RESUMEN
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 500â gram scale (1.3â mols of product).
RESUMEN
[This corrects the article DOI: 10.1021/acs.oprd.2c00226.].
RESUMEN
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.