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【结 构 式】 
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【分子编号】18977 【品名】(8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl chloride 【CA登记号】 |
【 分 子 式 】C20H27ClO2 【 分 子 量 】334.88588 【元素组成】C 71.73% H 8.13% Cl 10.59% O 9.56% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The reaction of 3-oxo-4-androstene-17beta-carboxylic acid (I) with SOCl2/pyridine in THF gives the acyl chloride (II), which is condensed with 2,5-bis(trifluoromethyl)aniline (III) by means of pyridine in refluxing THF, yielding amide (IV). The oxidation of (IV) with KMnO4/NaIO4/Na2CO3 in refluxing tert-butanol/water affords the seco-steroid (V), which is cyclized with NH3 in ethylene glycol at 180 C to give the 5-unsaturated azasteroid (VI). The hydrogenation of (VI) with H2 over PtO2 in acetic acid yields the saturated azasteroid (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DCQ)/bis(trimethylsilyl)trifluoroacetamide in dioxane.
| 【1】 Ellsworth, K.; Mosley, R.T.; Chang, B.; Rasmusson, G.H.; Harris, G.S.; Patel, G.F.; Tolman, R.L.; Bakshi, R.K.; 4-Aza-3-oxo-5alpha-androst-1-ene-17beta-N-aryl-car. J Med Chem 1995, 38, 17, 3189. |
| 【2】 Graul, A.; Silvestre, J.S.; Castañer, J.; Dutasteride. Drugs Fut 1999, 24, 3, 246. |
| 【3】 Rasmusson, G.H.; Reynolds, G.F.; Steinberg, N.G.; Walton, E.; Patel, G.F.; Liang, T.; Cascieri, M.A.; Cheung, A.H.; Brooks, J.R.; Berman, C.; Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. J Med Chem 1986, 29, 11, 2298. |
| 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) | 14892 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid; 4-Androstene-3-oxo-17-beta-carboxylic acid | 7385-78-6 | C20H28O3 | 详情 | 详情 |
| (II) | 18977 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl chloride | C20H27ClO2 | 详情 | 详情 | |
| (III) | 22446 | 2,5-bis(trifluoromethyl)phenylamine; 2,5-bis(trifluoromethyl)aniline | 328-93-8 | C8H5F6N | 详情 | 详情 |
| (IV) | 22447 | (8S,9S,10R,13S,14S,17S)-N-[2,5-bis(trifluoromethyl)phenyl]-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide | C28H31F6NO2 | 详情 | 详情 | |
| (V) | 22448 | 3-((3S,3aS,5aS,6R,9aS,9bS)-3-[[2,5-bis(trifluoromethyl)anilino]carbonyl]-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl)propionic acid | C27H31F6NO4 | 详情 | 详情 | |
| (VI) | 22449 | (4aR,4bS,6aS,7S,9aS,9bS)-N-[2,5-bis(trifluoromethyl)phenyl]-4a,6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C27H30F6N2O2 | 详情 | 详情 | |
| (VII) | 22450 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-[2,5-bis(trifluoromethyl)phenyl]-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C27H32F6N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)2) Alternatively, oxoandrostenecarboxylic acid (VII) was converted into acid chloride (VIII) by treatment with oxalyl chloride and a trace of DMF in CH2Cl2. Subsequent condensation of (VIII) with amine (IV), prepared as before, yielded the corresponding amide (IX). The oxidative cleavage of (IX) with NaIO4 and KmnO4 afforded ketoacid (X), which was cyclized with ammonia in ethylene glycol at 180 C providing the azasteroid (XI). Catalytic hydrogenation of the double bond over PtO2 gave (XII), which was finally oxidized with phenylseleninic anhydride (XIII) in boiling chlorobenzene to furnish the 1,2-unsaturated compound.
| 【1】 Panzeri, A.; Nesi, M.; Di Salle, E. (Pharmacia & Upjohn AB); Phenylsubstd. 4-azasteroid fluoroderivs.. EP 0793671; JP 1998509188; US 5922728; WO 9710257 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 14982 | (2R,3R,7S,10R)-7-[(2S,3E,5E,7E,9S,11R)-11-(1,3-dithian-2-yl)-2-methoxy-3,9-dimethyl-3,5,7-dodecatrienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; (1S,2E,4E,6E,8S,10R)-10-(1,3-dithian-2-yl)-2,8-dimethyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4,6-undecatrienyl methyl ether | C29H48O4S2 | 详情 | 详情 | |
| (VIII) | 18977 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl chloride | C20H27ClO2 | 详情 | 详情 | |
| (IX) | 18978 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide | C29H33F6NO2 | 详情 | 详情 | |
| (X) | 18979 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3a,6-dimethyl-7-oxo-3-([[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]amino]carbonyl)dodecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C28H33F6NO4 | 详情 | 详情 | |
| (XI) | 18980 | (4aR,4bS,6aS,7S,9aS,9bS)-4a,6a-dimethyl-2-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C28H32F6N2O2 | 详情 | 详情 | |
| (XII) | 18981 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C28H34F6N2O2 | 详情 | 详情 | |
| (XIII) | 18982 | 3-Oxo-1,3-diphenyl-1lambda(4),3lambda(4)-diselenoxan-1-one; Benzeneseleninic anhydride | 17697-12-0 | C12H10O3Se2 | 详情 | 详情 |