JPH0157116B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides cefamycin C, 7β-(D-5-amino-5
-Carboxyvaleramide-7α-methoxy-3
-Carbamoyloxymethyl-3-cephem-4
-Using a compound in which the 7-position side chain amino group of a carboxylic acid is protected, the 3-position is converted to an S-heterocycle, and the 4-position carboxylic acid is esterified as a raw material, the 7-position side chain is converted to the desired acyl group. The present invention relates to a method in which the ester is then removed by acid treatment.

Conventional methods for this purpose include a method of acyl exchange using molecular sieves or zeolites as catalysts (Japanese Patent Application Laid-open No. 105687/1983), and a method of silylation followed by acyl exchange (Japanese Patent Laid-open No. 105687). 50
-85386), and as a method that does not perform such silylation treatment or use a catalyst, JP-A No. 55
-20723 etc. When performing such acyl exchange, it is necessary to protect the carboxyl group of the cefamycin derivative.

JP-A No. 55-20723 describes that particularly suitable protecting groups are phenacyl group and benzhydryl group, but as a starting material phenacyl group and benzhydryl group are used. In the case of phenacyl ester derivatives, if potassium or sodium salts of thiophenol are used to eliminate the phenacyl ester after acylation, a large amount of △ ² isomer will be produced, and the elimination reaction with zinc and acid will cause As a result, an exomethylene compound is produced, and the yield of the desired △ ³ -cephem-4-carboxylic acid is significantly reduced. Furthermore, benzhydryl ester has problems in industrial mass production. As a result of various studies on this direct acyl exchange method and the types of esters, the present inventors found that alkyloxymethyl esters or aralkyloxymethyl esters are effective, and that 1 equivalent is added to the halogenated hydrocarbon used as a solvent. The present invention was completed based on the discovery that the desired product could be obtained in good yield by combining the above conditions such as the presence of water and the use of an epoxide compound as a deoxidizing agent. That is, the present invention has the general formula "In the formula, R ¹ represents an aromatic acylamido group,
R ² represents a lower alkyl group or an aralkyl group,
R ³ is 1H-tetrazole- which may have a substituent
5-yl group, 1,3,4-thiadiazole-2-
yl group or 1H-1,2,3-triazole-
Indicates a 5-yl group. ] in a halogenated hydrocarbon solvent containing at least 1 equivalent of water based on the general formula (). (In the formula, R ⁴ represents an aryloxyalkyl group.) and the general formula R ⁵ -X () (In the formula, R ⁵ represents an acetyl group having a substituent, and X represents a halogen atom.) A general formula characterized by reacting with a compound that is The present invention relates to a method for producing a cephalosporin derivative represented by the formula (wherein R ³ and R ⁵ have the same meanings as defined above) and a pharmacologically acceptable salt thereof.

The compound having the general formula () used as a raw material of the present invention protects the amino group of the 7-position side chain of cefamycin C, converts the 3-position carbamoyloxymethyl group to a heterothiomethyl group, and It is obtained by converting the carboxyl group of the chain and the carboxyl group at the 4-position into an alkyloxymethyl or aralkyloxymethyl ester.

By using the method of the present invention, it is possible to successively convert the 3- and 7-positions of cefamycin C obtained by culturing microorganisms into the desired group, and it is possible to produce a compound with stronger antibacterial activity. This provides an industrially extremely useful method.

7β-(D-5-
Amino-5-carboxyvaleramide)-7α-
Methoxy-3-substituted thiomethyl-3-cephem-
As the protecting group for the amino group contained in the substituent R ¹ of the 4-carboxylic acid derivative, benzoyl, p-nitrobenzoyl, 3,5-dinitrobenzoyl, toluoyl, p-chlorobenzoyl, 3,5-dichlorobenzoyl, p-Brombenzoyl or p
Examples include aromatic acyl groups such as -tert-butylbenzoyl, and particularly preferred groups are p-nitrobenzoyl and p-chlorobenzoyl.

Also, as a substituent for the substituted thiomethyl group at the 3-position, 1
-Methyl-1H-tetrazol-5-yl group, 1
-Dimethylaminoethyl-1H-tetrazole-
5-yl group, 5-methyl, 1,3,4-thiadiazol-2-yl group or 1-methyl-1H-1,
A 2,3-triazol-5-yl group is mentioned. The protecting group for the carboxyl group at the 7-position side chain and the carboxyl group at the 4-position includes ester-forming groups such as methoxymethyl, ethoxymethyl, benzyloxymethyl, or p-nitro or p-chlorobenzyloxymethyl, but these are preferred. For example, methoxymethyl or benzyloxymethyl ester.

