Enantioselective Synthesis of ((1R,2R)-Cyclohexane-1,2-diyl)bis(methylene)dimethanesulfonate, a Lurasidone Hydrochloride Intermediate

摘要

A concise, economical, and highly enantioselective synthesis of bismesylate intermediate of lurasidone HCl, an antipsychotic, has been developed. The key steps involved in the synthesis are thionyl chloride-catalyzed esterification of tetrahydrophthalic anhydride in MeOH, epimerization of cis to trans isomer, hydrolysis of the diester, resolution of the diacid, reduction with Red-Al, and finally bismesylation of the corresponding diol, which provided the desired intermediate ((1R,2R)-cyclohexane-1,2-diyl)bis(methylene) dimethanesulfonate in overall good yield.