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【结 构 式】

【药物名称】NSC-659687, NSC-D-659687, S-16020-2

【化学名称】N-[2-(Dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide dihydrochloride

【CA登记号】156055-46-8 (free base)

【 分 子 式 】C22H26Cl2N4O2

【 分 子 量 】449.38412

【开发单位】Servier (Originator)

【药理作用】Oncolytic Drugs, Alkaloids, DNA Topoisomerase II Inhibitors

合成路线1

Tetrahydropyridine (II), obtained by NaBH4 reduction of the 1-benzylpyridinium salt (I), was condensed with 5-methoxyindole (III) in refluxing 50% AcOH to produce, through a biomimetic sequence, the aminoethyl carbazole compound (IV). Catalytic debenzylation of (IV) led to the primary amine (V), which was converted to the oxalic acid mono-amide (VI) upon heating with diethyl oxalate. Cyclization of amide (VI) in the presence of POCl3 under Vilsmeier conditions furnished the pyridocarbazole tetracyclic system (VII). Dehydrogenation of (VII) over Pd/C in boiling diphenyl ether led to a mixture of the desired aromatized compound (VIII) and the decarbethoxylated byproduct (IX), which were separated by column chromatography. N-Methylation of the pyrrole ring of (VIII) to give (X) was performed by using dimethyl carbonate in DMF in the presence of K2CO3 and crown ether. Reaction of ester (X) with 2-(dimethylamino)ethylamine (XI) at 115 C gave amide (XII). Finally, the desired 9-hydroxy derivative was obtained by methyl ether cleavage in (XII) employing boron tribromide. Alternatively, the title compound was obtained by demethylation of ether (X) and subsequent reaction with 2-(dimethylamino)ethylamine (XI).

1 Jasztold-Howorko, R.; Landras, C.; Pierré, A.; Atassi, G.; Guilbaud, N.; Kraus-Berthier, L.; Leonce, S.; Rolland, Y.; Prost, J.F.; Bisagni, E.; Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)-6H-pyrido[4, 3-b]carbazole-1-N-[(dialkylamino)alkyl]carboxamides, a new promising series of antitumor olivacine derivatives. J Med Chem 1994, 37, 15, 2445.
2 Bisagni, E.; Jasztold-Howorko, R.; Atassi, G.; Pierre, A. (ADIR et Cie.); Ellipticine derivs. with antitumor activity. EP 0591058; FR 2696465; JP 1994211852; US 5498611 .
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) 59757 1-Benzyl-4-(2-methyl-1,3-dioxolan-2-yl)pyridinium C16H18NO2 详情 详情
(II) 59758 1-benzyl-4-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,6-tetrahydropyridine C16H21NO2 详情 详情
(III) 25902 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole 1006-94-6 C9H9NO 详情 详情
(IV) 59759 N-benzyl-2-(6-methoxy-1-methyl-9H-carbazol-2-yl)-1-ethanamine; N-benzyl-N-[2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethyl]amine C23H24N2O 详情 详情
(V) 59760 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)-1-ethanamine; 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethylamine C16H18N2O 详情 详情
(VI) 59761 ethyl 2-{[2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethyl]amino}-2-oxoacetate C20H22N2O4 详情 详情
(VII) 59762 ethyl 9-methoxy-5-methyl-4,6-dihydro-3H-pyrido[4,3-b]carbazole-1-carboxylate C20H20N2O3 详情 详情
(VIII) 59764 ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate C20H18N2O3 详情 详情
(IX) 59763 methyl 5-methyl-6H-pyrido[4,3-b]carbazol-9-yl ether; 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole C17H14N2O 详情 详情
(X) 59765 ethyl 9-methoxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate C21H20N2O3 详情 详情
(XI) 14881 N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine 108-00-9 C4H12N2 详情 详情
(XII) 59766 N-[2-(dimethylamino)ethyl]-9-methoxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide C23H26N4O2 详情 详情
Extended Information