3-amino-2,4-dimethylphenol

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

実験手順: A mixture of 10 g of 3-acetamido-2,4-dimethylphenol (55.9 mmol), 250 ml of concentrated sulfuric acid and 200 ml of ethanol was refluxed for 30 minutes and, then, concentrated under reduced pressure. The residue was dissolved in water and the solution was made alkaline with ammonia water and extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate (dehydration) and concentrated under reduced pressure. The residue was recrystallized from ethanolhexane to give 5.3 g (69%) of the title compound as colorless plates, m.p. 177°-179° C. was refluxed for 30 minutes concentrated under reduced pressure The residue was dissolved in water extracted with ether The ether layer was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate (dehydration) concentrated under reduced pressure The residue was recrystallized from ethanolhexane

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

実験手順: To a solution of 3-(3-fluorophenyl)-5-methoxy-benzoic acid (intermediate III(i)) (1.4 g, 5.7 mmol, 1.0 eq) in CH2Cl2 (15 mL) were added (COCl)2 (2.2 g, 17.3 mmol, 3.0 eq) and DMF (0.01 mL). The reaction mixture was stirred at room temperature for 1.5 h then the solvent and excess reagent removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (791 mg, 5.77 mmol, 1.0 eq) in THF (20 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 1:1) to give the title compound as a white solid (1.2 g, 57%). the solvent and excess reagent removed under reduced pressure The residue obtained to warm to room temperature stirred for 1 h extracted with EtOAc The combined organic extracts were washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 1:1)

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

実験手順: To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (intermediate III(e)) (597 mg, 2.4 mmol, 1.1 eq) in CH2Cl2 (15 mL) was added (COCl)2 (916 mg, 7.2 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 2 h, then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (300 mg, 2.2 mmol, 1.0 eq) and NaHCO3 (920 mg, 10.9 mmol, 5.0 eq) in THF (20 mL) at 0° C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was then poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (588 mg, 73%). the solvent and excess reagent were removed under reduced pressure The residue obtained After the addition to warm to room temperature stirred for a further 1 h extracted with EtOAc The combined organic layers were washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1)

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

実験手順: To a solution of 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (intermediate III(k)) (400 mg, 1.5 mmol, 1.1 eq) in CH2Cl2 (8 mL) was added (COCl)2 (585 mg, 4.6 mmol, 3.3 eq) and DMF (3 drops). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent and the residue obtained was dissolved in THF (8 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (192 mg, 1.4 mmol, 1.0 eq) and NaHCO3 (587 mg, 7.0 mmol, 5.0 eq) in THF (6 mL) at 0° C. After the addition was complete the reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 5:1, then DCM: MeOH, 20:1) to give the title compound as a yellow solid (436 mg 82%). The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent the residue obtained After the addition to warm to room temperature was stirred for 2 h extracted with EtOAc The combined organic extracts were washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The residue obtained was purified by column chromatography (petroleum ether

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

実験手順: To a solution of 5-(3-fluorophenyl)-2,3-dimethyl-benzoic acid (intermediate III(m)) (0.4 g, 1.6 mmol, 1.0 eq) in CH2Cl2 (15 mL) was added (COCl)2 (0.62 g, 4.9 mmol, 3.0 eq) and DMF (0.01 mL). The reaction mixture was stirred at room temperature for 1.5 h, then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (260 mg, 1.9 mmol, 1.2 eq) and K2CO3 (0.9 g, 6.5 mmol, 4.0 eq) in THF (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h, then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 15:1 to 3:1) to give the title compound as a colorless oil (300 mg, 51%) the solvent and excess reagent were removed under reduced pressure The residue obtained The reaction mixture was stirred at room temperature for 1 h extracted with EtOAc The combined organic extracts were washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The residue was purified by column chromatography (petroleum ether: EtOAc, 15:1 to 3:1)

