2,3,4-三氟苯甲醛

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

实验步骤: Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H). The resulting mixture was heated The water was removed from time to time (3 hour intervals) the toluene was removed the residue was diluted with ethyl acetate (1.5 L) washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL) The organic layers were dried over sodium sulphate the solvent was removed under vacuum The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities The fraction obtained at 75-85° C. (0.1 mm of Hg)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a microwave vial 2,3,4-trifluorobenzaldehyde (1.5 g, 9.4 mmol) was dissolved in 1,4-dioxane (6 mL) and hydrazine (6 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 664 mg (46%) of 6,7-difluoro-1H-indazole as a light brown powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.10 (d, J=3.4 Hz, 1H), 7.47 (dd, J=8.9, 4.0 Hz, 1H), 7.05 (ddd, J=10.6, 8.9, 6.6 Hz, 1H). The vial was sealed The reaction was quenched with water extracted with EtOAc The organic layer was washed with brine then dried over MgSO4 concentrated The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a microwave vial 2,3,4-trifluorobenzaldehyde (1.5 g, 9.4 mmol) was dissolved in 1,4-dioxane (6 mL) and hydrazine (6 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 664 mg (46%) of 6,7-difluoro-1H-indazole as a light brown powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.10 (d, J=3.4 Hz, 1H), 7.47 (dd, J=8.9, 4.0 Hz, 1H), 7.05 (ddd, J=10.6, 8.9, 6.6 Hz, 1H). The vial was sealed The reaction was quenched with water extracted with EtOAc The organic layer was washed with brine then dried over MgSO4 concentrated The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

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

实验步骤: A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue wasdistilled under high vacuum to give the title compound (23.07 g, 71.7%). washed successively with aq. sodium bicarbonate solution, water, and brine The organic layer dried over sodium sulfate concentrated

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

实验步骤: A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue wasdistilled under high vacuum to give the title compound (23.07 g, 71.7%). washed successively with aq. sodium bicarbonate solution, water, and brine The organic layer dried over sodium sulfate concentrated

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

实验步骤: Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H). The resulting mixture was heated The water was removed from time to time (3 hour intervals) the toluene was removed the residue was diluted with ethyl acetate (1.5 L) washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL) The organic layers were dried over sodium sulphate the solvent was removed under vacuum The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities The fraction obtained at 75-85° C. (0.1 mm of Hg)

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

实验步骤: A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue was distilled under high vacuum to give the title compound (23.07 g, 71.7%). washed successively with aq. sodium bicarbonate solution, water, and brine The organic layer dried over sodium sulfate concentrated The residue was distilled under high vacuum

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

实验步骤: A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue was distilled under high vacuum to give the title compound (23.07 g, 71.7%). washed successively with aq. sodium bicarbonate solution, water, and brine The organic layer dried over sodium sulfate concentrated The residue was distilled under high vacuum

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

实验步骤: Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H). The resulting mixture was heated The water was removed from time to time (3 hour intervals) the toluene was removed the residue was diluted with ethyl acetate (1.5 L) washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL) The organic layers were dried over sodium sulphate the solvent was removed under vacuum The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities The fraction obtained at 75-85° C. (0.1 mm of Hg)

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

实验步骤: Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H). The resulting mixture was heated The water was removed from time to time (3 hour intervals) the toluene was removed the residue was diluted with ethyl acetate (1.5 L) washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL) The organic layers were dried over sodium sulphate the solvent was removed under vacuum The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities The fraction obtained at 75-85° C. (0.1 mm of Hg)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a microwave vial 2,3,4-trifluorobenzaldehyde (1.5 g, 9.4 mmol) was dissolved in 1,4-dioxane (6 mL) and hydrazine (6 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 664 mg (46%) of 6,7-difluoro-1H-indazole as a light brown powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.10 (d, J=3.4 Hz, 1H), 7.47 (dd, J=8.9, 4.0 Hz, 1H), 7.05 (ddd, J=10.6, 8.9, 6.6 Hz, 1H). The vial was sealed The reaction was quenched with water extracted with EtOAc The organic layer was washed with brine then dried over MgSO4 concentrated The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

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

实验步骤: A solution of 2,3,4-trifluorobenzaldehyde (25 g, 156.16 mmol), 2,2-dimethoxypropane (58.1 ml, 468.48 mmol), and 4-methylbenzenesulfonic acid (0.269 g, 1.56 mmol) was stirred at room temperature overnight. The reaction mixture diluted with ether and washed successively with aq. sodium bicarbonate solution, water, and brine. The organic layer dried over sodium sulfate and concentrated. The residue wasdistilled under high vacuum to give the title compound (23.07 g, 71.7%). washed successively with aq. sodium bicarbonate solution, water, and brine The organic layer dried over sodium sulfate concentrated