Stereoselective Synthesis of ABBV-992 Enabled by a Flow Diazotization and a Partial Reduction of a Pyridone

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-07-12 DOI:10.1021/acs.oprd.4c00077

Patrick B. Brady, Kaid C. Harper, Bryan K. Sorensen, Stephen N. Greszler, Chunqiu Lai, Alan S. Florjancic, Gang Zhao, Bhadra H. Shelat, Gregory E. Storer, Rodger F. Henry, T. Matthew Hansen

引用次数: 0

Abstract

Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor signaling and has been clinically validated as a target by small molecule inhibition for the treatment of a variety of cancers. ABBV-992 (1) was identified as a novel, potent, selective BTK inhibitor and advanced to Phase I clinical trials. An enantioselective synthesis of 1 was developed and scaled to provide 63 g for preclinical characterization. The route features a diazotization enabled by flow chemistry, a novel, selective partial reduction of a pyridone, a stereoselective Ellman imine reduction, and an improved acrylamide formation using 3-chloropropionyl chloride in a masked acrylate strategy.

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通过流式重氮化和吡啶酮的部分还原实现 ABBV-992 的立体选择性合成

布鲁顿酪氨酸激酶（BTK）参与 B 细胞受体信号传导，已被临床验证为治疗多种癌症的小分子抑制剂靶点。ABBV-992 (1) 是一种新型、强效、选择性 BTK 抑制剂，已进入 I 期临床试验阶段。我们开发了 1 的对映体选择性合成方法，并将其放大到 63 克，用于临床前表征。该路线的特点是通过流动化学进行重氮化，对吡啶酮进行新颖、选择性的部分还原，立体选择性的埃尔曼亚胺还原，以及在掩蔽丙烯酸酯策略中使用 3-氯丙酰氯改进丙烯酰胺的形成。

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.