A report (Org Process Res Dev 2014, ASAP article) out of Jamison’s group at MIT, provides a 3-step synthesis of Rufinamide in 92% overall yield. The process illustrates a continuous and convergent method, moving away from the isolation of a key organic azide intermediates and a Cu coiled-tube reactor for the cycloaddition reaction to the corresponding desired triazole.
Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of the synthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield.
Give it a flow: A continuous-flow process for the synthesis of a 1,2,3-triazole precursor of Rufinamide has been developed. The protocol involves a solvent- and catalyst-free operation and utilizes reaction temperatures above the melting point of the target product to prevent microreactor clogging, resulting in a decrease of the operating time from hours to minutes.
Solvent- and Catalyst-Free Huisgen Cycloaddition to Rufinamide in Flow with a Greener, Less Expensive Dipolarophile
Article first published online: 23 SEP 2013