A fully continuous-flow process for the synthesis of 4-nitropyrazole

Abstract

A fully continuous-flow nitration and post-processing protocol has been introduced into the preparation of 4-nitropyrazole. The process started from the nitration reaction of pyrazole with mixed acid, followed by continuous quenching, neutralization, extraction and separation. After the collected organic phase was rotationally evaporated to recover the solvent, the final product 4-nitropyrazole was obtained with 96.9% yield, 99.3% purity and 381 g/h productivity. By establishing a kinetics model and MATLAB simulation calculation, it worked out to achieve the preferable selectivity conditions of mono-nitration product 4-nitropyrazole. The process of post-processing solved the problems of solid precipitation and extractant hydrolysis. The extraction process was determined by the distribution coefficient and twice extraction was used to reduce the amount of organic solvent.

Graphical Abstract