In the pharmaceutical industry, H₂O₂-mediated oxidation reactions are commonly used in chemical syntheses but they can also introduce unexpected safety hazards. Our labs recently reported on the discovery of oxygen evolution during the LiOH/H₂O₂-mediated cleavage of Evans oxazolidinone. Faced with this previously unexpected hazard, the authors, herein, report on the development and demonstration of a methodology for the safe scale-up of this O₂-releasing reaction. It was found that O₂ in the headspace could be controlled by a combination of N₂ sweeping and modulation of the LiOH addition rate. A design of experiment study was used to probe the multivariate parameter space in order to minimize formation of the unstable peracid intermediate, thus avoiding accumulation and subsequent risk of rapid and uncontrolled O₂ release. To support scale-up, the well-mixed vapor headspace assumption was tested using computational fluid dynamics, and it was found that N₂ sparging is effective at reducing heterogeneity in the headspace. Condenser conditions were evaluated to balance recovery of solvent—because of the high N₂ sweep—and avoid the risk of condenser freezing—because of the presence of water in the condensate. An additional fail safe was developed, using a pH buffer to rapidly halt the base-catalyzed reaction in the case of an unexpectedly high headspace O₂ concentration. The final process was validated and executed at up to 215 kg scale.

中文翻译：

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伊万斯恶唑烷酮与过氧化氢的放氧裂解的安全放大

在制药工业中，H ₂ O ₂介导的氧化反应通常用于化学合成中，但是它们也会带来意想不到的安全隐患。我们的实验室最近报道了在LiOH / H ₂ O ₂介导的Evans恶唑烷酮裂解过程中氧释放的发现。面对这种先前未曾预料到的危险，本文的作者报告了该O ₂释放反应的安全放大方法的开发和论证。发现顶空中的O ₂可以通过结合N ₂来控制扫描和调制LiOH添加速率。实验研究的设计用于探测多元参数空间，以最大程度地减少不稳定的过酸中间体的形成，从而避免积累以及随后发生的迅速和不受控制的O ₂释放的风险。为了支持放大，使用计算流体动力学测试了充分混合的蒸气顶空假设，发现N ₂喷射可有效减少顶空的不均匀性。对冷凝器条件进行了评估，以平衡溶剂的回收-因为高N ₂由于冷凝物中存在水，因此要进行扫除，并避免冷凝器冻结的风险。在意外的高顶空O ₂浓度的情况下，使用pH缓冲液迅速停止了碱催化的反应，从而开发了另一种故障保险。最终工艺已得到验证，最大加工规模为215公斤。