【结 构 式】 |
【药物名称】Dutasteride, GI-198745X, GI-198745, GG-745, Avodart, Avolve, Duagen 【化学名称】N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide 【CA登记号】164656-23-9 【 分 子 式 】C27H30F6N2O2 【 分 子 量 】528.54275 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, DERMATOLOGIC DRUGS, Hair Growth Stimulants, Oncolytic Drugs, Prostate Cancer Therapy, RENAL-UROLOGIC DRUGS, Steroid 5alpha-Reductase Type 1 Inhibitors, Steroid 5alpha-Reductase Type 2 Inhibitors |
合成路线1
【1】 Davis R,Millar A, et 2002. Preparation of 3-oxo-4-azasteroids via stereoselective hydrogenation.W0 2002046207 |
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) | 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 | |
(III) | 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 | |
(IV) | 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 | |
(V) | 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 |
合成路线2
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3
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 |