Total Synthesis of Fexuprazan

초록

A novel and practical synthetic route to fexuprazan was developed. The synthesis relied on efficient access to an N-sulfonyl alpha-amino ester bearing the N1, C2, and C3 substituents of fexuprazan, accessible via two complementary approaches: (1) a Strecker reaction between 2,4-difluorobenzaldehyde and 3-fluorobenzenesulfonamide followed by methanolysis of the resulting nitrile, or (2) reductive amination of methyl 2-(2,4-difluorophenyl)-2-oxoacetate with the sulfonamide. Subsequent Michael reaction of the alpha-amino ester with acetylenedicarboxylate followed by an intramolecular nonclassical Wittig reaction involving the carbonyl in the ester provided the N-sulfonyl dihydropyrrole-4,5-dicarboxylate, which was oxidized to the corresponding pyrrole-4,5-dicarboxylate. Selective C5-decarboxylation and conversion of the C4-carboxylic acid moiety into an N-methylaminomethyl group delivered fexuprazan. Notably, most intermediates, as well as the final product, were isolated by simple recrystallization, and the target compound was obtained on a gram scale, underscoring the practicality of this route.

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