2-bromo-4-methoxyphenol

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-bromo-4-methoxyphenol (20.00 g, 98.04 mmol) in 1,2-di-chloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide (12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) in water (150 mL). The mixture was stirred at reflux for 24 h and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 1H NMR (250 MHz, CDCl3) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t, 2H), 3.75 (t, 3H), 3.71 (s, 3H). at reflux for 24 h extracted with ethyl acetate (3×150 mL) The combined organic extracts were washed with brine dried (Na2SO4) After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue

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

Procedure: To a solution of 2-bromo-4-methoxyphenol (20.00 g, 98.04 mmol) in 1,2-di-chloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide (12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) in water (150 mL). The mixture was stirred at reflux for 24 h and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 1H NMR (250 MHz, CDCl3) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t, 2H), 3.75 (t, 3H), 3.71 (s, 3H). at reflux for 24 h extracted with ethyl acetate (3×150 mL) The combined organic extracts were washed with brine dried (Na2SO4) After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue

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

Procedure: To a solution of 4-methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL) was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction was allowed to warm to room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 1H NMR (250 MHz. CDCl3) d 7.49 (b, 1H), 6.96 (d, 1H), 6.72-6.62 (m, 2H), 3.71 (s, 3H). was quenched with water extracted with ethyl acetate (3×200 mL) The combined organic extracts were washed with brine dried (Na2SO4) Removal of the solvent under reduced pressure

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

Procedure: To a solution of 4-methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL) was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction was allowed to warm to room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 1H NMR (250 MHz. CDCl3) d 7.49 (b, 1H), 6.96 (d, 1H), 6.72-6.62 (m, 2H), 3.71 (s, 3H). was quenched with water extracted with ethyl acetate (3×200 mL) The combined organic extracts were washed with brine dried (Na2SO4) Removal of the solvent under reduced pressure

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

Procedure: A solution of 2.6 mL (100 mmol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes to a solution of 12.4 gm (100 mMol) 4-methoxyphenol in 20 mL carbon disulfide at 0° C. After 30 minutes an additional 1 mL of bromine in 10 mL carbon disulfide are added dropwise. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 11.6 gm (57%) of the desired compound as a crystalline solid. The reaction mixture was then concentrated under reduced pressure the residue was dissolved in diethyl ether This solution was washed sequentially with 100 mL water and 100 mL saturated aqueous sodium chloride dried over magnesium sulfate concentrated under reduced pressure eluting with a gradient of hexane containing from 0 to 20% ethyl acetate Fractions containing product concentrated under reduced pressure

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

Procedure: To a solution of 2-bromo4methoxyphenol (20.00 g, 99.04 mmol) in 1.2-di-chloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide (12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) in water (150 mL). The mixture was stirred at reflux for 24 h and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 1H NMR (250 MHz, CDCl3) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t, 2H), 3.75 (t, 3H). 3.71 (s, 3H). at reflux for 24 h extracted with ethyl acetate (3×150 mL) The combined organic extracts were washed with brine dried (Na2SO4) After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue

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

Procedure: To a solution of 2-bromo4methoxyphenol (20.00 g, 99.04 mmol) in 1.2-di-chloroethane (50.00 mL, 0.63 mol) was added sodium hydroxide (12.00 g, 0.29 mol) and benzyltriethylammonium chloride (3.00 g) in water (150 mL). The mixture was stirred at reflux for 24 h and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue gave 14.20 g (66% over two steps) of the title compound as a yellow oil: 1H NMR (250 MHz, CDCl3) d 7.09 (d, 1H), 6.82-6.72 (m, 2H), 4.27 (t, 2H), 3.75 (t, 3H). 3.71 (s, 3H). at reflux for 24 h extracted with ethyl acetate (3×150 mL) The combined organic extracts were washed with brine dried (Na2SO4) After removing the solvent under reduced pressure, flash chromatography (1:1 diethyl ether/hexane) of the residue

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

Procedure: To a solution of 4methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL) was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction was allowed to warm room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 1H NMR (250 MHz, CDCl3) d 7.49 (b, 1H), 6.96 (d. 1H), 6.72-6.62 (m, 2H). 3.71 (s, 3H). was quenched with water extracted with ethyl acetate (3×200 mL) The combined organic extracts were washed with brine dried (Na2SO4) Removal of the solvent under reduced pressure

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

Procedure: The title compound was prepared (0.31 g, 87%, mp 196°-198° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 20) by the reaction of 5-methoxy-3-benzo[b]furanpropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine. 5-Methoxy-3-benzo[b]furanpropanol tosylate was prepared from 2-bromo-4-methoxyphenol in a manner analogous to the preparation of 5-fluoro-3-benzo[b]furanpropanol tosylate (Example 21).

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

Procedure: The title compound was prepared (0.31 g, 87%, mp 196°-198° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 20) by the reaction of 5-methoxy-3-benzo[b]furanpropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine. 5-Methoxy-3-benzo[b]furanpropanol tosylate was prepared from 2-bromo-4-methoxyphenol in a manner analogous to the preparation of 5-fluoro-3-benzo[b]furanpropanol tosylate (Example 21).

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the product from Step A (1.01 g, 5 mmol), 2-bromo-1,1-diethoxyethane (1.05 g, 5.25 mmol) and Cs2CO3 (2.04 g, 6 mmol) in DMF (10 mL) was stirred at 120° C. for 2 hrs. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluted with PE:EtOAc=6:1) to the title compound (2.7 g, 85%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.12 (d, J=3.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0, 3.0 Hz, 1H), 4.87 (t, J=5.2 Hz, 1H), 4.02 (d, J=5.2 Hz, 2H), 3.84-3.78 (m, 2H), 3.77 (s, 3H), 3.73-3.67 (m, 2H), 1.27 (t, J=7.1 Hz, 6H) ppm. The reaction was cooled to room temperature washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated The residue was purified by column chromatography (eluted with PE:EtOAc=6:1) to the title compound (2.7 g, 85%) as an oil