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With 5%-palladium/activated carbon; hydrogen In methanol; water for 6 h; Inert atmosphere
To a 3 liter round bottom flask was charged with 500 ml H2SO4. Fuming nitric acid was added (40 mL) and the mixture gently stirred. 2-Bromo-5-fluorobenzoic acid (60 g, 219 mmol) was added in 5 g portions over 90 minutes at 5-10°C. The mixture was stirred for 60 minutes at which time the reaction was completed. The mixture was poured into 1 liter of an ice/water mixture and extracted with EtOAc (3x600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 minutes. The soild was collected on filter to provide 2-bromo-5-fluoro-3-nitrobenzoic acid as yellow solid (35 g, 49percent). To the solution of 2-bromo-5-fluoro-3-nitrobenzoic acid (35 g) in MeOH (400 mL) was added SOCl2 (40 mL) drop-wise at 10-15 °C. The reaction was then stirred at 65°C for 1 h. After cooling to room temperature, the solvent was evaporated in vacuum to afford a residue, which was chromatographed on silica gel using gradient eluant of 0-100percent EtOAc in hexane to provide methyl 2-bromo-5-fluoro-3-nitrobenzoate (20g, 84percent). To a solution of 2-bromo-5-fluoro-3-nitrobenzoate (20 g, 278 mmol) in EtOH/CH3COOH (200 mL/ 200 mL) was added iron powder (25 g, 55mmol). The mixture was vigorously stirred and heated to 85 °C for 1h. After cooling, the mixture was diluted with water and basified with NaHCO3 (PH=8), extracted with ethyl acetate (450mlx3). The combined organic layer was washed with brine (500ml), dried over MgSO4, filtered, and evaporated in vacuum. The residue was applied to flash column chromatography (silica gel) to give methyl 3-amino-2-bromo-5- fluorobenzoate (15.6 g,87percent) as red oil. To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5percent, 50percent water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88percent) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=l .8 Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H),6.58 (m, 1H), 3.82 (s, 3H).
88%
With 5%-palladium/activated carbon; hydrogen In methanol for 6 h;
To a solution of 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) in MeOH (80 mL) was added Pd/C (0.5 g, 5percent, 50percent water), the mixture was stirred at atmosphere of hydrogen for about 6.0 h. Then the mixture was filtered, washed with MeOH (10 mL). The filtrate was concentrated and recrystallized with MeOH (2.5 mL) to afford methyl 3-amino-5-fluorobenzoate (1.48 g, 88percent) as a brown solid. 1H NMR (DMSO-d6) δ 7.04 (t, 1H, J=1.8 Hz), 6.74-6.76 (m, 1H), 6.55-6.80 (m, 1H), 6.58 (m, 1H), 3.82 (s, 3H).
88%
With 5%-palladium/activated carbon; hydrogen In water at 20℃; for 6 h;
Methyl 3-amino-2-bromo-5-fluorobenzoate (2.48 g, 10 mmol) was dissolved in methanol (80 mL) and palladium on carbon (0.5 g, 5percent, 50percent water) added. The mixture was stirred for 6 hours at room temperature under a standard atmosphere of hydrogen. The reaction mixture was filtered through celite, washed with methanol (10ml) and the filtrate was concentrated. Recrystallization from methanol (2.5mL) gave methyl 3-amino-5-fluorobenzoate (1.48g, 88percent) as a brown solid.
Example 1347-Fluoro-3 ,3 -dimethyl-2- (3 -morpholin-4-yl-phenyl) - 1 ,2,3 ,4-tetrahydro-quinoline-5- carboxylic acid To a stirred solution of 3-amino-5-fiuoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0 °C . Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fiuoro- benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FN02 (M+H)+: 170.16, observed: 169.9.
100%
at 0℃; for 12 h; Reflux
To a stirred solution of 3-amino-5-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3.x.100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
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