Development of Two Synthetic Routes to a Benzofuran Intermediate for Fruquintinib

Two practical routes were developed for the synthesis of a key benzofuran intermediate used to prepare fruquintinib, both of which commence from readily available monoprotected resorcinol derivatives. The first route involves constructing a 2-methylbenzofuran-3-carboxylic acid core from 2-bromo-5-methoxyphenol and a 2-butynoic acid derivative using Michael addition chemistry, followed by intramolecular Heck cyclization. Final deprotection afforded the benzofuran intermediate in 45% overall yield over three steps (or in 58% yield over five steps when starting from ethyl 2-butynoate ester) using the same bromide employed in the current industrial route. In contrast, the second route began with significantly less expensive 2-hydroxy-4-methoxybenzaldehyde. Condensation of the aldehyde with acrylonitrile afforded 3-cyano-2H-chromene, which underwent a base-catalyzed rearrangement to give a benzofuran-3-carbonitrile. Subsequent conversion of the nitrile into the corresponding N-methylamide, followed by demethylation, provided the target intermediate in an improved overall yield of 60% over five steps from more cost-effective starting materials.