(4-氨基苯基)-二乙氧基磷酰甲醇

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

实验步骤: A mixture of diethyl 4-amino-α-hydroxybenzylphosphonate (50 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (54 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (38 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (43 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (2 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-(4-[(diethylphosphono)(hydroxy)methyl]phenyl}propionamide (52 mg, 58%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 171–172° C. MS (ESI+): 609 (M+H) the reaction mixture was extracted with ethyl acetate (2 ml) The organic layer was concentrated introduced into preparative HPLC purified

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

实验步骤: To a mixed solution of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.42 g) and methanol (30 mL) was added 10% palladium-carbon (0.14 g) and the mixture was stirred at room temperature under an atmospheric hydrogen pressure for 3 hrs. Palladium-carbon was removed from the reaction mixture by filtration and the filtrate was concentrated to give diethyl 4-amino-α-hydroxybenzylphosphonate as a solid (1.02 g, yield 80%). Palladium-carbon was removed from the reaction mixture by filtration the filtrate was concentrated

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and MeOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. LC-MS showed that the reaction was complete. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (18.5 mg, yield: 27%). 1H NMR (CD3OD, 400 MHz): δ=1.21 (dt, J=0.8, 7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.35 (s, 3 H), 3.93-4.14 (m, 4 H), 4.61 (d, J=15.2 Hz, 1 H), 7.18 (dt, J=1.2, 7.6 Hz, 1 H), 7.34 (dd, J=2.0, 8.4 Hz, 2 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 7.62-7.66 (m, 3 H), 8.34 (s, 1 H), 8.46 (m, 1 H). MS (ES+): m/z 568.11 [MH+]. HPLC: tR=3.31 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and MeOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. LC-MS showed that the reaction was complete. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (18.5 mg, yield: 27%). 1H NMR (CD3OD, 400 MHz): δ=1.21 (dt, J=0.8, 7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.35 (s, 3 H), 3.93-4.14 (m, 4 H), 4.61 (d, J=15.2 Hz, 1 H), 7.18 (dt, J=1.2, 7.6 Hz, 1 H), 7.34 (dd, J=2.0, 8.4 Hz, 2 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 7.62-7.66 (m, 3 H), 8.34 (s, 1 H), 8.46 (m, 1 H). MS (ES+): m/z 568.11 [MH+]. HPLC: tR=3.31 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and EtOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (8.4 mg, yield: 12%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (dt, J=0.8, 7.6 Hz, 6 H), 1.30 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.47-3.57 (m, 2 H), 3.95-4.15 (m, 4 H), 4.72 (d, J=16.0 Hz, 1 H), 7.18 (dt, J=1.2, 7.6 Hz, 1 H), 7.35 (dd, J=2.0, 8.4 Hz, 2 H), 7.49 (dd, J=1.6, 8.8 Hz, 1 H), 7.63-7.65 (m, 3 H), 8.34 (s, 1 H), 8.45 (m, 1 H). MS (ES+): m/z 582.17 [MH+]. HPLC: tR=3.44 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)

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

实验步骤: The title compound was prepared using the procedure for Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol). The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 13.8 mg of the desired product (yield: 18%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.6 Hz, 3 H), 1.31 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.91-4.08 (m, 4 H), 4.12-4.18 (m, 2 H), 4.95 (d, J=14.8 Hz, 1 H), 7.18 (t, J=7.2 Hz, 1 H), 7.36 (d, J=8.4 Hz, 2 H), 7.49 (dt, J=2.4, 7.6 Hz, 1 H), 7.64 (dd, J=1.6, 7.6 Hz, 1 H), 7.68 (d, J=7.6 Hz, 2 H), 8.35 (s, 1 H), 8.43 (m, 1 H). MS (ES+): m/z 636.14 [MH+]. HPLC: tR=1.59 min (UPLC TOF, polar—3 min). The title compound was prepared The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM)

