4-Bromo-2,5-difluorobenzoic acid

(a) 4-bromo-2, 5-difluorobenzoic acid To a 780C solution of 1, 4-dibromo-2, 5-difluorobenzene (2.72 g, 9.99 mmol) in dry Et20 (30 mL) under an inert atmosphere was added 2.5 M n-butyllithium solution in hexanes (4 mL, 9.99 mmol) drop-wise and the mixture left stirring for 2 h. Crushed CO2 pellets were added slowly and the mixture was allowed to warm to ambient temperature and left stirring for 1 h. After quenching with 1M aqueous HCI (10 mL) the mixture was basified with 1M aqueous NaOH (70 mL) and then washed with Et20 (2 x 50 mL). The aqueous layer was acidified with 1M aqueous HCI (80 mL) and extracted with Et20 (3 x 100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and solvent was removed in vacuo to give 4-bromo-2, 5-difluoro benzoic acid (2.3 g, 97 percent) as an off-white solid, which was used without further purification.1H NMR (Method B) (CDCI3): O ppm 9.50 (brs, 1H), 7.78 (dd, J= 8.2, 6.1 Hz, 1H), 7.46 (dd, J= 9.3, 5.4 Hz, 1H); LC-MS (Method C) 234.9/236.9 [M-H] RT 3.43 mmTo a -78°C solution of 1 , 4-dibromo-2, 5-difluorobenzene (2.72 g, 9.99 mmol) in dry EtUnder an argon atmosphere, to a solution of 1, 4-dibromo-2, 5-difluorobenzene (1) (20.00 g, 73.6mmol) in diethyl ether (160 mL) was added dropwise 1.6 M n-butyl lithium solution in hexane(1.05 eq, 49 mL) at -78 °C, and the mixture was stirred at same temperature for 2 min. Themixture was added quickly to the mixture of dry ice (about 100 g) and diethyl ether (200 mL), and the mixture was warmed up to room temperature. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was treated with water (50 mL) and 1 M hydrochloric acid (150 mL), and extracted with diethyl ether. The organic layer was washed with brine and dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was washed with hexane, dried in vacuo to obtain 4-bromo-2, 5-difluorobenzoic acid ( 14.8 g, 85 percent) as a pale yellow solid: 1H NMR (DMSO-d6) δ 7.78(1H, dd, J = 6.4, 8.3 Hz), 7.89 (1H, dd, J = 5.9, 9.8 Hz).To the solution of XLVII-1 (13.55 g, 50 mmol), in EtUnder an argon atmosphere, to a solution of 1, 4-dibromo-2, 5-difluorobenzene (10, 70.00 g) in diethyl ether (500 mL) was added dropwise 1.58 M n-butyl lithium solution in hexane (171 mL) at -78 °C, and the mixture was stirred at same temperature for 2 min. The mixture was added quickly to the mixture of dry ice (about 300 g) and diethyl ether (600 mL), and the mixture was warmed up to room temperature. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was treated with water (100 mL) and 1 M hydrochloric acid (500 mL), and extracted with diethyl ether. The organic layer was washed with brine and dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was washed with hexane, dried in vacuo to obtain 11a (53.29 g, 83percent) as a pale yellow solid: To the solution of 1, 4- dibromo-2, 5-difluorobenzene (i-6a) (27.0 g, 100 mmol) in THF(500 ml) was added n-BuLi (60 ml, 2M) dropwise at -78°C and stirred for 3 h which was protected by NTo a solution of 1, 4-dibromo-2, 5-difluorobenzene (i-6a) (27.0 g, 100 mmol) in THF(500 ml) was added n-BuLi (60 ml, 2M) dropwise at -78°C and the reaction mixture was kept stirring for 3h. Then excess dry ice was added into the reaction mixure portwise over 0.5 h. The reaction mixture wasquenched with 300 ml water and extracted with EA (100 mlx 3). The aqueous solution was acidified with HC1 (2M), extracted with EA (150 mlx3), and the organic layer was dried and concentrated. The crude material was purified by chromatography column (EA:PE = 1:10) to afford 18.24 g product (76percent). LCMS (ESI) calc’d [M+H]: 237.00, found: 237.1.1, 4-Dibromo-2, 5-difluorobenzene (51.2 g, 188 mmol) was dissolved in 1, 2-diethoxyethane (400 ml), and a 2.5 M n-butyllithium/ hexane solution (76.0 ml, 190 mmol) was slowly added dropwise thereto at −78° C. in the presence of nitrogen gas. [0674] After the reaction