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【结 构 式】 
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【药物名称】Tipifarnib, NSC-702818, R-115777, Zarnestra 【化学名称】(+)-(R)-6-[1-Amino-1-(4-chlorophenyl)-1-(1-methylimidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one 【CA登记号】192185-72-1, 192185-68-5 (racemate), 192185-70-9 (racemic; diHCl), 192185-69-6 (racemic; fumarate) 【 分 子 式 】C27H22Cl2N4O 【 分 子 量 】489.40859 |
【开发单位】Janssen (Originator), National Cancer Institute (Codevelopment) 【药理作用】Bladder Cancer Therapy , Brain Cancer Therapy, Breast Cancer Therapy, Glioblastoma MultiformeTherapy, Leukemia Therapy, Lung Cancer Therapy, Melanoma Therapy, Myeloid Leukemia Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
Cyclization of 3-(3-chlorophenyl)-N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)quinolin-2(1H)-one (V), which is methylated with iodomethane and NaOH/benzyltrimethylammonium chloride in THF to provide 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.
| 【1】 Sorbera, L.A.; Castaner, J.; Fernandez, R.; R-115777. Drugs Fut 2001, 26, 5, 453. |
| 【2】 Venet, M.G.; Angibaud, P.R.; Muller, P.; Sanz, G.C. (Janssen Pharmaceutica NV); Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivs.. EP 0865440; JP 1998511405; US 6037350; WO 9721701 . |
| 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) | 46720 | (E)-3-(3-chlorophenyl)-N-phenyl-2-propenamide | C15H12ClNO | 详情 | 详情 | |
| (II) | 46721 | 4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone | C15H12ClNO | 详情 | 详情 | |
| (III) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
| (IV) | 46722 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone | C22H15Cl2NO2 | 详情 | 详情 | |
| (V) | 46723 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone | C22H13Cl2NO2 | 详情 | 详情 | |
| (VI) | 46724 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone | C23H15Cl2NO2 | 详情 | 详情 | |
| (VII) | 38630 | 1-methyl-1H-imidazole | 616-47-7 | C4H6N2 | 详情 | 详情 |
| (VIII) | 46725 | 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone | C27H21Cl2N3O2 | 详情 | 详情 |