拓扑异构酶 I 抑制剂抗体-药物共轭有效载荷的路线设计与规模扩展

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-06-11 DOI:10.1021/acs.oprd.4c00175

William R. F. Goundry*, Andrew M. Poulton, Matthew Welham, Kuangchu Dai, Xiaohong Zhu, Haijun Tao, Canlin Tang, Fanny Magne and Bertrand Cottineau,

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引用次数: 0

摘要

阿斯利康（AstraZeneca）公司目前正在开发一种治疗癌症的抗体药物共轭物，其有效载荷为拓扑异构酶 I 抑制剂。该分子的药物部分是天然产品喜树碱的类似物。我们介绍了为满足临床前时限要求而进行的初步放大合成，包括缩短五个步骤的路线设计工作。我们还详细介绍了遇到的几个问题，其中最突出的是最后一步的低产。我们开发了第二代路线来解决这些问题，将总产率从 3.4% 提高到 7.8%，同时将工艺质量强度降低了 66%。我们讨论了整个过程中形成的杂质，并强调了我们去除杂质的工作步骤和纯化策略。

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Route Design and Scale-Up of a Topoisomerase I Inhibitor Antibody–Drug Conjugate Payload

AstraZeneca is currently developing an antibody–drug conjugate for the treatment of cancer with a topoisomerase I inhibitor payload. The drug portion of the molecule is an analogue of the natural product camptothecin. We describe the initial scale-up of the synthesis to meet preclinical timelines, including route design work to shorten the route by five steps. We also detail several problems we encountered, most notably a low-yield final step. We developed a second-generation route to address these issues, increasing the overall yield from 3.4% to 7.8% while reducing the process mass intensity by 66%. We discuss the impurities formed throughout the process and highlight our workup and purification strategy to remove them.

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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.