Safe Practices for Azide Chemistry Scale-up: A Case Study On a Pharmaceutical Intermediate

Azide chemistry offers an efficient entry to synthesize nitrogen containing compounds with a range of functionalities such as amines, isocyanates, sulfonamides, triazoles, tetrazoles, triazolines, aziridines and diazo compounds. Safety hazards, specifically exposure and explosivity are often associated with azide chemistry, and represent the major barrier to process scale-up. These hazards often originate from the formation of hydrazoic acid, HN₃, which is readily generated in the presence of protic compounds and hazards which may also result from the incompatibility of azide reagents with heavy metals, some chlorinated solvents and high temperatures.

In this case study, azide chemistry was successfully demonstrated on a 7 kg input scale, addressing the exposure and explosivity scale-up issues, to produce a valuable synthetic intermediate with high quality and yield through a successful control strategy of HN₃ based on understanding the solution, vapor and enriched condensate concentrations. A unique quantitative analysis of the vapor-liquid-condensate equilibrium, through a conservative Henry's Law evaluation, was conducted and compared to literature to identify safe operating conditions. This discussion aims to present general scale-up strategies for safe practices with azide chemistry, and focus specifically on the quantitative analysis of the hazards associated with HN₃ through this case study.