Methyl 5-amino-2,4-difluorobenzoate

Iron powder (12 3 g, 0 22 mol, 4 equiv) was added to a solution of methyl 2, 4-dιfluoro-5- nitrobenzoate intermediate 18 (12 0 g, 0 06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40 Intermediate 5; methyl 5-amino-2, 4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2, 4- difluoro-5-nitrobeπzoate intermediate 17 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40Intermediate 3; methyl 5-amino-2, 4-difluorobenzoate; Iron powder (12.3 g, 0.22 mol, 4 equiv) was added to a solution of methyl 2, 4-difluoro-5- nitrobenzoate intermediate 2 (12.0 g, 0.06 mol, 1 equiv) in acetic acid (150 mL) and water (150 mL) and the reaction was heated to 40To an ice cold solution of 5-amino-2, 4-difluoro-benzoic acid (1, 0 g, 0.017 mol) in methanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added. The resulting mixture was heated at 80°C for lh. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water was added to the reaction mixture. Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the product methyl 5-amino-2, 4-difluoro-benzoate (2.8 g, 86.0percent). LCMS (ESI positive ion) m/z: calculated: 187.15; Observed; 188.2 (M+l). 1H-NMR (400 MHz, CDC13): δ 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).A mixture of methyl 5-amino-2, 4-difluoro-benzoate (2, 3.0 g, 0.016 mol) and 2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (3.719 g, 0.021 mol) in diethylene glycol monomethyl ether (12 mL) was heated to 170C for 2.5h. Progress of the reaction was monitored by TLC. Water was added to the reaction mixture and extracted with ethyl acetate. The organic part was discarded. Then pH of the aqueous part was adjusted with sodium bicarbonate and extracted with ethyl acetate. Combined organic part was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography to afford the product (1.5 g, 29.9%). LCMS (ESI positive ion) m/z: calculated: 256.25; Observed; 257.0 (M+l).To an ice cold solution of 5-amino-2, 4-difluoro-benzoic acid (1, 0 g, 0.017 mol) in methanol (20.0 mL), thionyl chloride (2.514 mL, 0.035 mol) was added. The resulting mixture was heated at 80C for lh. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. DCM and water was added to the reaction mixture. Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the product methyl 5-amino-2, 4-difluoro-benzoate (2.8 g, 86.0%). LCMS (ESI positive ion) m/z: calculated: 187.15; Observed; 188.2 (M+l). 1H-NMR (400 MHz, CDC13): delta 7.35-7.39 (m, 1H), 6.82-6.87 (m, 1H), and 3.92 (s, 3H).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%)