisomer) represented by the general formula CI and its salts are such that the amino group at the 7-position is replaced by the general formula CI [where R1 has the same meaning as above. has. ] is attached to the group represented by .

The present invention will be further explained in detail below.

In this specification, unless otherwise specified, alkyl refers to linear or branched c1-14 alkyl, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, 56cm butyl, tert-
Butyl, pentyl, hexyl, heptyl, octyl, dodecyl, etc.; alkenyl means CZ~1o alkenyl,
For example, vinyl, allyl, isopropenyl, 2-pentenyl, phthynyl, etc.; Aryl means, for example, phenyl, tolyl, naphthyl, indanyl, etc.; Aralkyl means, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, etc. ; Acyl is 01-1
3-acyl, such as acetyl, propionyl, phthyryl, hivaloyl, pentanecarbonyl, cyclohexanecarbonyl, benzoyl, naphthoyl, 70yl, thenoyl, etc.; halogen atom means, for example, fluorine, chlorine, bromine, iodine atom, etc. It is. Moreover, the term "lower" means having 1 to 5 carbon atoms.

Furthermore, among the various terms used in this invention, for example, alkyl, alkenyl, aryl, aralkyl,
Terms such as acyl have the above meaning unless otherwise specified.

In each formula, R1 represents a carboxyl group or a lower alkyl group optionally substituted with a protected carboxyl group;
2 represents a hydrogen atom or a carboxyl protecting group. Examples of the carboxyl group-protecting group include those commonly used in the field of penicillin and cephalosporin compounds, specifically, those described in JP-A No. 57-99592;
Japanese Patent Application Publication No. 58-77RR6, Patent Application No. 57-200382
No., Patent No. 8j) 5 B-67871, Patent Application No. 1983
-113565 and Japanese Patent Application No. 114313/1983, etc., may be mentioned.

Furthermore, in each formula, R3 represents an optionally substituted heterocyclic group that forms a carbon-nitrogen bond with the exomethylene group at the 3-position. Indicates a divalent group which together with a sulfonyl group forms a 5-membered or 6-membered group. ) Examples include nitrogen-containing 5- or 6-membered heterocyclic groups such as 1.2.6-thiadiazine-1,1-dioxide and isothiazolidine-1,1-dioxide groups. More specifically, 1-(1,2,3,4-tetrazolyl)
, 2-(1,2,3,4-tetrazolyl), 1-(1,
2,:(-)riazolyl), 2-(1,2,3-triazolyl), 1-(1,2,4-)riazolyl), 4-(
1,2,4-)riazolyl), 2,3-dioxo-1,
2,3,4-tetrahydropyrazinyl, 3,6-thioxo 1.2.3.6-titrahydropyridazinyl, 6-
Oxo-1,6-dihydropyrimidinyl, 2-oxo-
1,2-dihydropyrazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1,2-dihydropyrimidinyl, 1,2,6-thiadiazin-1,1-dioxide-2-yl, iso Examples include thiazolidine-1,1-dioxide-2-yl group.

Examples of substituents on the heterocyclic group include a halogen atom, a nitro group, an alkyl group, an aralkyl group,
Aryl group, alkenyl group, hydroxyl group, alkoxy group, cyano group, amino group, alkylamino group, dialkylamino group, acylamino group, acyl group, acyloxy group, acylalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, carnocumoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group, sulfo group , sul 7 amoylalkyl group,
Examples include a sulfamoyl group, a carnocumoyl alkyl group, a carbamoylalkenyl group, an N-hydroxycarbamoylalkyl group, and the above-mentioned heterocyclic group may be substituted with one or more of these substituents. Among these substituents, the hydroxyl group and the amino group are
7-99592, Japanese Patent Application No. 5Fl-771 (No. 86, Japanese Patent Application No. 57-200382, Japanese Patent Application No. 58-67871, Japanese Patent Application No. 58-113565, and Japanese Patent Application No. 1987-i)
1431 and the like, and the carboxyl group may also be protected with the carboxyl group protecting group in R1 described above.

