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 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.