JPH0662635B2 - New production method of cefalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for producing cefalosporins, that is, a general formula useful as an antibacterial agent. The present invention relates to a method for producing cefalosporin (syn isomer) represented by or a salt thereof.

More specifically, the present invention has the general formula A compound (syn isomer) represented by the formula (Syn isomer) is reacted with cyanamide in the presence of a Lewis acid or a complex compound thereof in an organic solvent, and is represented by the general formula [II]. Body) or a method for producing a salt thereof.

The object of the present invention is to provide compounds of general formula [I] (syn isomers)
Alternatively, a salt thereof and cyanamide are reacted in an organic solvent in the presence of a Lewis acid or a complex compound thereof, and a useful general formula [I
It is intended to provide a novel production method for producing the cephalosporin (syn isomer) of [I] or a salt thereof.

The present inventors have previously found that the cephalosporin (syn isomer) of the general formula [II] or a salt thereof is an extremely useful compound as an antibacterial agent, and applied for a patent (JP-A-57).
-99592, 59-93085, 59-193893, 60-41
No. 91 and No. 60-6694).

After that, the present inventors have described a novel method for producing the compound of formula (II) (syn isomer) or a salt thereof,
As a result of intensive studies, it was found that a useful compound of formula [II] (syn isomer) or a salt thereof can be easily obtained from a compound of formula [I] (syn isomer) or a salt thereof. Then, the present invention has been completed.

The compound of general [I] (syn isomer) or a salt thereof in the present invention is a novel compound, and its structural characteristics are
The amino group at the 7-position has the following general formula [In the formula, R ¹ has the above-mentioned meaning. ] The group represented by In addition, the compound of formula (I) (syn isomer) or a salt thereof is useful as an intermediate for the synthesis of cefalosporin compounds.

Hereinafter, the present invention will be described in more detail.

In the present specification, unless otherwise specified, alkyl is linear or branched C _1-14 alkyl, for example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, hebutyl, octyl, dodecyl etc .; aryl is, for example, phenyl, tolyl,
Naphthyl, indanyl, etc .; Aralkyl is, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, etc .; Acyl is C _1-12 acyl, for example, acetyl, propionyl, butyryl, pivaloyl, pentanecarbonyl, cyclohexanecarbonyl. ,
Benzoyl, naphthoyl, furoyl, thenoyl and the like; the halogen atom means, for example, fluorine, chlorine, bromine, iodine atom and the like, respectively. The term "lower" means one having 1 to 5 carbon atoms.

Furthermore, even when there are various terms used in the present invention, such as alkyl, aryl, aralkyl, and acyl, they have the above-mentioned meanings unless otherwise specified.

In each formula, R ² represents an optionally substituted heterocyclic group that forms a carbon-nitrogen bond with the 3-position exomethylene group, and examples of the heterocyclic group include tetrazolyl, triazolyl, pyrazinyl, pyridanyl, Pyrimidinyl group and formula (In the formula, W represents a divalent group which forms a 5-membered ring or a 6-membered ring together with the adjacent nitrogen atom and sulfonyl group.), For example, 1,2,6- Examples thereof include nitrogen-containing 5- or 6-membered heterocyclic groups such as thiadiazin-1,1-dioxide-2-yl and isothiazolidin-1,1-dioxide-2-yl groups. More specifically, 1
-(1,2,3,4-tetrazolyl), 2- (1,2,3,4-tetrazolyl), 1- (1,2,3-triazolyl), 2- (1,2,3
-Triazolyl), 1- (1,2,4-triazolyl), 4
-(1,2,4-triazolyl), 2,3-dioxo-1,2,3,4
-Tetrahydropyrazinyl, 3,6-dioxo-1,2,3,6-
Tetrahydropyridazinyl, 6-oxo-1,6-dihydropyridazinyl, 2-oxo-1,2-dihydropyrazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1, 2-dihydropyrimidinyl, 1,2,6-thiadiazin-1,1-dioxide-2-yl, isothiazoline-1,1
-Dioxide-2-yl group and the like.