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

実験手順: To a solution of 3-(3-fluorophenyl)-5-methyl-benzoic acid (300 mg, 1.30 mmol, 1.1 eq) (III(q)) in CH2Cl2 (10 mL) was added (COCl)2 (610 mg, 4.81 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent. The residue obtained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (163 mg, 1.18 mmol, 1.0 eq) and NaHCO3 (612 mg, 7.30 mmol, 5.0 eq) in THF (20 mL) at 0° C. After addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The crude product obtained was purified by column chromatography (CH2Cl2: MeOH, 500:1 to 300:1) to give the title compound as a white solid (290 mg, 57%). The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent The residue obtained After addition to warm to room temperature stirred for 1 h extracted with EtOAc The combined organic extracts were washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The crude product obtained was purified by column chromatography (CH2Cl2: MeOH, 500:1 to 300:1)

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

実験手順: To a solution of 2-fluoro-5-(3-fluorophenyl)-3-methyl-benzoic acid (intermediate III(f)) (597 mg, 2.41 mmol, 1.1 eq) in CH2Cl2 (15 mL) and DMF (5 drops) was added (COCl)2 (916 mg, 7.22 mmol, 3.3 eq) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent and the residue obtained dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-2,4-dimethylphenol (intermediate X(c)) (300 mg, 2.18 mmol, 1.0 eq) and NaHCO3 (920 mg, 10.9 mmol, 5 eq) in THF (20 mL) at 0° C. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (270 mg, 34%). The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent the residue obtained After the addition the reaction mixture was stirred at room temperature for 1 h the aqueous layer extracted with EtOAc The organic extract was washed with water and brine dried (Na2SO4) filtered evaporated in vacuo The residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1)

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

実験手順: To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (632 mg, 2.7 mmol, 1.0 eq) and oxalyl chloride (1.03 g, 8.1 mmol, 3.0 eq) in DCM (30 mL) was added DMF (0.3 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to remove the solvent and excess oxalyl chloride then the residue obtained was dissolved in THF (20 mL). This solution was added dropwise to a suspension of 3-amino-2,4-dimethyl-phenol (370 mg, 2.7 mmol, 1.0 eq) and NaHCO3 (680 mg, 8.1 mmol, 3.0 eq) in THF (20 mL). After addition was complete, the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was adjusted to pH 3 by addition of 1M HCl and the aqueous layer extracted with EtOAc. The organic extract was dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (400 mg, 42%). The resulting mixture was concentrated to remove the solvent and excess oxalyl chloride the residue obtained After addition the reaction mixture was stirred at room temperature for 30 min the aqueous layer extracted with EtOAc The organic extract was dried (Na2SO4) filtered evaporated in vacuo purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1)

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

実験手順: To a solution of tert-butyl N-(3-hydroxy-2,6-dimethyl-phenyl)carbamate (657 mg, 2.8 mmol, 1.0 eq) in DCM (5 mL) was added TFA (5 mL) and the reaction stirred at room temperature overnight. The solvent was removed in vacuo. The residue was taken up in water and solution adjusted to pH 7 by addition of aqueous NaHCO3. The aqueous phase was extracted with EtOAc and the organic extract dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow solid (370 mg, 97%) which was used without further purification. The solvent was removed in vacuo solution adjusted to pH 7 by addition of aqueous NaHCO3 The aqueous phase was extracted with EtOAc the organic extract dried (Na2SO4) filtered evaporated in vacuo

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

実験手順: A mixture of 10 g of 3-acetamido-2,4-dimethylphenol (55.9 mmol), 250 ml of concentrated sulfuric acid and 200 ml of ethanol was refluxed for 30 minutes and, then, concentrated under reduced pressure. The residue was dissolved in water and the solution was made alkaline with ammonia water and extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate (dehydration) and concentrated under reduced pressure. The residue was recrystallized from ethanolhexane to give 5.3 g (69%) of the title compound as colorless plates, m.p. 177°-179° C. was refluxed for 30 minutes concentrated under reduced pressure The residue was dissolved in water extracted with ether The ether layer was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate (dehydration) concentrated under reduced pressure The residue was recrystallized from ethanolhexane