Yingju Xu
Merck & Co., Inc, USA
Title: Process development towards a green manufacturing route for letermovir exploiting novel asymmetric reactions
Biography
Biography: Yingju Xu
Abstract
Merck aims to develop the best chemistry at time of regulatory filing, with the ultimate goal of the zero waste API manufacturing process. Achieving this ambitious goal is enabled by an innovative, green by design, development strategy, to progress from initial route design through to a fully optimized sustainable commercial manufacturing process. Letermovir is an antiviral drug currently in late-stage development for the treatment of cytomegalovirus infections. This presentation will describe key aspects of the synthesis development that led to an efficient, robust and green manufacturing process. A chemically stable and fully recyclable organo catalyst has been discovered to promote this novel asymmetric aza-Michael cyclization. The remainder of the synthesis has been fully optimized to reduce catalyst loading, minimize the number and amount of solvents, employ telescoped processing where possible, and to maximize atom-economy. Implementation, demonstration and validation of the new process were successfully completed in 2016. Compared to the benchmark process used for the generation of the initial phase III clinical supplies, this revolutionary new synthesis reduces PMI by 73%, increases the overall yield by more than 60%, and reduces raw material costs by 93%. Life-cycle assessment reveals that the new process reduces carbon footprint and water usage by 89% and 90%, respectively.
