A Scalable andSafe Synthesis of Ramelteon: IntegratingBatch Steps with Asymmetric Hydrogenation and Microreactor Technology

Abstract Ramelteon, a melatonin receptor agonist approved by the FDA in 2005 for the treatment of insomnia, serves as the focus of this study. We present a comprehensive investigation into the development of an advanced and efficient synthetic route for ramelteon, enabling batch-scale production of the active pharmaceutical ingredient (API) to meet commercial demands. The four-step synthetic sequence commences with commercially available 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (2), proceeding through: Wittig–Horner reaction, asymmetric hydrogenation of the α,β-unsaturated nitrile double bond, continuous-flow microfluidic hydrogenation for nitrile reduction, and N-propionylation. The synthesized ramelteon exhibited exceptional quality, with a chromatographic purity exceeding 99.9% (by area normalization), enantiomeric excess (ee) >99.9%, and an overall yield of 40%. A key advantage of this approach is its circumvention of the conventional high-pressure batch hydrogenation typically employed in industrial ramelteon synthesis. Furthermore, the developed protocol demonstrates potential applicability for the reduction of other α,β-unsaturated nitrile pharmaceutical intermediates. This scalable and high-efficiency synthetic strategy not only establishes safer production conditions for ramelteon manufacturing but also provides novel insights into the catalytic reduction of α,β-unsaturated nitriles in pharmaceutical synthesis.