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With trichlorophosphate In toluene for 1 h; Heating / reflux
(4) Step of chlorination: Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6,7-dimethoxy-4-quinolone (1056 g), and the mixture was heated under reflux with stirring for one hr. The reaction solution was neutralized with an aqueous sodium hydroxide solution at 0°C. The resultant precipitate was collected by filtration and was slurried in water (10 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 4-chloro-6,7-dimethoxyquinoline (928 g, yield 87.6percent). 1H-NMR (400 MHz, DMSO-d6/ppm); δ 3.95 (s, 3H), 3.96 (s, 3H), 7.35 (s, 1H), 7.43 (s, 1H), 7.54 (d, 1H), 8.59 (d, 1H)
60%
at 130℃; for 1 h;
A mixture of 1 (1.0 g, 4.9 mmol) and POCl3 (0.68 mL, 7.3mmol) was heated at 130 °C (bath) for 1 h. The resulting liquid was allowed to cool and was stirred with CH2Cl2 (10 mL) and aqueous NH3 (25percent; 10 mL). The organic layer was washed with H2O (10 mL), dried over MgSO4 and the solvent removed. The residue was dissolved in a mixture of t-BuOMe (5 mL) and CH2Cl2 (2 mL) at 50 °C (bath), and the solution was kept at –30 °C overnight. The resulting crystals were collected and dried (0.65 g, 60percent); mp. 132–133 °C (lit.15,19 130–131 °C); IR (neat): 1470, 1221, 1139,1006, 853 cm–1; 1H NMR (300 MHz, CDCl3) δ 4.02 (s, 3H), 4.03 (s, 3H), 7.33 (d, J = 4.9 Hz, 1H), 7.36 (s,1H), 7.42 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 56.4, 56.5, 101.9, 108.1, 119.8,122.3, 140.9, 146.1, 147.4, 151.0, 153.4; HRMS (FAB) m/z 224.0434 (calcd 224.0473 for C11H11NO2Cl,[M+H]+).
35%
Stage #1: for 1 h; Heating / reflux Stage #2: With ammonium hydroxide In water
Step 2: 4-Chloro-6,7-dimethoxyquinoline (4) A suspension of the quinolone 3 (6.54 g, 31.9 mmol) in SOCl2 (70 ml) and DMF (cat) was heated to reflux for 1 hr. The reaction mixture was cooled to room temperature and concentrated. The residue was basified with NH4OH solution and then extracted with DCM. The extract was dried over anhydrous Na2SO4, filtered then concentrated. The residue was purified by column chromatography (eluent a gradient of 20percent EtOAc/hexane to 100percent EtOAc) to afford title compound 4 (2.5 g, 35percent yield) as a brown solid. LRMS (M+1): 224.1 (75percent)/226.1 (25percent).
Reference：
[1] Patent: EP1559715, 2005, A1, . Location in patent: Page/Page column 19
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[3] Heterocycles, 2016, vol. 93, # 1, p. 323 - 332
[4] Patent: US2008/4273, 2008, A1, . Location in patent: Page/Page column 61
[5] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[6] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 23, p. 2935 - 2940
[7] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 3, p. 755 - 758
[8] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[9] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4242 - 4251
[10] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0213-0216
2
[ 127285-54-5 ]
[ 190728-25-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[3] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 23, p. 5117 - 5133
[4] Patent: CN103739550, 2016, B,
[5] Heterocycles, 2016, vol. 93, # 1, p. 323 - 332
3
[ 127285-54-5 ]
[ 228559-87-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
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