5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (2 g, 11.16 mmol) in EtOH (10 mL) was added hydrazine (1.263 g, 33.5 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL), and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (100% EA, 12 g silica column). All fractions found to contain product by TLC (EA, Rf=0.3) were combined and concentrated to yield an off-white oil of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.459 mmol, 22.03% yield): 1H NMR (400 MHz, CD3OD) δ 5.58 (s, 1H), 1.47 (s, 6H). ES-LCMS m/z 194 (M+H). Then the mixture was concentrated to give the residue which extracted with DCM (20 mL×2) The combined organic extracts were washed with brine (20 mL) dried over Na2SO4 filtered concentrated The crude product was purified by silica column chromatography (100% EA, 12 g silica column) concentrated

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of acetonitrile (3.22 g, 44.1 mmol) in THF (60 mL) at −78° C. was added n-BuLi (17.63 mL, 44.1 mmol, 2.5 mol/L). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (5 g, 29.4 mmol) dropwise. Then the mixture was stirred for another 1 h. The mixture was quenched with saturated NH4Cl solution (50 mL), extracted with EA (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to yield a crude product as a yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g, 16.75 mmol, 57.0% yield): 1H NMR (400 MHz, CD3OD) δ 3.75 (s, 2H), 1.40 (s., 6H). Then the mixture was stirred for another 1 h The mixture was quenched with saturated NH4Cl solution (50 mL) extracted with EA (100 mL×2) The organic layer was dried over Na2SO4 filtered concentrated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) in EtOH (10 mL) was added methylhydrazine (3.33 g, 28.9 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column). All fractions found to contain product by TLC (EA:PE=1:2, Rf=0.2) were combined and concentrated to yield a white solid of 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.293 mmol, 41.1% yield): 1H NMR (400 MHz, CD3OD): δ 5.48 (s, 1H), 3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H). Then the mixture was concentrated to give the residue which extracted with DCM (20 mL×2) The combined organic extracts were washed with brine (20 mL) dried over Na2SO4 filtered concentrated The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column) concentrated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) in EtOH (10 mL) was added methylhydrazine (3.33 g, 28.9 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column). All fractions found to contain product by TLC (EA:PE=1:2, Rf=0.2) were combined and concentrated to yield a white solid of 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.293 mmol, 41.1% yield): 1H NMR (400 MHz, CD3OD): δ 5.48 (s, 1H), 3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H). Then the mixture was concentrated to give the residue which extracted with DCM (20 mL×2) The combined organic extracts were washed with brine (20 mL) dried over Na2SO4 filtered concentrated The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column) concentrated

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of acetonitrile (3.22 g, 44.1 mmol) in THF (60 mL) at −78° C. was added n-BuLi (17.63 mL, 44.1 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (5 g, 29.4 mmol) dropwise. Then the mixture was stirred for another 1 h. The mixture was quenched with saturated NH4Cl solution (50 mL), and extracted with EA (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g, 16.75 mmol, 57.0% yield): 1H NMR (400 MHz, CD3OD): δ 3.75 (s, 2H), 1.40 (s, 6H). Then the mixture was stirred for another 1 h The mixture was quenched with saturated NH4Cl solution (50 mL) extracted with EA (100 mL×2) The organic layer was dried over Na2SO4 filtered concentrated

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

実験手順: To a mixture of hydroxylamine hydrochloride (23.2 g, 336 mmol) in water (300 mL) cooled to 0° C. was added NaHCO3 (30 g, 351 mmol) and pH=7.5 adjusted. Then to the mixture was added a solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (30 g, 167.4 mmol) in MeOH (40 mL). The mixture was stirred at 65° C. for 15 h. After cooled, the mixture was acidified with conc. HCl to pH=1 and then refluxed for 2 h. After cooling to rt, the mixture was neutralized by 4 M NaOH to pH=8. The mixture was extracted with EA (300 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1˜3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.6) were combined and concentrated to yield a red solid of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (19.5 g, 100.5 mmol, 60% yield): 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 3.96 (s., 2H), 1.53 (s, 6H); ES-LCMS m/z: 195 (M+H). After cooled refluxed for 2 h After cooling to rt The mixture was extracted with EA (300 mL×2) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=8:1˜3:1) concentrated

