Synthesis Of The Intermediate Of Ramelteon 1, 2, 6, 7-Tetrahydro-8H-indeno-[5, 4-b]furan-8-one

Insomnia is the maladjustment of the excitement or restraint of CNS, which is mainly caused by the long-time double thinking, heavy mental load and several other diseases. Insomnia often shows as waking up early and the diffculty in falling asleep and its matainance. Making people can not meet the requirement of sleep; insomnia always influences the everyday life of the patients.Drugs used for the treatment of insomnia are barbiturate, BZDs, Non-BZDs, MT and other assisted drugs for example, antipsychotics,antidepressants, antihistamines, and alternative natural medications. Ramelteon, (S)-N-[2-(1,6,7,8-tetrahydro- 2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, is the first FDA-approved selective melatonin receptor agonist. Ramelteon works by selectively binding and exerting agonist activity at MT1 and MT2 receptors in the SCN, which leads to falling asleep. It was created by Takeda Chemical Industries,and came to the market in 2005. Compared with other sedative-hypnotic drugs that act on GABAA,Ramelteon has the trait of unique target.What's more,it shows no addiction property in animal trial and clinic study,which makes it now extensively used and have good clinic and market value.The synthesis routes of the pivotal intermediate 1,2,6,7-Tetrahydro-8H-indeno -[5,4-b]furan-8-one were researched in this thesis. Phenol was selected as the raw material, through being aether, cyclization, formylation, Horner-Emmons reaction, hydrogenation, bromination, hydrolysis, cyclization, debromination, then the target product was prepared in total yield 8.4%. During the synthesis of 1,2,6,7- Tetrahydro-8H-indeno-[5,4-b]furan-8-one, the key intermediates,2,3-dihydro- 1-benzofuran-5-carbaldehyde was synthesized in good yield because of the improvement that made to the routes.Still diethyl malonate was used to synthesize Diethyl 3-(6,7-Dibromo-2,3-dihydro-1-benzofuran-5-yl)-methyl-malonate through two routes.. Then bromination, hydrolysis, cyclization, debromination were accompanied to synthesize the target product.The structures of the key intermediate and the target product 1,2,6,7-Tetrahydro- 8H-indeno-[5,4-b]furan-8-one were confirmed by 1H NMR spectra.