The long-term manufacturing route to the Merck HCV NS5b viral RNA polymerase inhibitor Uprifosbuvir is described. The synthesis of the nucleoside core features a novel dynamic acylation and selective oxidation of readily available uridine to afford regioselectively 3’,5’-bis-pivaloylated 2’-keto uridine, which then undergoes methyl addition cleanly to give the corresponding 3o alcohol in high yield. Conversion to 2 can be achieved by either 1) catalyzed BSA-mediated anhydride formation and ring opening to the chloride, or 2) olefination of the ketone followed by hydrochlorination of the resulting olefin in high yield. The new endgame chemistry involves a novel, unprecedented dynamic asymmetric phosphorylation of nucleoside 2 with a P-diastereomeric mixture of chloro-phosphate 1 in the presence a chiral imidazole to furnish Uprifosbuvir in high yield and diastereoselectivity.

Uprifosbuvir: Innovating on the critical path

2019 Fall National Meeting

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