Method for preparing cilastatin acid

Abstract

The present invention discloses a novel method for preparing cilastatin acid. Under a strongly acidic condition, (E)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester in a mixed liquid which contains (Z)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester and (E)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester is directly isomerized to form a reaction liquid that contains pure (Z)-7-chlorine-((S)-2,2- dimethyl cyclopropane amido)-2-heptenoic ethyl ester, and then pure (Z)-7-chlorine-((S)-2,2- dimethyl cyclopropane amido)-2-heptenoic ethyl sodium is obtained to prepare cilastatin acid. The method has the advantages that the product is high in yield and good in purity; the preparation process consumes less energy, and the like.

Description

technical field [0001] The invention relates to a preparation method of cilastatin. Background technique [0002] Cilastatin is a kidney dehydrodipeptidase inhibitor synthesized by MERCK, represented by the following formula 1. (Z))-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid or its sodium salt is the key intermediate for preparing cilastat butyric acid, by following Formula 2 expresses. [0003] [0004] U.S. Patent No.5147868 discloses a kind of method for preparing cilastatin, specifically adopts the method that contains by formula 3 Represented E-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid and formula 2 The mixture of Z-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid is heated to 90°C under acidic conditions (PH=0.5--3.0) About 30 minutes of isomerization reaction, the E-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid isomerized to obtain pure Z-7 -Chloro-((S)-2,2-dimethylcyclopropaneamido)-2-hepteno...

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the E-type isomer is not treated, and the obtained (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid base The product purity of the metal salt is low, and the energy consumption of concentrating the aqueous phase is large

However, the disadvantage of this method is that E-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester in the mixture is destroyed during acid hydrolysis. The acid is hydrolyzed, and the yield of Z-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester is low, and the concentration process is required due to the multi-step operation, High energy consumption, not conducive to industrialization

Images