DEVELOPMENT OF AN EFFICIENT AND SAFE PROCESS FOR A GRIGNARD REACTION VIA REACTION CALORIMETRY

A Grignard reaction of reactant A and phenyl magnesium chloride is use d to make a pharmaceutical intermediate at the production scale. The e limination of protecting groups on A was proposed as a means to reduce synthesis costs. This new synthesis route, however, had process effic iency and safety issues associated with it: (1) build-up of unreacted A in the reactor, (2) influence of A's particle size on the reaction r ate, (3) the sensitivity of the reaction rate to the reaction temperat ure and to the (changing) solvent composition, and (4) the highly exot hermic nature of the reaction. The Mettler RC1 Reaction Calorimeter wa s used to quantify the influence of solvent composition, temperature, and particle size on the reaction rate. Results indicated a dramatic e ffect of solvent composition and reaction temperature on the reaction rate; for example, over a temperature range of just 30 degrees C, the reaction time decreased from more than a day to just a few minutes. At such high reaction rates, the vessel jacket could not remove the reac tion heat sufficiently and the internal temperature rose adiabatically . These results were used to make process design and operation recomme ndations for safe and efficient plant operation with this modified Gri gnard reaction system.