Optimization of Nitrosation Reaction for Synthesis of 4-Aminoantipyrine by Response Surface Methodology and Its Reaction Mechanism

A small-scale process of nitrosation reaction for the preparation of 4-aminoantipyrine (AA) is optimized. Response surface methodology combined with Box–Behnken design is used to build the model and optimize parameters. AT-SO4/sodium nitrite molar ratio, antipyrine (AT)/sulfuric acid molar ratio, reaction time, and reaction temperature are selected as independent variables, and the purity and yield of AA are the response values. The optimized reaction conditions are as follows: n(AT-SO4)/n(NaNO2) = 0.84, n(AT)/n(H2SO4) = 1.72, the reaction temperature is 17 °C, and the reaction time is 2 min. The AA yield and purity reach 90.60 and 75.19%, respectively. In addition, IR and liquid chromatography–mass spectrometry analyses are used to study the reaction mechanism. Secondary nitrosation reaction products are discovered to be formed, and an unprecedented reaction mechanism is proposed.