2-(3,4,5-trifluorophenyl)aniline

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B. were added Due to the exothermic nature of the reaction the temperature raised to 55° C Post-reaction by stirring for 1 hour at 55° C. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C Around 75° C. at 75° C. 73° C. The resulting slurry was filtered at 0° C. over a process filter the filter cake was washed with 10 kg toluene at 0° C After drying in the drying cabinet at 80° C.

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B. were added Due to the exothermic nature of the reaction the temperature raised to 55° C Post-reaction by stirring for 1 hour at 55° C. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C Around 75° C. at 75° C. 73° C. The resulting slurry was filtered at 0° C. over a process filter the filter cake was washed with 10 kg toluene at 0° C After drying in the drying cabinet at 80° C.

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B. were added Due to the exothermic nature of the reaction the temperature raised to 55° C Post-reaction by stirring for 1 hour at 55° C. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C Around 75° C. at 75° C. 73° C. The resulting slurry was filtered at 0° C. over a process filter the filter cake was washed with 10 kg toluene at 0° C After drying in the drying cabinet at 80° C.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 79.1 g (0.494 mol, 99% pure) of 1,3-dimethyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 483.0 g (0.489 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 70° C., the mixture was cooled to 20° C. with a cooling ramp of 5° C./h and stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 155.4 g (92%). The solution was evacuated to 400 mbar cooling to 70° C. the mixture was cooled to 20° C. with a cooling ramp of 5° C./h stirred overnight Subsequently, the mixture was cooled to 0° C. the solids were filtered off washed with cold toluene dried at 80° C. under reduced pressure The yield (without further processing of the mother liquor)

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 100.0 g (0.504 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 492.8 g (0.499 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in, after which stirring was continued for another 1 hour. After venting and cooling to 25° C. with a ramp of 10° C./h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solid constituents were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 177.7 g (92%). The solution was evacuated to 400 mbar was continued for another 1 hour cooling to 25° C. with a ramp of 10° C./h the mixture was stirred overnight Subsequently, the mixture was cooled to 0° C. the solid constituents were filtered off washed with cold toluene dried at 80° C. under reduced pressure The yield (without further processing of the mother liquor)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an autoclave, 2-(3,4,5-trifluorophenyl)aniline (5.29 g, 23.7 mmol), triethylamine (1.20 g, 11.8 mmol), palladium chloride (86 mg, 0.47 mmol), anhydrous potassium carbonate (6.55 g, 47.4 mmol) and 2,2-dimethyl-1,3-bis(diphenylphosphino)propane (313 mg, 0.71 mmol) were added to a solution of 4-bromo-3-difluoromethyl-1-methylpyrazole (5.00 g, 23.7 mmol) in acetonitrile (100 ml). The autoclave was flushed three times with 9 bar of nitrogen and then 3 times with 10 bar of carbon monoxide. The reaction mixture was stirred under a carbon monoxide pressure of 9 mbar at an external temperature of 130° C. for 20 h. The red-brown suspension obtained after cooling and venting was filtered, and the filtrate was freed from volatile components under reduced pressure. The residue was taken up in a mixture of tetrahydrofuran (60 ml) and methyl tert-butyl ether (MTBE, 60 ml), washed twice with hydrochloric acid (5% strength, in each case 40 ml) and once with water (30 ml), dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was triturated with diisopropyl ether (20 ml), and the solid was filtered off and dried under reduced pressure. 5.20 g (yield 54%) of N-(2-(3,4,5-trifluorophenyl)phenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide were isolated in a purity of 93%, according to HPLC analysis (Merck Chromolith SpeedROD RP-18e column, 50×4.6 mm; gradient: acetonitrile/water with 0.1% trifluoroacetic acid, 7 min from 10% to 95% acetonitrile). The autoclave was flushed three times with 9 bar of nitrogen The red-brown suspension obtained after cooling venting was filtered The residue was taken up in a mixture of tetrahydrofuran (60 ml) and methyl tert-butyl ether (MTBE, 60 ml) washed twice with hydrochloric acid (5% strength in each case 40 ml) and once with water (30 ml), dried over sodium sulfate filtered the solvent was removed under reduced pressure The residue was triturated with diisopropyl ether (20 ml) the solid was filtered off dried under reduced pressure

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B. were added Due to the exothermic nature of the reaction the temperature raised to 55° C Post-reaction by stirring for 1 hour at 55° C. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C Around 75° C. at 75° C. 73° C. The resulting slurry was filtered at 0° C. over a process filter the filter cake was washed with 10 kg toluene at 0° C After drying in the drying cabinet at 80° C.