methyl 4-bromo-2,6-dimethylbenzoate

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

Procedure: A mixture of 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.4 g, 14.2 mmol), N-bromosuccinamide (2.5 g, 14.2 mmol), and benzoyl peroxide (0.060 g, 0.25 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afford 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester. The product obtained was used without further purification. was heated was consumed (as analyzed by GC/MS) The resulting mixture was filtered the filtrate concentrated

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

Procedure: A mixture of 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.4 g, 14.2 mmol), N-bromosuccinamide (2.5 g, 14.2 mmol), and benzoyl peroxide (0.060 g, 0.25 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afford 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester. The product obtained was used without further purification. was heated was consumed (as analyzed by GC/MS) The resulting mixture was filtered the filtrate concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-2,6-dimethyl-benzoic acid (4.04 g, 17.6 mmol) in acetone (50 mL), was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.43 g, 21 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.44 g, 80%). GC-MS: m/z 244 M+. The solids were removed by filtration the filtrate evaporated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-2,6-dimethyl-benzoic acid (4.04 g, 17.6 mmol) in acetone (50 mL), was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.43 g, 21 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.44 g, 80%). GC-MS: m/z 244 M+. The solids were removed by filtration the filtrate evaporated under reduced pressure

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

Procedure: To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (2.81 g, 12.3 mmol) in DMF (30 mL) was added iodomethane (2.30 mL, 36.9 mmol) and potassium carbonate (5.09 g, 36.9 mmol) and reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure to yield an amber oil (3.06 g). 1H NMR (300 MHz, CDCl3): δ 7.22 (S, 2H), 3.92 (s, 3H), 2.30 (s, 6H). The reaction mixture was partitioned between water and ethyl acetate the organic layer was washed with brine The solvent was removed under reduced pressure

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

Procedure: To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (2.81 g, 12.3 mmol) in DMF (30 mL) was added iodomethane (2.30 mL, 36.9 mmol) and potassium carbonate (5.09 g, 36.9 mmol) and reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure to yield an amber oil (3.06 g). 1H NMR (300 MHz, CDCl3): δ 7.22 (S, 2H), 3.92 (s, 3H), 2.30 (s, 6H). The reaction mixture was partitioned between water and ethyl acetate the organic layer was washed with brine The solvent was removed under reduced pressure

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2,6-dimethylphenyl trifluoromethanesulfonate (1.439 g), palladium acetate (0.049 g), 1,3-bis(diphenylphosphino)propane (0.089 g) and triethylamine (1.336 mL) in methanol (10 mL)/dimethylsulfoxide (15 mL) was stirred at 75° C. overnight under an atmosphere of carbon monoxide. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (0.435 g). The organic layer was separated washed with water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As shown in step 6-i of Scheme 6, 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 2021, 920 mg, 3.47 mmol), methyl 4-bromo-2,6-dimethyl-benzoate (844 mg, 3.47 mmol), and Cs2CO3 (2.26 g, 6.94 mmol) were taken up in DMSO (12 mL) in a sealable tube. Nitrogen gas was bubbled through the solution for 5 minutes, dppfPdCl2 (141 mg, 0.174 mmol) added, and the vessel sealed. The reaction mixture was heated at 90° C. for 60 minutes under an atmosphere of nitrogen. After cooling, the mixture was poured into EtOAc/water. The organics were washed with water, brine, passed through a plug of Florisil®, and concentrated under reduced pressure to give a solid. The solid was suspended in MeOH and collected by filtration to provide methyl 4-(5,6-dimethoxy-3-pyridyl)-2,6-dimethyl-benzoate (Compound 2022, 310 mg). The filtrate was concentrated and purified by silica gel chromatography (0 to 50% EtOAc/hex) to provide an additional 400 mg of Compound 2022 (total yield 710 mg, 2.4 mmol, 68% yield). This compound was used in subsequent reactions as is. Nitrogen gas was bubbled through the solution for 5 minutes the vessel sealed After cooling The organics were washed with water, brine concentrated under reduced pressure to give a solid collected by filtration