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【结 构 式】 
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【分子编号】48081 【品名】2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine; 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine 【CA登记号】 |
【 分 子 式 】C19H17F3N2O3 【 分 子 量 】378.3508696 【元素组成】C 60.32% H 4.53% F 15.06% N 7.4% O 12.69% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(VIII)Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 LaMontagne, M.P.; Blumbergs, P. (Department of the Army); 4-Methyl-5-(unsubstd. and substd. phenoxy)-2,6-dimethoxy-8-(aminoalkylamino)quinolines. US 4617394 . |
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XIV) | 48075 | 6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine; 6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine | C18H15F3N2O2 | 详情 | 详情 | |
| (XV) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XVI) | 48076 | 2-[6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-1H-isoindole-1,3(2H)-dione | C26H17F3N2O4 | 详情 | 详情 | |
| (XVII) | 48077 | 8-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-1-quinoliniumolate | C26H17F3N2O5 | 详情 | 详情 | |
| (XVIII) | 48078 | 2-[6-methoxy-4-methyl-2-oxo-5-[3-(trifluoromethyl)phenoxy]-1,2-dihydro-8-quinolinyl]-1H-isoindole-1,3(2H)-dione | C26H17F3N2O5 | 详情 | 详情 | |
| (XIX) | 48079 | 2-[2-chloro-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-1H-isoindole-1,3(2H)-dione | C26H16ClF3N2O4 | 详情 | 详情 | |
| (XX) | 48080 | 2-chloro-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine; 2-chloro-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine | C18H14ClF3N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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 |