13522-98-0Relevant academic research and scientific papers
Development of a green and sustainable manufacturing process for gefapixant citrate (MK-7264) Part 2: Development of a robust process for phenol synthesis
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
, p. 2453 - 2461 (2020)
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.
