Customized flow equipment was utilized to develop and optimize the halo-amine coupling reaction. In this study, the development work was conducted through the statistical design of experiments (DoE) approach via a 2-factor interaction model. Experiments were conducted in two different reactor designs such as packed bed (type 1) and tubular reactor (type 2) set up. The effect of molar ratios of 4-methoxyaniline (1) and 1-(bromomethyl)-4-nitrobenzene (2), temperature, residence time, and base equivalence of N, N-Diisopropylethylamine were studied in detail. The data generated was in good agreement with significant improvements that were achieved in the overall reaction time and selectivity towards the desired product as compared to the batch process. The halo-amine coupling reaction in batch condition would take on an average of 90 to 120 min, which was effectively accomplished in 6 to 9 mins in both the flow reactor types. The advantage of type 2 over type 1 was found to be better towards the selectivity of the desired product with minimized impurities. A certain degree of back-mixing in the type 1 reactor was observed, which led to an increase in the impurity formation, whereas these impurities were practically less formed in the type 2 reactor. The reaction model is in good agreement with the reaction conditions.

Graphical abstract

利用定制的流动设备来开发和优化卤-胺偶联反应。在这项研究中，开发工作是通过两因素交互模型通过实验统计设计（DoE）方法进行的。实验在两种不同的反应器设计中进行，例如填充床（1型）和管式反应器（2型）的设置。4-甲氧基苯胺（1）和1-（溴甲基）-4-硝基苯（2）的摩尔比的影响），温度，停留时间和N，N-二异丙基乙胺的碱当量进行了详细研究。与分批过程相比，生成的数据与总体反应时间和对所需产物的选择性方面的显着改善非常吻合。间歇条件下的卤胺偶联反应平均需要90至120分钟，这在两种流动反应器类型中均有效地在6至9分钟内完成。发现类型2相对于类型1的优势对于具有最小杂质的所需产物的选择性更好。在1型反应器中观察到一定程度的反混，这导致杂质形成的增加，而这些杂质实际上在2型反应器中形成较少。

图形概要