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【结 构 式】 
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【分子编号】43039 【品名】2-methoxy-4,5-dinitrophenyl methyl ether; 1,2-dimethoxy-4,5-dinitrobenzene 【CA登记号】3395-03-7 |
【 分 子 式 】C8H8N2O6 【 分 子 量 】228.1614 【元素组成】C 42.11% H 3.53% N 12.28% O 42.07% |
合成路线1
该中间体在本合成路线中的序号：(XXX)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2
该中间体在本合成路线中的序号：(II)Treatment of veratrole (I) with aqueous HNO3 and H2SO4 yields 1,2-dinitrobenzene derivative (II), which is then converted into diamine (III) by hydrogenation over Pd/C in HOAc/EtOH or over PtO2. Finally, reaction of diamine (III) with phenyl glyoxal (IV) in EtOH and HOAc or HCl affords the desired product.
| 【1】 Bohmer, F.D.; Chen, J.; Gazit, A.; McMahon, G.; Levitzki, A.; App, H.; Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: Structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins. J Med Chem 1996, 39, 11, 2170. |
| 【2】 Treatment of platelet derived growth factor related disorders such as cancers using inhibitors of platelet derived growth receptor. EP 1000617; US 5700823; WO 9519169 . |
| 【3】 Levitzki, A.; Hirth, K.P.; Schwartz, D.P.; Tang, P.C.; Ullrich, A.; Haimichael, J.; Shawver, L.K.; Szekely, I.; Mann, E.; Orfi, L.; Slamon, D.; Keri, G.; Kabbinavar, F.F.; Gazit, A.; Bajor, T.; Lammers, R. (Sugen, Inc.); Treatment of platelet derived growth factor related disorders such as cancers. US 5990141 . |
| 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) | 17398 | 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene | 91-16-7 | C8H10O2 | 详情 | 详情 |
| (II) | 43039 | 2-methoxy-4,5-dinitrophenyl methyl ether; 1,2-dimethoxy-4,5-dinitrobenzene | 3395-03-7 | C8H8N2O6 | 详情 | 详情 |
| (III) | 34621 | 4,5-dimethoxy-1,2-benzenediamine; 2-amino-4,5-dimethoxyphenylamine | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 43040 | 2-oxo-2-phenylacetaldehyde | C8H6O2 | 详情 | 详情 |