Desymmetrization of pibrentasvir for efficient prodrug synthesis.

Autor: Voight EA; Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com., Greszler SN; Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com., Hartung J; Process Research and Development, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA., Ji J; Process Research and Development, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA., Klix RC; Process Research and Development, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA., Randolph JT; Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com., Shelat BH; Process Research and Development, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA., Waters JE; Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com., DeGoey DA; Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA eric.a.voight@abbvie.com.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2021 Jun 29; Vol. 12 (29), pp. 10076-10082. Date of Electronic Publication: 2021 Jun 29 (Print Publication: 2021).
DOI: 10.1039/d1sc02396a
Abstrakt: 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.
Competing Interests: 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.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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