Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates
Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates
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DOI：
10.1021/acs.oprd.1c00249
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发表时间：
2021-10-28
影响因子：
3.4
通讯作者：
Diwan, Moiz
中科院分区：
文献类型：
--
作者：
Cardinal-David, Benoit;Harper, Kaid C.;Diwan, Moiz
生产原料药和医药中间体需要开发可扩展、安全和环保的工艺。具有高放热性或其他危险性质的反应，以及涉及不稳定中间体形成的反应，可以从连续处理中受益。由于其固有的在低反应体积下操作的能力，该技术已在整个制药行业广泛采用，有助于改进温度控制，并安全地适应更高的压力。两个这样的工业相关的例子是芳香硝化和区域选择性芳基环金属化，然后用亲电试剂捕获。当在批处理中执行时，这两个反应类通常都面临放大的挑战。硝化反应通常以多相、混合敏感反应为特征，伴有大放热，可能导致形成潜在危险的过渗副产物。同样，芳基环的金属化反应通常需要低温条件，这在规模上是具有挑战性的。在本研究中，评估了混合-有限固-液-液（S-L-L）硝化反应，以了解输运现象。通过确定哈塔数和叶轮功率对动力学的影响，可以设计出安全、可扩展、高产且坚固的连续搅拌槽（CSTR）流动过程。对关键甲酰化反应参数的研究导致了第一代管流式反应器的设计，可以在中试工厂中处理100 - 10千克的底物。开发了一个更实用的串联CSTR反应堆系统，以支持补给输送。这种反应器配置实现了优越的温度控制，减轻了与盐形成相关的风险，并提高了吞吐量和产量。
Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from continuous processing. This technology has been broadly adopted across the pharmaceutical industry due to its intrinsic ability to operate at low reaction volumes, facilitate improved temperature control, and safely accommodate higher pressures. Two such industrially relevant examples are aromatic nitration and regioselective aryl ring metalation, followed by trapping with an electrophile. Both reaction classes commonly face scale-up challenges when performed in batch processing. The nitration reaction usually features a multiphase, mixing-sensitive reaction associated with a large exotherm that can lead to the formation of potentially hazardous overnitrated byproducts. Similarly, metalation reactions of aryl rings often require cryogenic conditions, which are challenging to achieve on scale. In this study, a mixing-limited solid-liquid-liquid (S-L-L) nitration reaction was evaluated to understand the transport phenomena. The determination of the Hatta number and impact of the impeller power on the kinetics enabled the design of a safe, scalable, high-yielding, and robust continuous stirred tank (CSTR) flow process. A study of critical formylation reaction parameters led to a first-generation tubular flow reactor design to process >10 kg of a substrate in the pilot plant. A more practical CSTR reactor system in series was developed to support a resupply delivery. This reactor configuration enabled superior temperature control, alleviated the risks associated with salt formation, and increased the throughput and yield.