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Stage #1: With boron tribromide In dichloromethane at 5 - 20℃; Inert atmosphere Stage #2: With sodium hydrogencarbonate In ethanol; dichloromethaneCooling
2-Fluoro-3-methoxyphenylboronic acid (1.1g, 6.5 mmol) was dissolved in 30 mL dichloromethane and cooled to 5 °C under nitrogen. 32 mL boron tribromide solution (1M in dichloromethane, 32 mmol) was added drop-wise with stirring. Upon addition, the mixture was stirred for 1 h at room temperature. The mixture was added drop-wise to 50 mL cold ethanol. The mixture was then neutralised with portion-wise addition of excess solid sodium bicarbonate with cooling. The mixture was stirred for 15 min, filtered and the filtrate evaporated. The residue was taken up in tetrahydrofuran, re-filtered and re-evaporated to give 0.96 g (96percent) of the title compound. 1H NMR (200 MHz, DMSO-d6) ppm 9.53 (1 H, s), 8.13 (2 H, m), 6.91 (3 H, m)
Reference：
[1] Patent: EP2196465, 2010, A1, . Location in patent: Page/Page column 30; 31
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10479 - 10497
[3] Patent: WO2006/5918, 2006, A1, . Location in patent: Page/Page column 89
2,2’-difluoro-3’-methoxy-[1,1‘-biphenyl]-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium phosphate; potassium dihydrogenphosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,2-dimethoxyethane; ethanol; water; at 60℃; for 5h;
(2-fluoro-3-methoxyphenyl)boronic acid (3.98 g, 23.4 mmol), monobasic potassium phosphate (2.49 g, 18.3 mmol), tribasic potassium phosphate (3.89 g, 18.3 mmol) and <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (4.00 g, 18.3 mmol) were added to a degassed mixture of DME (70 ml), water (52 ml) and EtOH (20 ml). The mixture was degassed and then PdCI2(dbpf)(436 mg, 0.9 mmol) was added and the reaction was stirred at 60 00 for 5 hours. Thereaction was reduced in volume and then diluted by the addition of 1 M NaOH solution (150ml) and washed with diethyl ether (150 ml). The layers were separated and the aqueouslayer was cooled to 0 00 and acidified by addition of HCI (37 %). The aqueous phase was filtered and the collected solid was dissolved in EtOAc (400 ml), washed with brine (100 ml), dried over Na2SO4 then filtered through a silica gel plug, washing with EtOAc. The organic phase was concentrated to give a solid which was triturated with a mixture of cyclohexane/EtOH at 70 00 for 1 hour. The mixture was then allowed to cool and wasfiltered. The collected solid was air dried to give the title compound as an off white solid (4.27 g, 88 % yield). MS (mlz) 264.8 (M+H).
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