An Improved Process for the Preparation of a Covalent Kinase Inhibitor through a C-N Bond-Forming SNAr Reaction

An improved API step for the formation of an aminopyrimidine-based kinase inhibitor is described. The presence of a reactive acrylamide functional group presented a considerable challenge during scale-up, resulting in side-product formation and low in-process yields for the final SNAr reaction. Impurity identification guided process development efforts, enabling rapid scale-up of a safe and phase-appropriate process to deliver the API to support toxicology studies.