Investigation On Synthesis Technique Of Ramelteon

Insomnia is a common,frequently occurring clinical disorder,and sedative hypnotic drugs are still the main treatment.Ramelteon is currently the only one available for the treatment of refractory insomnia melatonin receptor agonists,which also has the exact effect for chronic insomnia and short-term insomnia.Due to the dependence of the product and the tendency of drug abuse,ramelteon is classified as an unregulated hypnotic drug by FDA.This article focuses on the research background of Ramelteon and the recent research progress of synthesis.And its synthetic process is also described in detail.In terms of industrialization,convergent synthesis has much greater advantages.Through literature investigation,we select a simple and efficient synthetic route of easily realizing industrialized production.Ramelteon was systhesized through a five-step reaction from 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one by Wittig-Horner condensation,NaBH4 reduction,depratection,chiral separation and lysine propionylation.The total yield is 14.1%,and purity reaches to 99.8%.The convergent synthesis of target product,which not only overcomes the shortcoming of low yield caused by tedious reaction steps,but also increases the total yield.We optimized the process from feed ratio,reation temperature,reaction reagent,reaction time and post reaction treatment.The optimized laboratory scale process is verified by large-scale process.Proven process parameters are within the control range and the quality meets the specification.The structure of final product had been confirmed by HPLC data,1H-NMR and 13C-NMR spectroscopy.The improved process has the advantages of cheaper raw materials.Easier operation,higher yield and better product,and is quite suitable for industrialized production.