4-AMINO-3-METHOXYPHENYLBORONIC ACID, PINACOL ESTER

A mixture of Example 175C (45.0 g, 0.129 mole) in dichloromethane (270 mL) was cooled to <5 C. in an ice bath and treated with a 1:1 solution of TFA/dichloromethane (500 mL) while maintaining the reaction temperature below 5 C. The reaction was warmed to ambient temperature and stirred for 2 hours. The solvents were removed by evaporation at a pressure of 30 Torr and a bath temperature of <30 C. The residue was dissolved in dichloromethane (250 mL) and carefully washed with 2.5N sodium hydroxide (300 mL). The organic layer was extracted with brine (100 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (21.7 g, 68percent). 1H NMR (DMSO-d6, 400 MHz) ' 7.05 (d, 1H), 6.98 (d, 1H), 6.59 (d, 1H), 5.13 (s, 2H), 3.75 (s, 3H), 1.25 (s, 12H); reverse phase HPLC (Hypersil HS, 5 'm, 100 ?, 4.6'250 mm; 25percent-100percent acetonitrile/0.05M ammonium acetate over 10 minutes, 1 mL/min) Rt 11.03 min.[0590] A mixture of Example 175C (45.0 g, 0.129 mole) in dichloromethane (270 mL) was cooled to <5° C. in an ice bath and treated with a 1:1 solution of TFA/dichloromethane (500 mL) while maintaining the reaction temperature below 5° C. The reaction was warmed to ambient temperature and stirred for 2 hours. The solvents were removed by evaporation at a pressure of 30 Torr and a bath temperature of <30° C. The residue was dissolved in dichloromethane (250 mL) and carefully washed with 2.5N sodium hydroxide (300 mL). The organic layer was extracted with brine (100 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (21.7 g, 68percent). 1H NMR (DMSO-d6, 400 MHz) δ 7.05 (d, 1H), 6.98 (d, 1H), 6.59 (d, 1H), 5.13 (s, 2H), 3.75 (s, 3H), 1.25 (s, 12H); reverse phase HPLC (Hypersil HS, 5 μm, 100 A, 4.6.x.250 mm; 25percent-100percent acetonitrile/0.05M ammonium acetate over 10 minutes, 1 mL/min) Rt 11.03 min.A. A. A mixture of 246.6 g (1.22 mole) 4-bromo-2-methoxyaniline, 211.8 g (1.16 mole) benzophenone and 11.1 g (58.2 mmole) p-toluenesulfonic acid in 1000 g toluene is heated to boiling for 24 h under reflux, whereby the generated water is removed. Eventually obtained solid substance is filtered, the filtrate is distillatively freed from toluene. The crystallization of the residue is initiated by slow addition of methanol in the cold. The crystals are sucked off, washed with toluene and dried under vacuum. The thereby prepared solid is the protected amine benzhydryliden-(4-bromo-2-methoxyphenyl)-amine.Yield: 305.9 g (0.835 mole, 72percent).25.0 g (68.3 mmole) benzhydryliden-(4-bromo-2-methoxyphenyl)-amine are dissolved in 170 g dry THE and cooled to -78° C. At this temperature 20.4 g (75.1 mmole) of 2.5 M n-butyllithium solution in hexane is slowly added. The mixture is continually stirred for 60 min and then cooled to -85° C. 8.55 g (82.0 mmole) of trimethylborate are slowly added. The mixture is again stirred for 60 min, then left to warm up to -10° C. and then poured into a prepared solution of 11.1 g of 96percent sulphuric acid in 153 g water covered with a layer of 60 g toluene. The mixture is intensely stirred for one hour. After completion of phase separation the aqueous phase is covered with a layer of 230 g of fresh toluene and 9.69 g (82.0 mmole) pinacol are added. By adding 63.7 g of 10percent sodium hydroxide solution a pH-value of about 8.5 is set. The mixture is stirred intensely for 12 h, then again phase separation takes place. From the organic phase the bulk of the solvent is removed at 100-150 mbar. The residue is cooled to -5° C. The thereby obtained solid substance is sucked off, washed and dried under vacuum. Thus, colorless crystals of 4-aminophenylboronic acid pinacol ester are obtained.Yield: 11.7 g (47.1 mmole, 69percent).Yield over all steps: 50percent.Example 27E (500 mg, 2.47 mmol) in DMSO (5mL) solution was added bis(pinacolato)diboron(628.4 mg, 2.47 mmol), tetrakis triphenylphosphine palladium (150 mg, 0.13 mmol ) and potassium acetate (485 mg, 4.95 mmol) and the reaction mixture was stirred at 150 deg.C by microwave for 40 minutes. The reaction mixture was diluted with ethyl acetate (50mL) and water (30mL). The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether 1:: ethyl acetate = 10) to give the title compound (160 mg, 26percent yield) as a yellow oil.