Novel and Efficient Synthesis of Potassium-Competitive Acid Blocker Fexuprazan

Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). The conventional synthesis route involves preparing methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-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.