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

実験手順: To a mixture of hydroxylamine hydrochloride (23.2 g, 336 mmol) in water (300 mL) cooled to 0° C. was added NaHCO3 (30 g, 351 mmol) and pH=7.5 adjusted. Then to the mixture was added a solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (30 g, 167.4 mmol) in MeOH (40 mL). The mixture was stirred at 65° C. for 15 h. After cooled, the mixture was acidified with conc. HCl to pH=1 and then refluxed for 2 h. After cooling to rt, the mixture was neutralized by 4 M NaOH to pH=8. The mixture was extracted with EA (300 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1˜3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.6) were combined and concentrated to yield a red solid of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (19.5 g, 100.5 mmol, 60% yield): 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 3.96 (s., 2H), 1.53 (s, 6H); ES-LCMS m/z: 195 (M+H). After cooled refluxed for 2 h After cooling to rt The mixture was extracted with EA (300 mL×2) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=8:1˜3:1) concentrated

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

実験手順: To a mixture of MeCN (13.9 mL, 264 mmol) in THF (500 mL) cooled to −78° C. was added n-BuLi (106 mL, 264 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (30 g, 176 mmol) dropwise. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with aqueous NH4Cl (50 mL), extracted with EA (300 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a crude product of a yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (22 g, 122.9 mmol, 70% yield): 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 2H), 1.41 (s, 6H). The mixture was stirred at 25° C. for 10 h The mixture was quenched with aqueous NH4Cl (50 mL) extracted with EA (300 mL×3) The organic layer was dried over Na2SO4 filtered concentrated

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) and hydroxylamine hydrochloride (0.407 g, 5.86 mmol) in water (30 mL) was added NaOH (0.447 g, 11.16 mmol). Then the mixture was stirred at 100° C. for 3 h. After cooling to rt, the mixture was extracted with DCM (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a light yellow solid of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (700 mg, 3.39 mmol, 61% yield): 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 1H), 4.41 (s, 2H), 1.49 (s, 6H); ES-LCMS m/z 195 (M+H). After cooling to rt the mixture was extracted with DCM (50 mL×3) The organic layer was dried over Na2SO4 filtered concentrated

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

実験手順: To a mixture of MeCN (1.086 g, 26.5 mmol) in THF (300 mL) cooled to −78° C. was added n-BuLi (10.58 mL, 26.5 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (3 g, 17.63 mmol) dropwise. The mixture was quenched with aqueous NH4Cl and extracted with DCM/MeOH (10:1, 30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.5) were combined and concentrated to yield a light yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.30 mmol, 30% yield): 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 2H), 1.41 (s, 6H). The mixture was quenched with aqueous NH4Cl extracted with DCM/MeOH (10:1, 30 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=8:1) concentrated

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

実験手順: To a mixture of MeCN (1.086 g, 26.5 mmol) in THF (300 mL) cooled to −78° C. was added n-BuLi (10.58 mL, 26.5 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (3 g, 17.63 mmol) dropwise. The mixture was quenched with aqueous NH4Cl and extracted with DCM/MeOH (10:1, 30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.5) were combined and concentrated to yield a light yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.30 mmol, 30% yield): 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 2H), 1.41 (s, 6H). The mixture was quenched with aqueous NH4Cl extracted with DCM/MeOH (10:1, 30 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=8:1) concentrated

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

実験手順: To a mixture of hydroxylamine hydrochloride (3.10 g, 44.7 mmol) in H2O (25 mL) cooled to 0° C. was added NaHCO3 (3.94 g, 46.9 mmol) to adjust to pH=7.5. Then to the mixture was added a solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (4 g, 22.33 mmol) in MeOH (25 mL). The mixture was stirred at 65° C. for 15 h. After cooled, the mixture was acified with conc. HCl to pH=1.0 and then refluxed for 2 h. After cooling, the mixture was neutralized by 4 M NaOH to pH=8.0. The mixture was extracted with DCM/MeOH (10:1). The organic layer was dried over Na2SO4, filtered and concentrated to yield a white solid of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (2 g, 9.06 mmol, 40.6% yield): 1H NMR (400 MHz, CDCl3) δ 5.78 (s, 1H), 3.93 (s., 2H), 1.51 (s, 6H); ES-LCMS m/z 195 (M+1). After cooled refluxed for 2 h After cooling The mixture was extracted with DCM/MeOH (10:1) The organic layer was dried over Na2SO4 filtered concentrated