Study On The Synthesis Process Of Ramelteo

Sedative hypnotics drugs are used to treat insomnia,which can be roughly divided into barbiturates,benzodiazepines,non-benzodiazepines and melatonin.Ramelteon is the first melatonin receptor agonist approved by FDA for the treatment of insomnia.Compared with other Sedative hypnotics drugs,Ramelteon induces physiological sleep with fewer side effects and no addiction,which has broad application prospects.In this paper,the existing synthesis routes of Ramelteon are reviewed.These synthetic methods have their own characteristics,the main disadvantages are:expensive raw materials,the use of precious metal catalysts,inconvenient operation,long routes and complicated post-treatment.On the basis of integrating the existing synthetic methods,the synthetic route of Ramelteon was designed on the principle of cheap and easily available raw materials,few steps and simple operation.The key intermediate 10 was obtained from 2,3-dihydrobenzofuran by Vilsmeier-Haack reaction,Wittig condensation reaction,catalytic hydrogenation reaction,bromination reaction,Friedel-Crafts acylation reaction and cyclization reaction.After nucleophilic addition reaction,C=C double bond reduction,cyano reduction and deprotection,amino hydrochloride was obtained.After resolution,the required single S configuration was obtained,and then the target product Ramelteon was obtained through acylation reaction.Based on the designed synthetic route,the reaction conditions were optimized.Intermediate 3 introduces carboxylic acid groups directly to obtain intermediate 16,which reduces the subsequent hydrolysis steps.Compared with the literature reports,the yield of intermediate 8 was significantly improved by controlling the temperature.By changing the reagent and replacing thionyl chloride with chlorosulfonic acid,chlorination and Friedel-Crafts acylation were completed in one pot,which shortened the operation steps of intermediate 9 and simplified the operation.By optimizing the reaction conditions,the intermediate 14 was reduced to C=C double bond and cyano group simultaneously in the nickel chloride-sodium borohydride system,and the intermediate 18 was obtained by one-pot method,which shortened the operation steps and improved the production efficiency.Compared with the reported synthetic routes,this research route has shorter synthetic steps,avoids the use of precious metal catalysts,simplifies the operation and improves the production efficiency.The structures of all intermediates and final products were confirmed by ¹H NMR,¹³C NMR and MS.The chemical purity was over 99.8%and the optical purity was more than 99%by HPLC.The total yield of the route is 10.80%.The optimized process meets the industrial production standards,which lays the foundation for the pilot and industrial production of Ramelteon.