Some Issues and Their Solutions in the Process Development of Ethyl 2-(4-Aminophenoxy)thiazole-5-carboxylate: A Key Intermediate of P2X3 Antagonist

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-03-11 DOI:10.1021/acs.oprd.5c0001510.1021/acs.oprd.5c00015

Masahiro Hosoya*, Toshikatsu Maki and Takayuki Tsuritani,

引用次数: 0

Abstract

Ethyl 2-(4-aminophenoxy)thiazole-5-carboxylate is a key intermediate of several P2X₃ antagonists required for clinical trials. The synthesis at the early R&D stage delivered this thiazole derivative via a nucleophilic aromatic substitution reaction in highly variable yields, from 7 to 85%. We describe the process development of the initial route of synthesis carefully considering the reaction conditions, process robustness and safety, operational improvement, and the impact on downstream steps. The optimized process was successfully replicated on a multikg scale in a pilot plant, allowing for the supply of the key intermediate in 90% isolated yield with high purity (>99 area%).

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P2X3拮抗剂关键中间体- 2-（4-氨基酚氧基）噻唑-5-羧酸乙酯工艺开发中的若干问题及对策

2-（4-氨基苯氧基）噻唑-5-羧酸乙酯是临床试验所需的几种P2X3拮抗剂的关键中间体。在早期的研发阶段，通过亲核芳香族取代反应合成了这种噻唑衍生物，收率从7%到85%不等。我们仔细考虑了反应条件、工艺稳健性和安全性、操作改进以及对下游步骤的影响，描述了合成初始路线的工艺发展。优化后的工艺在一个中试工厂成功地以多公斤的规模复制，允许以90%的分离率提供高纯度的关键中间体（>； 99%的面积%）。

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.