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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information