Development and Manufacture of a Curtius Rearrangement Using Continuous Flow Towards the Large-Scale Manufacture of AZD7648

Flow chemistry has been more frequently used in the development and manufacture of pharmaceuticals due to the progression of equipment and the availability of manufacturing facilities. This important tool for manufacture enables chemistries which were previously inefficient, hazardous, or not viable on scale in batch. Described herein is how continuous flow has been used to overcome issues with respect to the handling of hazardous materials in batch. The manufacturing step described is a Curtius reaction using diphenylphosphoryl azide (DPPA) as the azide precursor in the formation of a purinone at high temperatures with inline infrared monitoring.