Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.