Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

• DOI: 10.1021/acs.oprd.0c00241
• Publication Date: 2020-10-16T21:01:29Z
• Authors: Feng Peng; Guy R. Humphrey; Kevin M. Maloney; Dan Lehnherr; Mark Weisel; Francois Lévesque; John R. Naber; Andrew P. J. Brun...; Patrick Larpent; Si-Wei Zhang; Alfred Y. Lee; Rebecca A. Arvary; Claire H. Lee; Daniel Bishara; Karthik Narsimhan; Eric Sirota; Michael Whittington
• Keywords: 01 natural sciences; 0104 chemical sciences; 12. Responsible consumption

Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives initial four-step supply route. These new include a coumarin fragmentation approach in flow, rhenium-catalyzed isopropylation mequinol, and bromination/methoxylation 2-isopropylphenol. After exploring several approaches, robust two-step process for preparation 3 from commodity starting material 2-isopropylphenol was developed. The optimized route employs highly regioselective bromination. isolating bromophenol DABCO cocrystal, copper-catalyzed methoxylation delivers high yield. This is successfully demonstrated at plant scale with low mass intensity cost.