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

Abstract

A novel nitration process was developed for the production of 4-(4methoxy-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.

Process Safety in the Pharmaceutical Industry─Part II: Process Safety Labs and Instruments Used in Process Safety Labs for Thermal Hazards

“…This includes starting materials, intermediates, reactants, catalysts, and wastes; (b) the reaction at the desired process temperature; and (c) materials and reaction mixtures under the worst-case scenarios (e.g., undesired decomposition if the temperature control of an equipment malfunctions). There are several illustrations available in the literature where calorimetries helped PSLs in the chemical and pharmaceutical industries to successfully identify potential hazards and subsequently develop strategies to mitigate those risks. − For example, potential process safety hazards of 45 common peptide coupling reagents were studied using DSC (differential scanning calorimetry) and ARC (accelerating rate calorimetry), where these instruments helped scientists identify thermally unstable coupling reagents …”