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CC BY 4.0 · Pharmaceutical Fronts 2024; 06(01): e62-e68
DOI: 10.1055/s-0044-1780495
Original Article

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Zhonghua Luo
1   The State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan, People's Republic of China
2   Process Research & Development, HEC API Yichang Co., Ltd., Yichang, People's Republic of China
,
Guodong Sun
1   The State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan, People's Republic of China
,
Guowei Wang
2   Process Research & Development, HEC API Yichang Co., Ltd., Yichang, People's Republic of China
,
Xin Zhang
2   Process Research & Development, HEC API Yichang Co., Ltd., Yichang, People's Republic of China
,
Yang Zhang
2   Process Research & Development, HEC API Yichang Co., Ltd., Yichang, People's Republic of China
,
Ji Zhang
1   The State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan, People's Republic of China
› Author Affiliations Funding The work was supported by Enterprise Key Laboratory of Anti-viral Drug Development for Guangdong Province (Grant No. 2020B1212070003).
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Abstract

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.

Keywords

rimegepant - enantioselective synthesis - Ru-catalyzed - asymmetric transfer hydrogenation reaction


Publication History

Received: 10 December 2023

Accepted: 30 January 2024

Article published online:
11 March 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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