(467a) A Safer, Greener Grignard

Abstract:  While Grignard reactions are an extremely valuable tool in the preparation of active pharmaceutical ingredients, the scale-up to and large batch production of organomagnesium chemistry is fraught with safety and operational concerns.  Magnesium metal activation using hazardous chemicals, potential thermal events associated with the Grignard formation initiation, air and water sensitive reagents, and post reaction magnesium metal disposal just to name a few.  Implementing a Grignard reaction using sequestered magnesium metal in a series of continuous stirred reactors provides an inherently safer and more environmentally friendly process.  Using a single initiation event and substantially smaller process vessels, a flow Grignard is still able to provide the same throughput as a traditional, large scale, batch Grignard.  For the preparation of a pharmaceutical intermediate, a flow Grignard was implemented in 250mL vessels.  After a single magnesium metal activation and Grignard initiation event, the process consisting of Grignard formation, coupling reaction, acid quench, and carbonate wash was run for 100 hours.  During the run, the ability to replenish the magnesium metal in the Grignard formation vessel was demonstrated.