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【结 构 式】

【分子编号】22446

【品名】2,5-bis(trifluoromethyl)phenylamine; 2,5-bis(trifluoromethyl)aniline

【CA登记号】328-93-8

【 分 子 式 】C8H5F6N

【 分 子 量 】229.1248592

【元素组成】C 41.94% H 2.2% F 49.75% N 6.11%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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:(III)

2) The oxidation of 3-oxo-4-androstene-17beta-carboxylic acid (I) with KMnO4/NaIO4/Na2CO3 in refluxing tert-butanol/water affords the seco-steroid (VIII), which is cyclized with NH3 in ethylene glycol at 180 C, giving the 5-unsaturated steroid (IX). The hydrogenation of (IX) with H2 over PtO2 in acetic acid yields the saturated azasteroid (X), which is esterified with 2,2-dimethoxypropane/HCl in methanol to afford the corresponding methyl ester (XI). The dehydrogenation of (XI) with phenylseleninic anhydride in refluxing chlorobenzene gives the 1-unsaturated azasteroid (XII), which is hydrolyzed with KOH in refluxing methanol/water to yield the corresponding unsaturated free acid (XIII). The esterification of (XIII) with 2,2'-dipyridyl disulfide (XIV) by means of triphenylphosphine in toluene affords the 2-pyridyl thioester (XV), which is finally amidated with 2,5-bis(trifluoromethyl)aniline (III) by means of silver trifluomethanesulfonate in dichloromethane. 3) The previously obtained unsaturated free acid (XIII) can also be treated with SOCl2 in pyridine to give the corresponding acyl chloride (XVI), which is then condensed directly with 2,5-bis(trifluoromethyl)aniline (III) in pyridine.

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
(III) 22446 2,5-bis(trifluoromethyl)phenylamine; 2,5-bis(trifluoromethyl)aniline 328-93-8 C8H5F6N 详情 详情
(VIII) 22451 (3S,3aS,5aS,6R,9aS,9bS)-6-(2-carboxyethyl)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid C19H28O5 详情 详情
(IX) 13010 (4aR,4bS,6aS,7S,9aS,9bS)-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-carboxylic acid C19H27NO3 详情 详情
(X) 22453 (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid C19H29NO3 详情 详情
(XI) 13527 methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate C20H31NO3 详情 详情
(XII) 13009 methyl (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate C20H29NO3 详情 详情
(XIII) 13533 (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid C19H27NO3 详情 详情
(XIV) 22457 2,2'-Dithiodipyridine; 2-(2-pyridinyldisulfanyl)pyridine; 2,2'-Dipyridinyl disulfide 2127-03-9 C10H8N2S2 详情 详情
(XV) 22458 S-(2-pyridinyl) (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate C24H30N2O2S 详情 详情
(XVI) 18975 (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carbonyl chloride C19H26ClNO2 详情 详情
Extended Information