Process Development toward the Pilot Scale Synthesis of the Piperidine-Based Cocaine Analogue and Potent Dopamine and Norepinephrine Reuptake Inhibitor CTDP 31,446

(+)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate hydrochloride (CTDP 31,446) is known as a dopamine reuptake inhibitor. This cocaine analogue lacking the tropane skeleton is being considered for potential treatment of cocaine addiction. Herein we report the development of a scalable process for the preparation of this compound. This study was mainly aimed at improving the process throughput, eliminating chromatographic purifications for the separation of (±)-6-cis isomer from (±)-6-trans isomer, and developing a robust crystallization for isolation of pure (±)-6-cis in a single crop with a good mass recovery. The process development work also highlights an efficient recycle of (±)-6-trans via a kinetic epimerization followed by crystallization of the resulting (±)-6-cis isomer. The resolution of (±)-6-cis and the crystallization of the final HCl salt were optimized and implemented to afford CTDP-31,446 with high purity and good mass recovery.