Study On Pimecrolimus-synthetic Technology, Purification, Structure Identification

Pimecrolimus [commodity name] Elidel,a new generation of immunosuppressant drugs developed by Novartis company,and in 2002 the first listing in the United Kingdom. mainly used as immunosuppressive drugs and the treatment of atopic dermatitis, as an antipsoriasis drugs and the treatment of asthma drugs have entered Phase II clinical trial stage,as an anti-arthritis drug and treatment of G1 inflammatory drugs will soon enter clinical trials. Pimecrolimus is a derivative of antibacterials ascomycin (FK520) which belongs to macrolide antibiotic drug. Domestic manufacturers are not yet available, and the side products from the synthesis processes of pimecrolimus are unreported ascomycin derivatives. Therefore,the study of the drug synthesis method and the separation of the side products for the development of new drugs have some value.By comparison of the merits and demerits of the processes of the preparation of pimecrolimus,on the objective of being friendly to environment,employing less time,being suitable for industrial scale up and so on ,chose the better experiment route .In this paper, pimecrolimus was synthesized by using ascomycin as a starting material through esterification and chlorination. The optimal synthesis processes of the product is obtained through orthogonal experiments. The optimal synthesis processes of pimecrolimus were as follows:(1) the hydroxyl group conversion reaction: used trifuoromethanesulfonic anhydride as hydroxyl group conversion reagent, molar ratio of trifuoromethanesulfonic anhydride to ascomycin was 1:1.4, used 2,6-lutidine as base, base molar equivalents was 1.5 (based on ascomycin ), solvent was dichloromethane, reaction temperature was -20℃; (2) the chlorine substitution reaction: used benzyltriethylammonium chloride as chloride-ion reagen, chloride-ion reagen molar equivalents was 1.5 (based on ascomycin ), reaction temperature was 30℃, reaction time was 15hours. With this process, the purity was 62.5%, and the yield was 55.2%. Through orthogonal experiments, the synthesis process was improved and developed , the goal of yield was improved.,and the costs were reduced.The pure products were obtianed by columnchromatography and crystallization.The purity was beyong 95%, and the finally yield was 41.1%. The structure of pimecrolimus was confirmed by metling , 1H NMR, 13CNMR, and ESI/MS analysis.In this experiment, a few unreported ascomycin derivatives were separated and purified from the synthesis processes of pimecrolimus by combination of silica get chromatography and high speed countercurrent chromatography (HSCCC).The purity was beyong 95%.