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

• Published in: Organic process research & development Vol. 24; no. 11; pp. 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: 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; copper catalysis; Gefapixant; alkylation; phenol derivatization; methoxylation
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00241

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.