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 inOrganic 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
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LanguageEnglish
Published WASHINGTON American Chemical Society 20.11.2020
Amer Chemical Soc
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Abstract 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.
AbstractList 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.
Author Maloney, Kevin M
Lehnherr, Dan
Naber, John R
Weisel, Mark
Bishara, Daniel
Zhang, Si-Wei
Brunskill, Andrew P. J
Peng, Feng
Larpent, Patrick
Narsimhan, Karthik
Humphrey, Guy R
Lévesque, Francois
Lee, Alfred Y
Arvary, Rebecca A
Lee, Claire H
Whittington, Michael
Sirota, Eric
AuthorAffiliation Small Molecule Process Research and Development
AuthorAffiliation_xml – name: Small Molecule Process Research and Development
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Issue 11
Keywords copper catalysis
Gefapixant
alkylation
phenol derivatization
methoxylation
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Snippet Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to...
Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK 7264), are described, which provide better alternatives to...
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SubjectTerms Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
Title Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis
URI http://dx.doi.org/10.1021/acs.oprd.0c00241
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