Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester

Abstract

The invention belongs to the field of synthesis of cephalosporin drug intermediates and disclosesa preparation method of 7-phenylacetamide-3-chloromethyl-cephalosporanic acid p-methoxybenzyl ester (short for GCLE). According to the method, penicillin G potassium salt taken as an initial raw material reacts with 4-methoxybenzylchloride firstly, penicillin sulfoxide ester is prepared through oxidation with peracetic acid and reacts with 2-mercaptobenzothiazole firstly, then a product reacts with benzene sulfinic acid, a ring opening product is obtained and reacts with chlorine, sodium methoxide is used for ring closing under the action of a methanol solvent, and 7-phenylacetamide-3-chloromethyl-cephalosporanic acid p-methoxybenzyl ester is obtained. The solvent is simple and easy to recover, reaction conditions are mild, operation is simple and convenient, and industrial production is easy.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of 7-phenylacetamide-3-chloromethylcephalosporanic acid p-methoxybenzyl ester (GCLE for short). Background technique [0002] 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE for short) is an important antibiotic raw material, it is one of the important semi-synthetic antibiotic mother nuclei, it is both 7-ACA, 7- Another new mother nucleus after ADCA, using this as a lead compound, can produce a new generation of cephalosporins such as double bonds at the C3 position, thiomethyl groups, and quaternary ammonium salts. Such as cefixime, cefdinir, cefprozil, cefditoren pivoxil, ceftazidime. Because its 3 bits are -CH 2 Cl base, and more active, easier to synthesize new cephalosporins. The preparation method of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl mainly contains: [0003] O...

AI Technical Summary

Problems solved by technology

[0017] In DMF solution, use ammonia water or liquid ammonia to close the ring (add hydrochloric acid to terminate the reaction), the crude product is precipitated in the aqueous solution, recrystallized with methanol, the content is 95-96%, but the yield is low

Ring closed in the mixed solvent of methanol and ethanol, the mixed solvent is difficult to recover, increasing the manufacturing cost

[0018] Above-mentioned each method all fails to solve the problem that GCLE yield is low, industrialized production cost is high, and main deficiency is:

[0019] 1. Using DMF, acetone, and ethyl acetate system for esterification reaction, the reaction solvent needs to be concentrated, then dissolved in xylene, deoxidized, and the concentration process increases power consumption, large solvent loss, and high cost

[0020] 2. Toluene is generally used as a solvent for the ring opening in the existing method, but due to the high ring opening temperature, reflux at 116°C is required, which is not easy to control, the reaction has many impurities, dark color, and the conversion rate of ring opening is low

[0021] 3. Sodium hypochlorite chlorination or electrolytic chlorination requires complex equipment. Chlorination with sodium hypochlorite can easily form polychlorinated compounds

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