Benzoic acid, 3-amino-5-fluoro-, methyl ester

To a 3 liter round bottom flask was charged with 500 ml HTo 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. 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 CTo 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 CTo a 3 liter round bottom flask was charged with 500 ml HTo 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. 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 CTo 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 CMethyl 3-amino-5-fluorobenzoate (3.3 g, 19.6 mmol), water (15 mL), concentrated hydrochloric acid (15 mL) was then evaporated.An aqueous solution (10 mL) of sodium nitrite (2.1 g, 30 mmol) at -10 C was added dropwise.After 15 minutes of dropwise addition, the mixture was kept warm for 1.5 hours.An aqueous solution of SnCl 2 · 2H 2 O (19.4 g, 86 mmol) was added dropwise to the reaction mixture.(40 mL), the addition was completed in 30 minutes, and the stirring was continued for 1.5 hours.After the reaction was completed, 6N NaOH solution (30 mL) was added dropwise to the reaction mixture.It was extracted three times with dichloromethane (20 mL). Combine the methylene chloride layer, Wash with water (30 mL) and saturated brine (30 mL)Concentrated to dry product 3.3 g, yield 91.8%.General procedure: To a solution of compound 11a (154 mg, 1.0 mmol) in anhydrous CH2Cl2 (10 mL) was added 3, 5-dichlorobenzoyl chloride (209 mg, 1.0 mmol) and pyridine (241 mL 3.0 mmol) under ice bath. After stirring at room temperature for about 8 h, the solvent was removed in vacuum. The resulting residue was dissolved in NaOH (1 M) water solution (3 mL) and CH3OH (3 mL) and stirred for another 2 h. Then the solvent was removed under vacuum, and the residue was acidied to pH 2 or below with HCl (1 M) water solution. The solution was extracted with ethyl acetate twice and the combined organics were dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was puried by silica gel chromatography to give the desired compound as a white solid (234 mg, yield 85.0%)Under argon protection, To the reactor was added 1.31 g of zinc powder (20 mmol) and 0.47 g of anhydrous lithium chloride, Join anhydrous tetrahydrofuran 10mL stirring, 2.5 mol% 1, 2-dibromoethane was added dropwise for 10 minutes, Then a solution of 1.81 g (10 mmol)2- (2-bromoethyl) -1, 3-dioxolane in 10 mL of tetrahydrofuran, After stirring at room temperature for 3 hours, 4.50g of zinc bromide (20mmol) was added with stirring, Cooled to -15 , Then a solution of 3.22 g (12 mmol)A solution of 3-fluoro-5-methoxycarbonylbenzenediazonium tetrafluoroborate in 20 mL of tetrahydrofuran, After the addition is completed, Warmed to room temperature, 1.09 g (10 mmol) of Me3SiCl, 0.12 g of rhodium acetate, Heated to 87 C for 4 hours, Cool to room temperature, A small amount of dilute hydrochloric acid was added dropwise to heat to 35 C, After stirring for 2 hours, The reaction solution was extracted with ethyl acetate, The organic phase was dried and concentrated under reduced pressure.Flash column chromatography (Al2O3, ethyl acetate: petroleum ether = 1: 10), 2.06 g of a white solid was obtained, Yield 93.1%

Molecular Weight:169.15
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:169.05390666
Monoisotopic Mass:169.05390666
Topological Polar Surface Area:52.3
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes