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Safely Scaling Up Azide Chemistry

Process design reduces risk of forming explosive hydrazoic acid

by Jyllian Kemsley
October 22, 2012 | A version of this story appeared in Volume 90, Issue 43

Understanding and preventing generation of explosive hydrazoic acid (HN3) is key to safe and successful scale-up of azide chemistry, report researchers from Bristol-Myers Squibb (Org. Process Res. Dev., DOI: 10.1021/op3002646). Azide compounds are commonly used to synthesize nitrogen-containing species. But they present several safety challenges, one of which is possible accumulation of HN3 , which is explosive. As part of scaling up the synthesis of a pharmaceutical candidate, a team led by Francisco González-Bobes and Nathaniel Kopp was working on an enantioselective, palladium-catalyzed desymmetrization of a meso-bis-ester using trimethylsilylazide (TMSN3) as a nucleophile. Rather than using engineering controls to manage HN3, the team looked for ways to minimize its formation through process design. One approach involved tightly controlling unreacted azide by making TMSN3 the limiting reagent, but that sacrificed some of the meso-bis-ester starting material. The team then developed a method in which, after desymmetrization, the reaction solution is treated with sodium hydroxide to convert any residual TMSN3 to aqueous sodium azide. An extraction step removes the aqueous component. The team demonstrates that the end result is a safer process with better yield and less waste.


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