Methyl 2-bromo-6-fluorobenzoate

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

Procedure: To a solution of methyl 2-bromo-6-fluorobenzoate (53 g, 0.228 mol) and potassium trifluoro(vinyl)borate (33.63 g, 0.251 mol) in dioxane and H2O (3:1, 600 mL) was added Pd(dppf)Cl2 (5 g, 6.84 mmol) and sodium carbonate (69 g, 0.684 mol) at RT. The reaction mixture was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo, diluted with water, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2CO3, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (1-100%) and PE to give the title compound (31.4 g, 76.5%). 1H NMR (400 MHz, CDCl3) δ ppm 7.45-7.36 (m, 2H), 7.03-7.02 (m, 1H), 6.88-6.81 (m, 1H), 5.77-5.73 (m, 1H), 5.41-5.39 (d, J=10.8 Hz, 1H), 3.95 (s, 3H). The mixture was concentrated in vacuo diluted with water extracted with EtOAc (3×200 mL) The combined organic layers were washed with brine dried over anhydrous Na2CO3 filtered concentrated The crude product was purified by column chromatography eluting with a gradient of EtOAc (1-100%) and PE

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

Procedure: To a solution 2-bromo-6-fluorobenzoic acid (50 g, 0.229 mol) and potassium carbonate (31.6 g, 0.229 mol) in N,N-dimethylformamide (250 mL) was added dropwise methyl iodide (51.83 g, 0.365 mol) over a 30 minute period. The reaction mixture was stirred at RT for 3.5 hours. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with 1M aqueous HCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (53 g, 99.7%). extracted with EtOAc (3×300 mL) The combined organic layers were washed with 1M aqueous HCl (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: Methyl 2-bromo-6-fluorobenzoate (2, 11.29 g, 48.5 mmol), cyclopropylboronic acid (6.24 g, 72.7 mmol), K3PO4 (30.85 g, 145.4 mmol) and Pd(PPh3)4 (2.80 g, 2.4 mmol) were mixed under argon in a degassed mixture of toluene and water (20:1, 160 mL). The resulting brown suspension was heated at reflux for 2.5 h, cooled, filtered through Celite, and evaporated. The residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The layers were separated and organic layer was dried over magnesium sulfate and evaporated. The oily residue was suspended in hexane and the solid was removed by filtration. Evaporation of the filtrate afforded the title compound (9.30 g, 47.9 mmol, 99%) as a light brown oil. The resulting brown suspension was heated at reflux for 2.5 h cooled filtered through Celite evaporated The residue was partitioned between ethyl acetate (150 mL) and brine (150 mL) The layers were separated organic layer was dried over magnesium sulfate evaporated the solid was removed by filtration Evaporation of the filtrate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Bromo-6-fluorobenzoic acid (1, 12.50 g, 57 mmol) was dissolved in a mixture of methanol (60 mL) and conc. sulfuric acid (65 mL). The solution was heated to 80° C. and stirred for 12 h. The reaction mixture was cooled and 20% sodium carbonate solution (500 mL) was added slowly to reach pH=8. The mixture was extracted with dichloromethane (3×180 mL), and the combined organic layers were dried over magnesium sulfate and evaporated. The title compound (11.29 g, 48.5 mmol, 85%) was obtained as a brown oil. The reaction mixture was cooled The mixture was extracted with dichloromethane (3×180 mL) the combined organic layers were dried over magnesium sulfate evaporated