The Study Of The Synthetic Route For Melatonin Receptor Agonist Ramelteon

Ramelteon(Rozerem),a novel selective-agonist of melatonin(MT)receptor approved by USFDA in 2005,has been frequently prescribed for the treatment of insomnia.It can simulate the physiological role of pineal gland to release melatonin that regulating the sleep cycle and improving the sleep quality.Base on the reported synthetic methods of ramelteon,we developed a synthetic route suitable for the large-scale production of ramelteon.Accordingly,2,3-dihydrobenzofuran was employed as the starting material,which experienced a sequence of Vilsmeier-Haack reaction,Homer-Emmons condensation,catalytic hydrogenation,bromonization,hydrolysis,cyclization and debromination to furnish the key intermediate 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one.Then,it underwent Hormer-Emmons condensation,catalytic hydrogenation and chiral resolution to afford(s)-2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)ethylamine,which was condensed with propionyl chloride to yield ramelteon in the overall yield of 12.2%,which increased by 7.2%compared with the reported method.The structure of ramelteon was confirmed by IR,1H-NMR,13C-NMR and MS and the chiral purity was determined by chiral HPLC with e.e.value of 99.5%.Throughout the optimized procedure in the thesis,the starting material and reagents are widely available,reaction conditions are mild,as well as with high purity of ramelteon.