1. 3-Amino-2,5-dichlorobenzoic acid (1.74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.70 g) and 1-hydroxybenzotriazole hydrate (2.66 g) were dissolved in N,N-dimethylformamide (40 mL). Methanol (5 mL) was added to the solution and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated saline and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by ethyl acetate-hexane column chromatography to afford methyl 3-amino-2,5-dichlorobenzoate (1.45 g, 78% yield).
2. 3-Amino-2,5-dichlorobenzoic acid methyl ester (1.45 g) and 5-(methoxymethylenyl)-2,2-dimethyl-1,3-dioxohexane-4,6-dione (1.50 g) were suspended in 2-propanol (40 mL) and stirred at 70 °C for 30 min. Cooled to room temperature, the precipitate was collected by filtration and washed sequentially with methanol and ether. The resulting crystals were used directly in the next step of the reaction.
3. Suspend the above crystals with biphenyl (5.8 g) in diphenyl ether (25 mL) and stir at 220 °C for 30 min. Cooled to room temperature, the precipitate was collected by filtration and washed with chloroform. The resulting crystals (1.19 g) were used directly in the next step of the reaction.
4. A portion of the residue (0.59 g) was dissolved in N,N-dimethylformamide (20 mL), triethylamine (4 mL) and 10% palladium/carbon (0.59 g) were added, and stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered and washed with chloroform. Concentrated under reduced pressure and the residue was washed with methanol to give methyl 4-oxo-1,4-dihydroquinoline-7-carboxylate (187 mg, 28% overall yield in three steps).
5. 4-Oxo-1,4-dihydroquinoline-7-carboxylic acid methyl ester (650 mg) was suspended in diisopropylethylamine (7 mL), phosphorus trichloride (1.5 mL) was added, and stirred at 120 °C for 30 min. Water was added under cooling in an ice bath, the aqueous layer was neutralized with aqueous sodium bicarbonate, and the organic layer was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by acetone-chloroform column chromatography to afford methyl 4-chloroquinoline-7-carboxylate (609 mg, 86% yield).
