【结 构 式】 |
【分子编号】47571 【品名】(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 【CA登记号】 |
【 分 子 式 】C24H32F2O6 【 分 子 量 】454.5112864 【元素组成】C 63.42% H 7.1% F 8.36% O 21.12% |
合成路线1
该中间体在本合成路线中的序号:(VII)This compound has been obtained by several related ways: 1. The selective reduction of 6alpha,9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer is separated by column chromatography over Sephadex LH-20. 2. By selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (V) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol. 3. The selective reduction of fluocinolone acetonide (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane.
【1】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 . |
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) | 47567 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26F2O6 | 详情 | 详情 | |
(II) | 47568 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H28F2O6 | 详情 | 详情 | |
(III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
(IV) | 47569 | (4aS,4bR,5S,6aS,6bS,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 | |
(V) | 47570 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H32F2O6 | 详情 | 详情 | |
(VI) | 46292 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H30F2O6 | 详情 | 详情 | |
(VII) | 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 |
合成路线2
该中间体在本合成路线中的序号:(VIII)The intermediate 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregn-4-ene-3,20-dione (V) has been obtained in several related ways: 1. The selective reduction of 6alpha, 9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer, the intermediate (V), is separated by column chromatography over Sephadex LH-20. 2. The selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol also yields intermediate (V). 3. The selective reduction of fluocinolone acetonide (VII) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VIII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane to afford intermediate (V). The target compound is finally obtained by esterification of intermediate (V) with hexadecanoyl chloride (IX) in pyridine.
【1】 Axelsson, B.; Brattsand, R.; Kallstrom, L.; Thalen, A. (AstraZeneca plc); Novel steroid esters. JP 1994505233; US 5614514; US 5888995; WO 9213873 . |
【2】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 . |
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) | 47567 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26F2O6 | 详情 | 详情 | |
(II) | 47568 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H28F2O6 | 详情 | 详情 | |
(III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
(IV) | 47569 | (4aS,4bR,5S,6aS,6bS,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 | |
(V) | 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 | |
(VI) | 47570 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H32F2O6 | 详情 | 详情 | |
(VII) | 46292 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H30F2O6 | 详情 | 详情 | |
(VIII) | 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 | |
(IX) | 16480 | Palmitoyl Chloride; hexadecanoyl chloride | 112-67-4 | C16H31ClO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)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 |