Thermal Overman Rearrangement of a Glucal Derivative in a Tube Reactor on Pilot Plant Scale

The development of a continuous process for the thermal Overman rearrangement of O-[(2R,3S)-2-(tert-butyldimethylsilyloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-trichloro-ethanecarboximidate 3 to the corresponding trichloroacetamide 4 is described. Trichloroacetimidate 4 is an intermediate for an active pharmaceutical intermediate (API) under development at Actelion Pharmaceuticals Ltd. The instability of compounds 3 and 4 at temperatures above 100 °C prevented scale-up of the original batch mode procedure to the required multikilogram scale. This problem was solved by developing a flow chemistry process used for the successful production of 95 kg of 4.