Method for preparing cilastatin acid

A technology of cilastatin and sodium heptenoate, which is applied in sulfide preparation, organic chemistry, etc., can solve the problems of low product purity, high energy consumption, and the need for a concentration process, and achieve high yield and purity, and energy The effect of low consumption and simple operation steps

Active Publication Date: 2009-03-18
ZHUHAI UNITED LAB
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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-dimethylcyc

Method used

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  • Method for preparing cilastatin acid
  • Method for preparing cilastatin acid
  • Method for preparing cilastatin acid

Examples

Experimental program
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Example Embodiment

[0022] Example 1

[0023] The preparation method of cilastatinic acid includes the following steps:

[0024] A. 200g of ethyl 7-chloro-2-oxoheptanoate, 115g of (S)-2,2-dimethylcyclopropanecarboxamide, 2g of p-toluenesulfonic acid and 1L of toluene were refluxed and reacted for 10 hours. After the reflux reaction, the temperature was lowered to -2°C, 50 mL of concentrated hydrochloric acid was added, and the isomerization reaction was carried out for 15 hours. After separating the isomerized toluene layer, a pure (Z)-7-chloro-((S)- 2,2-Dimethylcyclopropanamido)-2-heptenoic acid ethyl ester reaction solution.

[0025] B. To the reaction solution containing pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester, add 300mL sodium hydroxide solution (30 %), hydrolysis reaction at room temperature for 5 hours, after the hydrolysis is complete, pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid sodium is obtained.

[0026] C. Add hydrochlor...

Example Embodiment

[0028] Example 2

[0029] This example is basically the same as Example 1, except that the reaction temperature of the direct isomerization reaction in step A is 30° C., and the reaction time is 5 hours.

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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...

Claims

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Application Information

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IPC IPC(8): C07C323/59C07C319/14
Inventor 许华锋潘祝松毛刚左斌海唐彬喜彭韪
Owner ZHUHAI UNITED LAB
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