Enabling Synthesis of Triple Reuptake Inhibitor (+)-BMS-820836, a Potential Therapeutic Agent for the Treatment of Depression

Herein, we describe the enabling synthesis of (+)-BMS-820836, a 4,7-disubstituted tetrahydroisoquinoline which was developed as a treatment for a range of neurological diseases, including depression and neurophatic pain. In order to advance the drug candidate into the Phase 1 clinical trials, an efficient and scalable synthesis was required. Three areas of improvement included the development of a regioselective Friedel–Crafts cyclization, a classical resolution for the purification of the desired enantiomer, and a robust Suzuki–Miyaura coupling. These improvements ultimately resulted in the isolation of (+)-BMS-820836 as a free-flowing white solid in 99 area% purity and 3% overall yield after 14 steps.