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【结 构 式】 
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【分子编号】29972 【品名】5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol 【CA登记号】 |
【 分 子 式 】C15H12N4O3 【 分 子 量 】296.28544 【元素组成】C 60.81% H 4.08% N 18.91% O 16.2% |
合成路线1
该中间体在本合成路线中的序号：(X)The acetylation of 2-methyl-3-aminobenzonitrile (I) with acetic anhydride in refluxing acetic acid gives 2-methyl-3-acetylaminobenzonitrile (II), which is reduced with Raney-Ni in refluxing 50% formic acid yielding 2-methyl-3-acetylaminobenzaldehyde (III). The condensation of (III) with malonic acid (IV) by means of piperidine in pyridine affords 2-methyl-3-acetylaminocinn acid (V), which is converted to the corresponding azide (VI) by reaction with ethyl chloroformate and sodium azide by means of triethylamine in acetone. The cyclization of (VI) by heating at 240 C in diphenyl ether gives 1-hydroxy-5-methyl-6-acetylaminoisoquinoline (VII), which is hydrolyzed with HCl in refluxing ethanol to 1-hydroxy-5-methyl-6-aminoisoquinoline (VIII). The condensation of (VIII) with 4-chloro-3-nitropyridine (IX) in DMF affords 1-hydroxy-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (X).
| 【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145. |
| 【2】 Van der Burg, W.J. (Akzo Nobel N.V.); Tetracyclic compounds. BE 0840362; CH 622261; DE 2614406; DK 142498; ES 446634; FR 2305986; GB 1543171; JP 76122099; NL 754075 . |
| 【3】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 29968 | N-(5-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)acetamide | C12H12N2O2 | 详情 | 详情 | ||
| (I) | 29963 | 3-amino-2-methylbenzonitrile | C8H8N2 | 详情 | 详情 | |
| (II) | 29964 | N-(3-cyano-2-methylphenyl)acetamide | C10H10N2O | 详情 | 详情 | |
| (III) | 29965 | N-(3-formyl-2-methylphenyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (IV) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (V) | 29966 | (Z)-3-[3-(acetamido)-2-methylphenyl]-2-propenoic acid | C12H13NO3 | 详情 | 详情 | |
| (VI) | 29967 | (Z)-3-[3-(acetamido)-2-methylphenyl]-2-propenoyl azide | C12H12N4O2 | 详情 | 详情 | |
| (VII) | 29969 | N-(1-hydroxy-5-methyl-6-isoquinolinyl)acetamide | C12H12N2O2 | 详情 | 详情 | |
| (VIII) | 29970 | 6-amino-5-methyl-1-isoquinolinol | C10H10N2O | 详情 | 详情 | |
| (IX) | 29971 | 4-chloro-3-nitropyridine | C5H3ClN2O2 | 详情 | 详情 | |
| (X) | 29972 | 5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol | C15H12N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Compound (X) is reduced with H2 over Pd/C in acetic acid to 1-hydroxy-5-methyl-6-[(3-amino-4-pyridyl)amino]isoquinolin (Xl). The treatment of (XI) with NaNO2 in acetic acid yields 1-(1-hydroxy-5-methyl-6-isoquinolyl)triazolo[4,5-c]pyridine (XII), which is converted into 1-hydroxy-5-methyldipyrido[4,3-b][3,4-f]indole (XIII). The reaction of (XIII) with PCl5 in refluxing POCl3 gives 1-chloro-5-methyldipyrido[4,3-b][3,4-f]indole (XIV), which is finally condensed with 3-(diethylamino)propylamine (XV) by heating at 150 C.
| 【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145. |
| 【2】 Van der Burg, W.J. (Akzo Nobel N.V.); Tetracyclic compounds. BE 0840362; CH 622261; DE 2614406; DK 142498; ES 446634; FR 2305986; GB 1543171; JP 76122099; NL 754075 . |
| 【3】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 29972 | 5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol | C15H12N4O3 | 详情 | 详情 | |
| (XI) | 29973 | 6-[(3-amino-4-pyridinyl)amino]-5-methyl-1-isoquinolinol | C15H14N4O | 详情 | 详情 | |
| (XII) | 29974 | 5-methyl-6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-1-isoquinolinol | C15H11N5O | 详情 | 详情 | |
| (XIII) | 29975 | 6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolin-10-ol | C15H11N3O | 详情 | 详情 | |
| (XIV) | 29976 | 10-chloro-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline | C15H10ClN3 | 详情 | 详情 | |
| (XV) | 29977 | N-(3-aminopropyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,3-propanediamine | 104-78-9 | C7H18N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)1-hydroxy-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (X) is heated with phosphorous chloride oxide to give 1-chloro-5-methyl-6-[(3-nitro-4-pyridyl)amino]isoquinoline (XVI), which is reduced with H2 over Raney-Ni giving 6-[(3-amino-4-pyridyl)amino]-1-chloro-5-methylisoquinoline (XVII). This compound is treated with sodium nitrite to give 1-(1-chloro-5-methyl-6-isoquinolyl)triazolo[4,5-c]pyridine (XVIII), which is cyclized to 1-chloro-5-methylpyrido[4,3-b][3,4-f]indole (XIV), which is finally condensed with 3-(diethylamino)propylamine (XV) by heating at 150 C.
| 【1】 Rivalle, C.; Lhoste, J.M.; Bisagni, E.; Duerocq, C.; Synthesis of 10-substituted 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinolines. J Chem Soc - Perkins Trans I 1979, 142-145. |
| 【2】 Hopkins, S.J.; Serradell, M.N.; Castaner, J.; BD-40. Drugs Fut 1984, 9, 2, 96. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 29972 | 5-methyl-6-[(3-nitro-4-pyridinyl)amino]-1-isoquinolinol | C15H12N4O3 | 详情 | 详情 | |
| (XIV) | 29976 | 10-chloro-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline | C15H10ClN3 | 详情 | 详情 | |
| (XV) | 29977 | N-(3-aminopropyl)-N,N-diethylamine; N(1),N(1)-diethyl-1,3-propanediamine | 104-78-9 | C7H18N2 | 详情 | 详情 |
| (XVI) | 29978 | N-(1-chloro-5-methyl-6-isoquinolinyl)-N-(3-nitro-4-pyridinyl)amine; 1-chloro-5-methyl-N-(3-nitro-4-pyridinyl)-6-isoquinolinamine | C15H11ClN4O2 | 详情 | 详情 | |
| (XVII) | 29979 | N-(3-amino-4-pyridinyl)-N-(1-chloro-5-methyl-6-isoquinolinyl)amine; N(4)-(1-chloro-5-methyl-6-isoquinolinyl)-3,4-pyridinediamine | C15H13ClN4 | 详情 | 详情 | |
| (XVIII) | 29980 | 1-chloro-5-methyl-6-(1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)isoquinoline | C15H10ClN5 | 详情 | 详情 |