Process Study On Synthesis Of The Key Intermediate Of Cilastatin

Cilastatin is an important inhibitor of dehydropeptidase-1, which can enhance the antibacterial activity of Imipenim and has widely clinic applications. It was synthesized through two key intermediates S-(+)-2,2-dimethylcyclopropanecarboxylic acid and 7-chloro-2-oxohepanoate. S-(+)-2,2-dimethylcyclopropanecarboxylic acid was synthesized through cyclopropanation; and the ethyl 7-chloro-2-oxohepanoate was synthesized through Grignard method. The target compounds and intermediate products were charcaterized by MS, 1H NMR and IR, and the reaction mechanism was discussed in this paper.Using 2-methylbutenoic acid as starting material, the intermediate S-(+)-2,2-dimethylcy-clopropanecarboxylic acid was synthesized via esterification, cyclopropanantion, hydrolysis and resolution. Methyl senecioate was obtained with 94.4% yield and 99% purity under the optimun reaction conditions which the raw material molar ratio was n(2-methylbutenoic acid): n(CH3OH)=1:3, reacted 3h at reflux temperature in the presence of [MIMPS][HSO4] as catalyst.2,2-dimethyl cyclopropanecarboxylate was obtained with 72.6% yield under the optimun reaction conditions which the raw material molar ratio was n(Methyl senecioate): n(CH2Br2):n(Zn)=1:4:8, reacted 12h at reflux temperature in the presence of ethanoyl chloride as catalyst, and the solvent was dichloromethane.2,2-dimethyl cyclopropanecarboxylic acid was obtained with 98% yield via hydrosis, reacted 3h at reflux temperature in the presence of NaOH. S-(+)-2.2-dimethylcyclopropanecarboxylic acid was obtained with 23% yield under the optimun reaction conditions which the raw material molar ratio was n(2,2-dimethylcyclopropanecarboxylic acid):n(SOCl2)=1:1.2, reacted 3h at reflux temperature; n(2,2-dimethylcyclopropanecarboxylic acid):n((S)-Methyl 2-hydroxy-2-phenyl-acetate)=1:1, reacted 3h at 0-5℃.The intermediate ethyl 7-chloro-2-oxohepanoate was synthesized via two steps:through addition of mono-Grignard reagent of 1-bromo-5-chloro-pentane to diethyl oxalate. The optimun reaction conditions were as follows:n(1-bromo-5-chloro-pentane):n(Mg):n(diethyl oxalate)=1:1.1:1. The reaction of Grignard reagent was taken at 30℃; and the reaction of addition was taken at -25℃for 1h. The yield of ethyl 7-chloro-2-oxohepanoate was up to 58% and higher than 98% purity(by GC).