Early Development of Ibuzatrelvir: Navigating Polymorph and Crystallization Challenges in a Protecting Group-Free Direct Amidation and Amidation-Dehydration Sequence

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-09-11 DOI:10.1021/acs.oprd.6c00128

María González-Esguevillas, Aaron F. Baldwin, Pablo J. Cabrera, Yanfei Guan, Chintelle James, Nahian Khan, Samir A. Kulkarni, Johnny W. Lee, Melissa Lee, Emily Lennert, Yiyang Liu, Jeffrey M. Massicott, Asaad Nematalla, Robert J. Pearson, David W. Place, Giselle P. Reyes, Hud Risley, Philipp C. Roosen, Michael Stanley, Jeanene E. Tickner, Aining Wang, Rebecca B. Watson, Gerald A. Weisenburger, Christophe Allais

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引用次数: 0

Abstract

Ibuzatrelvir is an orally bioavailable, next-generation clinical candidate developed for the treatment of COVID-19 infections. It was identified during the pandemic, prior to the approval of PAXLOVID, and displays a more favorable pharmacokinetic profile than nirmatrelvir. Consequently, the initial development of ibuzatrelvir proceeded under highly accelerated timelines. This report details the optimization of the end-stage synthesis sequence and its advancement throughout the initial clinical production campaigns. The study highlights an efficient protecting group-free amidation of tert-leucine and describes a complex isolation process following a telescoped amidation-dehydration cascade leading to ibuzatrelvir with a 30% increase in yield. The finalized synthetic route was successfully scaled up, enabling the manufacture of several hundred kilograms to support clinical research initiatives.

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布扎特里韦的早期开发：在无基直接酰胺化和酰胺化脱水序列中导航多晶型和结晶挑战

Ibuzatrelvir是一种口服生物可利用的新一代临床候选药物，用于治疗COVID-19感染。它是在大流行期间被发现的，在PAXLOVID获批之前，并显示出比nirmatrelvir更有利的药代动力学特征。因此，ibuzatrelvir的最初开发是在高度加速的时间内进行的。本报告详细介绍了终阶段合成序列的优化及其在初始临床生产活动中的进展。该研究强调了对叔亮氨酸的有效保护无基酰胺化，并描述了一个复杂的分离过程，该过程是在伸缩酰胺化-脱水级联之后，导致布扎特里韦的产量增加30%。最终的合成路线成功地扩大了规模，使数百公斤的生产能够支持临床研究计划。

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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.