Catalyst-free aza-Michael addition for C–N coupling in active pharmaceutical ingredient synthesis: Modelling of thermodynamic, reaction kinetics and mass transfer considerations

Abstract

The present research study describes a combined experimental-modelling approach to examine the three-phased catalyst-free reversible aza-Michael addition of NH3 to the vinyl sulfone pharmaceutical intermediate in water. A series of batch experiments using gaseous NH3 were performed to thoroughly evaluate the impact of reaction temperature, NH3 pressure, starting material loading, and starting material quality on reactant solubility, convective mass transfer, and reaction kinetics in the system. A rigorous in-house mechanistic mathematical model was developed. All unknown parameters were determined through nonlinear regression fitting of experimental and simulated quantitative results. Aza-Michael addition kinetics and starting material equilibrium solubility were found to be highly temperature-dependent and had the biggest applicative effect on the maximum aza-Michael reaction rate, which was also confirmed by sensitivity analysis technique. Boundary diffusion of reactants was shown not to be the limiting controlling factor under the chosen operating conditions. Ammonia pressure was found to be important through its impact on the saturated concentration of NH3. Varying starting material load had impact solely on the time required to reach system equilibrium due to solute concentration limitations. Reverse NH3 elimination reaction kinetics was shown to be independent on changing all input operating conditions. The specific methodology grants a novel engineering approach for treating complex interrelated multi-phased heterogeneous compositions in active pharmaceutical ingredient reaction systems, which may be applied early in industrial process development, when a small continuous amount of raw data sets is available, the quantity of impurities varies, and simulations can aid intensification. It may be easily transferred to other similar environments for assistance in process development, optimization, and scale-up.