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二部分。Evans辅助-非对称1,4加成CSTR工艺的发展

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-08-04 DOI:10.1021/acs.oprd.5c00184

Qiang Yang*, Derek R. Starkey, Radhe K. Vaid, Xavier Ortiz-Medina, Charles B. Held, Mark D. Argentine, Derek Berglund, Molly Hess, Alison Campbell Brewer, Kayla L. Mathews, Ping Huang, Mo Jia, Peng Liu, Jing Chen, Chaoyi Deng and Fangyun Yang,

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引用次数: 0

摘要

以(S)-5-（2,2-二甲基四氢- 2h -吡喃-4-基）- 1h -吲哚为中间体，采用Evans辅助不对称1,4加成法，建立了可扩展的8步合成途径。间歇工艺的主要挑战包括铜配合物的稳定性，反应的高放热性，以及关键非对映异构体杂质的控制。通过开发CSTR工艺来制备铜配合物，解决了这些挑战，实现了“按需”制备，并改善了传热以控制反应温度。设计了一种简单的浆液纯化来分离亚稳多晶，有效地将非对映异构体杂质降低到可接受的水平。优化后的工艺成功地放大到400 kg，证明了其鲁棒性。

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 II. Development of a CSTR Process for Evans Auxiliary-Assisted Asymmetric 1,4-Addition

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A scalable 8-step route incorporating Evans auxiliary-assisted asymmetric 1,4-addition was developed for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate of orforglipron. The main challenges of the batch process included the copper complex’s stability, the high exothermicity of the reaction, and the control of a key diastereomeric impurity. These challenges were addressed by developing a CSTR process to prepare the copper complex, enabling “on-demand” preparation and improved heat transfer to control the reaction temperature. A simple slurry purification was devised to isolate a metastable polymorph that effectively reduced the diastereomeric impurity to acceptable levels. The optimized process was successfully scaled up to >400 kg, demonstrating its robustness.

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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.