Evolution of the Synthetic Process to an Advanced GPR40 Agonist

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-01-02 DOI:10.1021/acs.oprd.3c00433

Xiaoping Hou*, Lucas W. Hernandez*, Elizabeth A. Jurica*, Rulin Zhao, Bei Wang, Michael Wong, Jung-Hui Sun, Dawn Sun, Dauh-Rurng Wu, Changxia Yuan, Michael Hay, Miao Yu, Ximao Wu, Yanting Huang, Bruce A. Ellsworth, Francisco Gonzalez Bobes, Arvind Mathur and James Kempson,

引用次数: 0

Abstract

Herein we describe a series of synthetic efforts to prepare an advanced GPR40 agonist (compound 1), with focus on phase-appropriate processes that circumvented key reagents with short supply in the original synthesis. The key transformations refined for large-scale production were an asymmetric aldol reaction, O-alkylation of an unstable intermediate, selective (Z)-olefination, and reduction of a Weinreb amide to aldehyde. Additionally, the new route circumvented stability issues of the core pyrrolidine fragment through de novo synthesis, achieving high d.r. during ring formation. The new improved route was efficiently scaled up to prepare more than 100 g API for toxicology studies.

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高级 GPR40 激动剂合成过程的演变

在本文中，我们介绍了制备高级 GPR40 激动剂（化合物 1）的一系列合成工作，重点介绍了规避原始合成中供应短缺的关键试剂的阶段性适当工艺。为实现大规模生产而改进的关键转化过程包括不对称醛醇反应、不稳定中间体的 O-烷基化、选择性 (Z) 烯化以及将 Weinreb 酰胺还原成醛。此外，新路线通过从头合成规避了核心吡咯烷片段的稳定性问题，在成环过程中实现了高 d.r.。改进后的新路线可有效地扩大规模，制备出超过 100 克的原料药，用于毒理学研究。

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.