Case – Azide Chemistry Made Safe

Sodium azide is the reagent of choice to prepare sterically hindered amines, triazoles and tetrazoles, functional moieties often encountered in new APIs (Active Pharmaceutical Ingredients). However, the use of azides in batch-wise productions is severely hampered by safety risks. Sodium azide is highly toxic, can form easily the even more lethal hydrazoic acid, and many metal-azides are shock sensitive and explosive.

Azide chemistry made safely
Flow chemistry, or continuous manufacturing, enables the safe application of sodium azide, since there is no accumulation of hazardous mixtures. At Innosyn we have successfully designed 3D metal printed flow reactors and applied them in scalable production processes using sodium azide safely, yielding sterically hindered amines, tri- and tetrazoles.

The introduction of an amine functionality proceeds via the substitution of an organic halide with azide, followed by a reduction.

For the flow recipe one needs to keep sufficient distance from the on-set temperature, and the flow reactor needs to resist the heat and gas release of a runaway situation: ΔTad=38˚C, ΔP=8 bar

For the azide substitution reaction we designed and ‘printed’ a static mixer tube reactor as shown below, fulfilling all requirements for safe and smooth operation. The continuously produced alkyl-azide using the set-up as schematically shown, is not stored or alike, but immediately extracted continuously with water and an organic solvent. The obtained organic-azide solution is immediately reduced by a fed-batch hydrogenation, as such preventing any accumulation.

Static mixer tube reactor

Narrow residence time distribution

High pressure resistance

Good heat transfer capability

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