Improving the reaction efficiency of condensation amidation of piperazine with benzoic acid based on kinetics study in microreactors

Here we developed a continuous flow microreactor system to synthesis N-benzoylpiperazine, which is an important intermediate of novel nootropic Sunifiram. And the kinetics of the condensation amidation of piperazine and benzoic acid using HATU as coupling reagent was revealed in microreactor. A kinetic model was established, all the reactions kinetics parameters, including the reaction order of each reactant, rate constants, pre-exponential factors and activation energies were acquired. With this model the selectivity vs. reaction temperature/molar flow ratio were obtained to help understand this kind of reaction and further optimize operating conditions. Under the condition of using equivalent piperazine, 95.6% of selectivity and 91.2% of yield were obtained in microreactor with 50 s. To further expand the scope of carboxylic acid, cyclopropanecarboxylic acid was tried as acylating agent, and 92.8% of selectivity and 86.1% of yield were obtained in microreactor.