2-amino-3-fluorophenol

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

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

Procedure: To a solution of 2-nitro-3-fluorophenol(1 g, 6.4 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(650 mg, 80.2%). 1H NMR (CD3OD): d 6.41-6.17 (m, 3H). The mixture was flushed with argon hydrogen was bubbled through the solution for 10 min. a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite the celite was washed with methanol The solvent was evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was consumed. The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide. To a mixture of N-(2-fluoro-6-hydroxyphenyl)acetamide (399 mg, 2.36 mmol) and potassium carbonate (652 mg, 4.72 mmol) in DMF (5 ml) epibromohydrin (388 mg, 2.8 mmol) was added and the mixture was stirred at 70° C. for 3 hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by RP-HPLC (10-40% CH3CN) to give the desired product as a solid (242 mg, 1.08 mmol). was consumed The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide was added the organic phase separated dried concentrated The resulting residue was purified by RP-HPLC (10-40% CH3CN)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was consumed. The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide. To a mixture of N-(2-fluoro-6-hydroxyphenyl)acetamide (399 mg, 2.36 mmol) and potassium carbonate (652 mg, 4.72 mmol) in DMF (5 ml) epibromohydrin (388 mg, 2.8 mmol) was added and the mixture was stirred at 70° C. for 3 hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by RP-HPLC (10-40% CH3CN) to give the desired product as a solid (242 mg, 1.08 mmol). was consumed The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide was added the organic phase separated dried concentrated The resulting residue was purified by RP-HPLC (10-40% CH3CN)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: PPA (10 ml) at 50° C. was added to a stirred mixture of 2-aminonicotinic acid (2 g) and 2-amino-3-fluoro-phenol (1.841 g). The resulting suspension was stirred at 200° C. for 16 hours. The mixture was cooled and quenched with ice and water (100 ml) and the pH was adjusted to 12 with an aqueous solution of sodium hydroxide (6N then 2N). The resultant solid was filtered and washed with water. The solid was dried under reduce pressure with phosphorus pentoxide. The solid was adsorbed on silica gel with methylene chloride (100 ml) and methanol (10 ml) and purified by flash chromatography on silica gel eluting with 20 to 30% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (2.060 g) as a solid. NMR Spectrum: (CDCl3): 6.78 (dd, 1H), 6.97 (bs, 2H), 7.09 (dd, 1H), 7.31 (ddd, 1H), 7.38 (d, 1H), 8.30 (d, 1H), 8.33 (bs, 1H); Mass spectrum: M+H+ 230 The mixture was cooled quenched with ice and water (100 ml) The resultant solid was filtered washed with water The solid was dried purified by flash chromatography on silica gel eluting with 20 to 30% ethyl acetate in dichloromethane The solvent was evaporated to dryness

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

Procedure: 1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131-3° C. washed with 2N HCl and saline dried (MgSO4) evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%)

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

Procedure: 1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131–3° C. washed with 2N HCl and saline dried (MgSO4) evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%)

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

Procedure: 1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131–3° C. washed with 2N HCl and saline dried (MgSO4) evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%)

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 2-nitro-3-fluorophenol(1 g, 6.4 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2Cl2) gave the desired product(650 mg, 80.2%). 1H NMR (CD3OD): δ 6.41-6.17 (m, 3H). The mixture was flushed with argon hydrogen was bubbled through the solution for 10 min. a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite the celite was washed with methanol The solvent was evaporated