高效、可扩展地对映体选择性合成 Rimegepant 的关键中间体:一种口服 CGRP 受体拮抗剂

Zhonghua Luo, Guodong Sun, Guowei Wang, Xin Zhang, Yang Zhang, Ji Zhang
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引用次数: 0

摘要

Rimegepant 是一种降钙素基因相关肽拮抗剂,用于偏头痛的急性治疗和预防。我们在此尝试探索一种高效、实用的方法,用于放大、区域和对映体选择性合成 (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1),它是 Rimegepant 的一种关键中间体。在这项工作中,Ru 催化的不对称转移加氢(ATH)反应是一个关键步骤。反应条件的优化包括对催化剂、碱和溶剂等反应参数的探索。结果表明,以甲酸为氢供体的 Ru 催化 ATH 反应可在温和条件下以较低的催化剂负载量(0.5 摩尔%)进行操作,从而获得高产率(92.1% 收率,99.8% 纯度)和令人满意的目标产物对映体选择性(99.9% ee)(1)。该研究首次报道了 Ru 催化 ATH 工艺合成利美喷司关键中间体的过程。优化后的 ATH 工艺易于实现且具有成本效益,因此特别适用于大规模生产。
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Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist
Rimegepant is a calcitonin gene-related peptide antagonist used for acute treatment and prevention of migraine. We herein attempt to explore an efficient and practiced method for scale-up, regio- and enantioselective synthesis of (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1), a key intermediate of rimegepant. In this work, a Ru-catalyzed asymmetric transfer hydrogenation (ATH) reaction was a key step. The optimization of the reaction conditions involved exploring the reaction parameters including catalysts, bases, and solvents. The results suggested that the Ru-catalyzed ATH process using formic acid as the hydrogen donor could be operated under mild conditions at a low catalyst loading (0.5 mol%), affording a high yield (92.1% yield with 99.8% purity) and gratifying enantioselectivity (99.9% ee) of the target product (1). This work first reported the Ru-catalyzed ATH process in the synthesis of key intermediates of rimegepant. The optimized ATH process was easy to implement and cost-effective, making it particularly suitable for manufacturing scale production.
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审稿时长
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