Sustainable Manufacturing of trans-4-Trifluoromethyl-l-proline via Stereochemical Editing: A Combined In Silico and Experimental Approach

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-07-31 DOI:10.1021/acs.oprd.4c00202

Russell F. Algera, Christophe Allais, Pablo J. Cabrera, María González-Esguevillas, Yanfei Guan, Chintelle James, Johnny W. Lee, Jeffrey M. Massicott, Emma L. McInturff, Robert J. Pearson, Hud Risley, Rebecca B. Watson

引用次数: 0

Abstract

Ibuzatrelvir (1) is a second-generation, orally bioavailable, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor clinical candidate. Herein, we report the implementation of an in silico and high-throughput experimentation strategy leading to the identification of a rapid, efficient, and sustainable route to trans-4-trifluoromethyl-l-proline (2), a key building block for ibuzatrelvir. This novel synthetic route features a key stereochemical editing step to enable an efficient and scalable protocol that operates under mild conditions with high stereoselectivity, providing effective access to more than 235 kg of trans-4-trifluoromethyl-l-proline 2 in a five-step synthetic sequence from readily available starting materials.

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通过立体化学编辑实现反式-4-三氟甲基-l-脯氨酸的可持续制造：硅学与实验相结合的方法

Ibuzatrelvir（1）是一种可口服的第二代严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）主要蛋白酶抑制剂临床候选药物。在本文中，我们报告了通过实施硅学和高通量实验策略，最终确定了快速、高效和可持续的反式-4-三氟甲基-l-脯氨酸（2）合成路线，而反式-4-三氟甲基-l-脯氨酸是 ibuzatrelvir 的关键构件。这条新合成路线的特点是采用了一个关键的立体化学编辑步骤，实现了一个高效、可扩展的方案，该方案在温和的条件下操作，具有很高的立体选择性，通过五步合成序列，从现成的起始材料中有效地获得了超过 235 千克的反式-4-三氟甲基-l-脯氨酸 2。

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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.