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Org. Process Res. Dev. 2024, 28, 1494 − 1503. DOI: 10.1021/acs.oprd.3c00113 ◆ Seltorexant (1) is currently under
clinical development as a selective orexin-2 antagonist for the treatment of
major depressive disorder with insomnia symptoms. ◆ Relying on the (3 + 2) cycloaddition
approach for the synthesis of fused bicyclic ring system 10 provided two
opportunities to introduce the pyrimidine early in the design ◆ Route 1, going through the same dipole for
the (3 + 2) cycloaddition step as the original route, was envisioned first.
However, the synthesis of intermediate 16 was not successful. ◆ The cycloaddition attempt between 19 and 2
together with aqueous formaldehyde solution in refluxing toluene unfortunately
did not provide the desired cycloadduct 17. However, the product formed was
isolated and identified as the intermediate oxazolidinone 21 ◆ We then focused our efforts on a thermal
cycloaddition of 2 with 21, anticipating a higher activation energy for 21 to
form the
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