As the substituent in the heterocyclic group, for example, a halogen atom, a nitro group, an alkyl group, an aralkyl group,
Aryl 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, carbamoyl group , Aminoalkyl group, N-alkylaminoalkyl group, N, N-dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group,
Examples thereof include a sulfo group, a sulfamoylalkyl group, a sulfamoyl group, a carbamoylalkyl group and an N-hydroxycarbamoylalkyl group, and the heterocyclic group described above may be substituted with one or more of these substituents. Among these substituents, the carboxyl group may be protected with a carboxyl protecting group, and examples of the carboxyl group protecting group include those conventionally used in the field of conventional penicillin and cephalosporin compounds. JP-A-57-99592, 58-77886, and 59-9308.
No. 5, No. 59-193893, No. 60-4191 and No. 60-6694
And the protecting group for the carboxyl group described in the publication No.

As the carboxyl protecting group for R ^{3 in} each formula, the same carboxyl protecting groups as those described for R ² can be used, and an acyloxyalkyl group is particularly preferable.

Examples of the salt of the compound (syn isomer) of the general formula [I] or [II] include salts in the chloric group or acidic group well known in the field of penicillin and cephalosporin compounds. Examples of the salt in the chlorine group include, for example,
Salts with mineral acids such as chlorine, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid; methanesulfonic acid, Examples include salts with sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid),
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; calcium,
Examples thereof include salts with alkaline earth metals such as magnesium; ammonium salts; salts with nitrogen-containing organic bases such as triethylamine, trimethylamine, aniline, N, N-dimethylaniline, pyridine and dicyclohexylamine.

The present invention also extends to all optical isomers, crystal forms and hydrates of the compounds of formulas [I] and [II] (syn isomers) and salts thereof.

Next, an embodiment of the present invention will be described. The compound of the general formula [I] (syn isomer) or a salt thereof and cyanamide are reacted in the presence of a Lewis acid or a complex compound thereof in an organic solvent to give a cephalosporin (syn) of the general formula [II]. Isomer) or a salt thereof can be obtained. Examples of the Lewis acid or the Lewis acid of its complex compound used in this reaction include zinc chloride, boron trifluoride, tin tetrachloride, and the like, and examples of the Lewis acid complex compound include those mentioned above. Examples thereof include complex compounds of Lewis acid and carboxylic acid ester such as ethyl acetate, and complex compounds of sulfolane. The amount of the Lewis acid or its complex compound used is 1 to several times mol, preferably 1 to 3 times mol, of the compound of general formula [I] or its salt. The amount of cyanamide used is 1 to several times mol, preferably 1.
It is 5 to 3 times the molar amount. Any organic solvent may be used as long as it does not adversely affect the reaction, and examples thereof include methylene chloride, chloroform, ethylene chloride,
Examples thereof include nitromethane, dioxane, tetrahydrofuran, sulfolane, etc., and two or more kinds of these solvents may be mixed and used.

This reaction is usually performed at 10 to 50 ° C. for 30 minutes to 24 hours.
Complete in time. Further, if water is present in the reaction system, undesired side reactions such as cleavage of the β-lactam ring may occur, so it is desirable to keep the reaction system anhydrous. In order to satisfy this condition, a suitable dehydrating agent such as anhydrous magnesium sulfate or molecular sieve may be added to the reaction system.

The cephalosporin of the general formula [II] thus obtained or a salt thereof can be isolated and purified by a conventional method, and a general formula in which R ³ is a carboxyl-protecting group can be obtained by a conventional method. The compound of [II] or a salt thereof is converted to R
It can be easily converted into a compound of the general formula [II] or a salt thereof in which ³ is a hydrogen atom.

