(4-fluoro-3-methoxyphenyl)methanamine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF (25 mL) and cool to −78° C. Slowly add a pre-mixed solution of 4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooled solution over 1 h. Stir the resulting mixture at −78° C. for 1 h, then warm to RT and stir for 4 h. Remove all solids by filtration and wash with THF (5 mL). Concentrate the filtrate and re-dissolve the crude material in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate the organic and aqueous layers and extract the aqueous phase with additional EtOAc (30 mL). Combine the organic solutions dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the title compound as a white solid (1.36 g, 28%). MS (ES−) 356.1 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd, 1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H). warm to RT stir for 4 h Remove all solids by filtration wash with THF (5 mL) Concentrate the filtrate re-dissolve the crude material in EtOAc (30 mL) wash with 1N HCl (30 mL) Separate the organic and aqueous layers extract the aqueous phase with additional EtOAc (30 mL) Combine the organic solutions dry filter concentrate Purify the crude material by flash chromatography

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

実験手順: Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), seal the vessel, and agitate the reaction. After 8 hours stop the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon and return the filtrate for product isolation. Concentrate the crude solution, re-dissolve in CH2Cl2 (80 mL) and washe with 5N NaOH (35 mL). Separate the organic and aqueous phases and extract the aqueous with additional CH2Cl2 (20 mL). Combine the organic solutions, dry, filter and concentrate to give the crude material 2.08 g (100%). The title compound as the major product (Rf=0.12, 10% MeOH/CH2Cl2) is used without further purification. MS (ES+) 156.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80 (m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H). Purge the reaction vessel with nitrogen purge the reaction vessel with hydrogen seal the vessel the reaction purge the vessel with nitrogen Filter the reaction mixture to remove the 5% palladium on carbon Concentrate the crude solution re-dissolve in CH2Cl2 (80 mL) Separate the organic and aqueous phases extract the aqueous with additional CH2Cl2 (20 mL) Combine the organic solutions, dry filter concentrate

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

実験手順: Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), seal the vessel, and agitate the reaction. After 8 hours stop the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon and return the filtrate for product isolation. Concentrate the crude solution, re-dissolve in CH2Cl2 (80 mL) and washe with 5N NaOH (35 mL). Separate the organic and aqueous phases and extract the aqueous with additional CH2Cl2 (20 mL). Combine the organic solutions, dry, filter and concentrate to give the crude material 2.08 g (100%). The title compound as the major product (Rf=0.12, 10% MeOH/CH2Cl2) is used without further purification. MS (ES+) 156.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80 (m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H). Purge the reaction vessel with nitrogen purge the reaction vessel with hydrogen seal the vessel the reaction purge the vessel with nitrogen Filter the reaction mixture to remove the 5% palladium on carbon Concentrate the crude solution re-dissolve in CH2Cl2 (80 mL) Separate the organic and aqueous phases extract the aqueous with additional CH2Cl2 (20 mL) Combine the organic solutions, dry filter concentrate

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

実験手順: To a solution of 1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid (150 mg, 0.501 mmol, Preparation #34) in DMF (4 mL) was added (4-fluoro-3-methoxyphenyl)methanamine (93 mg, 0.601 mmol, WO 2008/083056), N-ethyl-N-isopropylpropan-2-amine (194 mg, 1.504 mmol, Spectrochem) and followed by HATU (286 mg, 0.752 mmol, Molekule). The reaction mixture was stirred at RT for 16 h. and was quenched with ice cold water (10 mL). The product was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulphate and evaporated to dryness under vacuum. The residue obtained was purified by silica gel column chromatography by eluenting with 40-60% EtOAc in hexane. The relevant fractions containing the product were combined and evaporated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxamide 90 mg, (41.1%) as pale yellow solids. 1H NMR (400 MHz, DMSO) δ 9.159-9.127 (m, 1H), 8.143 (s, 1H), 7.422-7.331 (m, 5H), 7.167-7.117 (m, 2H), 6.886-6.849 (m, 1H), 5.812-5.763 (m, 1H), 4.436-4.420 (d, J=6.4 Hz, 2H), 3.964-3.892 (m, 1H) 3.819 (s, 3H), 3.781 (s, 3H), 3.508-3.443 (m, 1H). MS m/z 437.3 (M+H)+; was quenched with ice cold water (10 mL) The product was extracted with EtOAc (3×20 mL) The combined organic layers were dried over sodium sulphate evaporated to dryness under vacuum The residue obtained was purified by silica gel column chromatography The relevant fractions containing the product evaporated under reduced pressure

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H). The solvents were removed in vacuo the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL) The layers were separated the aqueous layer extracted with EtOAc (1×150 mL) The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL) dried over sodium sulphate evaporated to dryness The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane Relevant fractions containing the target compound evaporated to dryness under reduced pressure

