Chloroperoxidase one-step catalytic method for synthesizing chiral drug fosfomycin preparation

Abstract

The invention relates to a method for synthesis of a chiral drug fosfomycin preparation through a chloroperoxidase one-step catalytic method. The method comprises the steps: firstly, adding cis-propenylphosphonic acid into a phosphate buffer solution to obtain a mixed solution, adjusting the pH value of the mixed solution to 4-6 with a sodium-source alkali or a calcium-source alkali, and thus preparing a substrate initial aqueous solution; then adding an oxidizing agent and chloroperoxidase into the substrate initial aqueous solution, mixing uniformly, and then carrying out a reaction for 0.5-3.5 h; after completion of the reaction, heating to evaporate the reaction liquid, carrying out cooling crystallization, and thus obtaining the chiral drug fosfomycin preparation. The reaction is carried out in the aqueous solution, the concentration of the oxidizing agent is low, the yield is high, no resolution problem exists, the needed time is short, the reaction can be completed in about three hours, and the conditions are mild; the product has the advantages of higher stereoselectivity, and high optical purity. The used chloroperoxidase is a finished product enzyme but not a bacterial strain, no biological inhibition function exists in the synthesis process, and the process is simple and easy to implement.

Description

【Technical field】 [0001] The invention belongs to the technical field of green synthesis, and in particular relates to a method for synthesizing a chiral drug fosfomycin preparation by a one-step catalyzed method of chloroperoxidase. 【Background technique】 [0002] Fosfomycin [(-)-1R, 2S-epoxypropyl phosphate] is an important clinical broad-spectrum antibiotic that inhibits bacterial cell wall synthesis and belongs to phosphoric acid derivatives in structure. There are mainly two forms of fosfomycin antibiotic preparations currently used, the calcium salt is mainly used for oral administration, and the sodium salt is mainly used for intravenous drip or intramuscular injection. Fosfomycin sodium salt [chemical name: (-)-(1R,2S)-1,2-epoxypropyl phosphate sodium] is a high-efficiency, low-toxicity, broad-spectrum antibiotic that does not bind to plasma proteins and has no Antigenic, strong penetrating power. Because fosfomycin sodium is highly alkaline, in order to make its p...

AI Technical Summary

Problems solved by technology

The method of industrial synthesis of fosfomycin is to use chemical methods to obtain its racemic body first, and the catalysts used in the industrial preparation of fosfomycin are mostly sodium tungstate or sodium molybdate. After forming racemic epoxide, use (+)-alpha-phenethylamine carries out the resolution of racemate, and the output of fosfomycin is lower than 32% in the resolution process, and dextroracemate is discarded, has caused the great waste of raw material, and these The disadvantage of solid catalysts is that they can only be used once and there are environmental pollution problems

In 2008, the Hongchang Shi research group of Tsinghua University used chiral ketones and chiral amines to epoxidize cis-propenyl phosphate to synthesize fosfomycin, and reacted at zero for 72 hours. This reaction takes a long time, and in organic and In the mixed system of water, the concentration of hydrogen peroxide is also very high. Due to the energy consumption of the reaction, the pollution of the catalyst and the organic solvent to the water body is relatively large, which is not conducive to industrial production.

This has promoted people's exploration in the biological synthesis of fosfomycin. In 2001, Shi Jiaji's research group studied the use of Penicillium strains to epoxidize cis-propenyl phosphate to directly synthesize fosfomycin. The synthesis method is characterized by the use of biological strains Direct reaction has high stereoselectivity, there is no problem of chemical resolution, and the reaction conditions are mild, the pollution of the environment is less, and the optical purity of the obtained product is high, but this method also has its disadvantages: the use of biological strains The reaction carried out, the fosfomycin produced will have a bioinhibitory effect on it, and the steps are cumbersome

Based on this, the biosynthesis method of fosfomycin has attracted the attention of researchers at home and abroad. After that, many methods of biosynthesis of fosfomycin have been studied, but most of them are fluorescent labeling and genetic engineering methods, with cumbersome steps and high requirements.

Images