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Published on: November 30, 2022
Desymmetrization of pibrentasvir for efficient prodrug synthesis
Eric A Voight1, Stephen N Greszler1, John Hartung2
1Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com.
Abstract:
A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C 2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.
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