1,1,2,2-tetrafluoro-N,N-dimethylethanamine

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In toluene, 4-(difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (T-1, 4.02 g, 10 mmol) prepared according to a publicly known method, propargyl alcohol (2.96 mL, 50 mmol), triethylamine (4.16 g, 30 mmol) and manganese dioxide (17.4 g, 200 mmol) were stirred at 50° C. for 14 hours. The resultant reaction suspension was allowed to cool to room temperature, and then subjected to Celite filtration, a manganese residue was washed with acetone (120 mL), and thus the resulting filtrate was concentrated. The resulting concentrated residue was dissolved into hexane, and cooled to −78° C., and a resulting deposit was sucked and taken by filtration and dried under reduced pressure to give (T-2) (4.57 g, 10 mmol) as a pale yellow solid. (T-2) contained an enal intermediate corresponding to 4.32 g (9.45 mmol, 95%) and 3-propargyloxy-2-propene-1-al corresponding to 0.25 g (0.55 mmol) (calculated from 1H-NMR). The resulting pale yellow solid (4.57 g) was dissolved in 1,2-dichloroethane (20 ml), 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (3.51 ml, 30 mmol) and a 70% hydrogen fluoride-pyridine complex (390 mL, 15 mmol) were added thereto, and the resulting mixture was heated at 70° C. for 65 hours. After completion of the reaction, the reaction mixture allowed to cool to room temperature was poured into a saturated aqueous solution of sodium hydrogencarbonate (300 mL), and extracted with chloroform (240 mL×2). Combined organic layers were dried over anhydrous magnesium sulfate, the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane), and then the resulting white solid (2.38 g) was dissolved into hexane at room temperature and cooled to −78° C., and a precipitated crystal was sucked and taken by filtration, and then dried under reduced pressure to give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No. 38). The resultant reaction suspension to cool to room temperature subjected to Celite filtration a manganese residue was washed with acetone (120 mL) thus the resulting filtrate was concentrated The resulting concentrated residue was dissolved into hexane cooled to −78° C. taken by filtration dried under reduced pressure to give (T-2) (4.57 g, 10 mmol) as a pale yellow solid the resulting mixture was heated at 70° C. for 65 hours After completion of the reaction to cool to room temperature extracted with chloroform (240 mL×2) Combined organic layers were dried over anhydrous magnesium sulfate the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane) the resulting white solid (2.38 g) was dissolved into hexane at room temperature cooled to −78° C. taken by filtration dried under reduced pressure to give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In toluene, 4-(difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (T-1, 4.02 g, 10 mmol) prepared according to a publicly known method, propargyl alcohol (2.96 mL, 50 mmol), triethylamine (4.16 g, 30 mmol) and manganese dioxide (17.4 g, 200 mmol) were stirred at 50° C. for 14 hours. The resultant reaction suspension was allowed to cool to room temperature, and then subjected to Celite filtration, a manganese residue was washed with acetone (120 mL), and thus the resulting filtrate was concentrated. The resulting concentrated residue was dissolved into hexane, and cooled to −78° C., and a resulting deposit was sucked and taken by filtration and dried under reduced pressure to give (T-2) (4.57 g, 10 mmol) as a pale yellow solid. (T-2) contained an enal intermediate corresponding to 4.32 g (9.45 mmol, 95%) and 3-propargyloxy-2-propene-1-al corresponding to 0.25 g (0.55 mmol) (calculated from 1H-NMR). The resulting pale yellow solid (4.57 g) was dissolved in 1,2-dichloroethane (20 ml), 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (3.51 ml, 30 mmol) and a 70% hydrogen fluoride-pyridine complex (390 mL, 15 mmol) were added thereto, and the resulting mixture was heated at 70° C. for 65 hours. After completion of the reaction, the reaction mixture allowed to cool to room temperature was poured into a saturated aqueous solution of sodium hydrogencarbonate (300 mL), and extracted with chloroform (240 mL×2). Combined organic layers were dried over anhydrous magnesium sulfate, the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane), and then the resulting white solid (2.38 g) was dissolved into hexane at room temperature and cooled to −78° C., and a precipitated crystal was sucked and taken by filtration, and then dried under reduced pressure to give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No. 38). The resultant reaction suspension to cool to room temperature subjected to Celite filtration a manganese residue was washed with acetone (120 mL) thus the resulting filtrate was concentrated The resulting concentrated residue was dissolved into hexane cooled to −78° C. taken by filtration dried under reduced pressure to give (T-2) (4.57 g, 10 mmol) as a pale yellow solid the resulting mixture was heated at 70° C. for 65 hours After completion of the reaction to cool to room temperature extracted with chloroform (240 mL×2) Combined organic layers were dried over anhydrous magnesium sulfate the resulting residue concentrated under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane) the resulting white solid (2.38 g) was dissolved into hexane at room temperature cooled to −78° C. taken by filtration dried under reduced pressure to give 2.29 g (4.78 mmol, two steps, 47.8%) of a target compound (No

