Development of a Mechanism-Based Kinetic Model and Process Optimization Incorporating Imidazole Autocatalysis in a 1,1′-Thiocarbonyldiimidazole-Mediated Thiocarbonyl Transfer

The synthesis of mixed thiourea 4 was performed via a 1,1′-thiocarbonyldiimidazole (TCDI)-mediated coupling with 1 to form intermediate isothiocyanate 2 prior to reaction with amine 3. A critical undesired thiourea impurity5is formed via the overreaction of 2 with an additional equivalent of 1. This work describes a mechanism-based kinetic model toward understanding the formation of 2 and impurity 5. Critical to the construction of this model is the inclusion of imidazole autocatalysis. This experimentally validated model allows for the identification of improved process conditions for reducing the level of formation of 5. This report also describes the newfound role of imidazole in the decomposition of 4 and the impact of imidazole on the solubility of both 4 and 5.