2-fluoro-6-phenylmethoxyaniline

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-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (balloon) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125-6° C. The catalyst is removed by filtration through a pad of celite the filtrate concentrated

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

Procedure: 2-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (balloon) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125-6° C. The catalyst is removed by filtration through a pad of celite the filtrate concentrated

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

Procedure: To a solution of 1-benzyloxy-3-fluoro-2-nitrobenzene (10.0 g, 40.5 mmol) in 100 mL of EtOH and 50 mL of 1N HCl is added SnCl2 (38.3 g, 202.5 mmol) and the solution is refluxed for 2 h. After cooling the mixture to RT, it is adjusted to PH>7 with solid K2CO3 and extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the product as a yellow liquid. the solution is refluxed for 2 h extracted with EtOAc The organic layer is washed with water and brine dried over sodium sulfate The solvent is removed under reduced pressure

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

Procedure: A mixture of 2-benzyloxy-6-fluoroaniline (950 mg, 4.37 mmol), methyl bromoacetate (456 μL, 737 mg, 4.82 mmol), and potassium carbonate (1.21 g, 8.76 mmols) in DMF (10 mL) is heated at 60° C. for 18 h. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The organic layer is dried, filtered, and the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate) to afford methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate as an oil. MS (M+1)+=290; NMR (CDCl3): δ 7.39 (m, 5H), 6.67 (m, 3H), 5.10 (s, 2H), 4.57 (br s, 1H), 4.11 (m, 2H), 3.72 (s, 3H). extracted once with water and five times with brine The organic layer is dried filtered the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate)

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

Procedure: A mixture of 2-benzyloxy-6-fluoroaniline (950 mg, 4.37 mmol), methyl bromoacetate (456 μL, 737 mg, 4.82 mmol), and potassium carbonate (1.21 g, 8.76 mmols) in DMF (10 mL) is heated at 60° C. for 18 h. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The organic layer is dried, filtered, and the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate) to afford methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate as an oil. MS (M+1)+=290; NMR (CDCl3): δ 7.39 (m, 5H), 6.67 (m, 3H), 5.10 (s, 2H), 4.57 (br s, 1H), 4.11 (m, 2H), 3.72 (s, 3H). extracted once with water and five times with brine The organic layer is dried filtered the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate)

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

Procedure: To a solution of 2-benzyloxy-6-fluorophenylamine (7.29 g, 33.6 mmol) in MeOH/HOAc (3:1 v/v, 30 mL) at 0° C. is added bromine (2.2 mL, 47 mmol) in MeOH/HOAc (3:1 v/v, 4 mL) drop wise. After it is stirred for 4 h, the reaction is completed by LC/MS. The reaction mixture is concentrated, and the residue is stirred with EtOAc and 1N NaOH to dissolve solid. Additional base is added to make the aqueous alkaline, and then EtOAc layer is separated. The organic phase is washed with brine, dried and filtered. The concentrated residue is purified to give the title compound: 1H NMR (CDCl3) 7.39 (m, 5H), 6.86 (dd, 1H, J=9.8, 2.0 Hz), 6.81 (m, 1H), 5.05 (s, 2H), 3.77 (br s, 2H); MS (M+H)+=296, 298. The reaction mixture is concentrated the residue is stirred with EtOAc and 1N NaOH to dissolve solid Additional base is added EtOAc layer is separated The organic phase is washed with brine dried filtered The concentrated residue is purified

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

Procedure: To a solution of 2-benzyloxy-6-fluorophenylamine (7.29 g, 33.6 mmol) in MeOH/HOAc (3:1 v/v, 30 mL) at 0° C. is added bromine (2.2 mL, 47 mmol) in MeOH/HOAc (3:1 v/v, 4 mL) drop wise. After it is stirred for 4 h, the reaction is completed by LC/MS. The reaction mixture is concentrated, and the residue is stirred with EtOAc and 1N NaOH to dissolve solid. Additional base is added to make the aqueous alkaline, and then EtOAc layer is separated. The organic phase is washed with brine, dried and filtered. The concentrated residue is purified to give the title compound: 1H NMR (CDCl3) 7.39 (m, 5H), 6.86 (dd, 1H, J=9.8, 2.0 Hz), 6.81 (m, 1H), 5.05 (s, 2H), 3.77 (br s, 2H); MS (M+H)+=296, 298. The reaction mixture is concentrated the residue is stirred with EtOAc and 1N NaOH to dissolve solid Additional base is added EtOAc layer is separated The organic phase is washed with brine dried filtered The concentrated residue is purified

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

Procedure: A mixture of 1-benzyloxy-3-fluoro-2-nitrobenzene (1.32 g, 5.34 mmol), SnCl2 (4.96 g, 26.2 mmol), and 1N HCl (5.5 mL, 5.5 mmol) in EtOH (25 mL) is refluxed for 18 h. The mixture is concentrated and stirred with EtOAc and 1N NaOH solution. Solid NaOH is added until strongly basic. The precipitate is removed by filtration, and the organic phase is separated. It is then dried and concentrated. The residue is purified to give the title compound: MS (M+H)+=218. is refluxed for 18 h The mixture is concentrated Solid NaOH is added until strongly basic The precipitate is removed by filtration the organic phase is separated It is then dried concentrated The residue is purified

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

Procedure: 2-(Benzyloxy)-6-fluoroaniline (Step 2, 5.00 g, 0.0230 mol) and 10% palladium on carbon (0.5 g) in methanol (100 ml) are stirred under a hydrogen atmosphere (balloon) for 2 h. The catalyst is removed by filtration through a pad of celite and the filtrate concentrated to give pure product as a tan solid (2.9 g, 99%); mp 125–6° C. The catalyst is removed by filtration through a pad of celite the filtrate concentrated