The Curtius rearrangement is synthetically a very powerful transformation for converting carboxylic acids into amines.  As a direct chemical interconversion, this process has tremendous value, as well as an important strategic impact due to the prevalence of the amide bond in many pharmaceutical compounds.  Despite the many advantages offered by this reaction, its use at scale has been avoided because of significant safety concerns regarding the generation and use of potentially explosive and highly toxic azide promoters and the associated acyl azide intermediates.There are significant advantages of using continuous flow processing, especially when it comes to the safe use of hazardous reagents or conditions.  Diphenylphosphoryl azide (DPPA) is a highly popular reagent for the Curtius rearrangement that serves as both a carboxylic acid activation agent and as an azide source.  Unfortunately, procuring large amounts of this material is difficult due to the mass transfer limitations in its synthesis, in addition to shipping concerns due to its propensity to hydrolyze into hydrazoic acid, which is a shock sensitive high explosive.  Using a continuous flow approach, the on-demand synthesis of DPPA and its scaling to the molar level will be described, including its application to acyl azide formation and the subsequent Curtius rearrangement.

Risk evaluation for the use of azide reagents in pharmaceutical development:  DPPA on-demand

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.