Study On Synthesis Method Of Key Intermediate Of Ramelteon

Ramelteon(Ramelteon),chemical name is(S)-N-[2-(1,2,6,7-tetrahydro-8Hindeno [5,4-b] furan-8-yl)] Propionamide.It is a safe,no addiction drug which help to regulate the sleep cycle and improve the quality of sleep.FDA did not classify it as a controlled drug,the first of its kind in hypnotics.This paper proposed a new synthetic route of the important intermediate about Ramelteon,which's chemical name is 2-(2,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-8-yl)ethyl acetate.The synthesis of 2-(2,6,7,8-tetrahydro-1H-indeno [5,4-b] furan-8-yl)ethyl acetate has been reported in the literature include process of current: 2,3-two hydrogen benzofuran as the starting material,through Vilsmeier-Haack reaction,Wittig-Horner reaction,hydrogenation,Bromination and hydrolysis of double protection,chloride,intramolecular Friedel-Crafts reaction,Wittig-Horner reaction,hydrogenation,debromination.The synthesis method has eleven steps.Although the current synthetic methods have been applied to the production of industrialization,but the route is long,and the efficiency is low(the total yield is 14-18%).At the same time,many reactions in the synthesis route do not meet the requirements of green chemical synthesis.A new synthetic route of 2-(2,6,7,8-tetrahydro-1H-indene[5,4-b]furan-8-yl)ethyl acetate with short synthetic route,high selectivity and high yield(~21.1%)has been developed.Starting from cheap and readily available 1,3-dimethoxybenzene,eight steps including reaction with ethylene oxide,ring closure,Friedel-Crafts reaction,protection of trifluoromethane sulfonic acid,carbonyl reduction,Heck reaction,Bromination and free radical ring closure.The synthesis route of the key intermediate 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b] furan-8-yl)ethyl acetate is greener and more economical,which can provide a reference for the synthesis of other key intermediates of Ramelteon and lay a foundation for further industrialization.