The Synthesis Of Cilastatin Sodium

This dissertation focused on the synthesis of (S)-2,2-dimethylcyclopropane carboxamide utilizing chiral reagents via several steps. And the synthesis of cilastatin sodium started from (S)-2,2-dimethyl cyclopropane carboxamide,7-chloro-2-oxoheptanoate ethyl ester and L-cysteine, and which gave the product in the optimal conditions.Firstly,2,2-dimethyl cyclopropane carboxylic acid was resolved by chiral 1,1'-binaphthol derivatives such as (R)-1,1'-binaphthol, (R)-1,1'-binaphthol monomethyl ether or (R)-1,1'-binaphthol monoethyl ether, and (S)-2,2-dimethyl cyclopropane carboxamide was obtained with 18.1%-33.7% yields via three steps: formed ester diastereomers, recrystallization or column chromatography separation, and ammonolysis. Then, the synthesis of (S)-2,2-dimethyl cyclopropane carboxamide started from 2,2-dimethyl cyclopropane carboxylic acid and quinidine via three steps: formed ester diastereomers, recrystallization separation, and ammonolysis. And the total yield of the three steps was 20.5%. At last, we reported two methods for the resolution of 2,2-dimethyl cyclopropane carboxylic acid, wherein the L-phenylglycine methyl ester was the chiral auxiliary, with 5.8% yield via some steps:converted to acid chloride, recrystallization separation, Hofmman rearrangement reaction and saponification, ect; or with 6.6% yield via several steps:ammonolysis, recrystallization separation, saponification and oxidation.Cilastatin sodium was synthesized via tow steps. Firstly, (S)-2,2-dimethyl cyclopropane carboxamide was reacted with 7-chloro-2-oxoheptanoate ethyl ester which gave ethyl 7-chloro-2-((1S)-2,2-dimethyl cyclopropanecarboxamide)-2-oxoheptanoate ethyl ester. Secondly, alkyl cilastatin ester was produced by the reaction of L-cysteine methyl ester hydrochloride and hetenoic ester in different conditions. And alkyl cilastatin ester was synthesized with 74.1% yield in the optimal route at a material ratio of 1.5:1 using K3PO4 as alkali via 4 equivalents at 80℃under THF as solvent. Cilastatin sodium was obtained by saponification with 49.6% yield. In this paper, synthesis of alkyl cilastatin ester was avoided the use of stronge alkali and anhydrous reaction conditions in the reaction system, and the reaction conditions were mild, simple operation and more suitable for industrial production.The structure of produces was confirmed by 1HNMR,13C NMR, HPLC and GC etc.