2,2-二甲基环丙烷甲酸的合成与拆分

Synthesis and Chiral Resolution of 2,2- dimethylcyclopropane Carboxylic Acid

S-(+)-2,2-二甲基环丙烷甲酸是合成西司他丁(一种肾脱氢二肽酶抑制剂)的关键中间体,今设计了一条新的2,2-二甲基环丙烷甲酸合成路线并改进了拆分工艺,它是以异戊烯酸为原料,经酸的酯化、烯键的环丙烷化、酯水解制得2,2-二甲基环丙烷甲酸,收率为44.1%。其中,环丙烷化反应用锌粉/氯化亚铜-乙酰氯作为催化剂,二溴甲烷作为环丙烷化试剂,这样可以在温和的条件下进行反应,降低成本。此外用L-肉碱草酸盐作为手性拆分试剂,经酰化、成盐、部分结晶、水解得到S-(+)-2,2-二甲基环丙烷甲酸。收率为16.7%,手性纯度大于95%。此路线工艺简单、环境友好、成本较低,易于工业化。

(S)-(+)-2,2-dimethylcyclopropane carboxylic acid is the key intermediate of Cilastatin (an excellent inhibitor of dehydropeptidase-I). Using 2-methylbutenoic acid as raw material, 2,2-dimethylcyclopropane carboxylic acid was achieved via esterification, cyclopropanantion and hydrolysis, the yield is 44.1%. Specially, using zinc powder/copper (I) chloride-acetyl chloride as catalysts, the cyclopropanation proceedes easily with dibromomethane. Then 2,2-dimethylcyclopropane carboxylic acid is converted to acid chloride and reacted with L-carnitine oxalate (the chiral reagent for resolution). After fractional crystallization and hydrolysis, (S)-(+)-2,2-dimethylcyclopropane carboxylic acid was prepared with 16.7% yield. Thus a new synthesis route of 2,2-dimethylcyclopropane carboxylic acid was designed and its chiral resolution procedure was improved, this new route and improved procedure are clean, convenient to operate and apt for industrialization with lower cost.