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【结 构 式】 
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【分子编号】13527 【品名】methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate 【CA登记号】 |
【 分 子 式 】C20H31NO3 【 分 子 量 】333.47108 【元素组成】C 72.04% H 9.37% N 4.2% O 14.39% |
合成路线1
该中间体在本合成路线中的序号：(I)L-654066 has been obtained by three related ways: 1) Reaction of methyl (5alpha)-3-oxo-4-azaandrostene-17beta-carboxylate (I) with potassium hydroxide, followed by treatment with pyridyl disulfide, gives S-(2-pyridyl) (5alpha)-3-oxo-4-azaandrostene-17beta-thiocarboxylate (II). Compound (II) is reacted with isobutylmagnesium chloride (III) in THF to give (5alpha)-23-methyl-4-aza-21-norcholane-3,20-dione (IV), which is finally dehydrogenated using benzeneseleninic anhydride in chlorobenzene. 2) Compound (I) is converted to its dehydro analogue methyl (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylate (V) with benzeneselenic anhydride, followed by reaction with isobutylmagnesium bromide (VI) in THF in the presence of hexamethyldisilazane. 3) Reaction of (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylic acid (VII) with carbonyldiimidazole in THF gives 1-[[(5alpha,17beta)-3-oxo-4-azaandrost-1-en-17-yl]carbonyl]-1H-imidazole (VII), which is treated with isobutylmagnesium chloride (III) in THF in the presence of ferric chloride.
| 【1】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Substd.-4-aza-5alpha-androstenones and their use as 5alpha-reductase inhibitors. AU 8539167; EP 0155096; EP 0314199; ES 8702430; JP 1985222497; JP 1989093600; US 4760071 . |
| 【2】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Acyl-4-aza-5alpha-androst-1-en-3-ones as 5alpha-reductase inhibitors. EP 0271219; JP 1988139196 . |
| 【3】 Gormley, G.J.; Stoner, E. (Merck & Co., Inc.); Pharmaceutical combination for the treatment of prostatic hyperplasia, containing a 5alpha-reductase inhibitor and an antiandrogen. JP 1994506227; WO 9216213 . |
| 【4】 Bhattacharya, A.; Dolling, U.H.; Amato, J.S.; Williams, J.M. (Merck & Co., Inc.); Methods of synthesizing benign prostatic hypertropic agents and their intermediates. EP 0367502 . |
| 【5】 Williams, J.M. (Merck & Co., Inc.); Process for making 17-beta alkanoyl 3-oxo-4-aza-5-alpha-androst-1-enes. US 5061803 . |
| 【6】 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. |
| 【7】 Bhattacharya, A.; Williams, J.M.; Amato, J.S.; Dolling, U.-H.; Grabowski, E.J.J.; Acylimidazolides as versatile synthetic intermediates for the preparation of sterically congested amides and ketones: A practical synthesis of Proscar(R). Synth Commun 1990, 30, 17, 2683. |
| 【8】 Prous, J.; Mealy, N.; Castaner, J.; L-654066. Drugs Fut 1993, 18, 8, 701. |
| 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) | 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 | |
| (II) | 13528 | S-(2-pyridinyl) (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate | C24H32N2O2S | 详情 | 详情 | |
| (III) | 13529 | Chloro(isopentyl)magnesium | C5H11ClMg | 详情 | 详情 | |
| (IV) | 13530 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-7-(3-methylbutanoyl)hexadecahydro-2H-indeno[5,4-f]quinolin-2-one | C23H37NO2 | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 13534 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-7-(1H-Imidazol-1-ylcarbonyl)-4a,6a-dimethyl-1,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-2H-indeno[5,4-f]quinolin-2-one | C22H29N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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 |