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【结 构 式】 
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【分子编号】47372 【品名】(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]dioxole-6b-carboxylic acid 【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：(VI)Hydrolysis of the known acetonide (I) with formic acid at 80 C afforded the trihydroxy compound (II) (1). Subsequent ketalization of (II) with butyraldehyde (III) in the presence of perchloric acid provided the butylidene ketal (IVa-b) as a 4:1 mixture of R/S epimers at C-20. Selective hydrogenation of the 1-2 double bond of (IVa-b) by iron pentacaarbonyl/sodium hydroxide gave (V). The carboxylate group of (V) was then activated as the mixed anhydride (VI) by reaction with diethyl chlorophosphate and Et3N. Condensation of anhydride (VI) with the sodium salt of N-hydroxypyridine-2-thione (VII) produced the pyridyl ester (VIII). Photolysis of ester (VIII) by irradiation with a tungsten lamp in the presence of dimethyl disulfide gave rise to the target methyl thioether as a diastereomeric mixture. The major (20R)-epimer was finally isolated by preparative HPLC.
| 【1】 Ashton, M.J.; et al.; Anti-inflammatory 17beta-thioalkyl-16alpha, 17alpha-ketal and -acetal androstanes: A new class of airway selective steroids for the treatment of asthma. J Med Chem 1996, 39, 25, 4888. |
| 【2】 Ashton, M.J.; Karlsson, S.J.-A.; Vacher, B.Y.J.; Withnall, M.T. (Aventis Pharma SA); New steroids. EP 0675897; JP 1996504806; WO 9414834 . |
| 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) | 59446 | (4aS,4bR,5S,6aS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a,8,8-tetramethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C23H28F2O6 | 详情 | 详情 | |
| (II) | 59447 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11,16,17-trihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid | C20H24F2O6 | 详情 | 详情 | |
| (III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IV) | 59448 | (4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H30F2O6 | 详情 | 详情 | |
| (V) | 59449 | (4aS,4bR,5S,6aS,8S,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H30F2O6 | 详情 | 详情 | |
| (VI) | 47372 | (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]dioxole-6b-carboxylic acid | C24H32F2O6 | 详情 | 详情 | |
| (VII) | 59450 | [(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]carbonyl diethyl phosphate | C28H39F2O9P | 详情 | 详情 | |
| (VIII) | 59451 | sodium 2-thioxo-1(2H)-pyridinolate | C5H4NNaOS | 详情 | 详情 | |
| (IX) | 59452 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-8-propyl-6b-({[2-thioxo-1(2H)-pyridinyl]oxy}carbonyl)-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 | C29H33F2NO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of carboxylic acid (I) with diethyl chlorophosphate (II) in the presence of Et3N furnished the corresponding mixed anhydride (III). This was then condensed with the sodium salt of alpha-mercapto-gamma-butyrolactone (IV) to produce the title thioester.
| 【1】 Biggadike, K.; Procopiou, P.A. (Glaxo Wellcome plc); Lactone derivs. of 17beta-carboxy, carbothio and amide androstane derivs.. JP 1999501675; US 6197761; WO 9724365 . |
| 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) | 47372 | (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]dioxole-6b-carboxylic acid | C24H32F2O6 | 详情 | 详情 | |
| (II) | 23623 | Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate | 814-49-3 | C4H10ClO3P | 详情 | 详情 |
| (III) | 47373 | [(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]carbonyl diethyl phosphate | C28H41F2O9P | 详情 | 详情 | |
| (IV) | 46294 | 3-sulfanyldihydro-2(3H)-furanone | C4H6O2S | 详情 | 详情 |