|
【结 构 式】 
|
【药物名称】PNU-157706 【化学名称】3-Oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]-4-aza-5alpha-androst-1-ene-17beta-carboxamide 【CA登记号】 【 分 子 式 】C28H32F6N2O2 【 分 子 量 】542.56984 |
【开发单位】Pfizer (Originator) 【药理作用】Acne Therapy, Benign Prostatic Hyperplasia Therapy, DERMATOLOGIC DRUGS, ONCOLYTIC DRUGS, RENAL-UROLOGIC DRUGS, Steroid 5alpha-Reductase Inhibitors |
合成路线1
Title compound was prepared by two synthetic ways: 1) Treatment of hexafluorophenylpropanol (I) with KH and then with trifluoromethane- sulfonic anhydride gave triflate (II), which was converted into azide (III) by reaction with NaN3 in trifluoroacetic acid. Reduction of azide (III) with Raney-nickel in isopropanol afforded the corresponding amine, which was isolated as the hydrochloride salt (IV). Acid chloride (VI) was prepared from acid (V) by treatment with SOCl2. Then, condensation of (VI) with amine (IV) in the presence of pyridine provided the target amide.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 18970 | 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol | 718-64-9 | C9H6F6O | 详情 | 详情 |
| (II) | 18971 | 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl trifluoromethanesulfonate | C10H5F9O3S | 详情 | 详情 | |
| (III) | 18972 | 1-[1-azido-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzene; 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl azide | C9H5F6N3 | 详情 | 详情 | |
| (IV) | 18973 | 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanamine hydrochloride | C9H8ClF6N | 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 | |
| (VI) | 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 | |
| (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 |
合成路线2
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 |