Development of New Catalytic Asymmetric Routes toward a Cost-Driving Building Block of Nirmatrelvir

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-05-28 DOI:10.1021/acs.oprd.4c00109

Robert Szpera*, Shanjun Huang, Harriet A. M. Fenton, William Waddington, Adam E. S. Gymer, Ian B. Moses, Julia Buck, Heather Ingram, Steven J. Fussell*, Robert Walton, Charles S. Shanahan*, Sarah L. Aleshire, Juliana M. S. Robey, Hanuman P. Kalmode, Michel C. Nuckols, Nageswara R. Kalikinidi, Venumadhav Janganati, Sipak Joyasawal, Chanaka M. Amarasekarage, Chris H. Senanayake and B. Frank Gupton,

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引用次数: 0

Abstract

Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease and is the active ingredient in Paxlovid. Nirmatrelvir presents a significant synthetic challenge, in no small part due to a cost-driving lactam-containing fragment with two stereogenic centers. Our goal was to help decrease the cost of nirmatrelvir by developing a scalable low-cost synthesis of this fragment, avoiding the use of cryogenic conditions reported in the initial route. Herein, we disclose three catalytic asymmetric routes toward this fragment, via (i) chiral Lewis acid (copper) catalysis, (ii) chiral Bro̷nsted base organocatalysis, and (iii) chiral bifunctional hydrogen-bond-donor organocatalysis.

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开发新的催化不对称路线，以获得成本驱动型 Nirmatrelvir 构建模块

Nirmatrelvir 是 SARS-CoV-2 主要蛋白酶的抑制剂，也是 Paxlovid 的活性成分。Nirmatrelvir 是一项重大的合成挑战，这在很大程度上是由于含有两个立体中心的内酰胺片段导致成本增加。我们的目标是通过开发一种可扩展的低成本合成方法来帮助降低奈马曲韦的成本，同时避免使用初始路线中报告的低温条件。在此，我们公开了通过 (i) 手性路易斯酸（铜）催化、(ii) 手性 Bro̷nsted 碱有机催化和 (iii) 手性双官能团氢键-捐赠者有机催化合成该片段的三种催化不对称路线。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.