Kinetics Research and Process Development for the Intensification of the Fully Continuous Flow Synthesis of 3-Amino-1-Adamantanol

3-Amino-1-adamantanol (3AA) is an important intermediate of vildagliptin. In this work, a fully continuous flow synthesis of 3-amino-1-adamantanol has been proposed. Selecting amantadine sulfate (AS) as the starting material, the effects of process parameters were systematically investigated, such as the molar ratio of reactants, the amount of sulfuric acid and reaction temperature. The kinetics of nitration reaction were carried out in both batch and continuous flow processes to explain the relationship between the amount of sulfuric acid and the reaction rate constant. Based on the apparent reaction rate constants and thermodynamic parameters, a fully continuous flow synthesis of 3AA combining nitration, hydrolysis and neutralization reaction has been realized. Compared with the batch method, the reaction time was shortened from 8 h to 36 min, the side reactions were significantly inhibited, and the yield increased from 87.8 % to 95.2 % by continuous flow strategy.