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【结 构 式】 
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【药物名称】Tafenoquine succinate, Etaquine, SB-252263, WR-238605 【化学名称】(±)-8-(4-Amino-1-methylbutylamino)-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline succinate 【CA登记号】106635-81-8, 106635-80-7 (free base) 【 分 子 式 】C28H34F3N3O7 【 分 子 量 】581.59428 |
【开发单位】Walter Reed Army Institute (Originator), GlaxoSmithKline (Licensee) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
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
Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 48082 | 2-(4-iodopentyl)-1H-isoindole-1,3(2H)-dione | C13H14INO2 | 详情 | 详情 | |
| (XI) | 57248 | 1,4-dibromopentane | C5H10Br2 | 详情 | 详情 | |
| (XII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (XIII) | 57249 | 2-(4-bromopentyl)-1H-isoindole-1,3(2H)-dione | C13H14BrNO2 | 详情 | 详情 |
合成路线3
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4
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 |
合成路线5
Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 LaMontagne, M.P.; Blumbergs, P.; Strube, R.E.; Antimalarials. 14. 5-(Aryloxy)-4-methylprimaquine analogues. A highly effective series of blood and tissue schizonticidal agents. J Med Chem 1982, 25, 9, 1094. |
| 【3】 LaMontagne, M.P.; Strube, R.E. (Department of the Army); 4-Methyl-5-(unsubstd. and substd. phenoxy)-6-methoxy-8-(aminoalkylamino)quinolines. US 4431807 . |
| 【4】 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 |
|---|---|---|---|---|---|---|
| (IV) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 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 | |
| (XXIX) | 17398 | 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene | 91-16-7 | C8H10O2 | 详情 | 详情 |
| (XXX) | 43039 | 2-methoxy-4,5-dinitrophenyl methyl ether; 1,2-dimethoxy-4,5-dinitrobenzene | 3395-03-7 | C8H8N2O6 | 详情 | 详情 |
| (XXXI) | 62902 | 4,5-dimethoxy-2-nitrophenylamine; 4,5-dimethoxy-2-nitroaniline | C8H10N2O4 | 详情 | 详情 | |
| (XXXII) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XXXIII) | 62903 | 5,6-dimethoxy-4-methyl-8-nitroquinoline; 5-methoxy-4-methyl-8-nitro-6-quinolinyl methyl ether | C12H12N2O4 | 详情 | 详情 | |
| (XXXIV) | 62904 | 6-methoxy-4-methyl-8-nitro-5-quinolinol | C11H10N2O4 | 详情 | 详情 | |
| (XXXV) | 62905 | 5-Chloro-4-methyl-8-nitro-6-quinolinyl methyl ether; 5-Chloro-6-methoxy-4-methyl-8-nitroquinoline | C11H9ClN2O3 | 详情 | 详情 | |
| (XXXVI) | 62906 | 6-Methoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline; 6-Methoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether | C18H13F3N2O4 | 详情 | 详情 |
合成路线6
Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 LaMontagne, M.P.; Strube, R.E. (Department of the Army); 4-Methyl-5-(unsubstd. and substd. phenoxy)-6-methoxy-8-(aminoalkylamino)quinolines. US 4431807 . |
| 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) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 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 | |
| (XXXII) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XXXIV) | 62906 | 6-Methoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline; 6-Methoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether | C18H13F3N2O4 | 详情 | 详情 | |
| (XXXVII) | 37586 | 2-fluoroanisole; 1-fluoro-2-methoxybenzene; 2-fluorophenyl methyl ether | 321-28-8 | C7H7FO | 详情 | 详情 |
| (XXXVIII) | 62907 | 2-Fluoro-4-nitrophenyl methyl ether; 2-Fluoro-1-methoxy-4-nitrobenzene | 455-93-6 | C7H6FNO3 | 详情 | 详情 |
| (XXXIX) | 20483 | 3-fluoro-4-methoxyphenylamine; 3-fluoro-4-methoxyaniline | 366-99-4 | C7H8FNO | 详情 | 详情 |
| (XL) | 62908 | N-(3-Fluoro-4-methoxyphenyl)acetamide | C9H10FNO2 | 详情 | 详情 | |
| (XLI) | 62909 | N-(5-Fluoro-4-methoxy-2-nitrophenyl)acetamide | C9H9FN2O4 | 详情 | 详情 | |
| (XLII) | 62910 | 5-Fluoro-4-methoxy-2-nitrophenylamine; 5-Fluoro-4-methoxy-2-nitroaniline | C7H7FN2O3 | 详情 | 详情 | |
| (XLIII) | 62911 | 5-Fluoro-4-methyl-8-nitro-6-quinolinyl methyl ether; 5-Fluoro-6-methoxy-4-methyl-8-nitroquinoline | C11H9FN2O3 | 详情 | 详情 |