【结 构 式】 ![]() |
【分子编号】69419 【品名】2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline 【CA登记号】 |
【 分 子 式 】C17H15ClN2O3 【 分 子 量 】330.77 【元素组成】C 61.73% H 4.57% Cl 10.72% N 8.47% O 14.51% |
合成路线1
该中间体在本合成路线中的序号:(VII)Treatment of 3’,4’-dimethoxyacetophenone (I) with cold concentrated nitric acid in the presence of a trace amount of NaNO2 gives the 2’-nitro-acetophenone derivative (II), which is then reduced to the corresponding ortho-amino-acetophenone (III) by catalytic hydrogenation over Pd/C in AcOH/MeOH. Condensation of 2’-amino-acetophenone (III) with ethyl formate using sodium methoxide in THF leads to 6,7-dimethoxyquinolin-4-one (IV), which is converted to the chloroquinoline (V) by treatment with POCl3 in refluxing toluene . Subsequent coupling of 4-chloro-6,7-dimethoxyquinoline (V) with 4-amino-3-chlorophenol (VI) by means of either sodium hydride in DMSO or potassium tert-butoxide in dimethylacetamide gives the phenoxyquinoline adduct (VII). Finally, tivozanib is obtained by reaction of 3-amino-5-methylisoxazole (VIII) with phenyl chloroformate in pyridine/dimethylacetamide followed by coupling of the acylating intermediate with the aniline derivative (VII) , or alternatively, by activation of aniline (VII) with triphosgene and triethylamine followed by addition of 3-amino-5-methylisoxazole (VIII) .
【1】 Matsunaga, N., Nakajima, T., Yoshino, A., Yoshida, S. (Kirin Brewery Co.,Ltd.). N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea salt in crystalline form. EP 1559715, US 2006052415, WO 2004035572. |
【2】 Suzuki, R. et al. Structure-activity relationship and antitumor activities of azolyl quinoline-urea derivatives as novel orally active selective VEGF receptor tyrosine kinase inhibitors. 23rd Med Chem Symp (Nov 24-26, Tsukuba) 2004, Abst 1P-30. |
【3】 Kubo, K., Sakai, T., Hasegawa, K., Fujiwara, Y., Isoe, T., Nagao, R. (Kirin Brewery Co., Ltd.). Quinoline derivative having azolyl group and quinazoline derivative. EP 1382604, EP 1652847, JP 2003012668, JP 2004224800, US 2003087907, US 6821987, WO 2002088110. |
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) | 69415 | 1-(3,4-dimethoxyphenyl)ethanone;3,4-Dimethoxyacetophenone;3',4'-Dimethoxyacetophenone | 1131-62-0 | C10H12O3 | 详情 | 详情 |
(II) | 69416 | 1-(4,5-dimethoxy-2-nitrophenyl)ethanone;4',5'-Dimethoxy-2'-nitroacetophenone | 4101-32-0 | C10H11NO5 | 详情 | 详情 |
(III) | 60236 | 2-Acetyl-4,5-dimethoxyaniline;4',5'-Dimethoxy-2'-aminoacetophenone;2'-Amino-4',5'-dimethoxyacetophenone;1-[2-amino-4,5-bis(methyloxy)phenyl]-1-ethanone | 4101-30-8 | C10H13NO3 | 详情 | 详情 |
(IV) | 69417 | 6,7-dimethoxyquinolin-4(1H)-one hydrate | C11H11NO3.H2O | 详情 | 详情 | |
(V) | 69418 | 4-chloro-6,7-dimethoxyquinoline | 35654-56-9 | C11H10ClNO2 | 详情 | 详情 |
(VI) | 54811 | 4-amino-3-chlorophenol | C6H6ClNO | 详情 | 详情 | |
(VII) | 69419 | 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline | C17H15ClN2O3 | 详情 | 详情 | |
(VIII) | 40340 | 5-methyl-3-isoxazolamine; 5-methyl-3-isoxazolylamine | 1072-67-9 | C4H6N2O | 详情 | 详情 |