Benzoic acid, 4-amino-2,6-difluoro-, methyl ester (9CI)

At RT, 0.5 ml of TFA was added to a solution of 36 mg(0.125 mmol) of methyl 4-[(tert-butoxycarbonyl)amino]-2, 6-difluorobenzoate in 1ml of dichloromethane, and the mixture was stirred at RT for 30 min. Thereaction mixture was then concentrated under reduced pressure and the residuewas co-evaporated repeatedly with dichloromethane and toluene and dried underreduced pressure. The crude product was used for the next step withoutpurification. Yield: 24 mg (quant.)4-Bromo-2, 6-difluorobenzoic acid (5.30 g, 23.7 mmol) was dissolved in methanol (35 ml). After cooling to 0° C., thionyl chloride (10 ml) was added dropwise thereto. The reaction solution was heated, and stirred at 95° C. for 12 hours. After the solvent was removed under reduced pressure, the obtained residue was dissolved in toluene (135 ml). To the solution, benzophenone imine (5.1 ml, 31 mmol), palladium(II) acetate (135 mg, 0.60 mmol), 2, 2′-bis(diphenylphosphino)-1, 1′-binaphthyl (500 mg, 0.80 mmol), and cesium carbonate (13.0 g, 40.0 mmol) were added. After purging with nitrogen gas, the mixture was stirred at 110° C. for 14 hours. After cooling to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a mixture solvent of tetrahydrofuran (80 ml) and water (30 ml), and concentrated hydrochloric acid (30 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with an aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6:1 to 2:1) to obtain the title compound (3.6 g, 81percent over three steps).

Molecular Weight:187.14
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:187.04448479
Monoisotopic Mass:187.04448479
Topological Polar Surface Area:52.3
Heavy Atom Count:13
Complexity:189
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes