JPS603399B2 - Novel derivatives of cephalosporin compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel cephalosporin derivative represented by the general formula or a salt thereof.

In the compound of the above general formula, R means a lower alkyl group.

Next, the salts of the compound represented by the above general formula (1) include pharmaceutically acceptable non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, ammonium salts, dicyclohexylamine salts, cyclohexylamine salts, etc. Examples include salts with organic bases such as amine salts, trimethylamine salts, ethanolamine salts, ornithine salts, and lysine salts.

Cephalosporin conductor (1) provided by the present invention
or its salt is a new compound that has antibacterial activity against both gram-enteric bacteria and gram-negative bacteria, and is especially effective against the latter, making it useful as a pharmaceutical, feed additive, food, and preservative for chemical industry products, etc. It is. The general formula (1)
The compound represented by can be produced by the following method.

(In the formula, X means a halogen atom.

R has the meaning given above. The reaction for producing the object compound (1) of the present invention by the above-mentioned method is to react 7-haloacetamidocephalosporin conductor (01a) or a salt thereof,
This is carried out by the action of an alkali metal salt of mercaptoisothiazole represented by the general formula (m-a).

The reaction is usually carried out in a solvent.

The solvent is not particularly limited as long as it does not participate in the reaction; for example, water, methanol, acetone, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof may be used. The reaction may also be carried out at room temperature or under cooling in the presence of a base.

In the compound (m-a), the mercapto group of lukatoisothiazole can usually be used as the alkali metal, but when used as is, the base may be triethylamine, N,N-dimethylaniline, N-ethylmorpholine, pyridine, etc. , collidine L 2.6-lutidine, or an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. . (Rho a) of 7-haloacetamidosefa 0 sporin derivative.

Gen atoms include chlorine atoms, bromine atoms, and fluorine atoms. The ratio of compound (Rho a) used in this reaction is 1 to 2 (m-a) per 1 mole of (Rho a).
Moles are appropriate. Isolation of the product from the reaction solution is carried out by conventional methods, such as separation by chromatography or extraction with a solvent.

These compounds can be converted into their non-toxic salts by conventional methods.

A commonly used method is, for example, to add an n-butanol solution of alkali metal 2-ethylhexanoate to these compounds, and then add an organic solvent with different solubility such as ether or ethyl acetate to obtain the target compound of the present invention. Alkali metal salts, also dicyclohexylamine,
By adding and reacting an organic base such as triethylamine, cyclohexylamine, trimethylamine, arginine, lysine, ornithine, or jetanolamine in an equal amount to a small excess amount, the organic base of the target compound of the present invention can be further added with aqueous ammonia. There is a method to obtain ammonium salt. Next, the manufacturing method of the present invention will be specifically explained with reference to Examples.

The isothiazole derivatives used as raw materials in the following examples are compounds described in the literature, but they are based on the method for producing 4-cyano-3-hydroxy-5-mercaptoisothiazole, which is a known isothiazole derivative (W. & H.
atc rd et al., J. 0rg. Chem. (28),2
1M), or by further processing the thus obtained isothiazole derivative by a conventional method.

Example 1 150 ml of sodium salt of 4-cyano-5-mercapto-3-methylthioisothiazole was dissolved in methanol and 7-bromoacetamide was added to this solution under ice cooling.
-(1-methyltetrazol-5-yl)thiomethyl-
△3-Cephemu 4-Carposoic acid 250 ml was added dropwise to a solution of 4 methanol, and the temperature was returned to room temperature.
Stir the time.

After the reaction, the reaction solvent was distilled off under reduced pressure, and a small amount of water was added to make a 5%
Adjust to pHI with hydrochloric acid water.

Extract with tear fluid using n-butanol-ethyl acetate (volume ratio 1:1), wash the organic layer with water, wash with saturated aqueous sodium chloride solution, and dry over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with a mixture of chloroform-methanol-formic acid (volume ratio 80:20:3) to obtain 7-(4-cyano-
3-Methylthioisothiazol-5-yl)thioacetamide 3-(1-methyltetrazol-5-yl)thiomethyl-Δ8-cephemu-4-carboxylic acid 180 of 3 is obtained.

Nuclear magnetic resonance spectrum (DMS○d6) 6 (legs):

Claims (1)

[Claims] 1 General formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R means a lower alkyl group. ) A novel cephalosporin derivative.