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H). The solvents were removed in vacuo the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL) The layers were separated the aqueous layer extracted with EtOAc (1×150 mL) The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL) dried over sodium sulphate evaporated to dryness The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane Relevant fractions containing the target compound evaporated to dryness under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A flame dried 50 mL round bottom flask was charged with lithium aluminum hydride (0.63 g, 16.6 mmol) and to this was added tetrahydrofuran (25 mL). The solution was cooled to 0° C. and 3-methoxy-4-fluorobenzonitrile (1.0 g, 6.62 mmol) was added in one portion. The ice bath was removed after an hour and the resulting mixture was stirred for 16 h after which it was cooled to 0° C. and quenched by adding 0.63 mL water, 0.63 mL 15% NaOH and 1.89 mL water drop-wise and in succession. The mixture was stirred for 20 min and filtered. The filtrate was concentrated in vacuo to obtain 890 mg (86%) of the title compound as an oil. NMR indicated no further purification was required. NMR (300 MHz, DMSO-d6): δ 7.1 (m, 2H), 6.85 (m, 1H), 3.84 (s, 3H), 3.7 (s, 2H). 13C NMR (75 MHz, DMSO-d6): δ 150.0 (d, J=240 Hz), 146.6 (d, J=10.5 Hz), 141.1 (d, J=3.75 Hz), 118.75 (d, J=6.75 Hz), 115.1 (d, J=18 Hz), 112.5, 55.75, 45.2. HRMS: Calc'd for C8H10FNO (M+H): 156.0819; Found: 156.0818. A flame dried 50 mL round bottom flask The ice bath was removed after an hour was cooled to 0° C. quenched by adding 0.63 mL water, 0.63 mL 15% NaOH and 1.89 mL water The mixture was stirred for 20 min filtered The filtrate was concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF (25 mL) and cool to −78° C. Slowly add a pre-mixed solution of 4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooled solution over 1 h. Stir the resulting mixture at −78° C. for 1 h, then warm to RT and stir for 4 h. Remove all solids by filtration and wash with THF (5 mL). Concentrate the filtrate and re-dissolve the crude material in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate the organic and aqueous layers and extract the aqueous phase with additional EtOAc (30 mL). Combine the organic solutions dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the title compound as a white solid (1.36 g, 28%). MS (ES−) 356.1 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd, 1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H). warm to RT stir for 4 h Remove all solids by filtration wash with THF (5 mL) Concentrate the filtrate re-dissolve the crude material in EtOAc (30 mL) wash with 1N HCl (30 mL) Separate the organic and aqueous layers extract the aqueous phase with additional EtOAc (30 mL) Combine the organic solutions dry filter concentrate Purify the crude material by flash chromatography

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

実験手順: Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium on carbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), seal the vessel, and agitate the reaction. After 8 hours stop the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon and return the filtrate for product isolation. Concentrate the crude solution, re-dissolve in CH2Cl2 (80 mL) and wash with 5N NaOH (35 mL). Separate the organic and aqueous phases and extract the aqueous with additional CH2Cl2 (20 mL). Combine the organic solutions, dry, filter and concentrate to give the crude material 2.08 g (100%). The title compound as the major product (Rf=0.12, 10% MeOH/CH2Cl2) is used without further purification. MS (ES+) 156.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.01(dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80 (m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H). Purge the reaction vessel with nitrogen purge the reaction vessel with hydrogen seal the vessel the reaction purge the vessel with nitrogen Filter the reaction mixture to remove the 5% palladium on carbon Concentrate the crude solution re-dissolve in CH2Cl2 (80 mL) wash with 5N NaOH (35 mL) Separate the organic and aqueous phases extract the aqueous with additional CH2Cl2 (20 mL) Combine the organic solutions, dry filter concentrate

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF (25 mL) and cool to −78° C. Slowly add a pre-mixed solution of 4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et3N (1.64 mL, 11.8 mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooled solution over 1 h. Stir the resulting mixture at −78° C. for 1 h, then warm to RT and stir for 4 h. Remove all solids by filtration and wash with THF (5 mL). Concentrate the filtrate and re-dissolve the crude material in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate the organic and aqueous layers and extract the aqueous phase with additional EtOAc (30 mL). Combine the organic solutions dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the title compound as a white solid (1.36 g, 28%). MS (ES−) 356.1 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd, 1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s, 1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H). warm to RT stir for 4 h Remove all solids by filtration wash with THF (5 mL) Concentrate the filtrate re-dissolve the crude material in EtOAc (30 mL) wash with 1N HCl (30 mL) Separate the organic and aqueous layers extract the aqueous phase with additional EtOAc (30 mL) Combine the organic solutions dry filter concentrate Purify the crude material by flash chromatography