Evolution of the Synthesis Route for CC-99677: From Discovery toward Commercialization

CC-99677 is an irreversible inhibitor of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) that sustainably reduces production of proinflammatory cytokines in vitro. The design and development of a concise synthetic route enabled production of multikilogram quantities for early-stage clinical trials. Continued synthesis at increasing scale required an improved route to fragment 21 to bypass the energetic chemical reactions and attendant process safety challenges posed within the enabling route. Subsequently, protecting groups and counterions were optimized and an improved API recrystallization was developed for the intended commercial route. Over the course of development, the step count was reduced from 19 to 7 (a 63% reduction), and overall yield increased from 1.3 to 37% (a nearly 30-fold improvement) while improving robustness, safety characteristics, and control overcritical quality attributes required of a commercial process.