A Grignard reaction of reactant A and phenyl magnesium chloride is used to make a pharmaceutical intermediate at the production scale. The elimination of protecting groups on A was proposed as a means to reduce synthesis costs. This new synthesis route, however, had process efficiency 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 rate, (3) the sensitivity of the reaction rate to the reaction temperature and to the (changing) solvent composition, and (4) the highly exothermic nature of the reaction. The Mettler RC1 Reaction Calorimeter was used to quantify the influence of solvent composition, temperature, and particle size on the reaction rate. Results indicated a dramatic effect 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 reaction heat sufficiently and the internal temperature rose adiabatically. These results were used to make process design and operation recommendations for safe and efficient plant operation with this modified Grignard reaction system.