Examples of the salt of the compound of general formula CI] or [■] include salts with basic groups or acidic groups that are conventionally known in the field of penicillin and cephalosporin compounds. Examples of salts with basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, and sulfuric acid; oxalic acid, succinic acid, gin-2-nulfonic acid, toluene-4
-sulfonic acid, mesitylene sulfonic acid (2,4,6-)limethylbenzenesulfonic acid), and salts with acidic groups include, for example,
Salts with alkali metals such as sodium and potassium; J+
Gai ・Su＾ l + I→ υ ＾ J,? a L+
Salts of small, l-mountain 11-Rhetium salts; ammonium salts; triethylamine.

Examples include salts with nitrogen-containing organic bases such as trimethylamine, aniline, N,N-dimethylaniline, pyridine, and dicyclohexylamine.

The present invention also covers all optical isomers of the cephalosporin (syn isomer) of the general formula [I] and its salts (for example, those occurring because the 4-position carbon atom of the thiazoline ring is an asymmetric carbon). This includes optical isomers, crystal forms, and hydrates.

The compound of the present invention and the compound of general formula [■] can be produced, for example, according to the method shown below.

space below c) R4 represents an optionally substituted alkyl, aralkyl or aryl group, and as a substituent, R3
Examples of substituents for the heterocyclic group include those exemplified. Furthermore, among these substituents, the hydroxyl group and the amino group may be protected by the hydroxyl and amino group protecting groups exemplified in R3, and the carboxyl group may be protected by the carboxyl group protecting groups exemplified in R1. .

Examples of the salts of the compounds of the general formulas CI), (:IV) and (V) include those exemplified as the salts of the compounds of the general formulas [I] and [■].

The compound of the general formula [VI] is disclosed in Japanese Patent Application No. 58-172254
It can be produced by the method described in the above (reaction with thiol, nitrosation, alkylation, halogenation, etc.) or by a method known per se.

(a) Method for producing a thiazoline compound of the general formula [■] or a salt thereof (ring-closing reaction) The thiazoline compound of the general formula [v] or a salt thereof can be obtained by reacting the compound of the general formula [VI] with thiourea. Japanese Patent Application No. 58-172254 describes a method for obtaining a thiazonyl compound by reacting a compound of the general formula (1) with thiourea. By collecting the crystals precipitated from within, the thiazoline compound (syn isomer) of general formula [v] or a salt thereof can be selectively obtained.

Examples of the solvent include ethyl acetate, acetone, dioxane, tetrahydrofuran, acetonitrile, acetic acid, monotyrene chloride, chloroform, benzene, and dimethyl cellosolve.

This reaction is usually carried out at -40 to 60°C, preferably at -30°C.
The reaction time is usually 30 minutes to 5 hours, preferably 30 minutes to 3 hours. When the syn isomer of the compound of general formula [VI] is used in the reaction, the amount of thiourea 1 to be used may be 1 mole or more per 1 mole of the syn isomer. When the compound of the general formula [VD is a mixture of the syn isomer and the anti isomer, the amount of thiourea to be used is determined as appropriate depending on the composition ratio of the syn isomer and the anti isomer of the compound of the general formula [VI'J]. be adjusted. In that case, the generated compound (syn isomer) of the general formula [VD] selectively precipitates as crystals from the reaction system, and the anti-isomer of the compound of the general formula [VI], which is an unreacted product, remains in the system. be able to. Next, add an acid such as dry hydrogen chloride or dry hydrogen bromide to the remaining anti-isomer to isomerize it to the syn isomer, and then perform the main ring-closing reaction again to isolate only the syn isomer. can do. In this way, only the syn isomer can be easily produced. The end point of this reaction can be easily confirmed by commonly used methods such as TLC.

And, the target compound is UV, , NMR, 13C-
It was confirmed by NMR etc. that it was a thiazoline compound.

