Safe Scale-up of an Oxygen-Releasing Cleavage of Evans Oxazolidinone with Hydrogen Peroxide

In the pharmaceutical industry, H2O2-mediated oxidation reactions are commonly used in chemical syntheses but they can also introduce unexpected safety hazards. Our labs recently reported on the discovery of oxygen evolution during the LiOH/H2O2-mediated cleavage of Evans oxazolidinone. Faced with this previously unexpected hazard, the authors, herein, report on the development and demonstration of a methodology for the safe scale-up of this O-2-releasing reaction. It was found that O-2 in the headspace could be controlled by a combination of N-2 sweeping and modulation of the LiOH addition rate. A design of experiment study was used to probe the multivariate parameter space in order to minimize formation of the unstable peracid intermediate, thus avoiding accumulation and subsequent risk of rapid and uncontrolled O-2 release. To support scale-up, the well-mixed vapor headspace assumption was tested using computational fluid dynamics, and it was found that N-2 sparging is effective at reducing heterogeneity in the headspace. Condenser conditions were evaluated to balance recovery of solvent-because of the high N-2 sweep-and avoid the risk of condenser freezing-because of the presence of water in the condensate. An additional fail safe was developed, using a pH buffer to rapidly halt the base-catalyzed reaction in the case of an unexpectedly high headspace O-2 concentration. The final process was validated and executed at up to 215 kg scale.