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【结 构 式】 
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【药物名称】8-Hydroxycarteolol 【化学名称】5-(3-tert-Butylamino-2-hydroxypropoxy)-8-hydroxy- 3,4-dihydro-2(1H)-quinolinone 【CA登记号】59826-22-1 【 分 子 式 】C16H24N2O4 【 分 子 量 】308.38068 |
【开发单位】Madaus (Originator) 【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, beta-Adrenoceptor Antagonists |
合成路线1
The nitration of 8-hydroxy-3,4-dihydrocarbostyril (I) with HNO3 in acetic acid-acetic anhydride gives 5-nitro-8-hydroxy-3,4-dihydrocarbostyril (II), which is reduced with SnCl2 in concentrated HCl yielding 5-amino-8-hydroxy-3,4-dihydrocarbostyril (III). The oxidation of (III) with FeCl3 in aqueous HCl affords 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril (IV), which by treatment with SO2 in water is converted into 5,8-dihydroxy-3,4-dihydrocarbostyril (V). The treatment of (V) with benzyl chloride (A) and potassium carbonate in acetone gives 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril (VII), which by reaction with epichlorohydrin (B) by means of piperidine affords 8-benzyloxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (VII). The opening of the epoxide ring of (VII) with tert-butylamine (C) in methanol yields 8-benzyloxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (VIII) (1,2), which is finally hydrogenated with H2 over Pd/C.
| 【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; 8-Hydroxycarteolol. Drugs Fut 1980, 5, 2, 78. |
| 【2】 Uchida, M.; et al.; Synthesis of 5-(3-tert-butylamino-2-hydroxypropxy)-8-3,4-dihydrocarbostyril hydochloride and its beta-adrenergic blocking agent. Yakugaku Zasshi 1976, 96, 5, 571-577. |
| 【3】 Nakagawa, K.; et al.; US 4072683 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (A) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (I) | 39062 | 8-hydroxy-3,4-dihydro-2(1H)-quinolinone | 22246-18-0 | C9H9NO2 | 详情 | 详情 |
| (II) | 39063 | 8-hydroxy-5-nitro-3,4-dihydro-2(1H)-quinolinone | C9H8N2O4 | 详情 | 详情 | |
| (III) | 39064 | 5-amino-8-hydroxy-3,4-dihydro-2(1H)-quinolinone | C9H10N2O2 | 详情 | 详情 | |
| (IV) | 39065 | 3,4,4a,8a-tetrahydro-2,5,8(1H)-quinolinetrione | C9H9NO3 | 详情 | 详情 | |
| (V) | 39066 | 5,8-dihydroxy-3,4-dihydro-2(1H)-quinolinone | C9H9NO3 | 详情 | 详情 | |
| (VI) | 39067 | 8-(benzyloxy)-5-hydroxy-3,4-dihydro-2(1H)-quinolinone | C16H15NO3 | 详情 | 详情 | |
| (VII) | 39068 | 8-(benzyloxy)-5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone | C19H19NO4 | 详情 | 详情 | |
| (VIII) | 39069 | 8-(benzyloxy)-5-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolinone | C23H30N2O4 | 详情 | 详情 | |
| (C) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
合成路线2
The diketone (IV) can also be obtained as follows: the nitration of 5-hydroxy-3,4-dihydrocarbostyril (IX) with HNO3 in acetic acid - acetic anhydride gives 5-hydroxy-8-nitro-3,4-dihydrocarbostyril (X), which is reduced with H2 over Pd/C affording 5-hydroxy-8-amino-3,4-dihydrocarbostyril (Xl). Finally, this compound is oxidized with FeCl3 in aqueous HCl.
| 【1】 Uchida, M.; et al.; Synthesis of 5-(3-tert-butylamino-2-hydroxypropxy)-8-3,4-dihydrocarbostyril hydochloride and its beta-adrenergic blocking agent. Yakugaku Zasshi 1976, 96, 5, 571-577. |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; 8-Hydroxycarteolol. Drugs Fut 1980, 5, 2, 78. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 39065 | 3,4,4a,8a-tetrahydro-2,5,8(1H)-quinolinetrione | C9H9NO3 | 详情 | 详情 | |
| (IX) | 31477 | 5-hydroxy-3,4-dihydro-2(1H)-quinolinone | C9H9NO2 | 详情 | 详情 | |
| (X) | 39070 | 5-hydroxy-8-nitro-3,4-dihydro-2(1H)-quinolinone | C9H8N2O4 | 详情 | 详情 | |
| (XI) | 39071 | 8-amino-5-hydroxy-3,4-dihydro-2(1H)-quinolinone | C9H10N2O2 | 详情 | 详情 |
合成路线3
The dihydroxy compound (V) can also be obtained as follows: the nitration of 8-hydroxycarbostyril (XII) with HNO3 in acetic acid-acetic anhydride gives 5-nitro-8-hydroxycarbostyril (XIII), which is reduced with SnCl2 yielding 5-amino-8-hydroxycarbostyril (XIV). The oxidation of (XIV) with FeCl3 affords 5,8-dioxo-5,8-dihydrocarbostyril (XV), which is reduced with SO2 giving 5,8-dihydroxycarbostyril (XVI). Finally, this compound is reduced with H2 over Pd/C. The 5-amino-8-hydroxy compound (XIV) can also be obtained by nitrosation of (XII) with NaNO2 in acetic acid acetic anhydride to give 5-nitroso-8-acetoxycarbostyril (XVII), which is then reduced with SnCl2 in concentrated HCl.
| 【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; 8-Hydroxycarteolol. Drugs Fut 1980, 5, 2, 78. |
| 【2】 Uchida, M.; et al.; Synthesis of 5-(3-tert-butylamino-2-hydroxypropxy)-8-3,4-dihydrocarbostyril hydochloride and its beta-adrenergic blocking agent. Yakugaku Zasshi 1976, 96, 5, 571-577. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 39066 | 5,8-dihydroxy-3,4-dihydro-2(1H)-quinolinone | C9H9NO3 | 详情 | 详情 | |
| (XII) | 39072 | 8-hydroxy-2(1H)-quinolinone | 15450-76-7 | C9H7NO2 | 详情 | 详情 |
| (XIII) | 39073 | 8-hydroxy-5-nitro-2(1H)-quinolinone | C9H6N2O4 | 详情 | 详情 | |
| (XIV) | 39074 | 5-amino-8-hydroxy-4a,5,8,8a-tetrahydro-2(1H)-quinolinone | C9H12N2O2 | 详情 | 详情 | |
| (XV) | 39075 | 4a,8a-dihydro-2,5,8(1H)-quinolinetrione | C9H7NO3 | 详情 | 详情 | |
| (XVI) | 39076 | 5,8-dihydroxy-2(1H)-quinolinone | C9H7NO3 | 详情 | 详情 | |
| (XVII) | 39077 | 5-nitroso-2-oxo-1,2,4a,5,8,8a-hexahydro-8-quinolinyl acetate | C11H12N2O4 | 详情 | 详情 |