A scalable, economical and practical synthesis of 4-(difluoromethyl)pyridin-2-amine, a key intermediate for lipid kinase inhibitors

A new scalable, rapid, high-yield and safe synthesis of 4-(difluoromethyl)pyridin-2-amine provides a key intermediate for the preparation of numerous protein kinase inhibitors and clinical candidates targeting phosphoinositide 3-kinase (PI3K) and the mechanistic target of rapamycin (mTOR) kinase. Starting from 2,2-difluoroacetic anhydride, an efficient five-step and two-pot procedure to prepare 4-(difluoromethyl)pyridin-2-amine (1) has been developed. Noteworthy, this procedure avoids using amination in sealed vessels. Each step of the synthetic route has been optimized, and key intermediates have been isolated and characterized prior to the final two-pot procedure, which has been successfully applied for large scale production.