(b) Process for producing acid halide of general formula [■
It can be easily obtained by reacting the compound of D or a salt thereof with a halogenating agent, which usually converts a thioloester into an acid halide, preferably, for example, chlorine or bromine. This reaction is usually carried out in a solvent, and any solvent may be used as long as it does not adversely affect this reaction. Examples include mixtures of two or more types. Further, the amount of the halogenating agent used is 1 to several equivalents relative to the compound of the general formula [VD or a salt thereof. The reaction is
It is usually carried out in the range of -30℃ to room temperature, and the reaction time is several minutes to
The duration is several hours, preferably 15 minutes to 2 hours.

C→ Process for producing a compound of the general formula [■] or a salt thereof (acylation reaction) A compound of the general formula CI) or a salt thereof is usually prepared by preparing a compound of the general formula [1ll] in an appropriate solvent in the presence or absence of a base. It can be obtained by reacting a compound of general formula [■] or a salt thereof with a compound of formula [■] or a salt thereof. Any solvent may be used as long as it does not adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, methyl acetate, acetic acid:t, tyl, N, N-. Examples include solvents such as dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, dimethyl cellosolve, dimethyl sulfoxide, and sulfolane, and mixtures of these solvents in an amount of 2'si or more. The bases used here include inorganic bases such as alkali hydroxide, alkali hydrogen carbonate, alkali carbonate, alkali acetate, etc., or trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, etc. Examples include tertiary amines and secondary amines such as dicyclohexylamine and diethylamine.

In addition, the compound of general formula [IV] or a salt thereof can be prepared, for example, by a conventional three-position conversion reaction of 7-amitusephalosboranic acid in the presence of an acid (Japanese Patent Application Laid-Open No. 57-99592, Japanese Patent Application No. -200382, 57-206873, 5
8-s7871, 58-113565, 58-
No. 114313) and then introduce a protecting group into the carboxyl group at the 4-position.

In addition, the compound of general formula [IV] or its salt can also be used as a reactive derivative in its amine group, and as the reactive derivative, for example, the compound of general formula [IV]
) compounds or their salts and silyl compounds such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, phosphorus trichloride,
[(:))CI,cn,-[>c”,gu,,O,PC
1, (CHs CL[xO)x-pcl, (cE, c
m, )Rpct, or (C4H
g) Those often used in acylation reactions, such as silyl derivatives, phosphorus derivatives or tin derivatives produced by reaction with tin compounds such as ssnol, can be mentioned.

The amount of the compound of general formula [III] or its salt to be used is not particularly limited, but is usually about 0.8 to 2.0 times the molar amount of the compound of general formula [IV) or its salt, preferably,
It is about 1.0 to 1.5 times the mole. This reaction is usually -5
The reaction is carried out at 0 to 50°C, preferably -35 to 25°C, and the reaction time is usually several minutes to several hours.

B) Method for producing a compound of general formula (n) or a salt thereof (dehydration reaction) A compound of general formula (n) or a salt thereof is obtained by subjecting a compound of general formula (I] or a salt thereof to a dehydration reaction.

This reaction is preferably carried out in a solvent, and any solvent may be used as long as it does not adversely affect the reaction, such as water, methanol, ethanol, acetone, acetonitrile, nitromethane, methyl acetate, ethyl acetate, Examples include solvents such as chloroform, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures of two or more of these solvents. Moreover, this reaction is preferably carried out in the presence of an acid. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-
Examples include protonic acids such as toluenesulfonic acid and mesitylenesulfonic acid; Lewis acids such as boron trifluoride, aluminum chloride, and zinc chloride; and complex compounds of Lewis acids such as boron trifluoride and diethyl ether. Further, the amount of acid used is not particularly limited, but is preferably 0.001 to 1.5 times the mole of the compound of general formula (I) or its salt. Furthermore, when the solvent used is a non-aqueous solvent, a suitable dehydrating agent, such as anhydrous magnesium sulfate or molecular sieve I, may be added to the reaction system. This reaction is usually carried out at room temperature or under cooling. The reaction time is usually several minutes to several tens of hours.