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

实验步骤: The title compound was prepared using the procedure for Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol). The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 13.8 mg of the desired product (yield: 18%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (t, J=7.6 Hz, 3 H), 1.31 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.91-4.08 (m, 4 H), 4.12-4.18 (m, 2 H), 4.95 (d, J=14.8 Hz, 1 H), 7.18 (t, J=7.2 Hz, 1 H), 7.36 (d, J=8.4 Hz, 2 H), 7.49 (dt, J=2.4, 7.6 Hz, 1 H), 7.64 (dd, J=1.6, 7.6 Hz, 1 H), 7.68 (d, J=7.6 Hz, 2 H), 8.35 (s, 1 H), 8.43 (m, 1 H). MS (ES+): m/z 636.14 [MH+]. HPLC: tR=1.59 min (UPLC TOF, polar—3 min). The title compound was prepared The crude product was purified by prep TLC (5% 7 N ammonia in MeOH in DCM)

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

实验步骤: A mixture of diethyl 4-amino-α-hydroxybenzylphosphonate (50 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (54 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (38 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (43 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (2 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-(4-[(diethylphosphono)(hydroxy)methyl]phenyl}propionamide (52 mg, 58%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 171–172° C. MS (ESI+): 609 (M+H) the reaction mixture was extracted with ethyl acetate (2 ml) The organic layer was concentrated introduced into preparative HPLC purified

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

实验步骤: To a mixed solution of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.42 g) and methanol (30 mL) was added 10% palladium-carbon (0.14 g) and the mixture was stirred at room temperature under an atmospheric hydrogen pressure for 3 hrs. Palladium-carbon was removed from the reaction mixture by filtration and the filtrate was concentrated to give diethyl 4-amino-α-hydroxybenzylphosphonate as a solid (1.02 g, yield 80%). Palladium-carbon was removed from the reaction mixture by filtration the filtrate was concentrated

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl[(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and MeOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. LC-MS showed that the reaction was complete. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (18.5 mg, yield: 27%). 1H NMR (CD3OD, 400 MHz): δ=1.21 (dt, J=0.8, 7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 2.90 (s, 3H), 3.35 (s, 3H), 3.93-4.14 (m, 4H), 4.61 (d, J=15.2 Hz, 1H), 7.18 (dt, J=1.2, 7.6 Hz, 1H), 7.34 (dd, J=2.0, 8.4 Hz, 2H), 7.49 (dd, J=1.6, 8.4 Hz, 1H), 7.62-7.66 (m, 3H), 8.34 (s, 1H), 8.46 (m, 1H). MS (ES+): m/z 568.11 [MH+]. HPLC: tR=3.31 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl[(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and EtOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (8.4 mg, yield: 12%). 1H NMR (CD3OD, 400 MHz): δ=1.22 (dt, J=0.8, 7.6 Hz, 6H), 1.30 (t, J=7.2 Hz, 3H), 2.90 (s, 3H), 3.47-3.57 (m, 2H), 3.95-4.15 (m, 4H), 4.72 (d, J=16.0 Hz, 1H), 7.18 (dt, J=1.2, 7.6 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 2H), 7.49 (dd, J=1.6, 8.8 Hz, 1H), 7.63-7.65 (m, 3H), 8.34 (s, 1H), 8.45 (m, 1H). MS (ES+): m/z 582.17 [MH+] HPLC: tR=3.44 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and MeOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. LC-MS showed that the reaction was complete. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (18.5 mg, yield: 27%). 1H NMR (CD3OD, 400 MHz): δ=1.21 (dt, J=0.8, 7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.35 (s, 3 H), 3.93-4.14 (m, 4 H), 4.61 (d, J=15.2 Hz, 1 H), 7.18 (dt, J=1.2, 7.6 Hz, 1 H), 7.34 (dd, J=2.0, 8.4 Hz, 2 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 7.62-7.66 (m, 3 H), 8.34 (s, 1 H), 8.46 (m, 1 H). MS (ES+): m/z 568.11 [MH+]. HPLC: tR=3.31 min (OpenLynx, polar—5 min). The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL) Layers were separated the aqueous layer was extracted with DCM (3×5 mL) The combined organic phases were dried over MgSO4 concentrated purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM)