A Practical and Scalable Route to 6-Bromo-2,4,5-trichloropyrrolo[2,1- <i>f</i> ][1,2,4]triazine: Process Optimization Guided by Thermal Safety Insights

Herein, we report a scalable and robust route for the synthesis of 6-bromo-2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine 1. The developed process involves modification of the known method for pentachlorination, followed by aromatization and N-amination, which has only been reported on a smaller scale and may not be safe to scale. The new method discussed in this paper is safe, scalable, and efficient, as inferred from safety and engineering studies using the Advanced Reactive System Screening Tool (ARSST) and Reaction Calorimeter (RC1mx). The highlight of this protocol involves regioselective bromination of a key fragment and the development of operationally simple workup and purification strategies to synthesize compound 1 with an overall yield of 26%.