Merging Biocatalysis, Flow, and Surfactant Chemistry: Innovative Synthesis of an FXI (Factor XI) Inhibitor

• Published in: Organic process research & development Vol. 24; no. 11; pp. 2780 - 2788
• Main Authors: Wu, Bin, Zhang, Sisi, Hong, Tao, Zhou, Yizong, Wang, Hui, Shi, Min, Yang, Hongwei, Tian, Xiangguang, Guo, Jing, Bian, Jianwei, Roache, James, Delgado, Pete, Mo, Ruowei, Fridrich, Cary, Gao, Feng, Wang, Jianhua
• Format: Journal Article
• Language: English
• Published: American Chemical Society 20-11-2020
• Subjects: scale-up; continuous manufacturing; FXI inhibitor; biocatalysis; surfactant
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00412

The scalable synthesis of an FXI (Factor XI) inhibitor employing multiple emerging technologies is described. The reduction of ketone to chiral alcohol was established through a biocatalysis approach. The Suzuki–Miyaura cross-coupling reaction was facilitated by surfactant chemistry. A harsh hydrolysis of the nitrile was performed in a continuous manufacturing mode. Extensive reaction optimization and process development led to a well-controlled protocol for scale-up. The alternative approach described here addressed issues from the discovery route and was utilized to deliver the desired target for preclinical studies.