Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core

• DOI: 10.1021/acs.oprd.0c00246
• Publication Date: 2020-10-20T11:44:10Z
• Authors: Kallol Basu; Dan Lehnherr; Gary E. Martin; Richard A. Desmond; Yu-hong Lam; Feng Peng; John Y. L. Chung; Rebecca A. Arvary; Michael A. Zompa; Si-Wei Zhang; Jinchu Liu; Zachary E. X. Dance; Patrick Larpent; Ryan D. Cohen; Francisco J. Guzman; Nicholas J. Rogus; Michael J. Di Maso; Hong Ren; Kevin M. Maloney
• Keywords: Formylation; Guanidine; Process development; Atom economy

The development of a safe, robust, and efficient manufacturing route for the synthesis diaminopyrimidine 1, key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding cyclization step in presence guanidine was established by performing isotopic labeling experiments identification impurities. Guided understanding, further attempts modify reaction employing additives reduce triazine (9) formation loading will also be presented. This newly developed method delivered compound 1 88–94% yield on commercial scale addressed shortcomings early synthetic including high PMI, low atom economy, long cycle-time, multiple purifications achieve desired quality.