Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 4: Formylation–Cyclization as a Flow–Batch Process Leads to Significant Improvements in Process Mass Intensity (PMI) and CO Generated versus the Batch–Batch Process

• Published in: Organic process research & development Vol. 24; no. 11; pp. 2478 - 2490
• Main Authors: Otte, Douglas A. L, Basu, Kallol, Jellett, Lisa, Whittington, Michael, Spencer, Glenn, Burris, Matthew, Corcoran, Emily B, Stone, Kevin, Nappi, Jarod, Arvary, Rebecca A, Donoghue, David, Ren, Hong, Maloney, Kevin M, Naber, John R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.11.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; formylation; green chemistry; PMI; process mass intensity; flow chemistry; CHEMISTRY
• DOI: 10.1021/acs.oprd.0c00252
• ISSN: 1083-6160

Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine (1) (AF-072) required a significant excess of ethyl formate (EF), potassium tert-butoxide (KOt-Bu), and guanidine•HCl (G•HCl) when both steps were run as batch processes. It was imperative to develop an alternative process that required less of each reagent and generated less carbon monoxide byproducts, as the annual production of the final active pharmaceutical ingredient (API) is expected to be over 50 MT. In addition, the second generation process was misaligned with our company’s strategy of having the best science in place at the first regulatory filing. The final flow–batch process described herein, which features a flow-based formylation combined with a batch cyclization, has been performed on a 500 kg scale and now requires 35% less EF (leading to a 70% reduction in waste carbon monoxide), 38% less KOt-Bu, and 50% less G•HCl. These improvements, along with a twofold increase in concentration, have resulted in a 54% reduction in the step process mass intensity (step-PMI) from the second generation two-step batch–batch process (PMI of 17.16) to the flow–batch process (PMI of 7.86), without sacrificing reaction performance.