4-amino-3-chlorophenol -Drug Synthesis Database

【结构式】

【分子编号】54811

【品名】4-amino-3-chlorophenol

【CA登记号】

【分子式】C₆H₆ClNO

【分子量】143.57248

【元素组成】C 50.19% H 4.21% Cl 24.69% N 9.76% O 11.14%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

6,7-Dimethoxy-4-quinazolone (II) was prepared by condensation of methyl 4,5-dimethoxyanthranilate (I) with formamide at 160 C. Chlorination of (II) by means of phosphorus oxychloride provided the 4-chloro quinazoline (III). Substitution of the 4-chloro group of (III) by the sodium salt of 4-amino-3-chlorophenol (IV) gave rise to the quinazolinyl ether (V). Finally, condensation of amine (V) with triphosgene, followed by addition of n-propylamine furnished the title urea derivative.

参考文献中间体

合成目标

【1】 Kubo, K.; Iwakubo, M.; Fujiwara, Y.; et al.; Synthesis and structure-activity relationship of quinazoline-urea derivatives as novel orally active VEGF tyrosine kinase selective inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 913.
【2】 Kubo, K.; Fujiwara, Y.; Isoe, T. (Kirin Brewery Co., Ltd.); Quinoline derivs. and quinazoline derivs.. EP 1153920; WO 0043366 .

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)	54810	2-Amino-4,5-dimethoxybenzoic acid methyl ester; Methyl 2-amino-4,5-dimethoxybenzoate; Methyl 4,5-dimethoxyanthranilate	26759-46-6	C₁₀H₁₃NO₄	详情	详情
(II)	18684	6,7-dimethoxy-4(3H)-quinazolinone	13794-72-4	C₁₀H₁₀N₂O₃	详情	详情
(III)	23765	4-chloro-6,7-dimethoxyquinazoline; 4-chloro-6-methoxy-7-quinazolinyl methyl ether		C₁₀H₉ClN₂O₂	详情	详情
(IV)	54811	4-amino-3-chlorophenol		C₆H₆ClNO	详情	详情
(V)	54812	2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline; 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenylamine		C₁₆H₁₄ClN₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

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) .

参考文献中间体

合成目标

【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