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【结 构 式】 
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【分子编号】48517 【品名】4-chloro-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile 【CA登记号】 |
【 分 子 式 】C18H20ClN3O3 【 分 子 量 】361.82792 【元素组成】C 59.75% H 5.57% Cl 9.8% N 11.61% O 13.27% |
合成路线1
该中间体在本合成路线中的序号：(I)Chloroquinoline derivative (I) was condensed with 2,4-dichloroaniline (II) in boiling ethoxyethanol in the presence of pyridine hydrochloride to furnish the title compound.
| 【1】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822. |
合成路线2
该中间体在本合成路线中的序号：(X)The alkylation of 4-hydroxy-3-methoxybenzoic acid methyl ester (I) with 3-(4-morpholinyl)propyl chloride (II) and tetrabutylammonium chloride in refluxing butanone gives 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoic acid methyl ester (III), which is nitrated with HNO3 in hot acetic acid to yield 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoic acid methyl ester (IV). The reduction of (III) with H2 over Pd/C in methanol/ethyl acetate to afford the corresponding 2-amino ester (V), which is condensed with dimethylformamide dimethylacetal (VI) by heating at 100 C to provide the 2-(dimethylaminomethyleneamino) derivative (VII). The cyclization of (VII) with acetonitrile (VIII) by means of BuLi and CO2 in THF gives 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IX), which is treated with refluxing SOCl2 to yield the 4-chloroquinoline derivative (X). Finally, this compound is condensed with 2-bromo-5-methoxyaniline by means of pyridine hydrochloride in 2-ethoxyethanol or NaH in THF (or DMF).
| 【1】 Wang, Y.D.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles, Part 1: optimization of the aniline headpiece at C-4. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 144. |
| 【2】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (III) | 50321 | methyl 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H23NO5 | 详情 | 详情 | |
| (IV) | 50322 | methyl 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoate | C16H22N2O7 | 详情 | 详情 | |
| (V) | 50323 | methyl 2-amino-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H24N2O5 | 详情 | 详情 | |
| (VI) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VII) | 50324 | methyl 2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C19H29N3O5 | 详情 | 详情 | |
| (VIII) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (IX) | 50325 | 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydro-3-quinolinecarbonitrile | C18H21N3O4 | 详情 | 详情 | |
| (X) | 48517 | 4-chloro-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile | C18H20ClN3O3 | 详情 | 详情 | |
| (XI) | 50326 | 2-Bromo-5-methoxyaniline | 129968-11-2 | C7H8BrNO | 详情 | 详情 |