Fluticasone propionate, FN-25, CCI-18781, Fluspiral, Flovent Diskus, Flusonal, Flovent DPI, Fluxonal, Flonase, Flunase, Flovent, Flixotide, Flutide, Cutivate, Flixonase, -Drug Synthesis Database

【结构式】

【药物名称】Fluticasone propionate, FN-25, CCI-18781, Fluspiral, Flovent Diskus, Flusonal, Flovent DPI, Fluxonal, Flonase, Flunase, Flovent, Flixotide, Flutide, Cutivate, Flixonase

【化学名称】(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

【CA登记号】80474-14-2

【分子式】C₂₅H₃₁F₃O₅S

【分子量】500.58202

【开发单位】GlaxoSmithKline (Originator), Almirall Prodesfarma (Licensee), Menarini (Licensee), Elan (Distributor)

【药理作用】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

合成路线1 合成路线2 合成路线3

合成路线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.

参考文献中间体

【1】 Edwards, J.A. (Syntex (USA), Inc.); 17beta-Thiocarboxylic acid esters of 6alpha,6beta-difluoro-3-oxoandrost-4-enes. US 4187301 .
【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 .
【3】 Castaner, J.; Prous, J.; Fluticasone Propionate. Drugs Fut 1991, 16, 5, 424.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	14475	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one	2557-49-5	C₂₂H₂₈F₂O₅	详情	详情
(II)	14476	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₁H₂₆F₂O₅	详情	详情
(III)	14477	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₄H₃₀F₂O₆	详情	详情
(IV)	14478	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid		C₂₄H₃₀F₂O₅S	详情	详情
(V)	14479	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-17-[[(chloromethyl)sulfanyl]carbonyl]-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate		C₂₅H₃₁ClF₂O₅S	详情	详情

合成路线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.

参考文献中间体

【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 .
【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.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	14476	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid	C₂₁H₂₆F₂O₅	详情	详情
(II)	14481	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid	C₂₁H₂₆F₂O₄S	详情	详情
(III)	14478	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid	C₂₄H₃₀F₂O₅S	详情	详情
(IV)	14479	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-17-[[(chloromethyl)sulfanyl]carbonyl]-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate	C₂₅H₃₁ClF₂O₅S	详情	详情
(V)	14484	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-17-[[(iodomethyl)sulfanyl]carbonyl]-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate	C₂₅H₃₁F₂IO₅S	详情	详情

合成路线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.

参考文献中间体

【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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	14475	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one	2557-49-5	C₂₂H₂₈F₂O₅	详情	详情
(II)	14476	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₁H₂₆F₂O₅	详情	详情
(III)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情
(IV)	14477	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₄H₃₀F₂O₆	详情	详情
(V)	54928	Dimethylthiocarbamoyl chloride; N,N-Dimethylthiocarbamoyl chloride	16420-13-6	C₃H₆ClNS	详情	详情
(VI)	54929			C₂₇H₃₅F₂NO₆S	详情	详情
(VII)	54930	Chlorofluoromethane; Monochloromonofluoromethane	593-70-4	CH₂ClF	详情	详情

Extended Information