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首页> 外文期刊>Organic process research & development >Rapid Development and Scale-Up of a 1H-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors
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Rapid Development and Scale-Up of a 1H-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors

机译：在连续推流反应器中化学法实现的1H-4-取代的咪唑中间体的快速开发和规模放大

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摘要

The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1H-4-substituted imidazole intermediate (S). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2. This material was further processed in batch equipment to deliver di-HCl salt 4. This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1—2 MT/year).
机译：在活塞流管式反应器（PFR）中以连续方式进行反应的开发为药物开发和放大工艺提供了独特的优势，并且还可以实现难以通过批处理进行的化学反应。在此，我们报告了关键1H-4-取代的咪唑中间体（S）的两种不同的连续流动方法的发展。在第一代方法中，在GMP条件下在PFR中证明了具有挑战性的环化反应的快速优化和扩大规模，可提供29千克受保护的产物2。该物料在间歇设备中进一步加工以提供二盐酸盐4。这种第一代方法强调了研究规模PFR中化学的快速发展以及在GMP条件下通过线性规模直至中试规模PFR的材料交付速度。在第二代工作中，开发了一种更有效的合成路线，并且具有自动采样，稀释和分析分析功能的PFR允许对关键环化反应和Boc保护基团的热去除进行快速且数据丰富的反应优化。这项工作最终以0.22 L PFR的两个连续步骤进行了1千克示范运行，并显示了从实验室通风柜占地面积（1-2吨/年）实现商业化的潜力。

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