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用于高效前药合成的比布伦特斯韦去对称化

Desymmetrization of pibrentasvir for efficient prodrug synthesis.

作者信息

Voight Eric A, Greszler Stephen N, Hartung John, Ji Jianguo, Klix Russell C, Randolph John T, Shelat Bhadra H, Waters Jan E, DeGoey David A

机构信息

Drug Discovery Science & Technology, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA

Process Research and Development, AbbVie, Inc. 1 North Waukegan Road North Chicago Illinois 60064-1802 USA.

出版信息

Chem Sci. 2021 Jun 29;12(29):10076-10082. doi: 10.1039/d1sc02396a. eCollection 2021 Jul 28.

DOI:10.1039/d1sc02396a
PMID:34349971
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8317637/
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 a one-pot di-Boc/mono-de-Boc selective -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 -symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

摘要

本文描述了一种新颖且实用的去对称化策略，用于制备一类新型的比米普明韦前药。通过结晶诱导选择性实现的一锅法双叔丁氧羰基/单脱叔丁氧羰基选择性叔丁氧羰基保护和甲醛加合物形成序列，对比米普明韦（PIB）的同位苯并咪唑进行了区分。第一步代表了统计放大的霍劳原理在对称多杂环区域选择性官能团化中的唯一已知应用。所得的通用中间体用于高产率制备几种比米普明韦前药候选物。

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