methyl 2-(4-bromophenyl)-2-hydroxyacetate

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (5.0 g, 22 mmol) in MeOH (10 mL) was added 2,2-dimethoxypropane (3.4 g, 33 mmol) and 4-methylbenzene-1-sulfonic acid (2.0 mg, 0.010 mmol). The resulting solution was stirred overnight at 55° C. and allowed to cool to rt. The resulting mixture was concentrated under reduced pressure and poured into water (100 mL). The solids were collected by filtration and washed with hexanes (2×20 mL) to obtain compound 50a as a gray solid. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.54-7.51 (m, 2H), 7.35-7.28 (m, 2H), 5.18-5.16 (m, 1H), 3.793 (s, 3H), 3.51-3.49 (m, 1H). to cool to rt The resulting mixture was concentrated under reduced pressure poured into water (100 mL) The solids were collected by filtration washed with hexanes (2×20 mL)

Conditions: temp:90.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degassed N,N-dimethylformamide (0.60 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 61.4 mg, 0.101 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 49.8 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.016 mmol) and potassium phosphate (65 mg, 0.31 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 95° C. for four hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (24.4 mg, 37%). Degassed N,N-dimethylformamide (0.60 mL) After replacement with nitrogen, the mixture was heated followed by extraction with diethyl ether The extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1)

Conditions: temp:91.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degassed N,N-dimethylformamide (0.26 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 22.4 mg, 0.0343 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 10.5 mg, 0.0428 mmol), tetrakis(triphenylphosphine)palladium (0) (6.2 mg, 0.0054 mmol) and potassium phosphate (14.1 mg, 0.0664 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 96° C. for five hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (7.0 mg, 32%). Degassed N,N-dimethylformamide (0.26 mL) After replacement with nitrogen, the mixture was heated followed by extraction with diethyl ether The extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1)

Conditions: temp:91.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degassed N,N-dimethylformamide (0.26 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 22.4 mg, 0.0343 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 10.5 mg, 0.0428 mmol), tetrakis(triphenylphosphine)palladium (0) (6.2 mg, 0.0054 mmol) and potassium phosphate (14.1 mg, 0.0664 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 96° C. for five hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (7.0 mg, 32%). Degassed N,N-dimethylformamide (0.26 mL) After replacement with nitrogen, the mixture was heated followed by extraction with diethyl ether The extract was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1)

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

Procedure: A solution of trimethylsilyldiazomethane in hexane (2 M, 1.4 mL, 2.8 mmol) was added to a solution of 4-bromo-phenyl-hydroxy-acetic acid (506 mg, 2.19 mmol) in benzene (2.1 mL)-methanol (1.0 mL) under cooling with ice, and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (500 mg, 93%). under cooling with ice The reaction mixture was concentrated under reduced pressure The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1)

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

Procedure: Dess-Martin periodinane (7.6 g, 17.96 mmol) was added to an ambient temperature solution of methyl (4-bromophenyl)(hydroxy)acetate (4 g, 16.33 mmol) in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded methyl (4-bromophenyl)(oxo)acetate. the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) extracted with methylene chloride The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

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

Procedure: Hydrogen chloride (4 M in 1,4-dioxane) (3 mL, 18 mmol) was added to an ambient temperature solution of 4-bromomandelic acid (5 g, 21.6 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl (4-bromophenyl)(hydroxy)acetate which was used in the subsequent step without further purification. the reaction mixture was concentrated in vacuo

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

Procedure: A mixture of 20 g (87 mmol) of (±)-4-bromo-α-hydroxyphenylacetic acid, 200 ml of methanol and 2 ml of concentrated sulfuric acid was stirred for 3 hours at room temperature. To the mixture 50 ml of water was added. After the solution was extracted with ethyl acetate, the organic extract was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and it was dried on anhydrous magnesium sulfate. After removing the solvent, the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1)), and 19.5 g of (±)-methyl 4-bromo-α-hydroxyphenylacetate was obtained (yield: 92%). After the solution was extracted with ethyl acetate the organic extract was washed with a saturated aqueous solution of sodium bicarbonate with water, and it was dried on anhydrous magnesium sulfate After removing the solvent the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1))

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

Procedure: Dess-Martin periodinane (7.6 g, 17.96 mmol) was added to an ambient temperature solution of methyl (4-bromophenyl)(hydroxy)acetate (4 g, 16.33 mmol) in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded methyl (4-bromophenyl)(oxo)acetate. the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) extracted with methylene chloride The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

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

Procedure: Hydrogen chloride (4 M in 1,4-dioxane) (3 mL, 18 mmol) was added to an ambient temperature solution of 4-bromomandelic acid (5 g, 21.6 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl (4-bromophenyl)(hydroxy)acetate which was used in the subsequent step without further purification. the reaction mixture was concentrated in vacuo

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

Procedure: A mixture of 20 g (87 mmol) of (±)-4-bromo-α-hydroxyphenylacetic acid, 200 ml of methanol and 2 ml of concentrated sulfuric acid was stirred for 3 hours at room temperature. To the mixture 50 ml of water was added. After the solution was extracted with ethyl acetate, the organic extract was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and it was dried on anhydrous magnesium sulfate. After removing the solvent, the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1)), and 19.5 g of (±)-methyl 4-bromo-α-hydroxyphenylacetate was obtained (yield: 92%). After the solution was extracted with ethyl acetate the organic extract was washed with a saturated aqueous solution of sodium bicarbonate with water, and it was dried on anhydrous magnesium sulfate After removing the solvent the residue was purified by chromatography (elution with toluene:ethyl acetate (2:1))

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

Procedure: According to a method similar to Example (31) and Example (17-4), from methyl (4-bromophenyl)(hydroxy)acetate (100 mg, 0.41 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (170 mg, 0.34 mmol) obtained in Example (22-4), the title compound was obtained as a grayish white powder (14 mg, yield: 8%).