Solvent Minimized Synthesis of Amides by Reactive Extrusion

Abstract Herein, we report on the translation of a small scale ball‐milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin‐screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid‐liquid, solid–liquid and solid‐solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7‐hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).