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.

[3+2] Cycloaddition of Alkynyl Boronates and in situ Generated Azomethine Ylide

“…1 C NMR (126 MHz, DMSO-d 6 ) δ 140.1, 128.3, 127.9, 126.3, 59.0, 58.1, 55.8, 18.9, 9.6. 19 F NMR (376 MHz, DMSO-d 6 ) δ À 142.0. All the spectral data corresponded to those reported in literature.…”

“…[10] On the other hand, recent trends in medicinal chemistry often rely on the preferential involvement of the structures with higher sp 3 -hybrid carbon fraction (F(sp 3 )) values due to their significantly improved physicochemical properties and lower attrition rate. [11][12][13][14][15][16][17] Being among most prominent motifs in biologically active molecules, saturated nitrogen heterocycles (in particular, pyrrolidine or its bicyclic analogues) can be found in a number of approved or investigational drugs [18,19] and naturally occurring compounds (Figure 1). Steadily increasing interest in saturated heterocycles, along with the high versatility of the boronate functional group in the synthesis of complex molecules, prompted us to develop efficient protocols for the preparation of boron-containing aza-heterocyclic building blocks.…”

Development of a solid-compatible continuous flow reactor for the paraformaldehyde slurry mediated α-hydroxymethylation of methyl vinyl ketone

“…[20][21][22][23] Studies addressing the use of solid reagents requiring accurate dosing into the flow reactor or handling formed precipitations are scarce. 24,25 This study presents the efforts to design a novel continuous flow setup to deal with the conditions required for paraformaldehyde slurry mediated chemistry.…”