Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability

Abstract

A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK 4/6. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Finally, efficient isolation of coupled product 3 was achieved through careful polymorph control via seeding and an optimized cooling protocol that avoids nucleation of a kinetically favored, slow-filtering polymorph.