methyl 2-(3-bromo-4-hydroxyphenyl)acetate

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

Procedure: To a solution of the title compound of Step C of this example (500 mg; 1.35 mmole) in toluene (30 ml) and THF (1.5 ml) was added successively 4-hydroxy-3-bromophenylacetic acid, methyl ester (1 g, 4 mmoles), sodium hydride (169 mg; 7 mmoles) and 15-crown-5 (10 mg). The reaction mixture was refluxed for 10 hours under nitrogen. It was then worked-up as in Step B of Example 8 to yield the title compound of this step. The reaction mixture was refluxed for 10 hours under nitrogen

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

Procedure: Compound 10 (12.3 g) was dissolved in 100 mL acetone and 7.6 g of potassium carbonate was added. 8.6 g of benzyl bromide was added with stirring. The solid was removed by suction filtration and the liquid was evaporated to product 11. The solid was removed by suction filtration the liquid was evaporated to product 11

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

Procedure: 3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (×3). The organic layers were collected, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g). was added concentrated under reduced pressure the solution extracted with diethyl ether (×3) The organic layers were collected washed with water and brine dried over MgSO4 concentrated in vacuo

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

Procedure: Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g). was added over 60 minutes concentrated by evaporation Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1)

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

Procedure: 3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (×3). The organic layers were collected, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g). was added concentrated under reduced pressure the solution extracted with diethyl ether (×3) The organic layers were collected washed with water and brine dried over MgSO4 concentrated in vacuo

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

Procedure: Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g). was added over 60 minutes concentrated by evaporation Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1)

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

Procedure: 3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (×3). The organic layers were collected, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g). was added concentrated under reduced pressure the solution extracted with diethyl ether (×3) The organic layers were collected washed with water and brine dried over MgSO4 concentrated in vacuo

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

Procedure: Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g). was added over 60 minutes concentrated by evaporation Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1)

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

Procedure: 3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (×3). The organic layers were collected, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g). was added concentrated under reduced pressure the solution extracted with diethyl ether (×3) The organic layers were collected washed with water and brine dried over MgSO4 concentrated in vacuo

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

Procedure: Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g). was added over 60 minutes concentrated by evaporation Product was purified from the residue over 300 g of silica gel (hexanes/ethyl acetate 5:1)

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

Procedure: Methyl iodide (2.05 mL, 4.68 g, 33 mmol) was added to a mixture of methyl 3-bromo-4-hydroxyphenylethanoate (Description 73, 7.35 g, 30 mmol) and potassium carbonate (8.29 g, 60 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 16 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 2×100 mL), water (2×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (7.65 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.47 (1 H, d, J 2.1 Hz), 7.18 (1 H, dd, J 8.4, 2.1 Hz), 6.85 (1 H, d, J 8.4 Hz), 3.88 (3 H, s), 3.70 (3 H, s), and 3.49 (2 H, s). the mixture was extracted with ethyl acetate (3×100 mL) The combined organic fractions were washed with aqueous sodium hydroxide (1M, 2×100 mL), water (2×100 mL) and brine (100 mL) dried (MgSO4) the solvent was evaporated under reduced pressure

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

Procedure: Bromine (16.59 g, 104 mmol) in chloroform (25 mL) was added dropwise to a stirred, cooled (0° C.) mixture of methyl 4-hydroxyphenylethanoate (17.25 g, 104 mmol) and acetic acid (10 mL) in chloroform (140 mL). The mixture was stirred at 0° C. for 1 h., diluted with dichloromethane (100 mL), washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (25.43 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.39 (1 H, d, J 2.0 Hz), 7.12 (1 H, dd, J 8.3, 2.0 Hz), 6.96 (1 H, d, J 8.3 Hz), 5.54 (1 H, br s), 3.70 (3 H, s), and 3.54 (2 H, s). cooled washed with water (2×200 mL) and brine (200 mL) dried (MgSO4) the solvent was evaporated under reduced pressure