Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-02-27 DOI:10.1021/acs.oprd.4c00507

Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong, Gengxiu Zheng

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引用次数: 0

Abstract

The H₂O₂-mediated cleavage of chiral auxiliary as a mild and selective method is commonly used in the pharmaceutical industry but they can also introduce unexpected safety hazards due to the O₂ release. Here, a novel safe and efficient continuous flow synthesis process for (3S,4S)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone (4-BMA), a key intermediate of meropenem was reported. The vertical dynamic reactor (VDR) effectively addresses the safety risk by preventing electrostatic accumulation and eliminating gas-phase space within the reactor. Compared to the current batch process, the continuous flow synthesis method reported in this paper not only significantly improved the safety of the process but also greatly shortened the reaction time (from 600 to 20 min) and increased the yield (from 85 to 91%) due to its high mass and heat transfer efficiency. These results indicated that the VDR provides great potential for the industrial scale-up of 4-BMA.

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垂直动态反应器安全高效连续流合成(3S,4S)-3-[(R)-1-（t-丁基二甲基硅氧基）乙基]-4-[(R)-1-羧乙基]-2-氮杂tizinone

h2o2介导的手性助剂裂解作为一种温和、选择性强的方法，在制药工业中得到广泛应用，但由于O2的释放，也会带来意想不到的安全隐患。本文报道了一种安全高效的新型连续流合成美罗培南关键中间体(3S,4S)-3-[(R)-1-（t-丁基二甲基硅氧基）乙基]-4-[(R)-1-羧乙基]-2-氮杂tizinone （4-BMA）的新工艺。垂直动力反应器（VDR）通过防止静电积聚和消除反应器内的气相空间，有效地解决了安全风险。与目前的间歇式工艺相比，本文报道的连续流合成方法不仅大大提高了工艺的安全性，而且由于其较高的传质和传热效率，大大缩短了反应时间（从600分钟缩短到20分钟），提高了产率（从85%提高到91%）。这些结果表明，VDR为4-BMA的工业规模化提供了巨大的潜力。

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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.