Next, a method for producing a compound of formula (I) (syn isomer) or a salt thereof, which is an intermediate for the production of cephalosporin of formula (II) (syn isomer) or a salt thereof, will be described.

The compound of the general formula [I] (syn isomer) or a salt thereof is
For example, it can be manufactured by the following manufacturing method.

The compounds of general formulas [III], [V] and [VI] are novel compounds and are useful as intermediates.

Examples of the salt of the compound of the general formula [IV] include those exemplified as the salt of the compound of the general formula [I] or [II].

The compound of the general formula [VII] can be produced by the method described in JP-A-60-64986 (reaction with thiol, nitrosation, alkylation, halogenation, etc.) or a method known per se.

(A) Method for producing compound (syn isomer) of general formula [VI] The compound (syn isomer) of general formula [VI] is
It can be obtained by reacting the compound of I] with N, N-dialkylthioformamide.

This reaction is usually carried out in an organic solvent, and examples of the solvent used include ethyl acetate, methyl acetate, acetone, dioxane, tetrahydrofuran, acetonitrile and the like, and two or more kinds of these solvents are mixed and used. You may. Examples of the N, N-dialkylthioformamide used include N, N-dimethylthioformamide.

When the compound of the general formula [VII] is a syn isomer, N, N-
The amount of dialkylthioformamide used may be equimolar or more to the syn isomer. When the compound of the general formula [VII] is a mixture of the syn isomer and the anti isomer, the amount of N, N-dialkylthioformamide used is the composition of the syn isomer and the anti isomer of the compound of the general formula [VII]. It is appropriately adjusted according to the ratio. In that case, the general formula [V
The syn isomer of the compound I] can be selectively obtained as a crystal from the reaction system and is a non-reacted compound of the general formula [VII]
It is possible to leave the anti-isomer of the compound in the system. Then, acid such as dry hydrogen chloride or dry hydrogen bromide is added to the remaining anti isomer to isomerize to the syn isomer, and then the reaction is performed again to isolate the syn isomer. You can In this way, the compound of formula [VI] (syn isomer) can be selectively produced.

This reaction is usually carried out at -5 to 50 ° C and completed in 30 minutes to 10 hours.

(B) Method for producing acid halide (syn isomer) of the general formula [V] The compound (syn isomer) of the general formula [V] has the general formula [VI]
Can be easily obtained by reacting the compound (syn isomer) of (1) with a halogenating agent capable of converting a thioloester into an acid halide, preferably 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 the reaction, and examples thereof include methylene chloride, chloroform, ethylene chloride and ethyl acetate. You may use it in mixture of 2 or more types. The amount of the halogenating agent used is 1 to several equivalents relative to the compound of formula (VI) (syn isomer). The reaction is usually carried out at -30 to 30 ° C, and the reaction time is usually 5 minutes to 3
The time is preferably 15 minutes to 2 hours.

(C) Method for producing compound (syn isomer) of general formula [III] (acylation reaction) A compound of general formula [III] (syn isomer) is a compound of general formula [V] in a suitable solvent. It can be obtained by reacting the (syn isomer) with a compound of the general formula [IV] or a salt thereof. As the solvent used, any solvent may be used as long as it does not adversely affect the reaction, for example, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide and the like can be mentioned.
You may use it in mixture of 2 or more types. The compound of the general formula [IV] or a salt thereof is used in an equimolar amount or more, preferably 1 to 1.5 times the molar amount of the compound of the general formula [V] (syn isomer).

The reaction is usually performed at -20 to 30 ° C and is completed in 5 minutes to 3 hours.

Further, the compound of the general formula [IV] or a salt thereof can be prepared, for example, by subjecting 7-aminocephalosboronic acid to an ordinary 3-position conversion reaction (JP-A-57-99592 and 59-93085).
No. 59-98089, No. 59-193893, No. 60-4191 and No. 60-6694), and if necessary, then 4
It can be easily obtained by introducing a protecting group into the carboxyl group at the position.

