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Name Fluticasone propionate;FN-25;CCI-18781;Fluspiral;Flovent Diskus;Flusonal;Flovent DPI;Fluxonal;Flonase;Flunase;Flovent;Flixotide;Flutide;Cutivate;Flixonase
Chemical 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) ester
      6alpha,9-Difluoro-11beta,17-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-carbothioic acid S-(fluoromethyl) ester 17-propionate
CAS 80474-14-2
Related CAS
Formula C25H31F3O5S
Structure
Formula Weight 500.58202
Stage 上市-1990
Company GlaxoSmithKline (Originator), Almirall Prodesfarma (Licensee), Menarini (Licensee), Elan (Distributor)
Activity/Mechanism Antiallergy/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, Corticosteroids
Syn. Route 3
Route 1
the 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 intermediates No.
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 2
new 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 intermediates No.
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-oxoazepanyl]acetate (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 3
the 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 intermediates No.
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-yl]oxy]-11-ethyl-4-methoxy-2,4,6,8,12,19-hexamethyl-13-oxa-15,18-diazatricyclo[10.6.2.0(15,20)]icos-1(18)-ene-7,9,14-trione (iii)
Reference 1:
    cooper, a.j.; chamberlin, s.a.; hufnagel, j.j.; barkalow, j.; hossain, a.; langridge, d.c. (abbott laboratories inc.); method for the preparation of fluticasone and related 17betaeta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods. wo 0162722 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名氟替卡松丙酸酯;英文名Fluticasone propionate;FN-25;CCI-18781;Fluspiral;Flovent Diskus;Flusonal;Flovent DPI;Fluxonal;Flonase;Flunase;Flovent;Flixotide;Flutide;Cutivate;Flixonase;CAS[80474-14-2]

 
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