JPH0157117B2 - - 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
- Concerning a method of protecting the 7-position side chain amino group of a carboxylic acid and using a compound obtained by esterifying the 4-position carboxylic acid as a raw material, converting the 7-position side chain into the desired acyl group, and then eliminating the ester. It is.

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 benzhydrin group, but the starting material is phenacyl group, which has a heterothiomethyl group at the 3-position of cefamycin C. In the case of phenacyl ester derivatives, if potassium or sodium salts of thiophenol are used to eliminate the phenacyl ester after acyl exchange, 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.

For this reason, when phenacyl ester is used, it is necessary that the 3rd position be a carbamoyloxymethyl group, which is a raw material for a heterothiomethyl group. Cefamycin-based compounds, in which the carboxylic acid moiety at the 7-position side chain and the carboxylic acid moiety at the 4-position are phenacyl esters, and which have a carbamoyloxymethyl group at the 3-position, have very good crystallinity and can be isolated and purified from the fermentation solution. It is an effective substance as one method.
However, when such a compound is reacted with an acyl halide in an inert solvent to perform acyl exchange, the reaction solution becomes colored and the yield is unsatisfactory, probably because the carbamoyloxymethyl group is sensitive to acids. It wasn't. As a result of various studies on this linear acyl exchange method, the present inventors have found that the desired product can be obtained in good yield by using an epoxide-based compound as a deoxidizing agent, and have completed the present invention. That is, the present invention is based on the general formula (In the formula, R ¹ represents a benzenesulfonylamino group, and R ² represents a hydrogen atom or a halogen atom.) In an inert solvent, a compound represented by the general formula (In the formula, R ³ represents a lower alkyl group, aryl group or aryloxyalkyl group.) and the general formula R ⁴ -X () (In the formula, R ⁴ is a cyanomethylthioacetyl group or a chloroacetyl group. X is a halogen atom. )
A general formula characterized by reacting with a compound represented by and then deesterifying The present invention relates to a method for producing a cephalosporin derivative represented by the formula (wherein R ⁴ has the same meaning 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 at the 7-position side chain of cefamycin C, and converts the carboxyl group at the 7-position side chain and the carboxyl group at the 4-position into a diphenacyl ester. Obtained by things.

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-
The protecting group for the carboxyl group at the 7-position side chain and the carboxyl group at the 4-position of the 4-carboxylic acid derivative may be an ester-forming group such as phenacyl or p-promphenacil, and preferably phenacyl ester.

The esterification method can be easily obtained by a conventional method. In other words, the raw material disodium salt and phenacyl bromide may be mixed in a suitable solvent,
Dimethylformamide is preferred as such a solvent.

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 an inert solvent. Examples of such solvents include acetone, tetrahydrofuran, dioxane, dichloromethane, chloroform, trichlene, etc., but 1,2-
A mixed solvent of dichloroethane and dioxane is most preferred.

Examples of the epoxide deoxidizer having the general formula () include propylene oxide, butylene oxide, styrene oxide, 1,2-epoxy-3-phenoxypropane, and 1,2-epoxy-3-(p-tolyloxy). Propane, 1,2-
Examples include epoxy-3-(p-chlorophenoxy)propane, but preferred are propylene oxide, butylene oxide, and styrene oxide. The amount used is for compound (),
The molar ratio is 3 to 10. Examples of the halogen atom represented by X in the general formula () 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
The temperature is 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 brought into contact with an organic acid and zinc, thereby making it possible to eliminate the ester moiety. Suitable examples of such organic acids include acetic acid and formic acid. Also, the amount of zinc used is 0.2 to 1.0 of the raw material.
It's double the amount. The reaction temperature is 0 to 30°C, and the reaction time is several tens of minutes to 3 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, as a suitable post-treatment method, after performing a deesterification reaction, the reaction mixture is brought into contact with methanol in the presence of an acid to convert only the by-produced acylaminoadipic acid into dimethyl ester, thereby converting the desired product into dimethyl ester. One method is to separate the compound 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. Such salts include lithium,
salts of inorganic metals such as sodium, potassium, calcium, magnesium or ammonium;
Mention may be made of ammonium warmers such as cyclohexylammonium, diisopropylammonium and triethylammonium, preferably sodium and potassium salts.

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

Example 1 7β-(D-5'-benzenesulfonylamino-
5′-carboxyvaleramide)-7α-methoxy-
3-Carbamoyloxymethyl-3-cephem-
When 5.9 g of 4-carboxylic acid is reacted in the same manner as in Example 1, 6.5 g of diphenacyl ester is obtained.

Nuclear magnetic absorption spectrum δppm (DMSO-d ₆ ) 1.31-2.35 Broad multiplet (7H) 3.1-3.77 Quadruplet (2H) 3.37 Singlet (3H) 4.8 Broad singlet (2H) 5.05 Singlet (1H) 5.18 Singlet Line (2H) 5.60 Singlet (2H) 6.45 Broad singlet (2H) 7.23~8.47 Multiplet (15H) 9.06 Broad singlet (1H) To 3.0g of the diphenacyl ester thus obtained, add 30ml of dioxane, 1 , 60 ml of 2-dichloroethane, 3.0 ml of butylene oxide and 3.0 g of cyanomethylthioacetyl chloride were added, and the mixture was refluxed for 6 hours with stirring. Then, the solvent was distilled off under reduced pressure, 100 ml of isopropyl ether was added, and the mixture was stirred well to remove the isopropyl layer. Add 40 ml of 90% formic acid to the residue, dissolve it, add 3 g of zinc powder while stirring in an ice water bath, and continue stirring for 1 hour. The reaction mixture was filtered and the liquid was concentrated under reduced pressure. Then add water to this
Add 30 ml and 30 ml of ethyl acetate, add 6N hydrochloric acid, shake well, and adjust the pH of the aqueous layer to 1.8. After removing the aqueous layer, the ethyl acetate layer was subjected to silica gel column chromatography, developed with ethyl acetate:benzene = 2:1, and separated and purified to produce 7β-cyanomethylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3. -Cefem-4-carboxylic acid
1.1g is obtained.

Nuclear magnetic resonance spectrum δppm (CD ₃ CN): 5.05 Singlet (1H) 4.81 Singlet (2H) 3.58 Singlet (2H) 3.50 Singlet (3H) 3.49 Singlet (2H) 3.47~3.50 Double doublet ( 2H)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a benzenesulfonylamino group, and R ² represents a hydrogen atom or a halogen atom.) A compound represented by the general formula (In the formula, R ₃ represents a lower alkyl group, aryl group or aryloxyalkyl group.) and the general formula R ⁴ -X (In the formula, R ⁴ represents a cyanomethylthioacetyl group or a chloroacetyl group, and X is a halogen A general formula characterized by reacting with a compound represented by (indicates an atom) and then removing the protecting group of the carboxylic acid. (In the formula, R ⁴ has the same meaning as above.)
A method for producing a cephalosporin derivative represented by and a pharmacologically acceptable salt thereof.