Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

• Published in: Organic process research & development 2019-06, Vol.23 (6), p.1204-1212
• Main Authors: Sun, Guodong, Jian, Weilin, Luo, Zhonghua, Sun, Tengfei, Li, Chao, Zhang, Jiancun, Wang, Zhongqing
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.9b00138

An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient ruthenium-catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr and 99.7% ee on a 100 g scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives a desirable total yield but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on a multigram scale to afford 1 with >99.9% de and >99.9% ee in 56.8% overall yield in nine steps.