Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)-1-Amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986104) as a Potent S1P1 Receptor Modulator

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• 作者：Michael G. YangZili Xiao ; T. G. Murali Dhar ; Hai-Yun Xiao ; John L. Gilmore ; David Marcoux ; Jenny H. Xie ; Kim W. McIntyre ; Tracy L. Taylor ; Virna Borowski ; Elizabeth Heimrich ; Yu-Wen Li ; Jianlin Feng ; Alda Fernandes ; Zheng Yang ; Praveen Balimane ; Anthony M. Marino ; Georgia Cornelius ; Bethanne M. Warrack ; Arvind Mathur ; Dauh-Rurng Wu ; Peng Li ; Anuradha Gupta ; Bala Pragalathan ; Ding Ren Shen ; Mary Ellen Cvijic ; Lois D. Lehman-McKeeman ; Luisa Salter-Cid ; Joel C. Barrish ; Percy H. Carter ; Alaric J. Dyckman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：11138-11147
• 全文大小：648K
• ISSN：1520-4804

文摘

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.