Abstract

Fast Mixing, Ketimine Additions, and the Application of Flow Chemistry to Verubecestat

John Naber, Director, Flow Chemistry and Lab Automation, Process Research & Development, Merck & Co., Inc

Alzheimer’s disease (AD) is an epidemic of ever increasing concern that affects over 24 million patients worldwide. Research suggests that the formation of ß-amyloid plaque is central to the onset of AD and that inhibition of the amyloid pathway could lead to a disease modifying therapy. One of the first steps in the formation of plaque involves the enzyme ß-secretase (BACE-1). Clinical programs for BACE inhibitors are progressing at a number of companies including MSD where Verubecestat (MK-8931) is in Phase III. During the commercial route development of MK-8931, it was determined that the nucleophilic addition to an imine could be improved by performing the reaction in flow. The enhanced mixing lead to an increase in the yield of the reaction while excellent heat transfer properties of a flow reactor lead to the elimination of the need for cryogenic conditions. The development of this process from an initial lab scale hit through a successful demonstration in the prep lab at multi kilogram scale to a pilot plant campaign on hundreds of kilograms is presented.