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

Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation o...

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Published in:Organic process research & development 2020-11, Vol.24 (11), p.2453-2461
Main Authors: Peng, Feng, Humphrey, Guy R, Maloney, Kevin M, Lehnherr, Dan, Weisel, Mark, Lévesque, Francois, Naber, John R, Brunskill, Andrew P. J, Larpent, Patrick, Zhang, Si-Wei, Lee, Alfred Y, Arvary, Rebecca A, Lee, Claire H, Bishara, Daniel, Narsimhan, Karthik, Sirota, Eric, Whittington, Michael
Format: Article
Language:English
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Summary:Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.0c00241