(4-bromophenyl)methanamine;hydrochloride

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

実験手順: A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil. The two layers were separated the aqueous layer was extracted with EtOAc (20 mL) The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo

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

実験手順: (4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) and sodium methoxide (2.376 mL, 10.39 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel with 100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz), 6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br. s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS:R.T.=2.12; [M+2]+=317.2. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel with 100% ethyl acetate

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

実験手順: (4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) and sodium methoxide (2.376 mL, 10.39 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel with 100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz), 6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br. s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS:R.T.=2.12; [M+2]+=317.2. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel with 100% ethyl acetate

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

実験手順: Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (300 mg, 1.69 mmol), and using 4-bromobenzylamine hydrochloride (342 mg, 1.54 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (422 mg) as a white solid. (Yield: 84%) Reaction

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

実験手順: Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (300 mg, 1.69 mmol), and using 4-bromobenzylamine hydrochloride (342 mg, 1.54 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (422 mg) as a white solid. (Yield: 84%) Reaction

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromobenzylamine hydrochloride (2.22 g) is suspended in water (5 mL) and neutralized with 2N aqueous NaOH (5 mL). The free amine is extracted with dichloromethane (2×25 mL). The organic layers are combined, washed with brine (5 mL), and dried with Na2SO4. The solution is concentrated in vacuo to afford 1.48 g of a clear, colorless oil which is then combined with ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.48 g) from Preparation No. 56 and heated to 190° C. for 3 hours. The reaction mixture is allowed to cool to room temperature, and the resulting solid is recrystallized in ethyl acetate to afford 0.44 g of the title compound as a white solid. The free amine is extracted with dichloromethane (2×25 mL) washed with brine (5 mL) dried with Na2SO4 The solution is concentrated in vacuo to afford 1.48 g of a clear, colorless oil which to cool to room temperature the resulting solid is recrystallized in ethyl acetate

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

実験手順: (4-Bromophenyl)methanamine hydrochloride (0.5 g, 2.25 mmol), 2-chloro-3,6-difluorobenzoic acid (0.52 g, 2.7 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetra methyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 2.7 mmol), and N,N-diisopropyl-ethylamine (1.17 mL, 6.75 mmol) were combined in DMF (6 mL) and then stirred at room temperature for 1 h. The reaction mixture was diluted in ethyl acetate and washed once with water and twice with an aqueous saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product was suspended in hot acetonitrile and then filtered to have the pure compound N-(4-bromobenzyl)-2-chloro-3,6-difluorobenzamide. washed once with water and twice with an aqueous saturated sodium bicarbonate solution The organic phase was dried over magnesium sulfate filtered concentrated in vacuum filtered

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

実験手順: (4-Bromophenyl)methanamine hydrochloride (0.5 g, 2.25 mmol), 2-chloro-3,6-difluorobenzoic acid (0.52 g, 2.7 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetra methyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 2.7 mmol), and N,N-diisopropyl-ethylamine (1.17 mL, 6.75 mmol) were combined in DMF (6 mL) and then stirred at room temperature for 1 h. The reaction mixture was diluted in ethyl acetate and washed once with water and twice with an aqueous saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product was suspended in hot acetonitrile and then filtered to have the pure compound N-(4-bromobenzyl)-2-chloro-3,6-difluorobenzamide. washed once with water and twice with an aqueous saturated sodium bicarbonate solution The organic phase was dried over magnesium sulfate filtered concentrated in vacuum filtered

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

実験手順: 2,6-Dichloro-4-(2-methoxyethoxy)benzoic acid (0.1 g, 0.23 mmol), (4-bromophenyl)methanamine hydrochloride (0.1 g, 0.27 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (0.17 g, 0.27 mmol), and triethylamine (0.15 mL, 0.7 mmol) were combined in DMF (3 mL) and then stirred at room temperature until reaction was completed. The reaction mixture was diluted with ethyl acetate and washed with water and twice with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The solid resulting was used for next step without further purification. washed with water and twice with a saturated sodium bicarbonate solution The organic phase was dried over magnesium sulfate filtered concentrated in vacuum The solid resulting was used for next step without further purification

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

実験手順: A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil. The two layers were separated the aqueous layer was extracted with EtOAc (20 mL) The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo

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

実験手順: A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117 (2.60 g, 90.9% yield) as a colorless oil. The two layers were separated the aqueous layer was extracted with EtOAc (20 mL) The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo

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

実験手順: (4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) and sodium methoxide (2.376 mL, 10.39 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel with 100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz), 6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br. s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS:R.T.=2.12; [M+2]+=317.2. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel with 100% ethyl acetate