Azide reactions should always be handled with care and choice of reaction conditions should be very deliberate. In this case, the reaction was an azide-bromide nucleophilic aliphatic substitution. Several aspects of this reaction appear to enhance safety. Phase-transfer catalysis enables the inventors to perform the reaction at a low temperature within a reasonable reaction time and use a non-polar solvent that makes two phases with water. Previous patent literature used DMSO or DMF and these solvents require more workup unit operations that require more handling of organic and inorganic azide. The fact that isopropyl acetate makes two phases with water enables the inventors to simply decant the aqueous phase, wash the organic phase once with aqueous salt and treat the inorganic azide in water safely and completely. DMSO or DMF cannot provide this advantage since they are water-miscible.
The PTC azide-bromide substitution is very atomically efficient so only 2.5 mole% excess of azide was used to achieve complete conversion of the azide-bromide substitution. This is obviously good for safety as well as for economics.
Tetrabutyl ammonium was used as the PTC quat. This is important since if any azide attacks the quat, it would make butyl azide which is more stable than methyl azide or ethyl azide that could potentially be made if methyl quats were used (like Aliquat 336 or methyl tributyl ammonium) or if ethyl quats were used (like benzyl triethyl ammonium).
The organic azide intermediate is not isolated and is reacted directly with the alkyne acid in the same solvent as the azide-bromide substitution reaction. The less handling of organic azide is good.
Finally, the purity of the product was 99.94% with only 0.06% of the wrong isomer (1-H). The inventors noted this as a major advantage.
Again, we see that PTC is the preferred method for azide nucleophilic aliphatic substitutions.
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