Method for synthesizing amoxicillin and generating byproduct of sodium phenylacetate solution by using semi-direct method

Abstract

The invention relates to a method for synthesizing amoxicillin and generating a byproduct of a sodium phenylacetate solution by using a semi-direct method and belongs to the technical field of medicine preparation. The method comprises the following steps: splitting benzylpenicillin potassium into 6-APA (Amino Penicillanic Acid) and phenylacetic acid under the action of penicillin acylase, extracting a splitting solution with dichloromethane to separate 6-APA from the phenylacetic acid, putting ammonia water into an extraction water phase, adjusting the pH value of a material liquid to be neutral, removing the dichloromethane, putting the solid 6-APA into the obtained 6-APA dissolving liquid, and synthesizing the amoxicillin together with D-methyl p-hydroxyphenylglycinate under the actionof amoxicillin synthetase. A sodium phenylacetate solution can be prepared by alkalizing the dichloromethane obtained by extracting the splitting solution, the sodium phenylacetate solution can be directly applied to fermentation production of penicillin, the step of recycling the phenylacetic acid is avoided, and the production cost is reduced.

Description

technical field [0001] The invention relates to a method for synthesizing amoxicillin and by-product sodium phenylacetate solution by a semi-straight-through method, belonging to the technical field of pharmacy. Background technique [0002] There are chemical and enzymatic methods for the synthesis of amoxicillin. Because the chemical method uses a large amount of toxic substances and the reaction conditions are relatively harsh, it has been replaced by the enzymatic method with mild reaction conditions and water phase reaction. The process of enzymatically synthesizing amoxicillin is as follows: 6-APA and D-hydroxyphenylglycine methyl ester synthesize amoxicillin under the action of penicillin G acylase, and the crude amoxicillin obtained is acidified, crystallized, washed and Dry to get amoxicillin. Penicillin potassium is subjected to the action of lyase to obtain a lysate containing 6-APA and phenylacetic acid, and the lysate is extracted, crystallized, washed and dri...

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Problems solved by technology

[0004] The above-mentioned patent has developed a method for the synthesis of amoxicillin by the straight-through method, but there are the following deficiencies: (1) the penicillin lysate is directly concentrated by nanofiltration without separating phenylacetic acid and 6-APA. phenomenon, so it is necessary to use high-pressure nanofiltration, and the use of high-pressure nanofiltration increases the energy consumption of the treatment process

(2) Lysis solution is directly acidified, so that phenylacetic acid and other impurities in the lysis solution are separated out simultaneously, which is unfavorable to the product quality of phenylacetic acid

At the same time, the above-mentioned patents do not effectively recover phenylacetic acid in the lysate

[0005] In addition to the deficiencies of the above-mentioned patent straight-through method for synthesizing amoxicillin, the problems of the straight-through method for synthesizing amoxicillin include: (1) there is phenylacetic acid residue in the 6-APA solution obtained after the lysate is extracted, and phenylacetic acid has no effect on amoxicillin. synthetase inhibitory

(2) In the process of preparing 6-APA by an enzymatic method, the substrate concentration of the existing immobilized penicillin acylase is low, resulting in a low concentration of 6-APA in the lysate, and finally the 6-APA in the aqueous phase obtained by extraction is low. -The low concentration of APA is not conducive to the improvement of the yield of subsequent amoxicillin synthesis

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