Development of a Continuous Schotten-Baumann Route to an Acyl Sulfonamide
Development of a Continuous Schotten-Baumann Route to an Acyl Sulfonamide
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DOI：
10.1021/op200344a
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发表时间：
2012-05-01
影响因子：
3.4
通讯作者：
Yates, Matthew H.
中科院分区：
文献类型：
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作者：
White, Timothy D.;Berglund, K. Derek;Yates, Matthew H.
公开了利用连续的Schotten-Baumann反应条件的他西磺草胺钠（5-溴-噻吩-2-磺酸2，4-二氯苯甲酰胺钠盐，下文称为他西磺草胺）的合成路线的开发和放大。设想了一种适合连续加工的细胞毒性API的新合成路线，该路线将通过减少单元操作的数量来最大限度地减少潜在的工人暴露，并允许在实验室通风柜中使用廉价的玻璃器皿进行商业规模的API生产。所开发的Schotten-Baumann条件包含比现有间歇工艺更少的单元操作，其通过利用由磺酰胺和酰氯直接形成最终钠盐而不分离游离酰基磺酰胺。将讨论批量开发、连续概念验证研究、5.2 g/h实验室规模示范和5 kg/天商业规模运行。他西磺兰API批工艺具有非常严格的放行质量标准，并详细说明了满足连续工艺这些要求的挑战。最后，将解决启动和关闭过渡期间产生的材料质量问题。
The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten-Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API amenable to continuous processing was envisioned that would minimize potential worker exposure by reducing the number of unit operations and would allow commercial-scale API production in laboratory fume hoods with inexpensive glassware. The developed Schotten-Baumann conditions contained fewer unit operations than the existing batch process by utilizing the direct formation of the final sodium salt from a sulfonamide and acid chloride without isolation of the free acyl sulfonamide. Batch development, continuous proof of concept studies, 5.2 g/h lab-scale demonstration and 5 kg/day commercial-scale runs will be discussed. Very stringent release specifications were in place for the tasisulam API batch process, and the challenges of meeting these requirements for the continuous process are detailed. Finally, the quality of material generated during startup and shutdown transitions will be addressed.