Synthesizing method of S-(+)-2, 2-dimethylcyclopropane carboxamide

Abstract

The invention relates to a synthesizing method of S-(+)-2, 2-dimethylcyclopropane carboxamide which is synthezied by using glycine ethyl ester hydrochloride as main starting material and sequentially comprising the following steps of: diazotization reaction, cyclopropanation reaction, hydrolysis reaction, acylation reaction, resolution reaction and ammonolysis reaction. The synthesizing method has short reaction time, moderate reaction condition, simple process, overall yield more than 17 percent and ee more than 98 percent.

Description

technical field The invention relates to a method for synthesizing S-(+)-2,2-dimethylcyclopropanecarboxamide. Background technique S-(+)-2,2-Dimethylcyclopropanecarboxamide, the CAS number is [75885-58-4], the molecular formula is as follows. S-(+)-2,2-dimethylcyclopropanecarboxamide is a key intermediate in the synthesis of cilastatin (a renal dehydrodipeptidase inhibitor), and the combination of cilastatin and imipenem The compound preparation Taineng is especially suitable for combined infection of multiple bacteria and mixed infection of aerobic and anaerobic bacteria. The synthetic methods of S-(+)-2,2-dimethylcyclopropanecarboxamide are generally divided into the following categories. 1. Microbial enzyme method There are many documents on the synthesis of S-(+)-2,2-dimethylcyclopropanecarboxamide by the method of microbial enzymes, such as US 5427934, EP0524604, EP 502525, etc., all of which utilize a specific enzyme to play a catalytic role to prepare the tar...

AI Technical Summary

Problems solved by technology

Some of these chiral resolution reagents are difficult to obtain, such as d-a-phenyl-β-phenethylamine, R-(+)-1-(3-methoxyphenyl)-ethylamine, 1-methylephedrine etc. Some are expensive, such as (-)-quinine, etc., and some steps are cumbersome, such as S-(+)-methyl mandelate and L-carnitine hydrochloride, etc.

In summary, the biological enzymatic method is not easy to be industrialized; in the asymmetric synthesis, the prospect of industrialization is limited due to the high price of chiral catalyst; there are various defects in the existing synthetic methods of 2,2-dimethylcyclopropanecarboxylic acid (or the environment is not friendly, or the raw materials are difficult to obtain, or the yield is not satisfactory, etc.); after the synthesis of 2,2-dimethylcyclopropanecarboxylic acid racemate, chiral resolution is carried out, but most of the resolution reagents exist Difficult or expensive preparation, cumbersome operation, low single resolution yield, high cost and other defects

Existing technical routes need to be improved in terms of environmental friendliness and cost