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【结 构 式】 
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【分子编号】60010 【品名】5,8-dibromo-2-(bromomethyl)-7-methoxy-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate 【CA登记号】 |
【 分 子 式 】C18H11Br3N2O4 【 分 子 量 】559.00842 【元素组成】C 38.68% H 1.98% Br 42.88% N 5.01% O 11.45% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Copper-catalyzed arylation of 3-methyl-6-nitroindazole (I) with 2-bromo-6-methoxybenzoic acid (II) furnished (III). Subsequent reduction of the nitro group of (III) to (IV) was effected by transfer hydrogenation with hydrazine hydrate in the presence of Pd/C. Intramolecular cyclization of carboxylic acid (IV) in hot PPA gave rise to the pyrazoloacridine system (V). The amino group of (V) was then converted to the bromide (VI) using a Sandmeyer reaction (1). Methyl ether cleavage in (VI) with HBr in hot AcOH provided phenol (VII), which was brominated with elemental bromine at low temperature to give (VIII). A formyl group was subsequently introduced in (VIII) by treatment with dichloromethyl methyl ether and TiCl4, yielding (IX). Oxidative cleavage of aldehyde (IX) under Baeyer-Villiger rearrangement conditions furnished the diphenol compound (X). Selective acetylation of one hydroxyl group of (X) affording (XI), followed by methylation of the remaining hydroxyl afforded (XII). Benzylic bromination of the side-chain methyl group of (XII) with NBS gave the bromomethyl derivative (XIII)
| 【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947. |
| 【2】 Mimura, Y.; Shida, Y.; Kasai, M.; Ashizawa, T.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); Pyrazoloacridone derivs.. EP 0487097; JP 1993001064; US 5220026 . |
| 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) | 59941 | 2-bromo-6-methoxybenzoic acid | C8H7BrO3 | 详情 | 详情 | |
| (II) | 59942 | 3-methyl-6-nitro-1H-indazole | 6494-19-5 | C8H7N3O2 | 详情 | 详情 |
| (III) | 60000 | 2-methoxy-6-(3-methyl-6-nitro-1H-indazol-1-yl)benzoic acid | C16H13N3O5 | 详情 | 详情 | |
| (IV) | 60001 | 2-(6-amino-3-methyl-1H-indazol-1-yl)-6-methoxybenzoic acid | C16H15N3O3 | 详情 | 详情 | |
| (V) | 60002 | 5-amino-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C16H13N3O2 | 详情 | 详情 | |
| (VI) | 60003 | 5-bromo-7-methoxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C16H11BrN2O2 | 详情 | 详情 | |
| (VII) | 60004 | 5-bromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H9BrN2O2 | 详情 | 详情 | |
| (VIII) | 60005 | 5,8-dibromo-7-hydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O2 | 详情 | 详情 | |
| (IX) | 60006 | 5,8-dibromo-7-hydroxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridine-10-carbaldehyde | C16H8Br2N2O3 | 详情 | 详情 | |
| (X) | 60007 | 5,8-dibromo-7,10-dihydroxy-2-methyl-6H-pyrazolo[4,5,1-de]acridin-6-one | C15H8Br2N2O3 | 详情 | 详情 | |
| (XI) | 60008 | 5,8-dibromo-7-hydroxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate | C17H10Br2N2O4 | 详情 | 详情 | |
| (XII) | 60009 | 5,8-dibromo-7-methoxy-2-methyl-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate | C18H12Br2N2O4 | 详情 | 详情 | |
| (XIII) | 60010 | 5,8-dibromo-2-(bromomethyl)-7-methoxy-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate | C18H11Br3N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Displacement of the benzylic bromide (XIII) with concomitant hydrolysis of the phenolic acetate with ethanolamine (XIV) gave amine (XV). A further aromatic bromide of (XV) was displaced with hot 1,3-propanediamine (XVI), yielding adduct (XVII). Hydrogenolysis of the remaining bromide of (XVII) using Pd/C furnished (XVIII). Finally, methyl ether cleavage in (XVIII) with hot HCl provided the title compound
| 【1】 Mimura, T.; Kato, N.; Sugaya, T.; Ikuta, M.; Kato, S.; Kuge, Y.; Tomioka, S.; Kasai, M.; An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (Stuttgart) 1999, 6, 947. |
| 【2】 Mimura, Y.; Shida, Y.; Kasai, M.; Ashizawa, T.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); Pyrazoloacridone derivs.. EP 0487097; JP 1993001064; US 5220026 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 60010 | 5,8-dibromo-2-(bromomethyl)-7-methoxy-6-oxo-6H-pyrazolo[4,5,1-de]acridin-10-yl acetate | C18H11Br3N2O4 | 详情 | 详情 | |
| (XIV) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XV) | 60011 | 5,8-dibromo-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C18H15Br2N3O4 | 详情 | 详情 | |
| (XVI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (XVII) | 60012 | 5-[(3-aminopropyl)amino]-8-bromo-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C21H24BrN5O4 | 详情 | 详情 | |
| (XVIII) | 60013 | 5-[(3-aminopropyl)amino]-10-hydroxy-2-{[(2-hydroxyethyl)amino]methyl}-7-methoxy-6H-pyrazolo[4,5,1-de]acridin-6-one | C21H25N5O4 | 详情 | 详情 |