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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information