(D) Method for producing compound of formula (I) (syn isomer) or salt thereof A compound of formula (I) (syn isomer) or salt thereof is
It can be obtained by reacting a compound of formula [III] (syn isomer) with alcohol. As the alcohol, for example, methanol, ethanol, propanol, butanol or the like is used. Reaction is usually 15
It is performed at ~ 40 ° C and is completed in 30 minutes to 2 hours. The compound obtained by each of the reactions described above can be isolated and separated by a conventional method, or can be used in the next reaction without isolation and separation.

Next, the present invention will be described with reference to reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 (1) Sodium nitrite (38.0 g) and 3-oxothiobutyric acid-S-methyl ester (66.1 g) were added to water (330 ml), and the temperature was 5 to 8 ° C.
While stirring, 210 ml of 4N sulfuric acid was added dropwise over 30 minutes. Then, after reacting for 30 minutes at the same temperature, the reaction solution is introduced into 500 ml of ethyl acetate. Separate the organic layer and use water 500
After washing with ml, it is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The obtained residue was dissolved in 650 ml of an aqueous solution containing 106 g of sodium carbonate and then dissolved in methanol.
Add 150 ml. Dimethylsulfuric acid 75.7g is added to this solution 15-2
After dropping at 0 ° C, the mixture is reacted at the same temperature for 2 hours. Then, the reaction solution is introduced into ethyl acetate 1, the organic layer is separated, washed with 300 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to give 2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (a mixture of syn and anti forms) having a boiling point of 80 to 86 ° C / 2 mmHg. ) 60.4 g (yield 68.9
%).

This mixture was separated and purified by column chromatography (Wako Silica Gel C-200, elution solvent; n-hexane-benzene) to give 2- (syn) -methoxyimino-3-oxothiobutyric acid-S-methyl oil. The ester and 2- (anti) -methoxyimino-3-oxothiobutyric acid-S-methyl ester are obtained.

2- (Syn) -methoxyimino-3-oxothiobutyric acid-S-methyl ester IR (neat) cm ⁻¹ ; ν _{c = o} 1720,1690,1670 NMR (CDCl ₃ ) δ value; 2.42 (3H, s ), 2.48 (3H, s), 4.18 (3H, s) 2- (anti) -methoxyimino-3-oxothiobutyric acid-S-methyl ester IR (neat) cm ^-1 ; ν _{c = o} 1750,1680 NMR (CDCl ₃ ) δ value; 2-methoxyimino-3-oxothiobutyric acid-S-obtained by 2.41 (3H, s), 2.42 (3H, s), 4.16 (3H, s) (2) (1) 10.0 g of methyl ester (a mixture of syn and anti forms) is dissolved in 150 ml of 1,4-dioxane, 20.1 g of pyridinium hydrobromide perbromide is added, and the mixture is reacted at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water were added to the obtained residue.
Add ml. The organic layer is separated, washed successively with 5% aqueous sodium hydrogen sulfite solution (100 ml), water (100 ml) and saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 11.6 g (yield 80.0%) of 4-bromo-2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (mixture of syn and anti forms).

This mixture was separated and purified by column chromatography (Wako Silica Gel C-200, elution solvent; n-hexane-benzene) to give 4-bromo-2- (syn) -methoxyimino-3-oxothiobutyric acid as an oily product. -S-methyl ester and 4-bromo-2- (anti) -methoxyimino-3-oxothiobutyric acid-S-methyl ester are obtained.

