Practical and Scalable Method for Manufacturing AZD4604, A Potent and Selective JAK1 Inhibitor

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2023-06-15 DOI:10.1021/acs.oprd.3c00077

Subhash Pithani*, Carl-Johan Aurell, Marika Lindhagen, Michael Nunn, Kristina Berggren and Hans Emtenäs,

引用次数: 1

Abstract

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/Buchwald–Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.

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高效选择性JAK1抑制剂AZD4604的制备方法

描述了用于吸入治疗哮喘的强效和选择性JAK1抑制剂的可扩展工艺的开发。最初的毫克级合成方案不适合大规模合成，因此对反应条件进行了系统评价，确定了Suzuki/ Buchwald-Hartwig偶联、脱保护tosyyl基团、化学选择性硝基还原的最佳反应条件，并开发了敏感氨基酸酰胺偶联的温和条件。这项工作还强调了与合成难溶化合物、浆料到浆料金属催化偶联方案相关的关键问题。优化后的手性氨基酸酰胺偶联条件下，得到了总收率高、高效液相色谱纯度高的活性药物成分(API)。

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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