NSC-659687, NSC-D-659687, S-16020-2
Chemical Name: N-[2-(Dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide dihydrochloride
CAS No. 156055-46-8 (free base)
项目整合开发状态: Phase II
项目研究机构: Servier (Originator)
合成路线: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).
📌 参考资料/链接：
参考文献标题:Ellipticine derivs.with antitumor activity
文献作者:Bisagni,E.; Jasztold-Howorko,R.; Atassi,G.; Pierre,A.(ADIR et Cie.)
参考来源:EP 0591058; FR 2696465; JP 1994211852; US 5498611
📄 详细内容
合成路线: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).
参考文献标题: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
文献作者:Jasztold-Howorko,R.; Landras,C.; Pierr? A.; Atassi,G.; Guilbaud,N.; Kraus-Berthier,L.; Leonce,S.; Rolland,Y.; Prost,J.F.; Bisagni,E.
参考来源:J Med Chem 1994,37(15),2445