Development of Commercial Manufacturing Processes for Acalabrutinib

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2022-12-06 DOI:10.1021/acs.oprd.2c00304

Paul A. Bethel, Lai Chun Chan, Katie Cooper, Gareth J. Ensor, Jerry Evarts, Rustam Garrey, J. Gair Ford, Daniel Harding, Shaun Hughes, Lucy Jackson, Michael Golden*, Kirsty Millard, Andrew Phillips, Andrew Robbins, David Short, Alex Telford and David T. E. Whittaker,

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Abstract

The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved in a short timeframe. Issues are discussed, such as the uncontrolled epimerization of a chiral center and the control of the acalabrutinib 1 crystallization step, which was prone to oiling. Specifically, work to understand the complex polymorph landscape of a key intermediate (to facilitate resolution of a filtration issue) is described.

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阿卡拉布替尼商业化生产工艺的发展

布鲁顿酪氨酸激酶抑制剂acalabrutinib 1生产工艺的发展，提高了产量、周期时间和可操作性，实现了强大的商业生产工艺。一个高度加速的临床项目意味着许多关键的过程挑战必须在短时间内解决。讨论了不受控制的手性中心外聚化和阿卡拉布替尼1结晶步骤的控制等问题。具体来说，描述了了解关键中间体的复杂多晶型景观的工作(以促进过滤问题的解决)。

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.

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