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【结 构 式】 
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【分子编号】18690 【品名】4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinol 【CA登记号】184475-71-6 |
【 分 子 式 】C15H11ClFN3O2 【 分 子 量 】319.7224632 【元素组成】C 56.35% H 3.47% Cl 11.09% F 5.94% N 13.14% O 10.01% |
合成路线1
该中间体在本合成路线中的序号：(VII)Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II), which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III). Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV), which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI). Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII), which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).
| 【1】 Gibson, K.H.; Grundy, W.; Barker, A.J.; et al.; Studies leading to the identification of ZD1839 (Iressa(TM)): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001, 11, 14, 1911. |
| 【2】 D'Souza, N.; Castañer, J.; Levin, M.; Iressa. Drugs Fut 2002, 27, 4, 339. |
| 【3】 Gibson, K.H. (AstraZeneca plc); Quinazoline derivs.. EP 0823900; JP 1999504033; US 5770599; WO 9633980 . |
| 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) | 18684 | 6,7-dimethoxy-4(3H)-quinazolinone | 13794-72-4 | C10H10N2O3 | 详情 | 详情 |
| (II) | 18685 | 6-hydroxy-7-methoxy-4(3H)-quinazolinone | 179688-52-9 | C9H8N2O3 | 详情 | 详情 |
| (III) | 18686 | 7-methoxy-4-oxo-3,4-dihydro-6-quinazolinyl acetate | 179688-53-0 | C11H10N2O4 | 详情 | 详情 |
| (IV) | 18687 | 4-chloro-7-methoxy-6-quinazolinyl acetate | 230955-75-6 | C11H9ClN2O3 | 详情 | 详情 |
| (V) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (VI) | 18689 | 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl acetate | 788136-89-0 | C17H13ClFN3O3 | 详情 | 详情 |
| (VII) | 18690 | 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinol | 184475-71-6 | C15H11ClFN3O2 | 详情 | 详情 |
| (VIII) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (IX) | 52653 | 4-(3-bromopropyl)morpholine | 125422-83-5 | C7H14BrNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)
| 【1】 Knesl P.Roeseling D,Jordis U 2006. Improved synthesis of substituted 6,7-rdihydroxy-4iuinazolinearninest: tandutinib, erlotinib and gefitinib. Molecules, 11(4):286~297 |
| 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) | 65853 | 5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one | C9H8N2O3 | 详情 | 详情 | |
| (II) | 66446 | 7-methoxy-4-oxo-1,4-dihydroquinazolin-6-yl acetate | C11H10N2O4 | 详情 | 详情 | |
| (III) | 18687 | 4-chloro-7-methoxy-6-quinazolinyl acetate | 230955-75-6 | C11H9ClN2O3 | 详情 | 详情 |
| (IV) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (V) | 66447 | 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride;6-Acetoxy-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride | 184475-70-5 | C17H13ClFN3O3.HCl | 详情 | 详情 |
| (VI) | 18690 | 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinol | 184475-71-6 | C15H11ClFN3O2 | 详情 | 详情 |
| (VII) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |