methyl 4-fluoro-3-hydroxybenzoate

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:

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: 0.5 g (2.94 mmol) of 4-Fluoro-3-hydroxy-benzoic acid methyl ester was dissolved in 30 ml of anhydrous tetrahydrofuran. To this solution was added 0.506 g (3.23 mmol) of 2-(4-chloro-phenyl)-ethanol, 2.93 g (equivalent to 8.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.53 g (8.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with tetrahydrofuran. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate/n-heptane (1/5) and the insoluble residue was removed by filtration. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5). The polymer was filtered off washed with tetrahydrofuran The solvent was removed under reduced pressure the insoluble residue was removed by filtration The solvent was removed under reduced pressure The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5)

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

Procedure: 0.5 g (2.94 mmol) of 4-Fluoro-3-hydroxy-benzoic acid methyl ester was dissolved in 30 ml of anhydrous tetrahydrofuran. To this solution was added 0.506 g (3.23 mmol) of 2-(4-chloro-phenyl)-ethanol, 2.93 g (equivalent to 8.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.53 g (8.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with tetrahydrofuran. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate/n-heptane (1/5) and the insoluble residue was removed by filtration. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5). The polymer was filtered off washed with tetrahydrofuran The solvent was removed under reduced pressure the insoluble residue was removed by filtration The solvent was removed under reduced pressure The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-fluoro-3-hydroxybenzoate (10 g, 58.8 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (20.4 g, 88 mmol), and Cs2CO3 (51 g, 157 mmol) were dissolved in 200 ml of THF and stirred at 65° C. overnight. Cooled to room temperature and diluted with EtOAc and brine. Layers were separated and the aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried (Na2SO4), and concentrated to yield 14.82 g (58.8 mmol, 100%). A solution of hydroxybenzoate intermediate (14.82 g, 58.8 mmol) in 150 ml of THF was cooled to 0° C., treated with LiAlH4 (3.95 g, 104 mmol), and allowed to warm to room temperature over 1 hour. Reaction quenched sequentially with 4 ml of water, 4 ml of 1 N NaOH, and 12 ml of water and left to stir for thirty minutes. Reaction was filtered and the filtrate concentrated to a yellow oil (13.33 g, 59 mmol, 100%). A solution of DMSO (10.26 ml, 145 mmol) in 10 ml of dry CH2Cl2 was added dropwise to a solution of oxalyl chloride (33.3 ml, 66.6 mmol) in an additional 100 ml of dry CH2Cl2 and stirred at −78° C. for 20 minutes. A solution of alcohol intermediate (13.33 g, 59 mmol) in 50 ml dry CH2Cl2 was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was treated with triethylamine (30.8 ml, 221 mmol) and stirred at −78° C. for 30 minutes. The reaction was warmed to 0° C., stirred for 30 minutes, and then allowed to warm to room temperature. Diluted with 1 N HCl and CH2Cl2. The aqueous layer was separated and extracted once with CH2Cl2. The organic layers were combined and washed sequentially with sat'd NaHCO3, 10 vol % bleach in water, and brine. The organic layer was dried (Na2SO4) and concentrated to a yellow solid (12.37 g, 55.7 mmol, 94%). Cooled to room temperature Layers were separated the aqueous layer was extracted twice with EtOAc dried (Na2SO4) concentrated to yield 14.82 g (58.8 mmol, 100%) to warm to room temperature over 1 hour Reaction quenched sequentially with 4 ml of water, 4 ml of 1 N NaOH, and 12 ml of water left to stir for thirty minutes Reaction was filtered stirred at −78° C. for 20 minutes the reaction was stirred at −78° C. for 30 minutes stirred at −78° C. for 30 minutes The reaction was warmed to 0° C. stirred for 30 minutes to warm to room temperature The aqueous layer was separated extracted once with CH2Cl2 washed sequentially with sat'd NaHCO3, 10 vol % bleach in water The organic layer was dried (Na2SO4)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-fluoro-3-hydroxybenzoate (10 g, 58.8 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (20.4 g, 88 mmol), and Cs2CO3 (51 g, 157 mmol) were dissolved in 200 ml of THF and stirred at 65° C. overnight. Cooled to room temperature and diluted with EtOAc and brine. Layers were separated and the aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried (Na2SO4), and concentrated to yield 14.82 g (58.8 mmol, 100%). A solution of hydroxybenzoate intermediate (14.82 g, 58.8 mmol) in 150 ml of THF was cooled to 0° C., treated with LiAlH4 (3.95 g, 104 mmol), and allowed to warm to room temperature over 1 hour. Reaction quenched sequentially with 4 ml of water, 4 ml of 1 N NaOH, and 12 ml of water and left to stir for thirty minutes. Reaction was filtered and the filtrate concentrated to a yellow oil (13.33 g, 59 mmol, 100%). A solution of DMSO (10.26 ml, 145 mmol) in 10 ml of dry CH2Cl2 was added dropwise to a solution of oxalyl chloride (33.3 ml, 66.6 mmol) in an additional 100 ml of dry CH2Cl2 and stirred at −78° C. for 20 minutes. A solution of alcohol intermediate (13.33 g, 59 mmol) in 50 ml dry CH2Cl2 was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was treated with triethylamine (30.8 ml, 221 mmol) and stirred at −78° C. for 30 minutes. The reaction was warmed to 0° C., stirred for 30 minutes, and then allowed to warm to room temperature. Diluted with 1 N HCl and CH2Cl2. The aqueous layer was separated and extracted once with CH2Cl2. The organic layers were combined and washed sequentially with sat'd NaHCO3, 10 vol % bleach in water, and brine. The organic layer was dried (Na2SO4) and concentrated to a yellow solid (12.37 g, 55.7 mmol, 94%). Cooled to room temperature Layers were separated the aqueous layer was extracted twice with EtOAc dried (Na2SO4) concentrated to yield 14.82 g (58.8 mmol, 100%) to warm to room temperature over 1 hour Reaction quenched sequentially with 4 ml of water, 4 ml of 1 N NaOH, and 12 ml of water left to stir for thirty minutes Reaction was filtered stirred at −78° C. for 20 minutes the reaction was stirred at −78° C. for 30 minutes stirred at −78° C. for 30 minutes The reaction was warmed to 0° C. stirred for 30 minutes to warm to room temperature The aqueous layer was separated extracted once with CH2Cl2 washed sequentially with sat'd NaHCO3, 10 vol % bleach in water The organic layer was dried (Na2SO4)

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

Procedure: Charge methyl 4-fluoro-3-hydroxybenzoate (519 mg, 3.05 mmol), 4-(bromomethyl)-1-fluorobenzene (577 mg, 3.05 mmol), K2CO3 (843 mg, 6.10 mmol) and ethanol (10 mL) to a flask. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture at 0° C., filtered, and the solid dried and purified by flash column chromatograph to give 571 mg of the title compound (67%). 1H NMR (400 MHz, CDCl3): δ 3.90 (3H, s), 5.13 (2H, s), 7.06-7.15 (3H, m), 7.41-7.45 (2H, m), 7.63-7.67 (1H, m), 7.71 (1H, dd, J=2.0 Hz, 8.4 Hz). filtered the solid dried purified by flash column chromatograph