The salts of the compounds of general formulas [1] to CXI) obtained in this manner can be isolated and separated by conventional methods, or can be used in the next reaction without isolation and separation. You can also use

Furthermore, a compound of general formula [II) or a salt thereof in which R2 is a carboxyl protecting group can be easily converted into a compound of general formula [II) or a salt thereof in which R2 is a hydrogen atom] by a conventional method. Furthermore, by a conventional method, a compound of general formula [■] in which R2 is a hydrogen atom or a salt thereof is added to sR.
It can be easily converted into a compound of general formula [II] or a salt thereof, in which " is a carboxyl protecting group.

At the same time, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto.

Example 1 Pivaloyloxymethyl-7-amino-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ3-cephemu-4-carpoxyle) 4.1 F
was dissolved in a mixed solvent of 32 g of ethyl acetate and 8 g of N,N-dimethylacetamide, and cooled to -30°C.

Then, 3,509 chloride of 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetic acid hydrobromide was added, and -30
React for 2 hours at ~-20°C. The reaction solution was diluted with 5 ethyl acetate.
0- and saturated hydrogen carbonate) is introduced into a mixed solvent of 10 g of an aqueous solution of IJ. Then, separate the organic layer and add 5 ml of water.
After washing with water, drying with anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, 50% of diethyl ether is added to the resulting residue, and the crystals are collected by filtration, resulting in a melting point of 85-87.
Piparoyloxymethyl = 7-C2 showing °C (decomposition)
-(2-amino-4-hydroxy-2-thiazoline-4
-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ3-cephemu 4-carboxylate 4.8 P ( A yield of 78.4 yen) was obtained.

IR(KBr)m-1iνC-01790,1750,
'h6r.

NIITIR (CDCl2) δ value; 1.19 (9H,s, -C(CHs)a).

2.50 (3H11I, N>worm).

3.29 (2H-s, C2H).

3.93 (3H,a,-QC horse).

5.73-6.03 (3H, m, (4H, -00%C0
-) UV (C, H, OH) i λmax 260 (ε=9375) Margin below C) *1. Pivaloyloxymethyl F-amitsu-3-
(5-chloro-1,2,4-)riazol-1-yl)
The oxalate salt of methyl-Δ3-cephemu 4-carboxylate was used as a raw material.

*2. Anhydrous methylene chloride was used instead of the mixed solvent of ethyl acetate and N,N-dimethylacetamide, and triethylamine was further used as a deoxidizing agent.

Example 2 2-(2-amino-4-hydroxy-2-thiazoline-
Instead of the hydrobromide salt of 4-yl)-2-(syn)-2-methoxyiminoacetic acid chloride, 2-(2-amino-
4-human Roxy2-thiazolin-4-yl)-2-
If the reaction is carried out in the same manner as in Example 1 using hydrobromide of (syn)-2-methoxyiminoacetic acid bromide, the melting point is 85.
Pivaloyloxymethyl showing ~87°C (decomposition) = 7-
C2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4-tetrazole-2- yl)methyl-Δ3-cephemu 4-carboxylate is obtained.

Reference example 1 (1) 2-hydroxyimino-3-oxothiobutyric acid-8
-Methyl ester20. Of is dissolved in N,N-dimethylformamide, 100-, and 17.1 t of potassium carbonate and 22.4 t of chloroacetic acid tert-butyl ester are sequentially added at 0 to 5°C, followed by reaction at room temperature for 3 hours. The reaction solution is introduced into a mixed solvent of 400 mj of ethyl acetate and 200 d of water. Then, separate the organic layer and add water 2
00 d, IN-hydrochloric acid 200- and saturated saline 200-
After sequentially washing with m and drying with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, diisopropyl ether 100IIi is added to the resulting residue, and the crystals are collected by filtration to obtain 2-tert-butoxycarbonylmethoxyimino-3-oxothiobutyric acid-S, which has a melting point of 75-77°C. −
Mel:r-:Xf: 14,4 t (yield: 42.29
6).

IR(KBr) cm-1iνc=o 1732.17
00.1664 NMR (CDCIs) δ value; 1.50 (9H,s, -C(CHs)3).

2.39 (3H, tI, -CH3).

