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【结 构 式】 
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【分子编号】65853 【品名】5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one 【CA登记号】 |
【 分 子 式 】C9H8N2O3 【 分 子 量 】192.1742 【元素组成】C 56.25% H 4.2% N 14.58% O 24.98% |
合成路线1
该中间体在本合成路线中的序号：(XX)Esterification of 2-amino-4,6-dimethoxybenzoic acid (XVI) with diazomethane in ethanol gives the corresponding methyl ester (XVII), which is cyclized with formamidine (XVIII) in refluxing 2-methoxyethanol to yield 5,7-dimethoxyquinazolin-4(3H)-one (IXX). Selective demethylation of compound (IXX) by means of MgBr2 in refluxing pyridine affords 5-hydroxy-7-methoxyquinazolin-4(3H)-one (XX), which is condensed with pivaloyloxymethyl chloride (POM-Cl) and NaH in DMF to provide the protected quinazolinone (XXI). Condensation of compound (XXI) with 4-hydroxytetrahydropyran (X) by means of PPh3 in dichloromethane gives 7-methoxy-5-(tetrahydropyran-4-yloxy)quinazolin-4(3H)-one (XXII), which is demethylated by means of PhSH and K2CO3 in NMP at 195 °C to yield the 7-hydroxyquinazolinone derivative (XXIII). Acylation of compound (XXIII) with acetic anhydride affords the 7-acetoxy derivative (XXIV) , which is treated with POCl3 at 80 °C to provide 7-acetoxy-4-chloro-5-(tetrahydropyran-4-yloxy)quinazoline (XXV). Condensation of (XXV) with 4-amino-5-chloro-1,3-benzodioxole (II) in hot isopropanol gives adduct (XXVI), which is treated with ammonia in methanol to afford the 7-hydroxyquinazoline derivative (IV). Finally, this compound is condensed with 1-(2-chloroethyl)-4-methylpiperazine (XXVII) by means of K2CO3 in DMF (3, 4). Scheme 3.
| 【3】 Oldham, K., Moore, N.C. (AstraZeneca AB; AstraZeneca plc). Quinazoline derivatives for the treatment of T cell mediated diseases. EP 1450808, US 2005038050, US 7160891, WO 2003045395. |
| 【4】 Hennequin, L.F., Allen, J., Breed, J. et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006, 49(22): 6465-88. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65838 | 5-chloro-1,3-benzodioxol-4-amine; 5-Chlorobenzo[1,3]dioxol-4-ylamine | 379228-45-2 | C7H6ClNO2 | 详情 | 详情 |
| (IV) | 65840 | C20H18ClN3O5 | 详情 | 详情 | ||
| (X) | 37750 | tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran | 2081-44-9 | C5H10O2 | 详情 | 详情 |
| (XVI) | 65850 | 2-Amino-4,6-dimethoxybenzoic acid | 21577-57-1 | C9H11NO4 | 详情 | 详情 |
| (XVII) | 65851 | Methyl 2-amino-4,6-dimethoxybenzoate | 379228-26-9 | C10H13NO4 | 详情 | 详情 |
| (XVIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (XIX) | 65852 | 5,7-dimethoxy-3,4-dihydroquinazoline-4-one | C10H10N2O3 | 详情 | 详情 | |
| (XX) | 65853 | 5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one | C9H8N2O3 | 详情 | 详情 | |
| (XXI) | 65854 | C15H18N2O5 | 详情 | 详情 | ||
| (XXII) | 65855 | C14H16N2O4 | 详情 | 详情 | ||
| (XXIII) | 65856 | C13H14N2O4 | 详情 | 详情 | ||
| (XXIV) | 65857 | C14H16N2O5 | 详情 | 详情 | ||
| (XXV) | 65858 | C14H15ClN2O4 | 详情 | 详情 | ||
| (XXVI) | 65859 | C21H20ClN3O6 | 详情 | 详情 | ||
| (XXVII) | 65860 | 1-(2-chloroethyl)-4-methylpiperazine | 5753-26-4 | C7H15ClN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)
| 【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 |