methyl 2-amino-5-bromo-3-methoxybenzoate

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

Procedure: A mixture of methyl 2-amino-5-bromo-3-methoxybenzoate (6.50 g, 25 mmol), methylboronic acid (3.0 g, 50 mmol), potassium fluoride (5.8 g, 100 mmol) and tri-t-butylphosphonium tetrafluoroborte (0.87 g, 3.0 mmol) in THF (200 mL) was deoxygenated and then backfilled with argon. Tris(dibenzylideneacetone)dipalladium(0) (1.43 g, 1.5 mmol), was added and the mixture was heated at 70° C. for 17 h under an argon atmosphere. The reaction mixture was concentrated and the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-methoxy-3-methylbenzoate (3.55 g, 73%) 1H NMR consistent. was deoxygenated The reaction mixture was concentrated the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes)

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

Procedure: A mixture of methyl 2-amino-5-bromo-3-methoxybenzoate (6.50 g, 25 mmol), methylboronic acid (3.0 g, 50 mmol), potassium fluoride (5.8 g, 100 mmol) and tri-t-butylphosphonium tetrafluoroborte (0.87 g, 3.0 mmol) in THF (200 mL) was deoxygenated and then backfilled with argon. Tris(dibenzylideneacetone)dipalladium(0) (1.43 g, 1.5 mmol), was added and the mixture was heated at 70° C. for 17 h under an argon atmosphere. The reaction mixture was concentrated and the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-methoxy-3-methylbenzoate (3.55 g, 73%) 1H NMR consistent. was deoxygenated The reaction mixture was concentrated the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes)

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

Procedure: To a solution of methyl 2-amino-3-methoxybenzoate (13.0 g, 71.8 mmol) in DMF (30 mL) was added NBS (14.38 g, 80.8 mmol) at room temperature and the resulting reaction mixture was stirred for 17 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-bromo-3-methoxybenzoate (13.7 g, 73%). 1H NMR consistent. the resulting reaction mixture The reaction mixture was filtered through Celite the filtrate was concentrated under reduced pressure The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes)

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

Procedure: To a solution of methyl 2-amino-3-methoxybenzoate (13.0 g, 71.8 mmol) in DMF (30 mL) was added NBS (14.38 g, 80.8 mmol) at room temperature and the resulting reaction mixture was stirred for 17 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-bromo-3-methoxybenzoate (13.7 g, 73%). 1H NMR consistent. the resulting reaction mixture The reaction mixture was filtered through Celite the filtrate was concentrated under reduced pressure The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes)

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

Procedure: To a solution of compound 54 (27.0 g, 103 mmol) in H2O (70 mL) and conc.HCl (70 mL) was added dropwise a solution of NaNO2 (21.5 g, 311 mmol) in H2O (50 mL) at 0° C. After being stirred for 1 hour, a solution of Cu(I)Cl in conc.HCl (80 mL) was added to the reaction mixture dropwise at 0° C. The mixture was stirred at room temperature for 18 hours. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 55 was dried under high vacuum and used without further purification (29.0 g, 100%) as a white solid. The mixture was stirred at room temperature for 18 hours extracted with EtOAc (500 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude product 55 was dried under high vacuum used without further purification (29.0 g, 100%) as a white solid

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

Procedure: To a solution of compound 53 (22.4 g, 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid. extracted with EtOAc (500 mL×2) The combined organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography

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

Procedure: To a solution of compound 53 (22.4 g, 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid. extracted with EtOAc (500 mL×2) The combined organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography

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

Procedure: A mixture of methyl 2-amino-5-bromo-3-methoxybenzoate (6.50 g, 25 mmol), methylboronic acid (3.0 g, 50 mmol), potassium fluoride (5.8 g, 100 mmol) and tri-t-butylphosphonium tetrafluoroborte (0.87 g, 3.0 mmol) in THF (200 mL) was deoxygenated and then backfilled with argon. Tris(dibenzylideneacetone)dipalladium(0) (1.43 g, 1.5 mmol), was added and the mixture was heated at 70° C. for 17 h under an argon atmosphere. The reaction mixture was concentrated and the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-methoxy-3-methylbenzoate (3.55 g, 73%) 1H NMR consistent. was deoxygenated The reaction mixture was concentrated the residue purified by column chromatography (silica gel, 0% to 5% EtOAc in hexanes)

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

Procedure: To a solution of methyl 2-amino-3-methoxybenzoate (13.0 g, 71.8 mmol) in DMF (30 mL) was added NBS (14.38 g, 80.8 mmol) at room temperature and the resulting reaction mixture was stirred for 17 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes) to afford methyl 2-amino-5-bromo-3-methoxybenzoate (13.7 g, 73%). 1H NMR consistent. the resulting reaction mixture The reaction mixture was filtered through Celite the filtrate was concentrated under reduced pressure The resulting residue was purified by column chromatography (silica gel, 2% to 5% EtOAc in hexanes)

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

Procedure: To a solution of compound 54 (27.0 g, 103 mmol) in H2O (70 mL) and conc.HCl (70 mL) was added dropwise a solution of NaNO2 (21.5 g, 311 mmol) in H2O (50 mL) at 0° C. After being stirred for 1 hour, a solution of Cu(I)Cl in conc.HCl (80 mL) was added to the reaction mixture dropwise at 0° C. The mixture was stirred at room temperature for 18 hours. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 55 was dried under high vacuum and used without further purification (29.0 g, 100%) as a white solid. The mixture was stirred at room temperature for 18 hours extracted with EtOAc (500 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude product 55 was dried under high vacuum used without further purification (29.0 g, 100%) as a white solid

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

Procedure: To a solution of compound 53 (22.4 g 123 mmol) in DMF (250 mL) was added N-bromosuccinimide (21.9 g, 123 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. To the mixture was added water and extracted with EtOAc (500 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the desired compound 54 (27.5 g, 86%) as a white solid. extracted with EtOAc (500 mL×2) The combined organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography

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

Procedure: To a solution of compound 54 (27.0 g, 103 mmol) in H2O (70 mL) and conc.HCl (70 mL) was added dropwise a solution of NaNO2 (21.5 g, 311 mmol) in H2O (50 mL) at 0° C. After being stirred for 1 hour, a solution of Cu(I)Cl in conc.HCl (80 mL) was added to the reaction mixture dropwise at 0° C. The mixture was stirred at room temperature for 18 hours. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 55 was dried under high vacuum and used without further purification (29.0 g, 100%) as a white solid. The mixture was stirred at room temperature for 18 hours extracted with EtOAc (500 mL) The organic layer was dried over MgSO4 filtered concentrated in vacuo The crude product 55 was dried under high vacuum used without further purification (29.0 g, 100%) as a white solid