甲氟格列酮中间体(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚的制备工艺研究第一部分：一种Evans辅助-辅助非对称1,4-加成路径的选择

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-08-05 DOI:10.1021/acs.oprd.5c00183

Qiang Yang*, Alison Campbell Brewer, Sarah J. Ryan, Derek R. Starkey, Radhe K. Vaid, Ping Huang, Mo Jia, Peng Liu, Lixuan Liang, Lingxing Meng, Manabu Wadamoto, Satoshi Tsuchiya, Fumiki Kawagishi, Akemi Mizutani and Minoru Yamawaki,

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引用次数: 0

摘要

介绍了两种键(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚中间体1的合成策略。根岸交叉偶联途径最初扩大到提供总共36.6公斤的化合物1，以支持orforglipron的生产，为早期临床试验提供资金。然而，这种途径是非对映选择性的，并且需要费力的手性SFC纯化才能获得光纯中间体。以Evans辅助不对称1,4加成为特征的对映选择性路线成功地产生了所需的产物，而无需在整个合成过程中进行不可扩展的色谱纯化，该路线被选中进一步发展为大规模生产的稳健工艺。

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 Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part I. Selection of an Evans Auxiliary-Assisted Asymmetric 1,4-Addition Route

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Two synthetic strategies for key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate 1 for orforglipron were demonstrated. The Negishi cross-coupling route was initially scaled up to deliver a total of 36.6 kg of compound 1 to support the production of orforglipron to fund early clinical trials. However, this route was nonenantioselective and required laborious chiral SFC purification to obtain an optically pure intermediate. An enantioselective route featuring Evans auxiliary-assisted asymmetric 1,4-addition successfully produced the desired product without necessitating nonscalable chromatographic purification throughout the synthesis, which was selected for further development into a robust process for large-scale production.

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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.