2-Propanone, 1-amino-3-(4-fluorophenyl)-, hydrochloride (1:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (prepared according to the procedure in Naidu, B. N. et al WO2005118593) (0.495 g, 1.5 mmol), 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (prepared according to the procedure in Maeda, S. et al Chem. Pharm. Bull. 1984, 32, 2536-2543; 0.406 g, 2 mmol), HATU (0.760 g, 2 mmol), Et3N (0.56 mL, 4 mmol) and DMAP (60 mg) in DMF (15 mL) was stirred at room temperature. After 4 h, the reaction mixture was diluted with Et2O (100 mL), washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give the title compound (0.57 g, 78% yield) as a viscous yellow oil which was used in the subsequent step without purification. 1HNMR (500 MHz, CDCl3) δ: 8.10-8.07 (1H, br s), 7.56 (2H, d, J=7.3 Hz), 7.34-7.28 (3H, m), 7.19 (2H, dd, J=8.6, 5.5 Hz), 7.03 (2H, t, J=8.6 Hz), 5.29 (2H, s), 4.30 (2H, d, J=4.9 Hz), 4.04-3.98 (4H, m), 3.75 (2H, s), 2.79 (6H, s), 1.62 (6H, s). HRMS (M+H) calcd for C26H27N3O5F: 480.1935. found: 480.1930. prepared washed with water (3×10 mL), brine (10 mL) dried (Na2SO4) filtered concentrated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS#93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows. the reaction solution was stirred at 0° C. for 1.5 hours the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS #93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows. the reaction solution was stirred at 0° C. for 1.5 hours the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (prepared according to the procedure in Naidu, B. N. et al WO2005118593) (0.495 g, 1.5 mmol), 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (prepared according to the procedure in Maeda, S. et al Chem. Pharm. Bull. 1984, 32, 2536-2543; 0.406 g, 2 mmol), HATU (0.760 g, 2 mmol), Et3N (0.56 mL, 4 mmol) and DMAP (60 mg) in DMF (15 mL) was stirred at room temperature. After 4 h, the reaction mixture was diluted with Et2O (100 mL), washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give the title compound (0.57 g, 78% yield) as a viscous yellow oil which was used in the subsequent step without purification. 1HNMR (500 MHz, CDCl3) δ: 8.10-8.07 (1H, br s), 7.56 (2H, d, J=7.3 Hz), 7.34-7.28 (3H, m), 7.19 (2H, dd, J=8.6, 5.5 Hz), 7.03 (2H, t, J=8.6 Hz), 5.29 (2H, s), 4.30 (2H, d, J=4.9 Hz), 4.04-3.98 (4H, m), 3.75 (2H, s), 2.79 (6H, s), 1.62 (6H, s). HRMS (M+H) calcd for C26H27N3O5F: 480.1935. found: 480.1930. prepared washed with water (3×10 mL), brine (10 mL) dried (Na2SO4) filtered concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (prepared according to the procedure in Naidu, B. N. et al WO2005118593) (0.495 g, 1.5 mmol), 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (prepared according to the procedure in Maeda, S. et al Chem. Pharm. Bull. 1984, 32, 2536-2543; 0.406 g, 2 mmol), HATU (0.760 g, 2 mmol), Et3N (0.56 mL, 4 mmol) and DMAP (60 mg) in DMF (15 mL) was stirred at room temperature. After 4 h, the reaction mixture was diluted with Et2O (100 mL), washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give the title compound (0.57 g, 78% yield) as a viscous yellow oil which was used in the subsequent step without purification. 1HNMR (500 MHz, CDCl3) δ: 8.10-8.07 (1H, br s), 7.56 (2H, d, J=7.3 Hz), 7.34-7.28 (3H, m), 7.19 (2H, dd, J=8.6, 5.5 Hz), 7.03 (2H, t, J=8.6 Hz), 5.29 (2H, s), 4.30 (2H, d, J=4.9 Hz), 4.04-3.98 (4H, m), 3.75 (2H, s), 2.79 (6H, s), 1.62 (6H, s). HRMS (M+H) calcd for C26H27N3O5F: 480.1935. found: 480.1930. prepared washed with water (3×10 mL), brine (10 mL) dried (Na2SO4) filtered concentrated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS# 93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows. the reaction solution was stirred at 0° C. for 1.5 hours the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of the product of example 4 (1.0 g, 2.4 mmol) in THF (10 ml) was added compound 1-amino-3-(4-fluoro-phenyl)-propan-2-one hydrochloride (1.0 g, 4.9 mmol), EDCI.HCl (560 mg, 2.9 mmol), HOBt (400 mg, 2.9 mmol) and TEA (1 g, 9.9 mmol) successively at room temperature. The mixture was stirred overnight, after which saturated sodium bicarbonate was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography (CH2Cl2/MeOH=100/1) to give