【结 构 式】 |
【分子编号】65850 【品名】2-Amino-4,6-dimethoxybenzoic acid 【CA登记号】21577-57-1 |
【 分 子 式 】C9H11NO4 【 分 子 量 】197.19068 【元素组成】C 54.82% H 5.62% N 7.1% O 32.45% |
合成路线1
该中间体在本合成路线中的序号:(XVI)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 |