Exploratory Process Development of a High-Temperature Thermal (3 + 2) Cycloaddition in Continuous Flow for the Synthesis of Seltorexant

Abstract

Seltorexant (1) is currently under clinical development as a selective orexin-2 antagonist for the treatment of major depressive disorder with insomnia symptoms. During the investigation of an improved synthesis route, a key (3 + 2) cycloaddition reaction was found to occur only at very high temperatures (>250 °C). An exploratory process development of such a challenging high-temperature cycloaddition was demonstrated in a continuous flow process. Together with the development of other steps, a proof of concept to the improved synthesis route to seltorexant was established.