Safely Scaling Up Azide Chemistry

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.