Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide

Abstract

This invention relates to process for synthesizing S-(+)-2,2-dimethyl cyclopropane formyl amide, using penteneic acid as main raw material, after procedures of: esterification, cyclopropanization, hydrolyzation, acylation, salifying, partial crystallization and ammonolysis. advantages are: short reaction time, mild reaction condition, simple process, total yield is more than 15%, ee is larger than 95.6%.

Description

Technical field: [0001] The invention relates to a method for synthesizing S-(+)-2,2-dimethylcyclopropanecarboxamide. Background technique: [0002] [0003] S-(+)-2,2-dimethylcyclopropanecarboxamide, whose molecular formula is shown in S-1, is a key intermediate for the synthesis of cilastatin (a kidney dehydrodipeptidase inhibitor), now Generally adopt the following two methods to make in the technology: [0004] Graham et al. (J. Med Chem. 1987, 30, 1074) reported that 2,2-dimethyl-1,3-propanediol was used as a raw material and synthesized through six steps. This method not only has a long reaction time, but also involves the use of highly toxic potassium cyanide as a reactant and expensive quinine as a resolution reagent, so the danger to the human body or the environment is large and the cost is high. [0005] S-1 is prepared by using the chiral raw material of S-(+)-2,2-dimethylcyclopropanecarboxylic acid with the molecular formula as S-2, through acid chloride an...

AI Technical Summary

Problems solved by technology

For example, in the patent CH682485, L-carnitine hydrochloride is used as the chiral resolution reagent, and S-2 is obtained through five steps of acylation, hydrochloride formation, ion exchange, oxalate formation, and hydrolysis; EP93511 uses (+ )-1,2-diphenylethylamine is a resolution reagent, although the yield and chiral purity of the product are higher, (+)-1,2-diphenylethylamine is expensive and the cost is high; in addition, there are JP60056942 uses 1-N-methylephedrine, US4487956 uses 1-menthol, EP474200 uses R-1-(3-methoxyphenyl)-ethylamine, EP461541 uses S-methyl mandelate, and US5427934 uses gene recombined Biological enzymes resolve 2,2-dimethylcyclopropanecarboxamide, etc. These methods currently have defects such as expensive resolution reagents or difficult preparations, low single resolution yields, cumbersome operations, and high costs.

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