4-Bromo-2- (syn) -methoxyimino-3-oxothiobutyric acid-S-methyl ester IR (nitro) cm ⁻¹ ; ν _{c = o} 1705,1665 NMR (CDCl ₃ ) δ value; 2.52 (3H _{, s, -SCH 3), 4.21} (3H, s, -OCH 3), 4.42 (2H, s, BrCH 2 -) 4- bromo-2- (anti) - methoxyimino-3
Oxothiobutyric acid-S-methyl ester IR (neat) cm ^-1 ; ν _{c = o} 1720,1655 NMR (CDCl ₃ ) δ value; 2.41 (3H, s, -SCH ₃ ), 4.21 (3H, s,- OCH ₃ ), 4.23 (2H, s, -BrCH _2- ) (3) (i) 4-bromo-2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (mixture of syn and anti forms) 25.4 g Dissolve in 254 ml of ethyl acetate and add 5.4 g of N, N-dimethylthioformamide while maintaining the temperature at 20-25 ° C.
Drop in 0 minutes. After the solution was reacted at the same temperature for 1 hour, the precipitated crystals were collected by filtration and washed with 50 ml of ethyl acetate to give 4- (N, N-dimethyl) iminiummethylthio-2 having a melting point of 108-110 ° C. -(Syn) -methoxyimino-3
-Oxothiobutyric acid-S-methyl ester bromide 17.8
g (51.9% yield) are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1690,1670 NMR (CDCl ₃ ) δ value; 2.42 (3H, s, -SCH ₃ ), 3.51 (3H, s, 3.86 (3H, s, The filtrate obtained in 4.15 (3H, s, -OCH ₃ ), 5.18 (2H, s, -SCH ₂ CO-), 11.00 (1H, s, = CHS-) (ii) (i) was added to 200 ml of water. After washing twice, dry over anhydrous magnesium sulfate and dry hydrogen chloride 2.
After introducing 5 g under ice-cooling, it is left to stand at room temperature for 5 hours.
Then, after washing with 200 ml of water and drying over anhydrous magnesium sulfate, 2.7 g of N, N-dimethylthioformamide was added and the reaction was carried out in the same manner as in (i), which showed a melting point of 108-110 ° C. 4- ( N, N-Dimethyl) iminiummethylthio-2-
(Syn) -methoxyimino-3-oxothiobutyric acid-S-
8.2 g (yield 23.9%) of methyl ester bromide is obtained.

The physical properties (IR, NMR) of this compound were the same as those obtained in (i).

(iii) 4-bromo-2- (syn) -methoxyimino-3
-Oxothiobutyric acid-S-methyl ester 25.4g and N, N-
If dimethylthioformamide (9.79 g) is reacted in the same manner as in (i), 4- (N, N-dimethyl) having a melting point of 108 to 110 ° C. is obtained.
Iminium methylthio-2- (syn) -methoxyimino-3-oxothiobutyric acid-S-methyl ester bromide
31.9 g (yield 93.0%) was obtained.

The physical properties (IR, NMR) of this compound were the same as those obtained in (i).

