Process Development and Scale-up of a Multi-Component Synthesis of a 3-Methyl-1-Aryl 1,2,4-Triazole Building Block

The classical preparation of 3-methyl-1-aryl-1,2,4-triazoles through an SNAr reaction pathway results in a mixture of N-regioisomers. Removal of the unwanted isomer reduces the yield and affects processability of the final product. In the presented case study, the target triazole was prepared by an SNAr route over three steps, in 24% overall yield, with a prohibitive Process Mass Index (PMI) of 300 that made the SNAr route inadequate for process scale implementation. Bristol-Myers Squibb scientists discovered an improved strategy that allows access to 3-methyl-1-aryl-1,2,4-triazoles directly from anilines and completely obviates formation of N-regioisomers. Further development of this new reaction manifold for process-scale application led to the production of the target triazole in kilogram quantities, as a single regioisomer, with a 3-fold improvement in yield and 7-fold improvement in PMI. Prescale-up thermal analysis indicated that the tosylamide oxime reagent was highly energetic and required proper controls for its scaled-up preparation and handling.