Improvement Of Synthesis Processes Of Ramelteon、Apremilast And Chalcone

AbstractThe synthetic methods of Ramelteon(anti-insomnia medication), Apremilast(anti-psoria sis medication) and Chalcone(key intermediate of chiral chemicals) were studied on the basis of the view of domestic and international literature. Due to the disadvantages of the existing methods, we propose the modified synthetic methods for them. Using chiral split method, microwave-assisted method and Pd-catalyzed Heck coupling reaction to improve the yields of them, the specific contents are as follows:(1) The first of this section is to resolute the enantiomer(±)-2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) acetic acid(which is one key intermediate of Ramelteon) using(S)-phenyethylamine as the resolution agent, the ee value of the s-isomer can reach as high as 97%, finally, Ramelteon could be gotten from it. Meanwhile, we resolute another key intermediate of Ramelteon: 2-(1,6,7,8-tetrahydro-2H--indeno [5,4-b] furan-8-yl) ethylamine which has an amino group, using L-(-)-DBTA as the resolution agent, and then Ramelteon with 99% ee value was prepared by reaction of it with propionyl chloride. Compared with the original route, this route can improve the ee value and yield.Meanwhile, we also have synthesized a series of chalcones through the method of Pd-catalyzed Heck-type coupling via C–N cleavage.(2) Apremilast is the first PDE4 inhibitor approved by FDA for plaque psoriasis therapy, the chiral key intermediate of Apremilast, can be efficiently synthesized via a new method employing microwave irradiation in 20 min, with ethanol as solvent, and Ts OH as catalyst, the ee value is 99%. We greatly reduce the reation time from 24 h to 20 min, and use more moderate solvent Et OH instead of Ac OH.(3) We also have synthesized a series of chalcones through the method of Pd-catalyzed Heck-type coupling via C–N cleavage. The best method was: Pd(OAc)2 as the catalyst, Ag2CO3 and Ag2O(1:1) as oxidizing agent, dimethyl sulfoxide as solvent, the reaction temperature was 120 oC. Compared with the original route, this route can be carried out under alkaline conditions, thus effectively expanding the scope of the reaction substrates. And it also can effectively reduce the production of by-products, thereby increasing the yield.