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【结 构 式】 
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【分子编号】57243 【品名】2,6-dimethoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether; 2,6-dimethoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline 【CA登记号】 |
【 分 子 式 】C19H15F3N2O5 【 分 子 量 】408.3337896 【元素组成】C 55.89% H 3.7% F 13.96% N 6.86% O 19.59% |
合成路线1
该中间体在本合成路线中的序号：(VII)Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl)phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI). Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl)phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 Ugwuegbulam, C.O.; Foy, J.E. (GlaxoSmithKline Inc.; GlaxoSmithKline plc); Process for the preparation of anti-malarial drugs. US 6479660; WO 9713753 . |
| 【3】 LaMontagne, M.P.; et al.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1728-32. |
| 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) | 57237 | 6-methoxy-4-methyl-2(1H)-quinolinone | C11H11NO2 | 详情 | 详情 | |
| (II) | 57247 | 5-chloro-6-methoxy-4-methyl-2(1H)-quinolinone | C11H10ClNO2 | 详情 | 详情 | |
| (III) | 57246 | 5-chloro-6-methoxy-4-methyl-8-nitro-2(1H)-quinolinone | C11H9ClN2O4 | 详情 | 详情 | |
| (IV) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 详情 | 详情 |
| (V) | 57245 | 6-methoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]-2(1H)-quinolinone | C18H13F3N2O5 | 详情 | 详情 | |
| (VI) | 57244 | 2-chloro-6-methoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline; 2-chloro-6-methoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether | C18H12ClF3N2O4 | 详情 | 详情 | |
| (VII) | 57243 | 2,6-dimethoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether; 2,6-dimethoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline | C19H15F3N2O5 | 详情 | 详情 | |
| (VIII) | 48081 | 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine; 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine | C19H17F3N2O3 | 详情 | 详情 | |
| (IX) | 48082 | 2-(4-iodopentyl)-1H-isoindole-1,3(2H)-dione | C13H14INO2 | 详情 | 详情 | |
| (X) | 48083 | 2-[4-([2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]amino)pentyl]-1H-isoindole-1,3(2H)-dione | C32H30F3N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 Ugwuegbulam, C.O.; Foy, J.E. (GlaxoSmithKline Inc.; GlaxoSmithKline plc); Process for the preparation of anti-malarial drugs. US 6479660; WO 9713753 . |
| 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) | 52237 | methyl 4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thiophenecarboxylate | C24H21NO4S | 详情 | 详情 | |
| (IV) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 详情 | 详情 |
| (VII) | 57243 | 2,6-dimethoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether; 2,6-dimethoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline | C19H15F3N2O5 | 详情 | 详情 | |
| (VIII) | 48081 | 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine; 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine | C19H17F3N2O3 | 详情 | 详情 | |
| (XXI) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XXII) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (XXIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XXIV) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXV) | 57239 | 2,5-dichloro-4-methyl-6-quinolinyl methyl ether; 2,5-dichloro-6-methoxy-4-methylquinoline | C11H9Cl2NO | 详情 | 详情 | |
| (XXVI) | 57240 | 5-chloro-2,6-dimethoxy-4-methylquinoline; 5-chloro-2-methoxy-4-methyl-6-quinolinyl methyl ether | C12H12ClNO2 | 详情 | 详情 | |
| (XXVII) | 57241 | 2-methoxy-4-methyl-6-quinolinyl methyl ether; 2,6-dimethoxy-4-methylquinoline | C12H13NO2 | 详情 | 详情 | |
| (XXVIII) | 57242 | 5-chloro-2,6-dimethoxy-4-methyl-8-nitroquinoline; 5-chloro-2-methoxy-4-methyl-8-nitro-6-quinolinyl methyl ether | C12H11ClN2O4 | 详情 | 详情 |