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Step B: Ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate: 2-((2-methoxyphenylamino)methylene)malonate (47.6 g, 162 mmol) was suspended in Dowtherm (100 mL) and heated to 250° C. in a sand bath overnight, then cooled to ambient temperature and diluted with pentane (750 mL). The solid was collected by filtration and washed with hexanes (25.7 g, 64percent). MS (APCI) m/z 248.0 (M+1).
With sodium hydroxide; In ethanol; for 1.5h;Reflux;
General procedure: Diethyl (ethoxymethylene) malonate (6.48 g, 30.00 mmol) and m-fluroaniline (2.78 g, 25.00 mmol) was stirred in refluxing ethanol (10 mL) for 1.5 h. The mixture was concentrated under reduced pressure. The residue was crystallized in petroleum ether, filtered off, and air-dried to get 1II. Compound 1II (2.80 g, 9.96 mmol) was stirred in Dowtherm-A (8 mL) for 0.5 h at 260 C. After the reaction was over by TLC, the mixture was cooled to room temperature and petroleum ether was added to get the crude ester, which was further washed with petroleum ether to afford 1III, as a white solid. 1III was hydrolyzed in refluxing NaOH solution (10%, 20 mL) for 1.5 h to give 1IV. Compound 1IV (1.24 g, 6 mmol) was stirred in Dowtherm-A (10 mL) for 1 h at 240 C. After the reaction was over as monitored by TLC, the reaction mixture was cooled to room temperatureand the crude was washed with petroleum ether to afford 1V as a white solid. To a solution of 1V (1.20 g, 7.36 mmol) in 1,2-dichloroethane (30 mL), POCl3 (1.35 g, 8.83 mmol) was added dropwise. The mixture was refluxed for 1 h. Saturated NaHCO3 solution was added to neutralize the reaction mixture, which was worked up with 1,2-dichloroethane. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel) using petroleum ether/ethyl acetate as an eluent (5:1) to produce 1VI as a white solid [17].
Step C: Ethyl 4-chloro-8-methoxyquinoline-3-carboxylate: A mixture of 4-hydroxy-8-methoxyquinoline-3-carboxylate (5.5 g, 22.2 mmol) and POCl3 (6.82 g, 44.5 mmol) was heated at reflux for 2 hours, then cooled to ambient temperature and carefully added to a cold solution of NH4OH (20 mL). The aqueous layer was extracted with dichloromethane. The combined organics were dried, filtered and concentrated, and the resulting crude solid was purified by flash column chromatography, eluting with hexanes/ethyl acetate (5:1) then hexanes/ethyl acetate (1:1) to give the desired product as a solid (5.5 g, 93%
Step B: Ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate: 2-((2-methoxyphenylamino)methylene)malonate (47.6 g, 162 mmol) was suspended in Dowtherm (100 mL) and heated to 250 C. in a sand bath overnight, then cooled to ambient temperature and diluted with pentane (750 mL). The solid was collected by filtration and washed with hexanes (25.7 g, 64%). MS (APCI) m/z 248.0 (M+1).
General procedure: Diethyl (ethoxymethylene) malonate (6.48 g, 30.00 mmol) and m-fluroaniline (2.78 g, 25.00 mmol) was stirred in refluxing ethanol (10 mL) for 1.5 h. The mixture was concentrated under reduced pressure. The residue was crystallized in petroleum ether, filtered off, and air-dried to get 1II. Compound 1II (2.80 g, 9.96 mmol) was stirred in Dowtherm-A (8 mL) for 0.5 h at 260 C. After the reaction was over by TLC, the mixture was cooled to room temperature and petroleum ether was added to get the crude ester, which was further washed with petroleum ether to afford 1III, as a white solid. 1III was hydrolyzed in refluxing NaOH solution (10%, 20 mL) for 1.5 h to give 1IV. Compound 1IV (1.24 g, 6 mmol) was stirred in Dowtherm-A (10 mL) for 1 h at 240 C. After the reaction was over as monitored by TLC, the reaction mixture was cooled to room temperatureand the crude was washed with petroleum ether to afford 1V as a white solid. To a solution of 1V (1.20 g, 7.36 mmol) in 1,2-dichloroethane (30 mL), POCl3 (1.35 g, 8.83 mmol) was added dropwise. The mixture was refluxed for 1 h. Saturated NaHCO3 solution was added to neutralize the reaction mixture, which was worked up with 1,2-dichloroethane. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel) using petroleum ether/ethyl acetate as an eluent (5:1) to produce 1VI as a white solid [17].
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