Novel and Efficient Synthesis of Potassium-Competitive Acid Blocker Fexuprazan
Abstract
Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1 H -pyrrole-3-carboxylate ( 7 ), a key intermediate associated with toxicity concerns, environmental pollution, and low yields. This article aims to develop an innovative synthetic strategy to overcome these limitations. Our approach utilizes 3-aminopropionitrile and methyl 2-(2,4-difluorophenyl)-2-oxoacetate ( 20 ) as key precursors for a streamlined one-pot synthesis of the cyano-containing pyrrole 23, achieving a 90.0% yield. A significant advancement is the subsequent implementation of hydrogen gas as an ecofriendly reductant for direct cyano-to-aldehyde conversion. Starting from cost-effective 1,3-difluorobenzene ( 18 ), the optimized six-step route delivers fexuprazan hydrochloride ( 1 ) with an overall yield of 42.6% at kilogram scale. This improved protocol demonstrates significant advantages in process economics, operational simplicity, and environmental sustainability, establishing a robust platform for industrial-scale manufacture.
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