2.4fi(3H,s,-CH5).

4.63 (2H, s, OC% Co) f21
2-tert-butoxycarbonylmethoxyimino-
3-oxothiobutyric acid-8-methyl ester 10, Of is added over 10 minutes into trifluoroacetic acid 50, which has been cooled to 0-5°C. After reacting at 0 to 5°C for 1 hour, the solvent is distilled off under reduced pressure, and 50 g of diisopropyl ether is added to the resulting residue and the crystals are collected by filtration.
2-carboxymethoxyimino-3-oxothiobutyric acid-8-methyl ester 7.2F (yield 90
．． 5).

I R (K B r ) cm-1; νc=o 173
4.1700.166ONMR (a6-, DMso)
δ value; 2.36 (3H0m, CHt') - 2,45 (3H
1fil-CH8) 14.85(2H,s,-CH2
CO) Reference Example 2 (1) Water 330 aI! Sodium nitrite38. Of
and 3-oxothiobutyric acid-8-methyl ester66.
12 was added thereto, and 4N sulfuric acid (210) was added dropwise over 30 minutes while stirring at 5 to 8°C. After completion of the dropwise addition, the reaction mixture was allowed to react at the same temperature for 30 minutes, and then the reaction solution was introduced into 500 d of ethyl acetate. The organic layer is separated, washed with 500 g of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was dissolved in an aqueous solution containing 1062 sodium carbonate 650 #+7! After dissolving in methanol 15
Add 0m. Add 75.79 ml of dimethyl sulfate to this solution.
After dropping at 5 to 20°C, the mixture is reacted at the same temperature for 2 hours.

Then, the reaction solution was introduced into ethyl acetate 11, and the organic layer was separated, washed with 300 d of water, and then dried over anhydrous magnesium sulfate. When the solvent is distilled off under reduced pressure and the resulting residue is distilled under reduced pressure, the boiling point is 80-86℃72wnH
2-methoxyimino-3-oxothiobutyric acid-8 showing g
-Methyl ester (mixture of syn and anti forms) 60
．． 49 (yield 6B, 9%) is obtained.

If this mixture is separated and purified by column chromatography (Wako silica gel C-200, elution solvent: n-hexane-benzene), each oily substance is 2-(syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester. and 2-(anti)-methoxyimino-3-oxothiobutyric acid-8-methyl ester are obtained.

0 2-(syn)-methoxyimino-3-oxothiobutyric m-5-methyl ester IR-))m-1; c-o 1720,1690
．． 167ONMR (CDCis) δ value; 2.42r3H, g).

2.48 (3H, s).

4.18 (3H, s) 02-(anti)-methoxyimino-3-oxothiobutyric acid-8-methyl ester'IR(=-t)o+rl; c-o 1750
, 168ONMR (CDCIs) δ value; 2.41 (3H, s).

2.42 (3H, s).

4.16(3H,Iri(2)2-methoxyimino-3-oxothiobutyric acid-8-
Methyl ester (mixture of syn and anti isomers) 10.
Or was dissolved in 150d of 1,4-dioxane, and pyridinium hydrobromide/perbromide 2o, 1t
and react at room temperature for 4 hours. Then, the solvent is distilled off under reduced pressure, and 100 ad of ethyl acetate and 100 ad of water are added to the resulting residue. Separate the organic layer and add 5% hydrogen sulfite) IJium aqueous solution 100+d, water 100wt
After sequentially washing with 100 tons of saturated saline and drying with anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 4-bromo-2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms) It and 6F (yield 80.0*) are obtained.

If this mixture is separated and purified by column chromatography (Wako silica gel C-200, elution solvent: n-hexane-benzene), each oily substance 4-bromo-2-(
Syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester and 4-bromo-2-(anti)-methoxyimino-3-oxothiobutyric acid-8-methyl ester are obtained.

o 4-bromo 2-(syn)-methoxyimino-3-
Oxothiobutyric acid-8-methyl ester IR(nee)) m-1; c-o 1705.166
5NMR (CDCi3) δ value; 2.52 (3H, s-SCH3).