Reference Example 2 4- (N, N-dimethyl) iminiummethylthio-2-
(Syn) -methoxyimino-3-oxothiobutyric acid-S-
Methyl ester bromide 3.43g methylene chloride 34.3ml
Dissolve in, and introduce 1.4 g of chlorine under ice cooling. After the crystals are deposited, the reaction is further performed at the same temperature for 30 minutes, and then the solvent is distilled off under reduced pressure. 15 ml of diisopropyl ether was added to the obtained residue, and the crystals were collected by filtration to give pale-yellow 4- (N, N-dimethyl) iminiummethylthio-2- (syn) -methoxyimino having a melting point of 70 to 71 ° C. 3.10 g (yield 93.5%) of 3-oxobutyric acid chloride bromide is obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1780,1703 ν _{c = N} 1625 NMR (CDCl ₃ ) δ value; 3.45 (3H, s, 3.81 (3H, s, _{4.19 (3H, s, -OCH 3} ), 4.44 (2H, s, -SCH 2 CO-), 8.85 (1H, s, = CHS-) Reference Example 3 Jifuenirumechiru = 7-amino-3- (5-methyl - 1,
2,3,4-tetrazol-2-yl) methyl-Δ ³ -cem-4-carboxylate (4.62 g) was dissolved in a mixed solvent of 50 ml of anhydrous methylene chloride and 15 ml of N, N-dimethylformamide, and the mixture was dissolved at 0 to 5 ° C. 4- (N, N-dimethyl) iminiummethylthio-2- (syn) -methoxyimino-3
Add 3.3 g of oxobutyric acid chloride bromide. After reacting for 30 minutes at the same temperature, the solvent is distilled off under reduced pressure.
30 ml of diethyl ether was added to the obtained residue and the crystals were collected by filtration and washed successively with 30 ml of ethyl acetate and 30 ml of diethyl ether to give diphenylmethyl = 7- [4- (N , N-Dimethyl) iminiummethylthio-2- (syn) -methoxyimino-3-oxobutyrylamino] -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-Δ ³ -Chem-4-
6.5 g (85.9% yield) of carboxylate bromide is obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1780,1730,1710,1680 NMR (CDCl ₃ ) δ value; 2.46 (3H, s, 3.24 (3H, s, 3.40 (2H, bs, C ₂ -H), 3.58 (3H, s, 4.08 (3H, s, -OCH ₃ ), 4.95 (2H, s, -SCH ₂ CO-), 5.00 (1H, d, J = 5Hz, C ₆ -H), 5.60 (2H, bs, 5.82 (1H, dd, J = 5Hz, J = 8Hz, C ₇ -H), 6.90 (1H, s, -CH), 7.28 (10H, bs, 9.22 (1H, d, J = 8Hz, -CONH-), 10.50 (1H, s, = CHS-) Reference Example 4 Diphenylmethyl = 7- [4- (N, N-dimethyl) iminiummethylthio-2- (syn) ) -Methoxyimino-3
-Oxobutyrylamino] -3- (5-methyl-1,2,3,
4-tetrazol-2-yl) methyl-Δ ³ -cem-4-carboxylate bromide 7.57 g in methanol
Dissolve in 40 ml and react at 20-25 ° C for 1 hour. Then, the solvent is distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water are added to the obtained residue, and the organic layer is separated. The organic layer is washed with 50 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the obtained residue and the crystals were collected by filtration to give diphenylmethyl = 7- [4
-Mercapto-2- (syn) -methoxyimino-3-oxobutyrylamino] -3- (5-methyl-1,2,3,4-
Tetrazol-2-yl) methyl-Δ ³ -cefm-4
-4.63 g of carboxylate (74.1% yield) are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1780,1720,1700,1680 NMR (CDCl ₃ ) δ value; 2.42 (3H, s, 3.22 (2H, s, C ₂ -H), 3.69 (2H, d, J = 8Hz, HS CH ₂ CO-), 4.04 (3H, s, -OCH ₃ ), 4.97 (1H, d, J = 5Hz, C ₆ -H), 5.46 (2H, ABq, J = 16Hz, 5.86 (1H, dd, J = 5Hz, J = 8Hz, C ₇ -H), 6.93 (1H, s, -CH), 7.30 (10H, bs, 7.84 (1H, d, J = 8Hz, -CONH-) Reference Example 5 Pivaloyloxymethyl = 7-amine-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl- Δ ³
-Chem-4-carboxylate 4.10 g was dissolved in a mixed solvent of 46 ml of anhydrous methylene chloride and 8 ml of N, N-dimethylformamide, and 4- (N, N-dimethyl) was added at 0-5 ° C.
After adding 3.4 g of iminium methylthio-2- (syn) -methoxyimino-3-oxobutyric acid chloride / promide, the mixture is reacted at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, 25 ml of methanol was added to the obtained residue, and the temperature was 20 to 25 ° C.
React for 1 hour. Then, the solvent was distilled off under reduced pressure,
50 ml of ethyl acetate and 50 ml of water are added to the obtained residue, and the organic layer is separated. After washing this organic layer with 50 ml of water,
It is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the obtained residue, and the crystals were collected by filtration to give pivaloyloxymethyl = 7- [4-methylcapto-2-] having a melting point of 98 ° C. (decomposition).
(Syn) -methoxyimino-3-oxobutyrylamino] -3- (5-methyl-1,2,3,4-tetrazole-2
3.41 g (60% yield) of -yl) methyl- [Delta] ³ -cephem-4-carboxylate are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1783,1745,1700,1680 NMR (CDCl ₃ ) δ value; 1.21 (9H, s, -C (CH ₃ ) ₃ ), 2.50 (3H, s, 3.30 (2H, bs, C ₂ -H), 3.92 (2H, d, J = 8Hz, HS CH ₂ CO-), 4.10 (3H, s, -OCH ₃ ), 5.03 (1H, d, J = 5Hz, C ₆ -H), 5.62 (2H, ABq, J = 16Hz, 5.88 (1H, dd, J = 5Hz, J = 8Hz, C ₇ -H), 5.88 (2H, s, -OCH ₂ O-), 7.78 (1H, d, J = 8Hz, -CONH-) The following compound was obtained.

