3-fluoro-4-methoxyphenol

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cs2CO3 (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 3-fluoro-4-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (81) (45.6 mg, 54%). ESI-MS m/z calc. 422.09. found 423.3 (M+1)+; Retention time: 1.65 minutes (3 minutes run). The reaction was filtered purified by reverse phase HPLC

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

Procedure: A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH 3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil. The solution was washed with saturated aqueous Na2CO3 filtered through a pad of SiO2 (CH2Cl2 as eluent) finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g) Volatiles were removed in vacuo the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH 3) The aqueous phase was extracted with EtOAc (2×) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.

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

Procedure: The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.

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

Procedure: A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil. The solution was washed with saturated aqueous Na2CO3 filtered through a pad of SiO2 (CH2Cl2 as eluent) finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g) Volatiles were removed in vacuo the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3) The aqueous phase was extracted with EtOAc (2×) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil. The solution was washed with saturated aqueous Na2CO3 filtered through a pad of SiO2 (CH2Cl2 as eluent) finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g) Volatiles were removed in vacuo the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3) The aqueous phase was extracted with EtOAc (2×) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil. The solution was washed with saturated aqueous Na2CO3 filtered through a pad of SiO2 (CH2Cl2 as eluent) finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g) Volatiles were removed in vacuo the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3) The aqueous phase was extracted with EtOAc (2×) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.

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

Procedure: A solution of 3′-fluoro-4′-methoxyacetophenone (10 g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30 g; 89 mmol) in CH2Cl2 (300 mL) was stirred at RT overnight. The solution was washed with saturated aqueous Na2CO3, then filtered through a pad of SiO2 (CH2Cl2 as eluent) and finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g). A solution of this crude material and LiOH.H2O (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1 mixture) was stirred at RT overnight. Volatiles were removed in vacuo, and the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3). The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give 3-fluoro-4-methoxy phenol (6.1 g; 72%) as an oil. The solution was washed with saturated aqueous Na2CO3 filtered through a pad of SiO2 (CH2Cl2 as eluent) finally chromatographed (SiO2; hex:EtOAc 4:1) to give the crude product (3′-fluoro-4′-methoxy phenyl acetate; 63 g) Volatiles were removed in vacuo the residue was partitioned between excess aqueous 1 M HCl and EtOAc (aqueous layer pH˜3) The aqueous phase was extracted with EtOAc (2×) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

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

Procedure: The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-4-methoxy-phenol (21.32 g; 0.15 mol) prepared according to literature [Freedman, J.; Stewart, K. T.; J. Heterocycl. Chem. 1989, 26, 1547-1554] is dissolved in dry dichloromethane (300 mL). The well stirred reaction mixture is cooled to −15° C. (ice/salt). A solution of bromine (23.97 g; 0.15 mol) in dry dichloromethane (75 mL) is dropped into the reaction mixture. After complete addition stirring is continued for one hour. Water (150 mL) containing sodium sulfite (3.0 g) is added to the reaction mixture. Stirring is continued at ambient temperature for 30 min. The organic layer is separated, ished with water (100 mL) and dried over MgSO4 in the presence of decolorizing charcoal. After filtration the solvent is completely removed under reduced pressure. The residue is crystallized from tert-butylmethylether/hexane to yield the title compound as a colorless solid. reaction mixture After complete addition stirring is added to the reaction mixture Stirring is continued at ambient temperature for 30 min The organic layer is separated dried over MgSO4 in the presence of decolorizing charcoal After filtration the solvent is completely removed under reduced pressure The residue is crystallized from tert-butylmethylether/hexane

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

Procedure: The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.