2-chloro-4-hydroxy-5-methoxybenzaldehyde

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: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 0.548 g, 2.94 mmol, prepared as described in Example 46, Scheme 45, step 1) was dissolved in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.200 g, 5.00 mmol) was added. After 20 minutes, 1-bromomethyl-4-chloro-2-fluoro-benzene (139, 685 μL, 5.00 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was concentrated to dryness in vacuo. The reaction was resuspended in water/saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%), consistent with the desired compound by 1H-NMR. The reaction was concentrated to dryness in vacuo extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%)

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

Procedure: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 0.548 g, 2.94 mmol, prepared as described in Example 46, Scheme 45, step 1) was dissolved in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.200 g, 5.00 mmol) was added. After 20 minutes, 1-bromomethyl-4-chloro-2-fluoro-benzene (139, 685 μL, 5.00 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was concentrated to dryness in vacuo. The reaction was resuspended in water/saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%), consistent with the desired compound by 1H-NMR. The reaction was concentrated to dryness in vacuo extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 2.30 g, 0.0123 mol) was dissolved in N,N-dimethylformamide (89.5 mL, 1.16 mol) and sodium hydride (60% dispersion in mineral oil, 541 mg, 0.0135 mol) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole (106, 2.05 g, 0.0123 mol) was added to the reaction. The reaction was stirred at 80° C. overnight. The reaction was concentrated in vacuo to an oil. Ethyl acetate was added and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%). MS (ESI) [M+H+]+=317.1, 319.1. The reaction was concentrated in vacuo to an oil Ethyl acetate was added washed with saturated sodium bicarbonate and brine The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 2.30 g, 0.0123 mol) was dissolved in N,N-dimethylformamide (89.5 mL, 1.16 mol) and sodium hydride (60% dispersion in mineral oil, 541 mg, 0.0135 mol) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole (106, 2.05 g, 0.0123 mol) was added to the reaction. The reaction was stirred at 80° C. overnight. The reaction was concentrated in vacuo to an oil. Ethyl acetate was added and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%). MS (ESI) [M+H+]+=317.1, 319.1. The reaction was concentrated in vacuo to an oil Ethyl acetate was added washed with saturated sodium bicarbonate and brine The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%)

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

Procedure: 2-Chloro-4,5-dimethoxy-benzaldehyde (135, 2.00 g, 0.00997 mol), dichloromethane (73.44 mL) and aluminum trichloride (2.50 g, 0.0187 mol) were combined under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%). MS (ESI) [M−H+]−=185.0, 187.0. extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%)

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

Procedure: 2-Chloro-4,5-dimethoxy-benzaldehyde (135, 2.00 g, 0.00997 mol), dichloromethane (73.44 mL) and aluminum trichloride (2.50 g, 0.0187 mol) were combined under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%). MS (ESI) [M−H+]−=185.0, 187.0. extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%)

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

Procedure: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 0.548 g, 2.94 mmol, prepared as described in Example 46, Scheme 45, step 1) was dissolved in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.200 g, 5.00 mmol) was added. After 20 minutes, 1-bromomethyl-4-chloro-2-fluoro-benzene (139, 685 μL, 5.00 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was concentrated to dryness in vacuo. The reaction was resuspended in water/saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%), consistent with the desired compound by 1H-NMR. The reaction was concentrated to dryness in vacuo extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 2.30 g, 0.0123 mol) was dissolved in N,N-dimethylformamide (89.5 mL, 1.16 mol) and sodium hydride (60% dispersion in mineral oil, 541 mg, 0.0135 mol) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole (106, 2.05 g, 0.0123 mol) was added to the reaction. The reaction was stirred at 80° C. overnight. The reaction was concentrated in vacuo to an oil. Ethyl acetate was added and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%). MS (ESI) [M+H+]+=317.1, 319.1. The reaction was concentrated in vacuo to an oil Ethyl acetate was added washed with saturated sodium bicarbonate and brine The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 30-70% ethyl acetate in hexane over 30 minutes to provide a white solid (137, 1.79 g, 46%)

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

Procedure: 2-Chloro-4,5-dimethoxy-benzaldehyde (135, 2.00 g, 0.00997 mol), dichloromethane (73.44 mL) and aluminum trichloride (2.50 g, 0.0187 mol) were combined under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%). MS (ESI) [M−H+]−=185.0, 187.0. extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%)