Manufacturing Process Development for Belzutifan, Part 6: Ensuring Scalability for a Deoxyfluorination Reaction
Michael T. Pirnot, Kevin Stone, Timothy J. Wright, David J. Lamberto, Jochen Schoell, Yu‐hong Lam, Kerstin Zawatzky, Xiao Wang, Stephen M. Dalby, Adam J. Fine, Jonathan P. McMullen
Abstract
The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities. These aspects were addressed through a series of mechanistic, range-finding, and mixing studies that enabled a robust process to be established. In particular, mixing studies led to the discovery of a second phase of perfluoro-1-butanesulfonyl fluoride in the reaction at cryogenic temperature, requiring the liquid–liquid dispersion to be controlled sufficiently to minimize the formation of side products. The changes implemented as a result of these investigations culminated in a process executed successfully on the pilot and commercial scales.