The Synthesis Of S-(+)-2, 2-Dimethylcyclopropane Carboxylic Acid Methyl Ester By Asymmetric Simmons-Smith Reaction

S-(+)-2,2-dimethylcycloproprane carboxylic acid methyl ester is the key intermediate in the synthesis of cilastain, a renal dehydropeptidase inhibitor, which can enhance the antibacterial activity of Imipenem and has widely clinic applications. This thesis is mainly about the research of new synthesis technic of S-(+)-2,2-dimethylcycloproprane carboxylic acid methyl ester, including the synthesis of 2,2-dimethylcycloproprane carboxylic acid methyl ester, the choose of chiral catalysts and the produce of S-(+)-2,2-dimethylcycloproprane carboxylic acid methyl ester by asymmetric Simmons-Smith reaction.At first, on the base of literatures, the synthesis technology of 2,2-dimethylcycloproprane carboxylic acid methyl ester was improved, which was prepared via esterification, cyclopropanantion using isopentene acid as starting material. Using zinc/copper as catalyst, the cyclopropanation proceeded easily with diiodomethane. Some factors which effect the reaction were also discussed, and the proper conditions were given as follows: n(isopentene acid methyl ester):n(diiodomethane):n(Zn-CuⅢ)=1:3.0:3.0; the mixed solvent isⅤ(methylene dichloride):Ⅴ(absolute ethyl ether)=6:1; and the reaction time is 9 hours under reflux temperature. Under the optimum conditions, the yield of 2,2-dimethylcycloproprane carboxylic acid methyl ester is 84.6%. This route has advantages such as simple procedure, higher yield and lower cost.Next, three kinds of C2-symmetrical chiral catalysts for asymmetric Simmons—Smith reaction are synthesized from (o, m, p)-nitrobenzene sulfonyl chloride and (1R,2R)-(-)-1,2-diaminocyclohexane under mild conditions. The optimum reaction conditions of ortho-,meta-,para-isomer chiral catalysts are determined as reaction temperature of 25℃and reaction time of 2h, the solvent for recrystallation ofⅤ(dichloromethane):Ⅴ(n-hexane)=1:3. The yields of ortho-meta-,para-isomer chiral catalysts were 75.0%,34.0%,76.1%.At last, S-(+)-2,2- dimethylcycloproprane carboxylic acid methyl ester was synthesized through asymmetric Simmons-Smith reaction. The effects of the catalytic activity and quantity were studied, and the reaction conditions were optimized. The experiments identified that the meta- and para- isomer chiral catalysts are effective for this reaction system, which could produced S-(+)-2,2- dimethylcycloproprane carboxylic acid methyl ester. And the suggested reaction conditions are:n (isopentene acid methyl ester):n (CH2Cl2):n (Zn-CuⅢ):n (p-NO2)=1:3.0:3.0:0.1; reaction time of 14h at atmospheric pressure and reflux temperature;Ⅴ(CH2Cl2):Ⅴ(absolute ether)=6:1.