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【结 构 式】 
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【分子编号】14477 【品名】(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 【CA登记号】 |
【 分 子 式 】C24H30F2O6 【 分 子 量 】452.4954064 【元素组成】C 63.71% H 6.68% F 8.4% O 21.21% |
合成路线1
该中间体在本合成路线中的序号：(III)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)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.
| 【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 |