The esterification method can be easily obtained by a conventional method. That is, a preferred method is to mix the raw material and chloromethyl alkyl ether or chloromethyl aralkyl ether and then add a base.

In the method of the present invention, the 7-position acyl group exchange reaction is
This can be easily carried out by bringing the compound having the general formula () into contact with the compounds having the general formulas () and () in a hydrous halogenated hydrocarbon solvent. Examples of such halogenated hydrocarbon solvents include dichloromethane, chloroform, and trichlene, and 1,2-dichloroethane is most preferred. In this case, the water content of the solvent is 1 to 3.0 equivalents, preferably 1.2 to 2.5 equivalents, relative to the general formula (). Examples of the epoxide deoxidizer having the general formula () include styrene oxide, 1,
2-epoxy-3-phenoxypropane, 1,2
-Epoxy-3-(p-tolyloxy)propane, 1,2-epoxy-3-(p-chlorophenoxy)propane, etc., but 1,2-epoxy-3-phenoxypropane is preferred; The amount used is 3 to 7 molar ratio to the compound (). The acetyl group having a substituent represented by R ⁵ in the general formula () is a thienyl acetyl group, a monochloro or dichloroacetyl group, a monobromo or dibromoacetyl group, a cyanomethylthioacetyl group, and a cyanomethylthioacetyl group represented by Examples of the halogen atom include chlorine and bromine. The amount of carboxylic acid halide () to be used is 1 to 15 molar ratio to the compound (2), preferably 5 to 12 molar ratio. The reaction temperature is usually 50
~100℃. The progress of the reaction can be followed by thin layer chromatography. The time required for the reaction is several tens of minutes to 10 hours.

After the 7-position acyl exchange in this manner, the solvent is distilled off from the reaction mixture, and the residue is replaced with a solvent that is mixed with water, such as methanol, ethanol, acetone, tetrahydrofuran, or acetonitrile, and treated with an acid. The methoxymethyl ester can be easily eliminated. In this case, mineral acids such as hydrochloric acid or sulfuric acid are suitable as the type of acid. Also, the amount of acid used is 0.2 to 0.2 of the raw material.
1.0 times the amount. The reaction temperature is 0 to 30°C, and the reaction time is several tens of minutes to 2 hours.

The compound of the general formula () obtained by this reaction can be collected by a conventional method. The solvent is distilled off from the reaction mixture, isopropyl ether is added to the residue, and the resulting crude product is treated with a suitable base such as dicyclohexylamine, dimethylbenzylamine,
It can be isolated as crystals by adding any base such as picoline, lutidine, etc., or it can be purified by various chromatography methods.

In addition, a suitable post-treatment method is to carry out a de-esterification reaction and then contact the reaction mixture with methanol in the presence of an acid to convert only the by-produced acylaminoadipic acid into dimethyl ester, thereby obtaining the desired product. One method is to separate the product as a basic aqueous solution, and then acidify this aqueous solution and extract with an organic solvent such as ethyl acetate to easily obtain the target product in free form with high purity.

