3-(methylamino)propanamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. The suspension obtained is heated to reflux washed with 3 times 25 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. The suspension obtained is heated to reflux washed with 3 times 25 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. The suspension obtained is heated to reflux washed with 3 times 25 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoro-quinoline, prepared as described in Application Example 1, and 3 g of N-methyl-N-(b-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. prepared The suspension obtained is heated to reflux washed with 3 times 25 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C

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

実験手順: A mixture of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (6C, 0.025 g, 0.053 mmol), 3-(methylamino)propanamide (5.37 mg, 0.053 mmol) and triethylamine (7.33 mL, 0.053 mmol) in DMF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×1.0 mL). The ethyl acetate extract was concentrated, and the residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 3-(methyl((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)amino)propanamide TFA (0.012 g., 0.493 mmol, 48%) as a viscous tan liquid. The product had an HPLC ret. time=4.02 min. (condition B). LC/MS M+1=497.07. 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (1H, d, J=7.92 Hz), 7.79 (2H, d, J=7.26 Hz), 7.32-7.77 (5H, m), 4.54 (2H, s), 3.23-3.44 (4H, m), 2.98-3.21 (4H, m), and 2.89 (3H, s). washed with water (3×1.0 mL) The ethyl acetate extract was concentrated the residue was chromatographed reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM)

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.4 g of sodium carbonate are added to a solution of 4 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline and 3 g of N-methyl-N-(β-aminocarbonylethyl)amine in 40 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 2 hours 30 minutes at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 25 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 4.7 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-aminocarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps. The suspension obtained is heated to reflux washed with 3 times 25 cm3 of water The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C