Pivaloyloxymethyl = 7- [4-mercapto-2-
(Syn) -methoxyimino-3-oxobutyrylamino] -3- (5-chloro-1,2,4-triazole-1-
Yl) Methyl-Δ ³ -cephem-4-carboxylate Melting point; 106 ° C. (decomposition) IR (KBr) cm ⁻¹ ; ν _{c = o} 1785,1750,1700,1680 NMR (CDCl ₃ ) δ value; 1.26 (9H , s, -C (CH ₃ ) ₃ ), 3.32 (2H, bs, C ₂ -H), 3.99 (2H, d, J = 8Hz, HS CH ₂ CO-), 4.14 (3H, s, -OCH ₃ ), 5.04 (1H, d, J = 5Hz, C ₆ -H), 5.32 (2H, ABq, J = 16Hz, 5.89 (1H, dd, J = 5Hz, J = 8Hz, C ₇ -H), 5.92 (2H, s, -OCH ₂ O-), 7.66 (1H, d, J = 8Hz, -CONH-), 7.84 ( 1H, s, Example 1 (1) Diphenylmethyl = 7- [4-mercapto-2-
(Syn) -methoxyimino-3-oxobutylamino]
3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl - [delta ³ - cephem-4-carboxylate 6.
Dissolve 21 g in 80 ml of anhydrous methylene chloride and add cyanamide.
84 g and 1.36 g of zinc chloride are added, and the mixture is reacted at 20 to 25 ° C for 5 hours. Then, 70 ml of water was added and the insoluble matter was filtered off.
-Adjust the pH to 1.5 with hydrochloric acid. The organic layer is separated, 70 ml of water is added, the pH is adjusted to 6.5 with sodium hydrogen carbonate, the organic layer is further separated, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the obtained residue is dissolved in 65 ml of ethyl acetate. Then, while stirring under water cooling,
A solution of dry hydrogen chloride in diethyl ether is added and the precipitated crystals are collected by filtration. The crystals are dissolved in a mixed solvent of 70 ml of ethyl acetate and 50 ml of water, adjusted to pH 6.5 with sodium hydrogen carbonate, the organic layer is separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 20 ml of diethyl ether was added to the obtained residue, and the crystals were collected by filtration to give a melting point of 102
Diphenylmethyl = 7- [2-
(2-Aminothiazol-4-yl) -2- (syn)-
Methoxyiminoacetamide] -3- (5-methyl-1,
4.3 g of 2,3,4-tetrazol-2-yl) methyl- [Delta] ³ -cephem-4-carboxylate (yield 66.7%) is obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1778,1720,1660 pivaloyloxymethyl = 7- [4-mercapto-2-
(Syn) -methoxyimino-3-oxobutyrylamino] -3- (5-chloro-1,2,4-triazole-1-
Anil) methyl-Δ ³ -cephem-4-carboxylate as a raw material, and an anhydrous solution prepared by dissolving a sulfolane complex compound of boron trifluoride (used in a 2-fold molar amount with respect to the raw material compound) instead of zinc chloride. With a methylene chloride solution,
Reaction was carried out in the same manner as above to obtain the following compound.

Pivaloyloxymethyl = 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-chloro-1,2,4-triazole-1- Yl) Methyl-Δ ³ -cephem-4-carboxylate Melting point; 118 to 122 ° C. (decomposition) IR (KBr) cm ⁻¹ ; ν _{c = o} 1780,1740,1675 (2) diphenylmethyl = 7- [2- ( 2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-Δ ³ -cem-4 -Dissolve 1.45 g of carboxylate in a mixed solvent of 7 ml of trifluoroacetic acid and 3.5 ml of anisole and react at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 10 ml of diethyl ether was added to the obtained residue, the crystals were collected by filtration, and sufficiently washed with diethyl ether to give a melting point of 123 to 125 ° C. (decomposition).
[2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-Δ ³
-Chem-4-carboxylic acid trifluoroacetate salt 1.17
g (91% yield) are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1790,1720,1635 Example 2 Pivaloyloxymethyl = 7- [4-mercapto-2-
(Syn) -methoxyimino-3-oxobutyrylamino] -3- (5-methyl-1,2,3,4-tetrazole-2
-Yl) Methyl-Δ ³ -cem-4-carboxylate (5.69 g) was dissolved in 80 ml of anhydrous methylene chloride, 0.84 g of cyanamide and 1.36 g of zinc chloride were added, and the mixture was stirred at 20 to 25 ° C for 5 minutes.
React for hours. Then, the solvent is distilled off under reduced pressure, 60 ml of ethyl acetate and 60 ml of water are added to the obtained residue, and the insoluble matter is filtered off. After separating the organic layer and washing with 60 ml of water,
It is dried over anhydrous magnesium sulfate, 12 ml of an ethyl acetate solution in which 1.2 g of mesitylenesulfonic acid monohydrate is dissolved is added, and the mixture is reacted at 20 to 25 ° C. for 2 hours. The precipitated crystals are collected by filtration,
If washed with 20 ml of ethyl acetate, melting point 218-220 ° C (decomposition)
Showing pivaloyloxymethyl = 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4- Tetrazol-2-yl) methyl-Δ ³ -cem-4-
4.7 g (59.2% yield) of carboxylate mesitylene sulfonate is obtained.

IR (KBr) cm ^-1 ; ν _{c = o} 1782,1745,1680

Continuation of the front page (56) Reference JP-A-57-99592 (JP, A) HETEROCYCLIC COMPO UNDS THIAZOLE AND I TS DERIVATIVES PART ONE Edited by Jacq ues V. Metzger P. 291 ~ 293 JOHN WILEY & SON S

Claims (4)

[Claims] 1. A general formula The compound represented by the formula (syn isomer) or a salt thereof is reacted with cyanamide in an organic solvent in the presence of a Lewis acid or a complex compound thereof, a general formula A method for producing cefalosporin (syn isomer) represented by or a salt thereof. 2. An optionally substituted 1,2,3,4-tetrazol-2-yl or 1,2,4-triazol-1-yl in which R ² forms a carbon-nitrogen bond with the 3-position exomethylene group. A process for producing cefalosporin (syn isomer) or a salt thereof according to claim (1), which is a group. 3. A process for producing cefalosporin (syn isomer) or a salt thereof according to claim (1) or (2), wherein R ³ is a hydrogen atom or an acyloxyalkyl group. 4. The cephalosporin (syn) according to any one of claims (1) to (3), wherein the Lewis acid or its complex compound is zinc chloride, boron trifluoride or a complex compound thereof. Isomer) or a salt thereof.