Improved Synthetic Process of Tradipitant

To address the production safety and environmental risks associated with highly toxic, malodorous, or hazardous reagents used in existing routes (such as thiophenol, n-butyllithium, and sodium azide), this study developed a safer and greener new synthetic route. The route starts from 2-chloropyridine and, through optimization of key steps, achieves improvements: replacing thiophenol with sodium phenylsulfinate to prepare intermediate 4, using lithium diisopropylamide (LDA) instead of n-butyllithium for α-sulfonyl substitution coupling, and azidotrimethylsilane (TMSN3) instead of sodium azide to prepare azide intermediate 8.

The improved process conditions are milder, significantly reduce safety risks, and increase the overall yield from 44.5% reported in the literature to 49.1% (based on 9), while also enhancing the quality and yield of key intermediates, making it more suitable for industrial production requirements.