In addition, the object compound () of the present invention can be converted into a pharmacologically acceptable salt form according to a conventional method, if necessary. Examples of such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, preferably sodium salts. salt and potassium salt.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 7β-(D-5′-p-nitrobenzoylamino-
5′-carboxyvaleramide)-7α-methoxy-
Dissolve 3 g of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid/ethyl acetate adduct in 75 ml of acetone, cool to 3°C in an ice-water bath, and add chloromethyl Add 0.7 ml of methyl ether and dropwise add a solution of 1.16 ml of triethylamine in 10 ml of acetone while stirring. The dropwise addition time was 20 minutes, and after the dropwise addition, the mixture was stirred for an additional 20 minutes to remove the precipitated triethylamine hydrochloride, the crystals were washed with acetone, the liquid and the washing liquid were combined, and the mixture was concentrated under reduced pressure. Add 50 ml of ethyl acetate to the remaining oil and stir at room temperature for about 15 minutes, and a small amount of triethylamine hydrochloride precipitates out, which is removed.
The crystals are washed with ethyl acetate, and the liquid and washing liquid are combined and concentrated and solidified under reduced pressure to obtain 3.2 g of dimethoxymethyl ester. To this was added 90 ml of 1,2-dichloroethane containing 120 mg of water to dissolve 1,2-epoxy-3-phenoxypropane.
3.0ml and monochloroacetyl chloride 4.5ml
and reflux for 3 hours while stirring. Then, concentrate under reduced pressure, add 60 ml of isopropyl ether to the residue, stir well, and remove the supernatant by decantation. Add 60ml of acetone and concentrated hydrochloric acid to the remaining oil.
Add 3.0ml and stir at room temperature for 45 minutes. Next, add 20 ml of methanol and stir for an additional hour. Then, the solvent is concentrated under reduced pressure, 40 ml of water and 50 ml of ethyl acetate are added, and while stirring, sodium bicarbonate powder is added little by little to adjust the pH of the aqueous layer to 6.5-7.0. Separate the layers, extract the ethyl acetate layer with saturated brine, and combine with the aqueous layer. Add 50ml of ethyl acetate to this aqueous layer and adjust the pH of the aqueous layer with hydrochloric acid.
Set it to 1.8. Shake well and separate the ethyl acetate layer.
The aqueous layer is further extracted twice with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure, and when the residue was mixed with isopropyl ether, it turned into powder, which was collected, washed with isopropyl ether, and dried to give 1.5 g.
7β-chloroacetamide-7α-methoxy-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained.

nmr spectrum δppm (heavy acetone) 3.5 (singlet, 3H) 3.67 (singlet, 2H) 3.98 (singlet, 3H) 4.42 (broad singlet, 2H) 5.08 (singlet, 1H) Example 2 Example 1 and A 1,2-
Add 90ml of dichloroethane and dissolve 1,2
-Epoxy-3-p-methylphenoxypropane
Add 3.0 ml and 5.0 ml of cyanomethylthioacetyl chloride, and reflux for 2 hours with stirring. Then, when treated in the same manner as in Example 1, 1.4g
7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained.

nmr spectrum δppm (heavy acetone) 3.50 (singlet, 3H) 3.60 (singlet, 2H) 3.5-3.7 (quartet, 2H) 3.70 (singlet, 2H) 3.98 (singlet, 3H) 4.3-4.6 (quadruplet, 2H) Double line, 2H) 5.10 (Singlet line, 1H) Example 3 7-β-(D-5′-p-nitrobenzoylamino-5′-carboxyvaleramide)-7α-methoxy-3-(1-methyl- 1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid/ethyl acetate adduct (2.6 g) was dissolved in 50 ml of acetone, and while stirring in an ice-water solution, 1.21 g of chloromethyl benzyl ether was added, and then 1 ml of triethylamine was dissolved in 10 ml of acetone. Add the solution dropwise. Addition time: 30 minutes. After the dropwise addition, the mixture was stirred for 30 minutes and treated as in Example 1 to obtain 3.12 g of dibenzyloxymethyl ester. Add 90 ml of 1,2-dichloroethane containing 100 mg of water to this and dissolve, 2.6 ml of 1,2-epoxy-3-phenoxypropane and 3.9 ml of monochloroacetyl chloride.
and reflux for 3 hours. Then, when treated as in Example 1, 7-β-chloroacetamide-7α-
Methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
1.1 g of carboxylic acid is obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents an aromatic acylamide group,
R ² represents a lower alkyl group or an aralkyl group,
R ³ is 1H-tetrazole- which may have a substituent
5-yl group, 1,3,4-thiadiazole-2-
yl group or 1H-1,2,3-triazole-
Indicates a 5-yl group. ] in a halogenated hydrocarbon solvent containing at least 1 equivalent of water to the compound having the general formula () [In the formula, R ⁴ represents an aryloxyalkyl group. ] and the general formula R ⁵ X [wherein R ⁵ represents an acetyl group having a substituent, and X represents a halogen atom. A general formula characterized by reacting with a compound represented by ] and then treating with an acid. [In the formula, R ³ and R ⁵ have the same meanings as described above. ] A method for producing a cephalosporin derivative and a pharmacologically acceptable salt thereof.