Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling
Duan, S., Place, D., Perfect, H.H., Ide, N.D., Maloney, M., Sutherland, K., Price Wiglesworth, K.E.; Wang, K., Olivier, M., Kong, F., Leeman, K., Blunt, J., Draper, J., McAuliffe, M., O’Sullivan, M., Lynch, D. , Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling", Org. Process Res. Dev. 2016, 20, 1191−1202.
Palbococlib received accelerated approval from the FDA for the treatment of advanced breast cancer in postmenopausal women. In this study, the authors describe their process development program to further develop and optimize the process for the commercial manufacture of Palbociclib to improve scalability, efficiency and quality of the enabling process. There was a need to reduce the usage factor of an advanced intermediate, therefore mechanistic studies were necessary to understand why the second equivalent of the intermediate was necessary.
ReactIR monitored reaction progress and provided some insight into the reaction mechanism. Data confirmed the instantaneous deprotonation of the advanced intermediate upon addition of LiHMDS. Subsequent addition of pyrimidine resulted in the formation of a small amount of desired product and a larger amount of an intermediate that slowly converted to desired product.
EasySampler enabled the researchers to collect multiple reaction samples, and automatically quench at the time of sampling. The high-quality samples were used for structure elucidation to understand the reaction mechanism.