Enantioselective and Step-Economic Synthesis of the Chiral Amine Fragment in the Tyrosine Kinase Inhibitor Repotrectinib by Direct Asymmetric Reductive Amination under Batch and Flow

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2023-07-06 DOI:10.1021/acs.oprd.3c00152

Lei Xu, Gang Wang, Nianxin Rong, Yang Gu, Le’an Hu, Hengzhi You* and Qin Yin*,

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Abstract

A one-step and highly enantioselective synthesis of (R)-2-(1-aminoethyl)-4-fluorophenol ((R)-I), a key chiral intermediate toward preparation of the tyrosine kinase inhibitor repotrectinib, has been developed. Starting from the easily available substrate 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (2a), the target product (R)-I was prepared in an optically pure form through a Ru-catalyzed asymmetric reductive amination with NH₄OAc as the nitrogen source and H₂ as the reducing agent. The reaction can be carried out on a 20 g scale using a continuous-flow reactor instead of a traditional batch reactor. The flow technology enables higher reaction efficiency and does not require column chromatography for product purification. Compared to the known procedures, this method avoids the use of expensive chiral auxiliaries and protecting group operations, making it a step-economical and cost-effective alternative strategy for production of repotrectinib.

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在间歇和流动条件下通过直接不对称还原胺化技术对酪氨酸激酶抑制剂 Repotrectinib 中的手性胺片段进行对映选择性和阶跃经济合成

(R)-2-(1-氨基乙基)-4-氟苯酚（(R)-I）是制备酪氨酸激酶抑制剂repotrectinib的关键手性中间体，本研究开发了一种一步法高对映体选择性合成方法。从易于获得的底物 1-(5-氟-2-羟基苯基)乙-1-酮 (2a)开始，以 NH4OAc 为氮源，H2 为还原剂，通过 Ru 催化的不对称还原胺化反应制备出光学纯的目标产物 (R)-I。利用连续流动反应器而不是传统的间歇反应器，该反应可以在 20 克的规模上进行。流动技术可提高反应效率，且无需柱层析来提纯产品。与已知程序相比，该方法避免了使用昂贵的手性助剂和保护基团操作，是生产 repotrectinib 的一种经济高效的替代策略。

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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.