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【结 构 式】 
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【分子编号】14479 【品名】(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 【CA登记号】 |
【 分 子 式 】C25H31ClF2O5S 【 分 子 量 】517.0336464 【元素组成】C 58.08% H 6.04% Cl 6.86% F 7.35% O 15.47% S 6.2% |
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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
该中间体在本合成路线中的序号：(IV)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.
| 【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 | CAS号 | 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 |