methyl 4-amino-3,5-dimethylbenzoate

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C. A suspension of 33 g dissolved in 400 ml The precipitate which formed was removed by filtration with suction washed with water dried recrystallized from ethyl acetate

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-bromo-2-(trifluoromethyl)benzoic acid (1.00 g, 0.00371 mol) in CH2Cl2 (15 mL) at room temperature are added methyl 4-amino-3,5-dimethylbenzoate (0.46 g, 0.00260 mol, see preparation 12) and triethylamine (1.10 ml, 0.00743 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 6.00 ml, 0.00929 mol) is added via syringe and stirred at room temperature. After 14 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) with 10-15% EtOAc to give the title compound as an off-white solid (0.45 g, 27.67%). Mass spectrum (m/z): 430.0 (M+1). stirred at room temperature After 14 hours extracted with dichloromethane dried over magnesium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) with 10-15% EtOAc

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-chloroquinoline-4-carboxylic acid (5.00 g, 0.0024 mol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (3.88 g, 0.02167 mol, see preparation 12) and N,N-diisopropylethylamine (12.5 ml, 0.07225 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 31.0 ml, 0.048 mol) is added via syringe and heated at 40° C. After 5 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification the solid is triturated with 20% diethyl ether in pentane and dried to give the title compound as a white solid (8.50 g, 96%). Mass spectrum (m/z): 369.1 (M+1). After 5 hours extracted with dichloromethane dried over magnesium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) After purification the solid is triturated with 20% diethyl ether in pentane dried

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

実験手順: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (6.00 g, 0.03508 mol) in CH2Cl2 (50 ml) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (5.65 g, 0.03157 mol), and N,N-diisopropylethylamine (15.1 ml, 0.0877 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 22.32 g, 0.07016 mol) is added via syringe and stirred at 60° C. After 3 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (8.70 g, 74%). Mass spectrum (m/z): 333.2 (M+1). stirred at 60° C After 3 hours the solvent is removed under reduced pressure the residue is diluted with water extracted with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel)

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

実験手順: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.70 g, 4.093 mmol, see preparation 1) in CH2Cl2 (6 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (0.74 g, 4.093 mmol, see preparation 12), and triethylamine (0.83 g, 8.187 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.60 g, 8.187 mmol) is added via syringe and stirred at ambient temperature. After 12 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (1.10 g, 81%). Mass spectrum (m/z): 333.2 (M+1). stirred at ambient temperature After 12 hours the solvent is removed under reduced pressure the residue is diluted with water extracted with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel)

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-bromo-2-methylbenzoic acid (2.0 g, 0.008 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (1.28 g, 0.0072, see preparation 12) and N,N-diisopropylethylamine (4.12 g, 0.032 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 7.63 g, 0.024 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 12% ethyl acetate in hexane to give the title compound as a white solid (2.9 g, 97%). Mass spectrum (m/z): 376.0 (M+1). stirred at 50° C After 16 hours the solvent is removed under reduced pressure the residue is diluted with water extracted twice with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel)

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-bromo-2-fluorobenzoic acid (3.50 g, 15.9 mmol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (2.86 g, 15.9 mmol, see preparation 12) and N,N-diisopropylethylamine (8.35 ml, 47.9 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 20.5 ml, 31.9 mmol) is added via syringe and stirred at ambient temperature. After 36 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (4.20 g, 69%). Mass spectrum (m/z): 380.2 (M+1). stirred at ambient temperature After 36 hours the solvent is removed under reduced pressure the residue is diluted with water extracted with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3,5-dimethyl-4-nitrobenzoate (10.0 g, 0.0478 mol) in methanol (100 mL), iron powder (15.7 g, 0.2869 mol) and 37% HCl (1.72 g, 0.0478 mol) is added at 0° C. The reaction is heated at 80° C. for 16 hours. The mixture is cooled to room temperature and filtered through Celite™ bed and washed with methanol followed by evaporation of filtrate to dryness to afford the title compound as a brown solid (7.8 g, 99%). Mass spectrum (m/z): 180.2 (M+1). The mixture is cooled to room temperature filtered through Celite™ bed washed with methanol followed by evaporation of filtrate to dryness

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

実験手順: To a suspension of potassium 6-chloropyridine-2-carboxylate (52 g, 265.8 mmoles) in dimethylformamide (676 mL) is added bis(2-oxo-3-oxazolidinyl)phosphonic chloride (115 g, 451.8 mmoles). The mixture is stirred at ambient temperature for 30 minutes. Methyl 4-amino-3,5-dimethyl-benzoate (42.9 g, 239.2 mmoles, see preparation 12) and diisopropylethylamine (115.9 mL, 664.5 mmoles) are added. The reaction is stirred at ambient temperature for 16 hours. The mixture is then poured into water (2000 mL) and is stirred for 30 minutes. The resulting solid is filtered and dried under reduced pressure at 45° C. The dry material is triturated with hexane (1400 mL) over 2 hours. The solid is filtered and dried under vacuum to give the title compound (69 g, 78%) as a white solid. Mass spectrum (m/z): 333.05 (M+1). 1H NMR (300 MHz, DMSO): 10.16 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.63 (d, J=8.2 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H), 2.28 (s, 6H). The reaction is stirred at ambient temperature for 16 hours is stirred for 30 minutes The resulting solid is filtered dried under reduced pressure at 45° C The dry material is triturated with hexane (1400 mL) over 2 hours The solid is filtered dried under vacuum

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C. A suspension of 33 g dissolved in 400 ml The precipitate which formed was removed by filtration with suction washed with water dried recrystallized from ethyl acetate

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C. A suspension of 33 g dissolved in 400 ml The precipitate which formed was removed by filtration with suction washed with water dried recrystallized from ethyl acetate

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50% dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of 4-amino-3,5-dimethyl-benzoic acid methyl ester were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C. A suspension of 33 g dissolved in 400 ml The precipitate which formed was removed by filtration with suction washed with water dried recrystallized from ethyl acetate