Flow process development and optimization of halo-amine coupling through customized flow processing equipment using DoE approach

Abstract

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.