Amide bond formation occupies a central role in the pharmaceutical industry. In recent years, this transformation has received increased attention, as process chemistry efforts have focussed on developing amidation methods which avoid stoichiometric activating agents. However, the strategies currently employed generally target C-N bond formation, often through condensation of an activated carboxylic acid with an amine. Alternative approaches have also been well documented, yet amongst these, C-C bond-forming amidation reactions are comparatively rare. By employing fragments embedded with a masked amide functionality, this “inverse” disconnection has the potential to offer a more direct and atom efficient alternative to traditional protocols (Scheme 1). Accordingly, our research has focused on exploiting rarely used synthons, harnessing modern analytical and synthetic technologies to develop novel amidation processes for use in pharmaceutical production. Here we present our studies into the synthesis and reactivity of carbamoyl synthons for amide formation. Radical and ionic approaches have both been investigated, and our studies have delivered valuable insights into these processes. Through the implementation of flow chemistry, we have developed a highly general, safe, mass efficient and scalable amidation process. Notably, a number of amides which are challenging to access by traditional approaches have been efficiently prepared using our strategy. Overall, this new methodology, underpinned by an inverse disconnection strategy, represents a new flow chemistry amidation process which operates with excellent atom economy, and is highly complementary to other reported methods.

Development of efficient and scalable amidation processes in flow: An inverse disconnection strategy

254th National Meeting (2017)

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