On the synthesis of diphenhydramine: Steady state ki, solvation effects, and in-situ raman and benchtop NMR as PAT

Diphenhydramine is a first-generation antihistamine that is available over-the-counter to treat maladies such as allergic reactions and insomnia. Despite its ubiquity in society and high demand, the kinetics for either step of diphenhydramine synthesis have not been explored in detail. In this work, for the first step, a methodology has been devised to obtain kinetics from the heterogeneous halogenation of benzhydrol with hydrochloric acid in a batch reactor equipped with in-situ Raman probe and further verified with ex-situ low-field NMR spectroscopy. For the second step, the kinetics of etherification have been explored using a microfluidic flow reactor and at-line NMR spectroscopy in a variety of solvents. Arrhenius and Eyring parameters are determined for Step 2. We find that the reaction performance is well correlated with the acceptor number of the solvent indicating that the Lewis acidity of the solvent plays a significant role in the overall performance