Synthesis of 4,4-Disubstituted Piperidine Analogs of (+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide

Abstract

Condensation of (±)-1-benzyl-3-methyl-4-piperidone (1) with aniline followed by trapping of the intermediate imine with cyanide generated a mixture of isomeric nitriles 2A and 2B, the structures of which were established unambiguously by obtaining an X-ray crystal structure on nitrile 2B. Subsequent elaboration of the nitrile intermediates provided analogs of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide having a second substituent (carbomethoxyl, carboethoxyl, methoxymethyl) at the piper-idine 4-position. The conversion of the carboxamide intermediates 3A and 3B to the carboalkoxyl intermediates 5A, 5B and 6A was accomplished utilizing a modified esterification procedure. Proton nmr data are presented for both the final products and the key synthetic intermediates.