氟替卡松丙酸酯 [CAS80474-14-2]合成路线图解——原料药厂家东康源.doc

武汉东康源氟替卡松丙酸脂 CAS:80474-14-2合成路线图解核心提示：NameFluticasone propionate;FN-25;CCI-18781;Fluspiral;Flovent Diskus;Flusonal;Flovent DPI;Fluxonal;Flonase;Flunase;Floven.NameFluticasone propionate;FN-25;CCI-18781;Fluspiral;Flovent Diskus;Flusonal;Flovent DPI;Fluxonal;Flonase;Flunase;Flovent;Flixotide;Flutide;Cutivate;FlixonaseChemical Name(6alpha,11beta,16alpha,17alpha)-6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid S-(fluoromethyl) ester6alpha,9-Difluoro-11beta,17-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-carbothioic acid S-(fluoromethyl) ester 17-propionateCAS80474-14-2Related CASFormulaC25H31F3O5SStructureFormula Weight500.58202Te18007166089 E-mail: qq:2847831942Company武汉东康源科技有限公司Activity/MechanismAntiallergy/Antiasthmatic Drugs, Asthma Therapy, Atopic Dermatitis, Agents for, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, CorticosteroidsSyn. Route3Route 1the oxidation of flumethasone (i) with oxygen and k2co3 in methanol gives 6alpha,9alpha-difluoro-11beta,17alpha-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-carboxylic acid (ii), which is partially acylated with propionic anhydride in pyridine to afford the corresponding 17alpha-propionyloxy derivative (iii) . the reaction of (iii) with dimethylthiocarbamoyl chloride and triethylamine in dichloromethane gives the corresponding carbothioic acid (iv), which is esterified with bromochloromethane and sodium bicarbonate in dimethylacetamide yielding the chloromethyl carbothioate ester (v). finally, this compound is treated with agf in acetonitrile.List of intermediatesNo.benzyl (2s)-2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-6-hydroxy-6-methylheptanoate(i)benzyl (2s)-6-azido-2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-6-methylheptanoate(ii)2-(3s)-7,7-dimethyl-2-oxoazepanyl-1h-isoindole-1,3(2h)-dione(iii)(3s)-3-amino-7,7-dimethyl-2-azepanone(iv)tert-butyl (3s)-7,7-dimethyl-2-oxoazepanylcarbamate(v)Reference 1:edwards, j.a. (syntex (usa), inc.); 17beta-thiocarboxylic acid esters of 6alpha,6beta-difluoro-3-oxoandrost-4-enes. us 4187301 . Reference 2:phillips, g.h.; bain, b.m.; williamson, c.; steeples, i.p.; laing, s.b. (glaxo wellcome plc); androstane 17beta-carbothioates. gb 2088877; nl 8100707; us 4335121 . Reference 3: castaner, j.; prous, j.; fluticasone propionate. drugs fut 1991, 16, 5, 424.Route 2new methods for the synthesis of fluticasone propionate have been reported:1) the reaction of 6alpha,9alpha-difluoro-11beta,17alpha-dihydroxy-16alpha-methyl-3-oxo and rosta-1,4-diene-17beta-carboxylic acid (i) with carbonyldiimidazole (cdi) and h2s in dmf gives the corresponding carbothioic acid (ii), which is selectively acylated with propionyl chloride and triethylamine in ch2cl2, yielding the 17alpha-propionyloxy derivative (iii). the reaction of (iii) with ch2brcl and nahco3 in dma affords the s-chloromethyl ester (iv), which by reaction with nai in refluxing acetone is converted to the s-iodomethyl ester (v). finally, this compound is treated with agf in acetonitrile.2) by esterification of thioacid (ii) with bromofluoromethane or fluoroiodomethane by means of k2co3 in dmf.List of intermediatesNo.benzyl (2s)-6-azido-2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-6-methylheptanoate(i)(3s)-3-amino-7,7-dimethyl-2-azepanone(iii)tert-butyl (3s)-7,7-dimethyl-2-oxoazepanylcarbamate(iv)methyl 2-(6s)-6-amino-2,2-dimethyl-7-oxoazepanylacetate(ii)1-(2-bromoethoxy)-1-methylethyl 2-bromoethyl ether(v)Reference 1: phillips, g.h.; bain, b.m.; williamson, c.; steeples, i.p.; laing, s.b. (glaxo wellcome plc); androstane 17beta-carbothioates. gb 2088877; nl 8100707; us 4335121 . Reference 2:phillips, g.h.; bailey, e.j.; bain, b.m.; et al.; synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17beta-carbothioates and -17beta-carboselenoates. j med chem 1994, 37, 22, 3717.Route 3the oxidation of flumethasone (i) with pd(oac)2, pph3 and io4h in dma gives the 17-beta-carboxylic acid (ii), which is selectively monoacylated with propionyl chloride (iii) and et2nh in acetone, yielding the 17-alpha-propionyloxy derivative (iv). the reaction of (iv) with n,n-dimethylthiocarbamoyl chloride (v), tea and nai in 2-butanone affords the thioanhydride (vi), which is finally treated with chlorofluoromethane and shna in dma to provide the desired fluoromethyl thioester.List of intermediatesNo.benzyl (2s)-2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-6-hydroxy-6-methylheptanoate(i)benzyl (2s)-6-azido-2-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-6-methylheptanoate(ii)2-(3s)-7,7-dimethyl-2-oxoazepanyl-1h-isoindole-1,3(2h)-dione(iv)(2r,4r,5r,6r,8s,11s,12r,19r,20r)-5-(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2h-pyran-2-yloxy-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-13-oxa-15,18-diazatricyclo(15,20)icos-1(18)-ene-7,9,14-trione(iii)Reference 1:cooper, a.j.; chambe