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

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• 作者：Paul C. Lobben ; Rasidul Amin ; Bang-Chi Chen ; Wenge Cui ; Min Hu ; Matthew Isherwood ; Shuang Liu ; Kassoum Nacro ; Brandon Miles ; Bingidimi Mobele ; Richard E. Olson ; Bei Wang ; Yuh-Lin Yang ; Rulin Zhao
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：January 15, 2016
• 年：2016
• 卷：20
• 期：1
• 页码：44-50
• 全文大小：278K
• ISSN：1520-586X

文摘

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.