4.21(3H,s,OCHm) -4,42(2
H,l, BrCH2-).

IscNMR (CDCI, ) δ value; 11.30 (-
8CHs).

29.76(BrCH*-→.

6.4,97 (-0CHs)-04-7'lomo2-(anti)-methoxyimino-3
-Oxothiobutyric acid-8-methyl ester IR(nee) cm-1; νc=o 1720,
1655 NMR (CDCI,) δ value; 2.41 (3[,s, -8CH3).

4.21 (3■#l I-0CHs) *4.2
3(2H,s 1rcH2-) The following compound was obtained in the same manner.

04-Bromo-2-carboxymethoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms) Melting point: 110-114°C -IR (KBr) 1-1 iνc=o 1724.1
652HMI-j (Ci, -DMSO) δ1 vertical; 2.5
o(3H,s, -8GH8).

4.61 (2H, S, BrCH, Co-).

4.95 (2H, S, -OCH, C0-).

9.27 (IH, b3-COOH) Furthermore, the above 4-bromo 2-carboxymethoxyimino-3-oxothiobutyric acid-8-methyl ester is reacted with diphenyldiazomethane by a conventional method, and then,
The following compound was obtained by column separation.

04-Bromo 3-oxo-2-(syn)-diphenylmethoxycarbonylmethoxyiminothiobutyric acid-8-methyl ester Melting point: 87-89°C IR (KBr) cm-1iνc=o 1750.1
714.1680.166ONMR (CDCJa) δ value; 2.46 (3H,s, 8CHs).

4.08 (2H1s, BrCI(2CO).

4.87 (2H, s, -OCH failure C0-).

6.95 (IH, s, -C■gu).

7.29rsoH,t< , -@X2) (3) (i)
25.4 f of 4-bromo-2-(syn)-methoxyimino-3-oxothiobutyric acid-8-methyl ester was dissolved in 200 m of ethyl acetate, and 7.6 ml of thiourea was dissolved at 15-20°C.
Add f over 10 minutes. Then, after reacting at the same temperature for 1 hour, the precipitated crystals are collected by filtration to obtain 2-(2-amino-
4-hydroxy-2-thiazolin-4-yl)-2-(
30.2 t (yield: 91.5%) of hydrobromide of methoxyiminothioacetic acid-8-methyl ester (30.2 t) is obtained.

IR(KBr) m-1; νc=o 1670.164
0ω) If the above reaction is carried out using acetone, dioxane, tetrahydrofuran, acetonitrile, acetic acid, methylene chloride, chloroform, benzene or dimethyl cellosolve as the solvent in place of ethyl acetate in (i) above, the same result will be obtained. obtain.

(The following compound was obtained in the same manner as in (i) above.

0 2-(2-Amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminothiobutyric acid-8-methyl ester hydrobromide IR (KBr) cm -1i νc=o 1760,17
40,1650(4) Hydrobromide of 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester8. Of 200 g of ethyl acetate and 10 g of water under water cooling.
Suspended in a mixed solvent of 4.0- and sodium bicarbonate. O
Add f and stir for 5 minutes.

The organic layer is then separated, washed with 1 ounce of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Add 30-benzene to the resulting residue and collect the crystals by filtration to obtain 2-(2-amino-
4-hydroxy-2-thiazolin-4-yl)-2-(
Syn)-methoxyiminothioacetic acid-8-methyl ester 5.29 (yield: 86.7) is obtained.

IR(KBr) cWL-1; νc=o 164ON
MR (d6-DMSO) δ value; 6.16 (IH, bs, -0H).

6.82 (2H, b a , -NHx )13ON
MR (d, -DMSO) δ value; 11.10 (-8CH3
).

43.51 (C-5).

62.19 (OCH3>.

102.43 (C-4).

161.85 (C-2).

MS (m/e); 250 (M++1) UV (02H, OH); λmax 232 (S) (ε=8167) The following compound was obtained in the same manner.

