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【结 构 式】

【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%

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:(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
Extended Information