Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview

• Published in: Organic process research & development Vol. 24; no. 11; pp. 2445 - 2452
• Main Authors: Ren, Hong, Maloney, Kevin M, Basu, Kallol, Di Maso, Michael J, Humphrey, Guy R, Peng, Feng, Desmond, Richard, Otte, Douglas A. L, Alwedi, Embarek, Liu, Wenjun, Zhang, Si-Wei, Song, Siqing, Arvary, Rebecca A, Zompa, Michael A, Lehnherr, Dan, Martin, Gary E, Chang, Hsieh Yao D, Mohan, Anne E, Guzman, Francisco J, Jellett, Lisa, Lee, Alfred Y, Spencer, Glenn, Fisher, Elizabeth S, Naber, John R, Gao, Hong, Lohani, Sachin, Ruck, Rebecca T, Campeau, Louis-Charles
• Format: Journal Article
• Language: English
• Published: American Chemical Society 20.11.2020
• Subjects: commercial process development; P2X3 antagonist; green chemistry; flow chemistry
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00248

A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.