Efficient and practical asymmetric synthesis of 1- tert-butyl 3-methyl (3 R,4 R)-4-(2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate, a useful intermediate for the synthesis of nociceptin antagonists

Abstract

An efficient and practical asymmetric synthesis of 1- tert-butyl 3-methyl (3 R,4 R)-4-(2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nociceptin antagonists, has been developed. This method includes the following key steps: (1) diastereoselective reduction of a chiral enaminoester 3 having ( R)-1-phenylethylamine as a chiral pool constituent with the use of a combined TFA–NaBH 4 reduction system and (2) efficient isomerization from 3,4- cis-substituted piperidine 8 to 3,4- trans-substituted piperidine 1 under basic conditions. The above methods proved to be applicable for large-scale operation and hundred grams of enantiomerically pure compound 1 (>98% ee) was obtained.