The classical preparation of 3-methyl-1-aryl-1,2,4-triazoles through an S_NAr 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 S_NAr route over three steps, in 24% overall yield, with a prohibitive Process Mass Index (PMI) of 300 that made the S_NAr 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.

中文翻译：

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3-甲基-1-芳基-1,2,4-三唑结构单元的多组分合成的工艺开发和规模放大

的3-甲基-1-芳基-1,2,4-三唑的制备古典通过S _Ñ氩反应途径导致的混合物Ñ -regioisomers。除去不需要的异构体会降低产率并影响最终产物的可加工性。在本案例研究中，目标目标三唑是通过S _N Ar路线分三步制备的，总收率为24％，过程质量指数（PMI）为300，这使S _N Ar路线不足以实现工艺规模。百时美施贵宝公司的科学家发现了一种改进的策略，该策略可以直接从苯胺中获得3-甲基-1-芳基-1,2,4-三唑，从而完全避免了N的形成。-区域异构体。这种用于过程规模应用的新型反应歧管的进一步开发导致以千克数量的目标三唑的生产成为一种区域异构体，产量提高了3倍，PMI提高了7倍。放大前的热分析表明，甲苯磺酰胺肟试剂具有很高的能量，需要对其放大制备和处理进行适当的控制。