Amide bond formation is one of the most important chemical transformations for a modern world. For example in active pharmaceuticals 8 of the top 10 small molecule pharmaceuticals by retails sales in 2021 contain at least one amide bond, and up to 50% of all medicinal chemistry routes contains at least one amide bond forming step. To this end, we have been exploring the ability to forge these amides in the absence of bulk reaction solvent using both ball-milling and twin-screw extrusion (TSE) approaches.

At the outset of this project, we were interested in the synthesis of amide bonds using esters and amines. This was achieved under solvent-free mechanochemical conditions using sub-stoichiometric potassium tert-butoxide as the base, alleviating the demand for activating agents i.e., CDI and increasing atom economy.

In our initial report we found that we could achieve direct amidation of esters with amines using a ball-mill. We further explored this process with the introduction of a temperature controlled ball milling system, permitting the reduction of base loadings. These discoveries have then been translated to a continuous solid-state extrusion process permitting formation of amide products on >100 gram scales with no reaction solvent.

It has been demonstrated that the use of mechanochemical conditions can remove the need for both bulk reaction solvent in the formation of amide bonds by directly reacting esters and amines. Furthermore, it has been shown that this methodology can be translated to a continuous TSE approach to deliver promising results on the scale up of this approach.

Paul Richardson

Pfizer

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