2-amino-6-fluorophenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)

反応条件: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-aminonicotinic acid (9.4 g), 2-amino-6-fluoro-phenol (8.65 g) and polyphosphoric acid (90 g) was stirred at 200° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, quenched with water and basified with sodium hydroxide solution 6N until pH 12 to give a solid which was collected by filtration and dried under vacuum; The resultant product was diluted in dichloromethane/methanol and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated to dryness to give 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (7.5 g) as a solid. NMR Spectrum: (DMSOd6) 6.76 (dd, 1H), 7.33-7.46 (m, 2H), 7.66 (bs, 2H), 7.68 (dd, 1H), 8.26 (dd, 1H), 8.30 (dd, 1H); Mass spectrum: M+H+ 230. to cool to room temperature quenched with water to give a solid which was collected by filtration dried under vacuum The resultant product was diluted in dichloromethane/methanol filtered through a plug of silica gel washed with ethyl acetate The filtrate was concentrated to dryness

反応条件: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-aminonicotinic acid (9.4 g), 2-amino-6-fluoro-phenol (8.65 g) and polyphosphoric acid (90 g) was stirred at 200° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, quenched with water and basified with sodium hydroxide solution 6N until pH 12 to give a solid which was collected by filtration and dried under vacuum; The resultant product was diluted in dichloromethane/methanol and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated to dryness to give 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (7.5 g) as a solid. NMR Spectrum: (DMSOd6) 6.76 (dd, 1H), 7.33-7.46 (m, 2H), 7.66 (bs, 2H), 7.68 (dd, 1H), 8.26 (dd, 1H), 8.30 (dd, 1H); Mass spectrum: M+H+ 230. to cool to room temperature quenched with water to give a solid which was collected by filtration dried under vacuum The resultant product was diluted in dichloromethane/methanol filtered through a plug of silica gel washed with ethyl acetate The filtrate was concentrated to dryness

反応条件: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-fluoro-phenol (0.586 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The precipitate was filtered, washed with water, diethyl ether, and dried. The compound was stirred in THF during 2 days, the insoluble was filtered, the filtrate was concentrated to dryness and dried under vacuum to give 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.475 g). NMR Spectrum: (DMSOd6) 7.37-7.48 (m, 2H), 7.69 (dd, 1H), 7.83 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309 The resulting mixture was cooled to room temperature The precipitate was filtered washed with water, diethyl ether dried The compound was stirred in THF during 2 days the insoluble was filtered the filtrate was concentrated to dryness dried under vacuum

反応条件: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-fluoro-phenol (0.586 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The precipitate was filtered, washed with water, diethyl ether, and dried. The compound was stirred in THF during 2 days, the insoluble was filtered, the filtrate was concentrated to dryness and dried under vacuum to give 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.475 g). NMR Spectrum: (DMSOd6) 7.37-7.48 (m, 2H), 7.69 (dd, 1H), 7.83 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309 The resulting mixture was cooled to room temperature The precipitate was filtered washed with water, diethyl ether dried The compound was stirred in THF during 2 days the insoluble was filtered the filtrate was concentrated to dryness dried under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 357 mg of 2-amino-6-fluorophenol, and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of N,N-dimethylformamide. 335 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following: The product is prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-amino-6-fluorophenol (4.0 g, 31.6 mmol) and nitrobenzene (20 mL) in a sealable reaction vessel was added in portions sulfuric acid (4.0 mL). Glycerol (12.0 g, 126 mmol) was added in one portion, and the solution turned to dark brown. The vessel was flushed with nitrogen, sealed and heated to 140° C. for 6 h. The reaction mixture was cooled to rt, diluted with 30 mL ice/water mixture, and washed 3 times with methyl t-butyl ether (removes most of the nitrobenzene). The aqueous phase was neutralized to pH=6-7 by slow addition of 6N NaOH. The resulting black precipitate was collected and the water solution was extracted with ethyl acetate 3 times. The organic extracts were combined with the black precipitate, concentrated in vacuo, and purified on silica gel column with 0-10% MeOH/DCM to give 2.67 g (51.7%) of 7-fluoro-8-quinolinol as an off-white solid. The vessel was flushed with nitrogen sealed The reaction mixture was cooled to rt diluted with 30 mL ice/water mixture washed 3 times with methyl t-butyl ether ( removes most of the nitrobenzene) The aqueous phase was neutralized to pH=6-7 by slow addition of 6N NaOH The resulting black precipitate was collected the water solution was extracted with ethyl acetate 3 times concentrated in vacuo purified on silica gel column with 0-10% MeOH/DCM

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH