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 <i>O</i>-[(2<i>R</i>,3<i>S</i>)-2-(<i>tert</i>-butyldimethylsilyloxymethyl)-3,6-dihydro-2<i>H</i>-pyran-3-yl]-trichloro-ethanecarboximidate <b>3</b> to the corresponding trichloroacetamide <b>4</b> is described. Trichloroacetimidate <b>4</b> is an intermediate for an active pharmaceutical intermediate (API) under development at Actelion Pharmaceuticals Ltd. The instability of compounds <b>3</b> and <b>4</b> 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 <b>4</b>.