Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation

Asymmetric synthesis of a novel non-benzodiazepine hypnotic drug Ramelteon (TAK-375) was accomplished via asymmetric hydrogenation. Development of the substrate design revealed that a novel class of substrate, allylic acylamine 4a, was hydrogenated with a Ru-BINAP catalyst in 95% ee and 98% yield. The effectiveness and robustness of the reaction were demonstrated on a 700-g scale.

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(S)-N-[2-(6-Methoxy-2,3-dihydro-1H-inden-1-yl)ethyl]propionamideC15H21NO2Ee = 99%[α]D25=-4.4 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)