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

実験手順: BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2-difluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3,5-di(difluoromethyl)-4-pyrazolecarboxylic acid ethyl ester (1.77 g, 5.98 mmol, 30%) was isolated as an orange oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred at room temperature for 30 minutes the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

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

実験手順: BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2,2-trifluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.29 g, 10.5 mmol, 53%) was isolated as a yellow oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred at room temperature for 30 minutes the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

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

実験手順: BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2,2-trifluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.29 g, 10.5 mmol, 53%) was isolated as a yellow oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred at room temperature for 30 minutes the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

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

実験手順: BF3.OEt2 (2.5 ml, 20.0 mmol) was added to a solution of TFEDMA (2.4 ml, 20.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (4.7 g, 60.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Phenyl hydrazine (3.0 ml, 30.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-Phenyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (4.47 g, 13.4 mmol, 67%) was isolated as a colourless solid. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1)

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

実験手順: (0.34 g, 5 mmol) as a 17% solution in acetonitrile (0.76 ml) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in CH3CN (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min. In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluorides (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.95 g) was obtained as a yellow oil. the mixture was stirred at room temperature for 15 min To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2)

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

実験手順: (0.34 g, 5 mmol) as a 17% solution in acetonitrile (0.76 ml) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in CH3CN (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min. In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluorides (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.95 g) was obtained as a yellow oil. the mixture was stirred at room temperature for 15 min To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2)

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

実験手順: BF3.OEt2 (1.24 ml, 10.0 mmol) was added to a solution of TFEDMA (1.20 ml, 10.0 mmol) in dry dichloromethane (10 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (10 ml). In a second Teflon flask, ethyl 4,4-difluoroacetoacetate (1.03 ml, 10.0 mmol) was added to a solution of pyridine (1.6 ml, 20.0 mmol) in dry acetonitrile (20 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.79 ml, 15.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (10:0-8:2). (10:0 to 8:2). N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (1.75 g, 6.89 mmol, 69%) was obtained as a colourless oil, which crystallized when left to stand. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (10:0-8:2)

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

実験手順: BF3.OEt2 (0.62 ml, 5.0 mmol) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in dry dichloromethane (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (5 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluoride (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.99 g, 3.64 mmol, 73%) was obtained as a yellow oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2)

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

実験手順: BF3.OEt2 (0.62 ml, 5.0 mmol) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in dry dichloromethane (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (5 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluoride (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.99 g, 3.64 mmol, 73%) was obtained as a yellow oil. was removed under reduced pressure To this were added dropwise, at −30° C. was brought to room temperature in the cold bath stirred overnight the mixture was stirred overnight The solvent was removed under reduced pressure the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2)

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

実験手順: 10.8 g of N-1,1,2,2-tetrafluoroethyldimethylamine were initially charged in 50 ml of acetonitrile under argon and 26 g of boron trifluoride as a 17% solution in CH3CN were added at RT. The mixture was stirred for 30 min and then admixed with 8.67 g of ethyl dimethylaminoacrylate. The mixture was stirred at RT for 2 h and then added slowly to the solution of 3.4 g of methylhydrazine in 10 ml of acetonitrile at 10° C. After stirring at RT for 2 h, the acetonitrile was removed completely under reduced pressure and the product was admixed with water and filtered off. Distillation under reduced pressure or washing with cyclohexane afforded 10 g of the product with the purity of 99% and an m.p. of 62-63° C. The mixture was stirred at RT for 2 h After stirring at RT for 2 h the acetonitrile was removed completely under reduced pressure filtered off Distillation under reduced pressure washing with cyclohexane