methyl 2-bromo-6-chlorobenzoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-6-chlorobenzoic acid (17.7 g, 75.2 mmol) in methanol (200 mL) at 0° C. was added (trimethylsilyl)diazomethane (2M in hexanes, 100 mL, 0.200 mol). The solution was stirred at 0° C. for 1.5 hours, then warmed to room temperature and washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 0-5% ethyl acetate in hexanes to provide methyl 2-bromo-6-chlorobenzoate as a pale yellow oil that gave proton NMR spectra consistent with theory. warmed to room temperature washed with aqueous sodium bicarbonate and brine dried over Na2SO4 filtered concentrated eluted with 0-5% ethyl acetate in hexanes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-6-chlorobenzoate (7.5 g, 0.03 mol) and potassium trifluoro(vinyl)borate (6.07 g, 0.045 mol) in dioxane and H2O (10:1, 100 mL) was added Pd(dppf)Cl2 (739 mg, 0.906 mmol), and sodium carbonate (6.4 g, 0.06 mol) at RT. The reaction mixture was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was subsequently concentrated in vacuo and diluted with water. The aqueous phase was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2CO3, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (6.7 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 7.39-7.41 (m, 1H), 7.22-7.26 (m, 2H), 6.55-6.62 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.31 (d, J=11.2 Hz, 1H). The mixture was subsequently concentrated in vacuo diluted with water The aqueous phase was extracted with EtOAc (3×100 mL) washed with brine dried over anhydrous Na2CO3 filtered concentrated The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041 mol) and potassium carbonate (8.6 g, 0.061 mol) in N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g, 0.081 mol) dropwise over a 10 minute period. The reaction mixture was stirred at RT for 3.5 hours and was subsequently diluted with water (500 mL). The aqueous phase was back-extracted with EtOAc (3×300 mL). The organic layers were combined, washed with 1M HCl aq (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (10.0 g, 99.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H), 3.9 (s, 3H). The aqueous phase was back-extracted with EtOAc (3×300 mL) washed with 1M HCl aq (100 mL) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of {(R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (600 mg, 1.64 mmol, intermediate 13), methyl 2-bromo-6-chlorobenzoate (430 mg, 1.72 mmol) [CAS 685892-23-3; commercially available], tri-o-tolyl-phosphane (100 mg, 329 μmol), potassium carbonate (568 mg, 4.11 mmol) and palladium(II) acetate (18.4 mg, 82.1 μmol) in THF (20.0 ml) and water (1.18 ml) was stirred at room temperature over night. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and concentrated in vacuo. The remaining residue was purified by chromatography (silica gel; DCM/EtOAc 100:0-90:10) and the title compound was obtained as colorless oil (385 mg, 58%). MS: 466.1 [M−H+OAc]−. extracted three times with EtOAc The combined extracts were washed with water and brine dried with Na2SO4 concentrated in vacuo The remaining residue was purified by chromatography (silica gel; DCM/EtOAc 100:0-90:10)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-6-chlorobenzoic acid (17.7 g, 75.2 mmol) in methanol (200 mL) at 0° C. was added (trimethylsilyl)diazomethane (2M in hexanes, 100 mL, 0.200 mol). The solution was stirred at 0° C. for 1.5 hours, then warmed to room temperature and washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 0-5% ethyl acetate in hexanes to provide methyl 2-bromo-6-chlorobenzoate as a pale yellow oil that gave proton NMR spectra consistent with theory. warmed to room temperature washed with aqueous sodium bicarbonate and brine dried over Na2SO4 filtered concentrated eluted with 0-5% ethyl acetate in hexanes