solution was stirred at −78° C. for 30 minutes, dry ice was added thereto, followed by stirring for further 30 minutes. After the temperature was gradually raised to room temperature, water (200 ml) was added to the reaction liquid. The reaction liquid was diluted with ethyl acetate, and washed with a 10percent aqueous sodium carbonate solution (200 ml×2). Then, the obtained aqueous layers were combined, and made acidic by adjustment with 1 N hydrochloric acid. The precipitated yellow solid was filtered and dried to obtain the title compound (30.0 g, 67percent). [0675] (Step 2) 4-Bromo-2, 5-difluorobenzoic acid (0236) (0237) 1, 4-Dibromo-2, 5-difluorobenzene (51.2 g, 188 mmol) was dissolved in 1, 2-diethoxyethane (400 ml), and a 2.5 M n-butyllithium/hexane solution (76.0 ml, 190 mmol) was slowly added thereto dropwise at −78° C. in the presence of nitrogen gas. The reaction solution was stirred at −78° C. for 30 minutes, then dry ice was added, and the resulting mixture was further stirred for 30 minutes. The temperature was gradually raised to room temperature, and then water (200 ml) was added to the reaction liquid. The reaction liquid was diluted with ethyl acetate, the resulting solution was washed with a 10percent aqueous solution of sodium carbonate (200 ml×2), then the obtained aqueous layers were combined, 1 N hydrochloric acid was added for adjustment to acidic pH, and the precipitated yellow solid was filtered and dried to obtain the title compound (30.0 g, 67percent). (0238) STEP 1 : SYNTHESIS OF 4-BROMO-2, 5-DIFLUOROBENZOIC ACIDIntermediate 24A: 4-Bromo-2, 5-difluorobenzoic acid A solution of 1, 4-dibromo-2, 5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n20 butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at -78 °C for 30mm, then was treated with a piece of dry ice. The cooling bath was removed after 5 mm and the mixture was stirred for another 30 mm while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCO3. The combined aqueous phases were acidified with 1 M aqueous HC1, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2, 5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).A solution of 1, 4-dibromo-2, 5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). A solution of l, 4-dibromo-2, 5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n- butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at -78 °C for 30 min, then was treated with a piece of dry ice. The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCC . The combined aqueous phases were acidified with 1 M aqueous HCI, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2, 5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).Trifluoromethanesulfonic acid (125 mL) was added to a solution of tert-butyl 4-bromo-2, 5-difluorobenzoate (27.4 g, 93.4 mmol) in dichloromethane (125 mL) at 0°C. The resulting mixture was stirred at room temperature 3 hr, and then concentrated underreduced pressure. Half-saturated brine (100 mL) was then added to the residue, and the mixture was extracted with dichloromethane (2 x 90 mL). The organic layers werecombined and the product was extracted with a 1 N aqueous solution of sodium hydroxide(1 x 90 mL and 1 x 50 mL). The combined aqueous layers were then acidified using a 3 Naqueous solution of hydrochloric acid (80 mL), and the product was extracted with EtOAc(3 x 100 mL). The combined organic layers were over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide 4-bromo-2, 5-difluorobenzoic acid (13.1 g, 59percent) as a solid. ‘H NMR (300 MHz, DMSO-d6) ppm 7.78 (dd, J 8.63, 6.23 Hz, 1 H), 7.90 (dd, J= 9.72, 5.58 Hz, 1 H), 13.72 (br s, 1 H).To stirred solution of

Molecular Weight:237.00
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:235.92845
Monoisotopic Mass:235.92845
Topological Polar Surface Area:37.3
Heavy Atom Count:12
Complexity:188
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes