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Desymmetrization of Pibrentasvir for Efficient Prodrug Synthesis

submitted on 22.04.2021, 12:48 and posted on 28.04.2021, 14:42 by Eric Voight, Stephen Greszler, John Hartung, Jianguo Ji, Russell C. Klix, John T. Randolph, Bhadra Shelat, Jan E. Waters, David A. DeGoey
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 C2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.


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Declaration of Conflict of Interest

The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. / All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.