A CALORIMETRIC INVESTIGATION TO SAFELY SCALE-UP A CURTIUS REARRANGEMENT OF ACRYLOYL AZIDE

N-Vinyl-O-benzyl urethane,vas prepared for use as a starting material in a multistep synthesis of a drug candidate. After unsuccessful attem pts to employ non-Curtius options to prepare this intermediate, we dec ided to assess the thermodynamic and kinetic parameters of the acyl az ide Curtius rearrangement and trapping of the intermediate isocyanate, (Prepared in analogy to the literature method of Hegedus et al.: Wieb er, G, M,; Hegedus, L, S.; Akermark, B,; Michalson, E, T, J, Org. Cher n, 1989,. 54, 4649-4653.) Reaction calorimetry was utilized to show th at the rate of the Curtius rearrangement was completely dose-rate cont rolled, and that under carefully defined conditions this reaction coul d be safely performed on limited scale. In addition to addressing the thermal hazard issues, profiling the reaction with reaction calorimetr y and interfaced technologies resulted in significant process improvem ents.