1-bromo-4-(2-phenylmethoxyethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a 1 L round bottom flask were charged 4-phenoxyphenol (95.0 g, 0.51 mol). THF (100 mL), sodium hydroxide (24 g, 0.6 mol), and DI water (80 mL). The mixture was magnetically stirred at room temperature for 30 minutes, followed by removal of solvent under reduced pressure. The white solid was then dried under vacuum (70 mTorr) at 150° C. overnight and cooled to room temperature. To the flask were then added 1-bromo-4-[2-(phenylmethoxy)ethyl]benzene (150 g, 0.51 mol) and anhydrous pyridine (100 mL). The mixture was purged with nitrogen for 15 minutes, followed by the addition of cuprous chloride (5 g, 0.05 mol). The mixture was then purge with nitrogen for additional 15 min and then sealed under nitrogen and magnetically stirred in a 130° C. oil bath for a week. After removal of pyridine under vacuum, the crude product was dissolved in methylene chloride (600 mL) and washed with 2N HCl (200 mL×3), 2N NaOH (200 mL×3). After removal of solvent under reduced pressure, the crude product was recrystallized from methanol/ethyl acetate (9/1, v/v). The product was then hydrogenated at 100 PSI in THF using palladium 10% on carbon as catalyst to give crude 2-[4-(4-phenoxyphenoxy)phenyl]ethanol. This crude product was then distilled under vacuum followed by recrystallization from hexanes/ethyl acetate (1/1, v/v) to give the product as white crystals (122 g, 78% over two steps). followed by removal of solvent under reduced pressure The white solid was then dried under vacuum (70 mTorr) at 150° C. overnight cooled to room temperature The mixture was purged with nitrogen for 15 minutes The mixture was then purge with nitrogen for additional 15 min sealed under nitrogen magnetically stirred in a 130° C. oil bath for a week After removal of pyridine under vacuum the crude product was dissolved in methylene chloride (600 mL) washed with 2N HCl (200 mL×3), 2N NaOH (200 mL×3) After removal of solvent under reduced pressure the crude product was recrystallized from methanol/ethyl acetate (9/1 to give crude 2-[4-(4-phenoxyphenoxy)phenyl]ethanol This crude product was then distilled under vacuum followed by recrystallization from hexanes/ethyl acetate (1/1

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 2-(4-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (25 mL) was added 55% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added benzyl bromide (0.77 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1) to give 1-[2-(benzyloxy)ethyl]-4-bromobenzene (1.35 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene. cooling the mixture was stirred at the same temperature for 15 minutes stirred at room temperature for 30 minutes the resulting mixture was extracted with diethyl ether The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1)

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

Procedure: To a solution of 2-(4-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (25 mL) was added 55% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added benzyl bromide (0.77 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1) to give 1-[2-(benzyloxy)ethyl]-4-bromobenzene (1.35 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene. cooling the mixture was stirred at the same temperature for 15 minutes stirred at room temperature for 30 minutes the resulting mixture was extracted with diethyl ether The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1)

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

Procedure: To a solution of 4-(2-benzyloxyethyl)-1-bromobenzene (6.8 g) in tetrahydrofuran (80 mL) was added n-butyl lithium (2.6 mol/L n-hexane solution, 8.98 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,N-dimethylformamide (20 mL), and the mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2-benzyloxyethyl)benzaldehyde (5.6 g). This material was dissolved in methanol (80 mL). To the solution was added sodium borohydride (1.77 g) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue (solid) was treated with n-hexane, collected by filtration and dried under reduced pressure to give the title compound (5.41 g). stirred for 2 hours the resulting mixture was extracted with ethylacetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

Procedure: To a suspension of sodium hydride (60%, 1.09 g) in 1,2-dimethoxyethane (25 mL) was added 2-(4-bromophenyl)ethanol (5 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added benzyl bromide (3.25 mL), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1-20/1) to give the title compound (6.8 g). cooling the mixture was stirred at 80° C. overnight the resulting mixture was extracted with diethyl ether The extract was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1-20/1)

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

Procedure: To a solution of 4-(2-benzyloxyethyl)-1-bromobenzene (6.8 g) in tetrahydrofuran (80 mL) was added n-butyl lithium (2.6 mol/L n-hexane solution, 8.98 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,N-dimethylformamide (20 mL), and the mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(2-benzyloxyethyl)benzaldehyde (5.6 g). This material was dissolved in methanol (80 mL). To the solution was added sodium borohydride (1.77 g) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue (solid) was treated with n-hexane, collected by filtration and dried under reduced pressure to give the title compound (5.41 g). stirred for 2 hours the resulting mixture was extracted with ethylacetate The organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

Procedure: To a suspension of sodium hydride (60%, 1.09 g) in 1,2-dimethoxyethane (25 mL) was added 2-(4-bromophenyl)ethanol (5 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added benzyl bromide (3.25 mL), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1-20/1) to give the title compound (6.8 g). cooling the mixture was stirred at 80° C. overnight the resulting mixture was extracted with diethyl ether The extract was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1-20/1)