the desired product (540 mg, 40% yield). extracted with ethyl acetate washed with brine dried over sodium sulfate The product was purified by column chromatography (CH2Cl2/MeOH=100/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of the product of example 1 (2.4 mmol) in THF (10 ml) was added compound 1-amino-3-(4-fluoro-phenyl)-propan-2-one hydrochloride (1.0 g, 4.9 mmol), EDCI.HCl (560 mg, 2.9 mmol), HOBt (400 mg, 2.9 mmol) and TEA (1 g, 9.9 mmol), successively at room temperature. The mixture was stirred overnight, after which saturated sodium bicarbonate was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography to give the desired product. successively at room temperature extracted with ethyl acetate washed with brine dried over sodium sulfate The product was purified by column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (1 g, 2.043 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF was then added and the mixture stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the crude acid chloride was diluted with dichloromethane (10 mL) and added to a stirred solution of 1-amino-3-(4-fluorophenyl)propan-2-one HCl (0.458 g, 2.247 mmol) and triethylamine (1.139 mL, 8.17 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 16 h then poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane) to afford the title compound (770 mg, 1.206 mmol, 59.0% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, br. s.), 7.49 (2H, d, J=5.80 Hz), 7.28-7.37 (8H, m), 7.15 (2H, dd, J=8.55, 5.49 Hz), 7.01-7.04 (2H, m), 6.79 (1H, br. s.), 5.32 (2H, s), 5.06 (2H, s), 4.17 (2H, d, J=4.88 Hz), 4.12 (2H, d, J=3.66 Hz), 3.69 (2H, s), 2.67-2.78 (2H, m), 2.47 (1H, br. s.), 1.89-2.01 (4H, m), 1.64-1.72 (2H, m). LCMS (M+H)=640.04. Solvent was removed under reduced pressure the crude acid chloride was diluted with dichloromethane (10 mL) The resulting solution was stirred at room temperature for 16 h extracted with dichloromethane (50 mL×3) dried (Na2SO4) filtered concentrated to give a yellow oil The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (400 mg, 0.817 mmol) in CH2Cl2 (8 mL) was added oxalyl chloride (0.114 mL, 1.307 mmol) followed by 1 drop of DMF. After stirring for 2 h, the mixture was concentrated under reduced pressure. The crude acid chloride was then diluted with dichloromethane (5 mL)) and added to a stirred solution of 1-amino-3-(4-fluorophenyl)propan-2-one HCl (183 mg, 0.899 mmol) and triethylamine (0.456 mL, 3.27 mmol) in CH2Cl2 (8.00 mL) and the resulting solution stirred at room temperature. After 16 h the reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane) to afford the title compound (400 mg, 0.626 mmol, 77% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, br. s.), 7.49 (2H, d, J=5.80 Hz), 7.28-7.37 (8H, m), 7.15 (2H, dd, J=8.55, 5.49 Hz), 7.01-7.04 (2H, m), 6.79 (1H, br. s.), 5.32 (2H, s), 5.06 (2H, s), 4.17 (2H, d, J=4.88 Hz), 4.12 (2H, d, J=3.66 Hz), 3.69 (2H, s), 2.67-2.78 (2H, m), 2.47 (1H, br. s.), 1.89-2.01 (4H, m), 1.64-1.72 (2H, m). LCMS (M+H)=640.04. the mixture was concentrated under reduced pressure The crude acid chloride was then diluted with dichloromethane (5 mL)) and the resulting solution stirred at room temperature extracted with dichloromethane (50 mL×3) dried (Na2SO4) filtered concentrated to give a yellow oil The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS#93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows. the reaction solution was stirred at 0° C. for 1.5 hours the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diethyl cyanophosphonate (0.12 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and triethylamine (0.54 mL) in DMF (2 mL), and the reaction solution was stirred at 0° C. for 30 minutes. A solution of 1-amino-3-(4-fluorophenyl)propan-2-one hydrochloride (CAS #93102-98-8, 158 mg) in DMF (1 mL) was added dropwise to the reaction solution over 20 minutes, and the reaction solution was stirred at 0° C. for 1.5 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 43 mg of the title compound. The property values of the compound are as follows. the reaction solution was stirred at 0° C. for 1.5 hours the organic layer was separated The resulting organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1)