2-(四氢吡喃-4-基)肼基甲酸叔丁酯

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

实验步骤: Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m, 1H), 1.59-1.69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d, J=11.62 Hz, 2H), 4.36 (br. s., 1H), 8.07-8.34 (m, 1H). The solvent was removed in vacuo The contents were stirred at room temperature for 60 h The solvent was removed in vacuo The layers were separated the aq. layer extracted with DCM The combined organic layers were washed with saturated NaHCO3, and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo

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

实验步骤: Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m, 1H), 1.59-1.69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d, J=11.62 Hz, 2H), 4.36 (br. s., 1H), 8.07-8.34 (m, 1H). The solvent was removed in vacuo The contents were stirred at room temperature for 60 h The solvent was removed in vacuo The layers were separated the aq. layer extracted with DCM The combined organic layers were washed with saturated NaHCO3, and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1). The mixture was concentrated After cooling to room temperature the mixture was concentrated the residue was purified by flash chromatography on silica gel using a 10-50% hexane the crude product was then extracted with ethyl acetate The combined extracts were washed with saturated sodium bicarbonate concentrated

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1). The mixture was concentrated After cooling to room temperature the mixture was concentrated the residue was purified by flash chromatography on silica gel using a 10-50% hexane the crude product was then extracted with ethyl acetate The combined extracts were washed with saturated sodium bicarbonate concentrated

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1). The mixture was concentrated After cooling to room temperature the mixture was concentrated the residue was purified by flash chromatography on silica gel using a 10-50% hexane the crude product was then extracted with ethyl acetate The combined extracts were washed with saturated sodium bicarbonate concentrated

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

实验步骤: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

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

实验步骤: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

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

实验步骤: A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g). concentrated under reduced pressure The residue was dissolved in THF (25 mL) acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added To the reaction mixture was added 8N aqueous sodium hydroxide solution the mixture was extracted with ethyl acetate The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

实验步骤: A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g). concentrated under reduced pressure The residue was dissolved in THF (25 mL) acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added To the reaction mixture was added 8N aqueous sodium hydroxide solution the mixture was extracted with ethyl acetate The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

实验步骤: tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g). cooling The reaction mixture was concentrated under reduced pressure

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1). The mixture was concentrated After cooling to room temperature the mixture was concentrated the residue was purified by flash chromatography on silica gel using a 10-50% hexane the crude product was then extracted with ethyl acetate The combined extracts were washed with saturated sodium bicarbonate concentrated

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

实验步骤: Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2 H), 1.39 (s, 9 H), 1.43-1.48 (m, 1 H), 1.59-1.69 (m, 2 H), 2.82-2.98 (m, 1 H), 3.20-3.32 (m, 2 H), 3.80 (d, J=11.62 Hz, 2 H), 4.36 (br. s., 1 H), 8.07-8.34 (m, 1 H). The solvent was removed in vacuo The contents were stirred at room temperature for 60 h The solvent was removed in vacuo The layers were separated the aq. layer extracted with DCM The combined organic layers were washed with saturated NaHCO3, and brine The organic layer was dried over MgSO4 filtered concentrated in vacuo