(5-Fluoro-2-methoxyphenyl)methanol

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) was added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution was then allowed to warn to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60° C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). 1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). to warn to room temperature On cooling the reaction solution was poured onto ice water The toluene layer was separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)

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

Procedure: To a solution of 2-Methoxy-5-fluorobenzaldehyde (11.093 g, 1 equiv.-available from Aldrich Chemical Company) in methanol at −10° C. under nitrogen atmosphere was added NaBH4 (7.515 g, 2.7 equiv.) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9.794 g, 87%). 1H NMR (300 MHz, CDCl3): δ 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, J=6.3 Hz), 6.78 (dd, 1H, J=8.9 and 4.3 Hz), 6.94 (td, 1H, J=8.5 and 3.1 Hz), 7.04 (dd, 1H, J=8.7 and 3.1 Hz). was removed under reduced pressure This solution was poured onto ice water further extracted with dichloromethane The organic fractions were collected dried (MgSO4) the solvent removed under reduced pressure

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

Procedure: Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2-methoxy-benzaldehyde (2.15 g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After 1 h, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCl. Separate the phases, wash the organic one twice with H2O, dry over Na2SO4 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2-methoxy-phenyl)-methanol (1.9 g, 12.17 mmol) in CHCl3 (10 ml) and stir at room temperature. After 1 h, separate the phases, wash the aqueous one with CH2Cl2, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid. 1H-NMR (CDCl3, 200 Mz): δ 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J=4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H). separate the phases wash the aqueous one with CH2Cl2 wash with H2O dry over Na2SO4 concentrate at vacuum to obtain a residue Purify the residue by column chromatography on silica gel eluting with hexane

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

Procedure: Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2-methoxy-benzaldehyde (2.15 g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After 1 h, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCl. Separate the phases, wash the organic one twice with H2O, dry over Na2SO4 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2-methoxy-phenyl)-methanol (1.9 g, 12.17 mmol) in CHCl3 (10 ml) and stir at room temperature. After 1 h, separate the phases, wash the aqueous one with CH2Cl2, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid. 1H-NMR (CDCl3, 200 Mz): δ 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J=4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H). evaporate the solvent dilute the residue in CH2Cl2 treat with aqueous 3M HCl Separate the phases wash the organic one twice with H2O dry over Na2SO4 concentrate at vacuum

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

Procedure: 19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure. evaporated under reduced pressure the mixture is cooled washed with saturated sodium bicarbonate solution and water dried over magnesium sulphate evaporated under reduced pressure

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

Procedure: 19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure. evaporated under reduced pressure the mixture is cooled washed with saturated sodium bicarbonate solution and water dried over magnesium sulphate evaporated under reduced pressure

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

Procedure: 20.0 g (0.13 mol) of 5-fluoro-2-methoxybenzaldehyde are dissolved in 205 ml of methanol. Under argon, 2.45 g (54.9 mol) of sodium borohydride are added in small portions. The solution is stirred at RT for 4 hours. The solution is concentrated and the residue is taken up in water and stirred for 30 min. The aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The solution is concentrated stirred for 30 min The aqueous phase is extracted with ethyl acetate the organic phase is dried over magnesium sulphate filtered evaporated under reduced pressure

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

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). the solution heated to 60° C On cooling the reaction solution is poured onto ice water The toluene layer is separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)

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

Procedure: To a solution of 2-methoxy-5-fluorobenzaldehyde (11.093 g, 1 eq, available from Aldrich Chemical Company) in methanol at −10° C. under nitrogen atmosphere is added NaBH4 (7.515 g, 2.7 equiv.) portionwise. The solution is allowed to warm to room temperature and after 30 minutes the reaction solvent is removed under reduced pressure and replaced with dichloromethane. This solution is poured onto ice water and further extracted with dichloromethane. The organic fractions are collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9.794 g, 87%). MW 156.16; C8H9FO2; 1H NMR (CDCl3): 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, 6.3 Hz), 6.78 (dd, 1H, 8.9 Hz and 4.3 Hz), 6.94 (td, 1H, 8.5 Hz and 3.1 Hz), 7.04 (dd, 1H, 8.7 Hz and 3.1 Hz). is removed under reduced pressure This solution is poured onto ice water further extracted with dichloromethane The organic fractions are collected dried (MgSO4) the solvent removed under reduced pressure

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

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

Procedure: Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H). the solution heated to 60° C On cooling the reaction solution is poured onto ice water The toluene layer is separated dried (MgSO4) the solvent removed under reduced pressure (60-80° C./0.05 mBarr)