0 2-(2-Amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminothioacetic acid-8-methyl ester Melting point: 140-142°C IR (KBr) cm -1; νc=o 1728.165
2NMR (d6-DMso) δ value; 2.36 (3H,s, 5CHI).

6.17 (IH, bg, -0H).

6.84 (3H=ba-NH2ICH<).

7.32(IOH,ll, (Jx2)(5) (i)
Dissolve 4-promo 2-methoxyimino-3-oxothiobutyric acid-8-methyl ester (mixture of syn and anti forms) so and sr in 400 d of ethyl acetate,
At 20° C. 7.62 ml of thiourea is added over 30 minutes. After reacting at the same temperature for 1 hour, the precipitated crystals were washed with 50 ml of ethyl acetate to obtain 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-
31.4 tons (yield: 47.5 tons) of hydrobromide of methoxyiminothioacetic acid-8-methyl ester are obtained. The IR of this compound was consistent with that obtained in Reference Example 2 (31(i)).

(j) The filtrate obtained in (i) above is washed twice with 300 m of water and dried over anhydrous magnesium sulfate.

Next, 5.02 ml of dry hydrogen chloride was introduced under water cooling, and after being left at room temperature for 5 hours, the reaction solution was again diluted with 300 Int of water.
Wash twice. After drying the organic layer over anhydrous magnesium sulfate, 3.9 f of thiourea is added over 30 minutes at 15-20°C.

After reacting at the same temperature for 1 hour, the precipitated crystals are collected by filtration and washed with ethyl acetate 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(synthyl). )−
Hydrobromic acid mIO,1F of methoxyiminothioacetic acid-8-methyl ester (yield 15.3%) is obtained.

The IR of this compound matched that obtained in Reference Example 2 (3) (i).

(6) (1) 4-promo 2-methoxyimino-3-
Oxothiobutyric acid-8-methyl ester (syn and anti-mixing cylinder) s o, o g is dissolved in acetone 250-, and thiourea 7,59 is added over 1 hour at -25 to -20'C. After reacting at the same temperature for 2 hours and collecting 1 precipitated crystal, it is washed with 50% of acetone, then 2-(2-
amino-4-hydroxy-2-thiazolin-4-yl)
-2-(syn)-methoxyiminothioacetic acid-8-methyl ester hydrobromide 3o,9ri (yield 47.5%)
get.

IFt(KBr)cm'; )c-01650(1
) The liquid e obtained in (1) above is concentrated under reduced pressure, and the resulting residue is dissolved in 200% of ethyl acetate. Then, after washing with 200 g of water, it is dried with anhydrous magnesium sulfate. After introducing 2.0 g of dry hydrogen chloride at 0 to 5°C and reacting at room temperature for 5 hours, the mixture is washed twice with 100% of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in acetate/120-2.
Add 5.09 g of thiourea over 1 hour at 5-20°C. After reacting at the same temperature for 2 hours, the precipitated crystals were collected and washed with acetone 20- to give 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxy The hydrobromide salt of iminothioacetic acid-8-methyl ester 1o, 19 (yield 15.5%) is obtained.

IR(KBr)c+++';-)O-01650
2-(2-) obtained in (1) and (1) on OiD
amino-4-hydroxy-2-thiazolin-4-yl)
= Hydrobromide of 2-(syn)-methoxyiminothioacetic acid-8-methyl ester was treated in the same manner as in Reference Example 2(4) to obtain 2-(2-amino-
4-Hydroxy-2-thiazoline-4-ethyl)-2-(syn)-methoxythioacetic acid-8-methyl ester was obtained.

Physical properties of this compound (IR, NMR, +3O-N) JR.

MS, UV) were consistent with those obtained in Reference Example 2 (4).

'7) Hydrobromide of 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminothioacetic acid-8-methyl ester 20. O
f was suspended in 100 tons of anhydrous methylene chloride, and 100 tons of anhydrous methylene chloride solution containing 8.62% chlorine was prepared at 0 to 5°C.
is added dropwise over a period of 10 minutes. Then, after reacting at the same temperature for 30 minutes, the precipitated crystals were collected by filtration and mixed with anhydrous methylene chloride 20
If washed twice with
Hydrobromide 14.6f of 2-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-1syn)-methoxyiminoacetic acid chloride (yield 75.7%)
get.

