|
【结 构 式】 
|
【分子编号】19938 【品名】5,8-dimethyl-9H-carbazol-3-yl methyl ether; 6-methoxy-1,4-dimethyl-9H-carbazole 【CA登记号】 |
【 分 子 式 】C15H15NO 【 分 子 量 】225.29024 【元素组成】C 79.97% H 6.71% N 6.22% O 7.1% |
合成路线1
该中间体在本合成路线中的序号：(III)The cyclization of 5-methoxy-1H-indole (I) with hexane-2,6-dione (II) by means of BF3 ethearate in refluxing dioxane gives 6-methoxy-1,4-dimethylcarbazole (III), which is formylated with N-methylformanilide (IV) and POCl3 in hot o-dichlorobenzene yielding the 3-formyl derivative (V). The condensation of (V) with 2-aminoacetaldehyde diethylacetal (VI) by heating at 100 C affords the expected imino derivative (VII), which is cyclized by acid (HCl) hydrolysis of the acetal group and cyclization of the resulting aldehyde by means of NaOH in water to the 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (VIII). The oxidation of (VIII) with m-chloroperbenzoic acid (MCPBA) in acetone gives the correponding N-oxide (IX), which is treated with BBr3 in dichloromethane yielding 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (X). Finally, this compound is treated with 1-bromo-3-methoxy-2-propanone in DMF to afford the desired quaternary salt.
| 【1】 Liu, Q.-R.; et al.; Aust J Chem 1967, 20, 2715. |
| 【2】 Harada, N.; et al.; Synthesis and antitumor activity of quaternary salts of 2-(2'-oxoalkoxy)-9-hydroxyellipticines. Chem Pharm Bull 1997, 45, 1, 134. |
| 【3】 Guthrie, R.W.; et al.; Ellipticine derivatives. J Med Chem 1975, 18, 7, 755. |
| 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) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
| (III) | 19938 | 5,8-dimethyl-9H-carbazol-3-yl methyl ether; 6-methoxy-1,4-dimethyl-9H-carbazole | C15H15NO | 详情 | 详情 | |
| (IV) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (V) | 27052 | 6-methoxy-1,4-dimethyl-9H-carbazole-3-carbaldehyde | C16H15NO2 | 详情 | 详情 | |
| (VI) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (VII) | 27053 | 1-ethoxy-2-[[(Z)-(6-methoxy-1,4-dimethyl-9H-carbazol-3-yl)methylidene]amino]-1-ethanol | C20H24N2O3 | 详情 | 详情 | |
| (VIII) | 27054 | 9-methoxy-1,4,5,11-tetramethyl-6H-pyrido[4,3-b]carbazole | C20H20N2O | 详情 | 详情 | |
| (IX) | 27055 | 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium-2-olate | C18H16N2O2 | 详情 | 详情 | |
| (X) | 27056 | 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium-2-olate | C17H14N2O2 | 详情 | 详情 | |
| (XI) | 27057 | 1-bromo-3-methoxyacetone | C4H7BrO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of 6-methoxy-1,4-dimethylcarbazole (I) with pivaloyl chloride and NaI in refluxing acetonitrile cleaved the methyl ether and afforded pivalate (II). The condensation of this with the Vilsmeier reagent from N-methylformanilide and phosphoryl chloride gave the formyl compound (III). Condensation of (III) with aminoacetaldehyde diethyl acetal in the presence of a catalytic amount of p-toluenesulfonic acid in refluxing toluene with azeotropic distillation of water, followed by hydrogenation of the intermediate imine in the presence of PtO2, afforded the corresponding amine, which was subsequently converted to the N-tosyl derivative (IV) on treatment with tosyl chloride and triethylamine. Refluxing (IV) with hydrogen chloride in aqueous dioxane effected cyclization, with simultaneous elimination of the tosyl and pivaloyl groups yielding the 9-hydroxyellipticine (V) (1). Glutaric acid monobenzyl ester (VIa) was converted to the active ester (VII) on treatment with 1-hydroxybenzotriazole (VIb) and dicyclohexyl carbodiimide, and this was condensed with (V) to afford diester (VIII). Finally, the benzyl ester was deprotected by hydrogenolysis in the presence of palladium-carbon and hydrogen.
| 【1】 Harada, N.; et al.; Synthesis and antitumor activity of 9-acyloxyellipticines. Chem Pharm Bull 1997, 45, 7, 1156. |
| 【2】 Tsujihara, K.; Harada, N.; Ozaki, K.; Ohashi, M.; Oda, K. (Tanabe Seiyaku Co., Ltd.); Ellipticine derivs. with antitumor activity. EP 0608876; JP 1994279441; US 5605904 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIb) | 10184 | 1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol | 2592-95-2 | C6H5N3O | 详情 | 详情 |
| (VIa) | 19943 | 5-(benzyloxy)-5-oxopentanoic acid | C12H14O4 | 详情 | 详情 | |
| (I) | 19938 | 5,8-dimethyl-9H-carbazol-3-yl methyl ether; 6-methoxy-1,4-dimethyl-9H-carbazole | C15H15NO | 详情 | 详情 | |
| (II) | 19939 | 5,8-dimethyl-9H-carbazol-3-yl pivalate | C19H21NO2 | 详情 | 详情 | |
| (III) | 19940 | 6-formyl-5,8-dimethyl-9H-carbazol-3-yl pivalate | C20H21NO3 | 详情 | 详情 | |
| (IV) | 19941 | 6-([(2,2-diethoxyethyl)[(4-methylphenyl)sulfonyl]amino]methyl)-5,8-dimethyl-9H-carbazol-3-yl pivalate | C33H42N2O6S | 详情 | 详情 | |
| (V) | 19942 | 5,11-dimethyl-6H-pyrido[4,3-b]carbazol-9-ol hydrochloride | C17H15ClN2O | 详情 | 详情 | |
| (VII) | 19944 | benzyl 5-(1H-1,2,3-benzotriazol-1-yloxy)-5-oxopentanoate | C18H17N3O4 | 详情 | 详情 | |
| (VIII) | 19945 | 1-benzyl 5-(5,11-dimethyl-6H-pyrido[4,3-b]carbazol-9-yl) pentanedioate | C29H26N2O4 | 详情 | 详情 |