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Desymmetrization of Pibrentasvir for Efficient Prodrug Synthesis

28 April 2021, Version 1
Working Paper
This content is a preprint and has not undergone peer review at the time of posting.

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 C2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Keywords

desymmetrization strategy
prodrugs
pharmaceutical
drug synthesis
Horeau principle
crystallization-induced diastereomer transformation

Supplementary materials

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Description
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Title
PIB Prodrug SI PDF
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Version History

Apr 28, 2021 Version 1

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv.14456259.v1
D O I: 10.26434/chemrxiv.14456259.v1 [opens in a new tab]

Author’s competing interest statement

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.

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