通过保护/去保护序列为 BMT-773752 开发可扩展的烷基化方法：Repotrectinib 合成路线中的关键中间体

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-05-08 DOI:10.1021/acs.oprd.4c00061

Han Zhang, Binfeng Li, Jin Yang, Changchun Xu, Rafaela Carmona, Jason Zhu, Bilal Hoblos and Steven Wisniewski*,

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引用次数: 0

摘要

本文介绍了 BMT-773752-02 这一 repotrectinib 关键起始原料的实用、可扩展合成路线的开发过程。最初的合成路线存在各种局限性，如使用发火有机锂试剂、收率低、非对映选择性差以及加工/纯化过程冗长。为了改善标题化合物的物理性质，还进行了盐筛选。新设计的合成策略的可扩展性已在数百公斤规模的生产中得到了验证，这种中间体的产量超过了一公吨。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib

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Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib

The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.

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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.