2-amino-4-fluorophenol

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: Starting from 2-amino-4-fluorophenol and mono-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (V-9) may be prepared and purified analogously to (V-8) (see 45.1). may be prepared purified analogously to (V-8) (see 45.1)

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

Procedure: 500 mg 2-amino-4-fluorophenol and 900 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated in 5 g polyphosphoric acid at 200° C. for 4 h. After cooling the reaction mixture is combined with ice water and made basic with 50% NaOH solution. The precipitate is suction filtered, washed with water and dried. 290 mg (V-8) are obtained as a solid. After cooling the reaction mixture filtered washed with water dried 290 mg (V-8) are obtained as a solid

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

Procedure: To 100 mg of 2-amino-4-fluorophenol was added 0.8 ml of 5N-hydrochloric acid, and a solution in which 65 mg of sodium nitrite was dissolved in 0.2 ml of water was added dropwise at 0° C., and stirred for 30 minutes. Then, a solution in which 249 mg of stannous chloride was dissolved in 0.46 ml of 5N-hydrochloric acid, was added dropwise at 0° C., and stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and 2.5 ml of ethanol and 81 μl of acetyl acetone were added, followed by heating at reflux for 4 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated solution of sodium hydrogen carbonate, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield 20.6 mg of the title compound. was added dropwise at 0° C. was added dropwise at 0° C. stirred at 0° C. for 30 minutes at room temperature for 2 hours The solvent was distilled off under reduced pressure, and 2.5 ml of ethanol and 81 μl of acetyl acetone were added by heating at reflux for 4 hours To the reaction mixture was added 50 ml of water extracted with 50 ml of ethyl acetate After the organic layer was dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1)

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

Procedure: 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol, and 120 mg of 10% palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for 1 hour. After the insoluble matter was filtered off, the filtrate was distilled off under reduced pressure to yield 211 mg of the title compound. After the insoluble matter was filtered off the filtrate was distilled off under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluoro-2-nitrophenol(1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(622 mg, 85%). 1H NMR (CD3OD): d 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H). to cool down poured into ice before being extracted with ethyl acetate The organic phase was washed with brine dried over MgSO4 filtered The solvent was evaporated

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

Procedure: In a 500-ml flask, place 39.3 g (0.25 m) of 4-fluoro-2-nitrophenol (2a) and 120 ml of isopropyl alcohol and warm to 40° C. Add 1.5 g of 5% Pd/C wet with 1.5 ml of water and stir the mixture vigorously. Add a solution of 84.1 g (1.0 m) of potassium formate in 85 ml of water in drop wise over an hour keeping the temperature at 45°-53° C. Stir the mixture at 50° C. for 2.5 hrs. Add 150 ml of propyl acetate and 100 ml of water and stir for a few min. Filter off catalyst and wash with 100 ml of propyl acetate and 100 ml of water. Separate propyl acetate solution, and wash with 150 ml water and 150 ml of brine containing 1-2 g sodium hydrosulfite. Dry propyl acetate solution over magnesium sulfate and concentrate to approximately 75 ml. Add 300 ml of heptane slowly with gentle stirring. Concentrate under a reduced pressure till most of propyl acetate evaporated. Add 150 ml of heptane to resulting mush and cool in an ice bath for about an hour. Collect solid, wash with heptane, and dry in a vacuum oven to give 29.0 g (91%) of 2-amino-4-fluorophenol (3a; X=F) as gray solids. at 45°-53° C Stir the mixture at 50° C. for 2.5 hrs stir for a few min Filter off catalyst wash with 100 ml of propyl acetate and 100 ml of water Separate propyl acetate solution, and wash with 150 ml water and 150 ml of brine containing 1-2 g sodium hydrosulfite Dry propyl acetate solution over magnesium sulfate and concentrate to approximately 75 ml Add 300 ml of heptane slowly with gentle stirring Concentrate under a reduced pressure till most of propyl acetate evaporated Add 150 ml of heptane to resulting mush cool in an ice bath for about an hour Collect solid wash with heptane dry in a vacuum oven

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

Procedure: To a mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g) and 2-amino-4-fluoro-phenol (0.586 g) placed in a round bottom flask was added polyphosphoric acid (10 g). The mixture was heated at 200° C. for 16 hours. After cooling, water (75 ml) was added and the mixture was stirred for 30 min. The mixture was basified to pH 12 with concentrated sodium hydroxide solution (6N and 2N). The solid was filtered, washed with water (150 ml×2), and ether (50 ml×2) to afford 5-bromo-3-(5-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (1.0 g). NMR Spectrum: (DMSOd6) 7.53 (ddd, 1H), 7.93 (dd, 1H), 7.99-8.06 (m, 3H), 8.52 (d, 1H), 8.56 (d, 1H); Mass spectrum: M+H+ 308-310 placed in a round bottom flask After cooling The solid was filtered washed with water (150 ml×2), and ether (50 ml×2)

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

Procedure: Prepared by the method of Example 15a), from 2-amino-4-fluorophenol (292 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluoro-2-nitrophenol (1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (622 mg, 85%). 1H NMR (CD3OD): δ6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H). to cool down poured into ice before being extracted with ethyl acetate The organic phase was washed with brine dried over MgSO4 filtered The solvent was evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluoro-2-nitrophenol(1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(622 mg, 85%). 1H NMR (CD3OD): δ 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H). to cool down poured into ice before being extracted with ethyl acetate The organic phase was washed with brine dried over MgSO4 filtered The solvent was evaporated