A kind of catalysis method of cephalosporin nucleolysis reaction

Abstract

The invention belongs to the field related to cephalosporin drug intermediate synthesis, and provides a cephalosporin parent nucleus enzymolysis reaction catalysis method which comprises the following steps: (1) by using p-methoxybenzyl 7-phenylacetylamino-3-vinyl-4-cephalosporanate as an initial raw material, adding into phenol, and heating to react; after the reaction finishes, extracting the intermediate product to a water phase, and adding penicillin acylase and polyethyleneglycol accounting for 5+ / -2 wt% of the penicillin acylase as an enzymolysis catalyst; and (2) while controlling the temperature at 20-25 DEG C, dropwisely adding a 5-10 wt% sodium carbonate solution, and controlling the pH value of the system at 7.0-7.5 to perform enzymolysis. According to the method, the enzymolysis speed and enzymolysis conditions are changed. On the premise of not increasing the 7-AVNA raw material cost, the enzymolysis reaction speed is enhanced, the operation time is shortened, and the enzymolysis process is performed under the conditions of low pH value and low temperature. The method has the advantages of high product purity, fewer impurities and high yield, and is very suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field related to the synthesis of cephalosporin drug intermediates, and relates to a catalytic method for the enzymatic hydrolysis reaction of cephalosporin nuclei, especially the preparation of cefixime nuclei 7-amino-3-vinyl-4-cephalosporin A catalytic method for enzymatic hydrolysis of acid (hereinafter referred to as 7-AVNA). 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 cores, and it is the cefixime core 7- AVNA, cefprozil core 7-APCA, starting material for cefditoren axetil core 7-ATCA, 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxy prepared by Wittig reaction using GCLE Benzyl ester (hereinafter referred to as GVNE) is the intermediate of the previous step of cefixime and cefdinir core 7-AVNA. It can remove the protective group of p-met...

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Problems solved by technology

[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 cores, and it is the cefixime core 7- AVNA, cefprozil core 7-APCA, starting material for cefditoren axetil core 7-ATCA, 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxy prepared by Wittig reaction using GCLE Benzyl ester (hereinafter referred to as GVNE) is the intermediate of the previous step of cefixime and cefdinir core 7-AVNA. It can remove the protective group of p-methoxybenzyl ester by reacting with phenol, and remove phenylacetic acid by enzymatic cleavage. The procedure is a key step in the preparation of 7-AVNA. The normal enzymatic hydrolysis process is to add penicillin acylase to the feed solution, maintain the enzymatic hydrolysis temperature at 28°C-32°C, and use 10% sodium carbonate aqueous solution to control the pH of the system at Between 7.8 and 8.2, the entire enzymatic hydrolysis time should last for 3 hours. The temperature of the enzymatic hydrolysis process is high, and the enzymatic hydrolysis solution is maintained at a high pH for a long time. 7-AVNA is easily degraded in the enzymatic hydrolysis solution, and impurities increase. Product yield drops

[0003] Chinese patent CN200710114782.1 reports the preparation method of 7-amino-3-vinyl-4-cephalosporanic acid, and proposes a preparation method that can remove phenylacetic acid by chemical cleavage and enzymatic cleavage, but does not describe the detailed process of enzymatic cleavage , there is no clear description of the enzymatic hydrolysis temperature, time, and pH;

[0004] Chinese patent CN201110100039.7 reported that GCLE was used as the initial raw material to prepare GVNE through wittig reaction. After reacting with phenol and catalyst, and through the extraction process, 7-AVNA was crystallized, but the chemical name and usage method of the catalyst were not specified.