2-amino-3-methylbenzamide

反応条件: temp:0.00; pressure:0.00; stir:

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: Oxalyl chloride (3.66 g, 0.0288 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxy-benzoic acid (3 g, 0.00144 mol) and dimethylformamide (0.1 ml) in dichloromethane (15 ml). The mixture was stirred at room temperature for 3 hours, then the solvent evaporated under vacuum and the residue azeotroped with hexane (3×50 ml). The crude acyl chloride was dissolved in dichloromethane (20 ml) and the solution added dropwise to a stirred solution of 2-amino-3-methylbenzamide (2.16 g, 0.0144 mol) in pyridine (40 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for a further 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (50 ml) and this solution then washed with saturated aqueous sodium carbonate solution (50 ml), 2N hydrochloric acid (50 ml) and brine (50 ml), then dried (Na2SO4) and evaporated under vacuum. Trituration of the residue with diethyl ether gave the title compound as a white solid (2.14 g, 44%), m.p. 214-216° C. the solvent evaporated under vacuum the residue azeotroped with hexane (3×50 ml) The crude acyl chloride was dissolved in dichloromethane (20 ml) to warm to room temperature stirred for a further 18 hours The solvent was removed by evaporation under vacuum the residue dissolved in dichloromethane (50 ml) this solution then washed with saturated aqueous sodium carbonate solution (50 ml), 2N hydrochloric acid (50 ml) and brine (50 ml) dried (Na2SO4) evaporated under vacuum

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

実験手順: The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colourless solid (71%), m.p. 140-142° C. the procedure of Preparation 5

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

実験手順: The title compound was prepared from 2-amino-3-methylbenzamide (Chem. Pharm. Bull., 1988, 36, 2955) and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colourless crystals (71%), m.p. 197-200° C. the procedure of Preparation 5

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

実験手順: Oxalyl chloride (3.66 g, 0.0288 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxybenzoic acid (3 g, 0.00144 mol) and dimethylformamide (0.1 ml) in dichloromethane (15 ml). The mixture was stirred at room temperature for 3 hours, then the solvent evaporated under vacuum and the residue azeotroped with hexane (3×50 ml). The crude acyl chloride was dissolved in dichloromethane (20 ml) and the solution added dropwise to a stirred solution of 2-amino-3-methylbenzamide (2.16 g, 0.0144 mol) in pyridine (40 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for a further 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (50 ml) and this solution then washed with saturated aqueous sodium carbonate solution (50 ml), 2N hydrochloric acid (50 ml) and brine (50 ml), then dried (Na2SO4) and evaporated under vacuum. Trituration of the residue with diethyl ether gave the title compound as a white solid (2.14 g, 44%), m.p. 214°-216° C. Found: C,66.81; H,5.98; N,8.16. C19H20N2O4 requires C,67.04; H,5.92; N,8.23%. the solvent evaporated under vacuum the residue azeotroped with hexane (3×50 ml) The crude acyl chloride was dissolved in dichloromethane (20 ml) to warm to room temperature stirred for a further 18 hours The solvent was removed by evaporation under vacuum the residue dissolved in dichloromethane (50 ml) this solution then washed with saturated aqueous sodium carbonate solution (50 ml), 2N hydrochloric acid (50 ml) and brine (50 ml) dried (Na2SO4) evaporated under vacuum

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

実験手順: The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colorless solid (71%), m.p. 140°-142° C. Found: C,69.39; H,6.58; N,8.98. C18H20N2O3 requires C,69.21; H,6.45; N,8.97%. the procedure of Preparation 5

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

実験手順: The title compound was prepared from 2-amino-3-methylbenzamide (Chem. Pharm. Bull., 1988, 36, 2955) and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colorless crystals (71%), m.p. 197°-200° C. Found: C,68.80; H,5.99; N,9.36. C17H18N2O3 requires C,68.44; H,6.08; N,9.39%. the procedure of Preparation 5

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-amino-3-methylbenzamide (0.5 g, 3.3 mmol) (prepared by conventional methods) and pyridine (0.35 ml, 4.3 mmol) in dry THF (15 ml), was added a solution of acetyl chloride (0.36 ml, 5.0 mmol) in THF (2 ml) dropwise, and the mixture was stirred overnight under nitrogen. The solvent was removed under vacuum and the remaining white slurry was resuspended in 2% aqueous sodium hydroxide solution and neutralised with aqueous hydrochloric acid, whereupon a white precipitate formed. The solid was collected and recrystallised from methanol-water to furnish the required quinazolinone (0.47 g, 81%) m.p. 217-220° C.; The solvent was removed under vacuum formed The solid was collected recrystallised from methanol-water

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-amino-3-methylbenzamide (1.50 g, 10.0 mmol) and DIEA (2.61 mL, 15 mmol) in THF (50 mL) at 0° C. was added ethyl chlorooxoacetate (1.23 mL, 11.0 mmol). The solution was allowed to warm to rt and stir for 16 h, then was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-6-methylphenylamino)-2-oxoacetate as a solid (490 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 2.17 (s, 3H), 4.30 (q, J=7.1 Hz, 2H), 7.28 (t, 1H), 7.33-7.57 (m, 3H), 7.82 (s, 1H), 10.67 (s, 1H). was concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes

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

実験手順: To solution of 2-amino-3-methylbenzoic acid (4.0 g, 26.5 mmol) in degassed DMF (40 mL) were added HOBt (4.28 g, 31.7 mmol), DIEA (5.52 mL, 31.7 mmol), and 2N NH3/MeOH (19 mL, 37.1 mmol). The solution was stirred at rt for 16 h, then the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-60% EtOAc/hexanes to afford 2-amino-3-methylbenzamide as a solid (2.52 g, 63%). 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 6.40-6.47 (m, 3H), 7.06 (m, 2H), 7.42 (d, 1H), 7.72 (br d, 1H). the mixture was concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with 10-60% EtOAc/hexanes

反応条件: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.02 g, 4.8 mmol) and 2-amino-3-methyl-benzamide (0.6 g, 4.0 mmol) were combined with trimethylsilyl polyphosphate (8.0 mL) and the mixture was heated at 115° C. for 18 h with vigorous stirring. The mixture was allowed to cool to rt, then the mixture was partitioned between water (15 mL) and ethyl acetate (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with ethyl acetate (30 mL×3). The combined organic layers were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes to afford 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-3H-quinazolin-4-one as an off-white solid (0.6 g, 29%). to cool to rt the mixture was partitioned between water (15 mL) and ethyl acetate (15 mL) The organic layer was separated the aqueous layer (pH˜1) was extracted with ethyl acetate (30 mL×3) The combined organic layers were separated dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes