A Novel, Safe, and Robust Nitration Process for the Synthesis of 4-(4-Methoxy-3-nitrophenyl)morpholine

A novel nitration process was developed for the production of 4-(4-methoxy-3-nitrophenyl)morpholine. Crude 4-(4-methoxyphenyl)morpholine produced in step 1 was converted to its nitric acid salt. The nitration reaction was carried out by adding a dichloromethane solution of the isolated salt to concentrated sulfuric acid. This protocol provided an easy and reliable way to obtain a 1:1 molar ratio of the substrate and nitric acid in the reaction mixture and was proven to be the most effective method to prevent under-/over-nitration. The incorporation of the protocol into the process resulted in substantial improvement of the robustness and safety profile of the whole process. In addition, 59% overall yield improvement, 30% capacity increase, 40% waste reduction, and simplified operations were achieved. A detailed thermal hazard analysis of the process was also performed.