IR(KBr)an-1; νc=o 1780 Furthermore, the following compound was obtained by using ethyl acetate as a solvent instead of anhydrous methylene chloride and reacting in the same manner as above.

0 Hydrobromide of 2,-(2-amino-4-hydroxy-2-thiazolin-4-yl)-2-(syn)-diphenylmethoxycarbonylmethoxyiminoacetic acid chloride Melting point: 118-120°C (decomposed) I R(KB r ) crn-1; νc=o 17
64.1740.1642(8) 2-(2-amino-4
Hydrobromide of -hydroxy-2-thiazolin-4-yl)-2-r-syn)-methoxyiminothioacetic acid-8-methyl ester20. Of is suspended in 200 m of anhydrous methylene chloride, and 10.6 F of bromine is added dropwise over 20 minutes at 0 to 5°C. After reacting at the same temperature for 30 minutes, the precipitated crystals were collected by filtration and washed twice with 20 m of anhydrous methylene chloride to obtain 2-(2-amino-4-
Hydrobromide salt of hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetic acid bromide 17,
Of (yield 77.4) is obtained.

IR(KBr') cm-1; νC=o I RI R Reference Example 3 Pivaloyloxy 1fk=7-C2-(2-72 no 4
-hydroxy-2-thiazolin-4-yl)-2-(syn)-methoxyiminoacetami)')-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ3 -cephemu 4-carboxylene) 6.12F
is dissolved in 60 mm of acetonitrile solution containing 0.1 mm of concentrated hydrochloric acid and allowed to react at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was mixed with 100 g of ethyl acetate and 10 g of water.
After sequentially adding 0m, pH was adjusted using sodium bicarbonate.
Adjust to 6.0. Then, separate the organic layer and add 100% water
-, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. If 30-diethyl ether is added to the resulting residue and the crystals are collected by filtration, the melting point is 127-12.
Obivaloyloxymethyl = 7-[2
-(2-aminothiazol-4-yl)-2-(syn)
-methoxyiminoacetami)-”]-3-(5-methyl-1,2,3,4-tetrasol-2-yl)methyl-Δ3-cephemu-4-carboxylate 5.63
A yield of 94.8 qA) is obtained.

I R(Kn r ) erg−” gνc=o 17
FTO, 1743, 1675 NMR (d, -DM80)
δ value: 1.15 (9H, a, -C(CHs)s).

3.47 (2H, bs, C2-H).

3.80 (3H, s, -0CHs) 15.15
(IHld, J=5Hz+C6-H).

5.63-5.98 (3H2m, Ct H, oc
Ti2o”).

7.14 (2H, ba, Nl[(2-).

9.58 (IH, d, J=8Hz, -CONK-)U
VTC, H50H)i λmax 235 (ε=x9394) λmax 26
0 (g=16061) Patent applicant: Toyama Chemical Industry Co., Ltd.

Claims (1)

[Claims] A cephalosporin (syn isomer) represented by: and a salt thereof. (Cephalosporin (syn isomer) according to claim (1), wherein 21R2 is an acyloxyalkyl group)
and its salt. (Optionally substituted 1.2.3.4-tetrazol-2-yl, 1,2.4-)riazol-1-yl or 2,3 in which 31R3 has a carbon-nitrogen bond with the exomethylene group at the 3-position -Dioxo-1,2,3,4-tetrahydropyrazin-1-yl group, the cephalosporin (syn isomer) and its salt according to claim (1) or (2). (4) 1.2.3.4-tetrazol-2-yl, 1.2, in which R3 may be substituted with an alkyl group or halogen atom that forms a carbon-nitrogen bond with the exomethylene group at the 3-position
．． The cephalosporin (syn isomer) according to claim (3), which is a 4-triazol-1-yl or 2<3-dioxo-1,2,3,4-tetrahydropyrazin-1-yl group and its salt.