methyl 5-bromo-2-chloro-4-hydroxybenzoate

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

Procedure: A solution of methyl 2-chloro-4-hydroxybenzoate (5.0 g, 26.8 mmol) in MeCN (100 mL) was cooled to −30° C. Triflic acid (2.60 mL, 29.48 mmol) was added followed by N-bromosuccinimide (5.25 g, 29.48 mmol) and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL). The solution was extracted with EtOAc (2×100 mL), the combined organic layers were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound as a white solid (2.60 g, 37%). The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL) The solution was extracted with EtOAc (2×100 mL) dried over magnesium sulphate concentrated in vacuo The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes

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

Procedure: A solution of methyl 5-bromo-2-chloro-4-hydroxybenzoate (Preparation 51, 2.5 g, 9.42 mmol) and lithium hydroxide monohydrate (395 mg, 9.42 mmol) in THF (10 mL) was stirred at room temperature for 10 minutes. Dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and left to stir at room temperature for 45 minutes before heating to 75° C. for 3 hours. Additional dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and the reaction stirred at 75° C. for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL), washed with brine (30 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting from 5-10% EtOAc in heptanes to afford the title compound as a white solid (1.70 g, 65%). left before heating to 75° C. for 3 hours the reaction stirred at 75° C. for 16 hours The reaction was cooled to room temperature washed with brine (30 mL) dried over magnesium sulphate concentrated in vacuo The residue was purified by silica gel column chromatography eluting from 5-10% EtOAc in heptanes

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

Procedure: A solution of methyl 2-chloro-4-hydroxybenzoate (5.0 g, 26.8 mmol) in MeCN (100 mL) was cooled to −30° C. Triflic acid (2.60 mL, 29.48 mmol) was added followed by N-bromosuccinimide (5.25 g, 29.48 mmol) and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL). The solution was extracted with EtOAc (2×100 mL), the combined organic layers were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound as a white solid (2.60 g, 37%). The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL) The solution was extracted with EtOAc (2×100 mL) dried over magnesium sulphate concentrated in vacuo The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes

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

Procedure: A solution of methyl 5-bromo-2-chloro-4-hydroxybenzoate (Preparation 51, 2.5 g, 9.42 mmol) and lithium hydroxide monohydrate (395 mg, 9.42 mmol) in THF (10 mL) was stirred at room temperature for 10 minutes. Dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and left to stir at room temperature for 45 minutes before heating to 75° C. for 3 hours. Additional dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and the reaction stirred at 75° C. for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL), washed with brine (30 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting from 5-10% EtOAc in heptanes to afford the title compound as a white solid (1.70 g, 65%). left before heating to 75° C. for 3 hours the reaction stirred at 75° C. for 16 hours The reaction was cooled to room temperature washed with brine (30 mL) dried over magnesium sulphate concentrated in vacuo The residue was purified by silica gel column chromatography eluting from 5-10% EtOAc in heptanes