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【结 构 式】 
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【药物名称】 【化学名称】16alpha,17alpha-[(R)-Butylidenedioxy]-6alpha,9-difluoro-11beta-hydroxy-21-[2-oxotetrahydrofuran-3(S)-ylsulfanyl]pregn-4-ene-3,20-dione 【CA登记号】193408-42-3 【 分 子 式 】C29H38F2O7S 【 分 子 量 】568.68281 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Glucocorticoids |
合成路线1
Ketal exchange of acetonide (I) with butyraldehyde (II) under acidic conditions provides the corresponding butylidene ketal (III). The primary alcohol group of (III) is then mesylated with methanesulfonyl chloride in pyridine to furnish (IV). Subsequent displacement of the mesylate group of (IV) by racemic alpha-mercapto-gamma-butyrolactone (V) gives rise to a mixture of the title compound along with its (R)-epimer (VI), which can be separated employing preparative HPLC. (1,2)
| 【1】 Angell, R.M.; Biggadike, K.; Farrell, R.M.; Flack, S.S.; Hancock, A.P.; Irving, W.R.; Lynn, S.M.; Procopiou, P.A.; Novel glucocorticoid antedrugs possessing a 21-(gamma-lactone) ring. J Chem Soc - Perkins Trans I 2002, 6, 831. |
| 【2】 Farrell, R.M.; Biggadike, K. (Glaxo Wellcome Inc.); 21-(2-Oxo-tetrahydrofuran)-thio pregnane derivs., a process for their production and pharmaceutical compsns. containing them. US 6013244; WO 9724367 . |
| 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) | 47571 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H32F2O6 | 详情 | 详情 | |
| (II) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (III) | 47572 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (IV) | 64290 | 2-[(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]-2-oxoethyl methanesulfonate | C26H36F2O8S | 详情 | 详情 | |
| (V) | 46294 | 3-sulfanyldihydro-2(3H)-furanone | C4H6O2S | 详情 | 详情 | |
| (VI) | 64291 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-6b-(2-{[(3R)-2-oxotetrahydro-3-furanyl]sulfanyl}acetyl)-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2 | C29H38F2O7S | 详情 | 详情 |
合成路线2
Mitsunobu coupling of alcohol (I) with thioacetic acid affords the thioacetate ester (II), which is further hydrolyzed to thiol (III) by means of hydrazine hydrate in cold THF. Treatment of (R)-alpha-hydroxy-gamma-butyrolactone (IV) with methanesulfonyl chloride and Et3N provides the chiral mesylate (V). This is then condensed with thiol (III) in the presence of K2CO3 in DMF to furnish the title compound. (2)
| 【1】 Angell, R.M.; Biggadike, K.; Farrell, R.M.; Flack, S.S.; Hancock, A.P.; Irving, W.R.; Lynn, S.M.; Procopiou, P.A.; Novel glucocorticoid antedrugs possessing a 21-(gamma-lactone) ring. J Chem Soc - Perkins Trans I 2002, 6, 831. |
| 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) | 47572 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (II) | 64292 | S-{2-[(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]-2-oxoethyl} ethanethioate | C27H36F2O6S | 详情 | 详情 | |
| (III) | 64293 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-8-propyl-6b-(2-sulfanylacetyl)-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O5S | 详情 | 详情 | |
| (IV) | 64294 | (3R)-3-hydroxydihydro-2(3H)-furanone | C4H6O3 | 详情 | 详情 | |
| (V) | 64295 | (3R)-2-oxotetrahydro-3-furanyl methanesulfonate | C5H8O5S | 详情 | 详情 |