4-amino-3-fluorophenol;hydrochloride

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

Procedure: To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%). by stirring at room temperature for 3 days The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a 1N aqueous solution of sodium hydroxide To the aqueous layer was added 5N hydrochloric acid this was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate The solvent was removed the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2) Fractions containing the target compound were concentrated under reduced pressure

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

Procedure: To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%). by stirring at room temperature for 3 days The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a 1N aqueous solution of sodium hydroxide To the aqueous layer was added 5N hydrochloric acid this was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate The solvent was removed the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2) Fractions containing the target compound were concentrated under reduced pressure

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

Procedure: To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%). by stirring at room temperature for 3 days The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a 1N aqueous solution of sodium hydroxide To the aqueous layer was added 5N hydrochloric acid this was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate The solvent was removed the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2) Fractions containing the target compound were concentrated under reduced pressure

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

Procedure: To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%). by stirring at room temperature for 3 days The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a 1N aqueous solution of sodium hydroxide To the aqueous layer was added 5N hydrochloric acid this was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate The solvent was removed the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2) Fractions containing the target compound were concentrated under reduced pressure

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

Procedure: A solution of 2-fluoro-4-hydroxyaniline hydrochloride (3 g) in MeOH (50 mL) was treated with aqueous NaOH (0.74 g in 10 mL deionized water) and the resulting clear solution was concentrated to dryness to provide a residue of crude aniline free base. A 0° C. solution of the crude aniline residue in 1:1 AcOH/deionized water (32 mL) in a pressure tube was treated with liquid ethylene oxide condensed at −78° C. (7.8 g), the tube was sealed, and the reaction mixture allowed to warm up to RT. The reaction mixture was stirred at RT 48 h then cooled, evaporated to dryness and purified by silica gel chromatography (0-7% MeOH/DCM) to provide N,N-bis-(2-hydroxyethyl)-2-fluoro-4-hydroxyaniline (2 g) as a grey powder. the resulting clear solution was concentrated to dryness to provide a residue of crude aniline free base the tube was sealed then cooled evaporated to dryness purified by silica gel chromatography (0-7% MeOH/DCM)