From Milligram to Kilogram Manufacture of AZD4573: Making It Possible by Application of Enzyme-, Iridium-, and Palladium-Catalyzed Key Transformations

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2021-07-21 DOI:10.1021/acs.oprd.1c00058

Staffan Karlsson*, Helen Benson, Calum Cook, Gordon Currie, Jerome Dubiez, Hans Emtenäs, Janet Hawkins, Rebecca Meadows, Peter D. Smith, Jeffrey Varnes

引用次数: 3

Abstract

With the first generation medicinal chemistry synthesis as a starting point, we describe herein process development of AZD4573, an oncology drug candidate. In addition to improved yields and removal of chromatographic steps, we have addressed other factors such as availability of starting materials as well as safety of the chemistry involved. With several steps involving volatile, reactive, and non-UV active materials, reaction optimization was facilitated by implementing off-line ¹H NMR analysis of crude mixtures. Key transformations targeted for process development included a Wolff–Kishner reduction, an iridium-catalyzed borylation, and enzymatic resolution of a racemic amino-ester.

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从毫克到千克AZD4573的生产:利用酶、铱和钯催化的关键转化使之成为可能

本文以第一代药物化学合成为起点，介绍了肿瘤候选药物AZD4573的工艺开发。除了提高收率和去除色谱步骤外，我们还解决了其他因素，如起始材料的可用性以及所涉及化学的安全性。涉及挥发性、活性和非紫外线活性物质的几个步骤，通过对原油混合物进行脱机1H NMR分析，促进了反应优化。工艺开发的关键转化包括Wolff-Kishner还原，铱催化的硼化和外消旋氨基酯的酶解。

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.