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

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.