N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a solution of O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.65 g, 2.4 mmol) prepared as described in example P15d, in dichloromethane (5 ml) was added triethylamine (0.844 ml, 6.0 mmol) followed by drop wise addition of a solution 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.519 g, 2.67 mmol) in dichloromethane at 0° C. After complete addition of acid chloride the mixture was stirred 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer were washed with 2N HCl, followed by saturated NaHCO3, then with water and finally with brine solution before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.51 g, 49%) as off white solid. m.p: 110-112° C. completion of the reaction extracted with dichloromethane (3×60 ml) The combined dichloromethane layer were washed with 2N HCl with water and finally with brine solution before drying over sodium sulfate and evaporation of the solvent The resulting crude mass was purified by column chromatography collected at 30% ethyl acetate in hexane as eluent

反応条件: temp:56.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (3.92 g, 0.014 mol) prepared as described in example P5a in xylene (30 g) was added an aqueous sodium hydroxide solution (30%, 2.3 g, 0.017 mol) in parallel to the addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (3.2 g, 0.046 mol) dissolved in xylene (10 g) at 56° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 56° C. The solution was washed twice with water (10 and 5 g) and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 7.4 g (sticky dark brown oil) was purified by crystallization from a mixture of xylene (7 g) and methylcyclohexene (14 g) to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]amide (5.3 g, 87.8%) as off white solid. m.p: 115-116° C. The solution was washed twice with water (10 and 5 g) the volatiles were removed from the organic layer under reduced pressure The resulting crude mass 7.4 g (sticky dark brown oil) was purified by crystallization from a mixture of xylene (7 g) and methylcyclohexene (14 g)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a in Xylene (90 g) was added triethylamine (5.6 g, 0.055 mol) followed by addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (40.1 g, 0.046 mol) at 70° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 70° C. The solution was washed twice with water and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 23.6 g (sticky dark brown oil) was purified by crystallization from a mixture of 16 g xylene and 36 g methylcyclohexene to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (17.0 g, 91.5%) as off white solid. m.p: 115-116° C. The solution was washed twice with water the volatiles were removed from the organic layer under reduced pressure The resulting crude mass 23.6 g (sticky dark brown oil) was purified by crystallization from a mixture of 16 g xylene and 36 g methylcyclohexene

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

実験手順: To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a, in dichloromethane (120 ml) was added triethylamine (7.7 ml, 0.055 mol) followed by dropwise addition of a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (9.1 g, 0.046 mol) in dichloromethane (10 ml) at 0° C. After complete addition of acid chloride the mixture was stirred 5 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was washed with 1N HCl (100 ml), followed by 1N NaOH (100 ml), then with water (2×100 ml) and finally with brine solution (50 ml) before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass 20.5 g of a sticky dark brown oil was purified by column chromatography using 60-120μ mesh silica gel and product collected at 40% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (7.9 g, 41%) as off white solid. m.p: 110-112° C. 1H NMR (400 MHz, CDCl3): δ1.38-1.39 (d, 3H), 3.20-3.26 (dd, 1H), 3.32-3.37 (dd, 1H), 3.70 (s, 3H), 3.97 (s, 3H), 4.88-4.93 (m, 1H), 7.02-7.29 (t, 1H), 7.27 (s, 2H), 7.81 (s, 1H) MS [M+H]+ 426/428/430 completion of the reaction the reaction mass was washed with 1N HCl (100 ml) with water (2×100 ml) and finally with brine solution (50 ml) before drying over sodium sulfate and evaporation of the solvent The resulting crude mass 20.5 g of a sticky dark brown oil was purified by column chromatography collected at 40% ethyl acetate in hexane as eluent

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

実験手順: To 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P3 (54.2 g; assay 98.4%; 0.20 mol) in acetic acid (115 g; 1.92 mol) was added sulphuric acid (22.5 g; assay 96%; 0.22 mol) at such a rate that the mixture could be kept at 20-23° C. Platinum on charcoal (5.9 g; Evonik F101 N/W 5%, water wet; assay 2.32% Pt) was added. The resulting mixture was transferred to an autoclave, which then was sealed and pressurized with hydrogen (0.8 MPa). The agitator of the autoclave was started and hydrogen pressure is maintained at 0.8 MPa. When no more hydrogen is consumed (usually after 5 hours), hydrogenation was interrupted by stopping agitation. Pressure was released and the atmosphere in the autoclave changed to nitrogen. The hydrogenation mixture was filtered in order to remove the heterogenous catalyst. To the filtrate was added water (220 g) and a pH-probe was mounted. Aqueous sodium hydroxide (304 g; assay 30%; 2.28 mol) was fed until pH is above 9. The resulting mixture was extracted with tert-butyl methyl ether (300 ml). Phases were allowed to separate. The (lower) aqueous phase was separated and discarded. The organic phase was washed with water (2×250 g) and evaporated to dryness. Crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (53.0 g; assay 93.7%; yield 92.4%) was obtained as clear oil. could be kept at 20-23° C then was sealed When no more hydrogen is consumed (usually after 5 hours), hydrogenation The hydrogenation mixture was filtered in order to remove the heterogenous catalyst To the filtrate was added water (220 g) The resulting mixture was extracted with tert-butyl methyl ether (300 ml) to separate The (lower) aqueous phase was separated The organic phase was washed with water (2×250 g) evaporated to dryness

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P4 (53.9 g; assay 99%; 0.20 mol) in methanol (100 g) was added hydrogen chloride gas (22.0 g; 0.60 mol), whereas internal temperature in maintained at 20-30° C. by external cooling. A colourless suspension was obtained. The reaction mixture was cooled to 15° C. and triethylamino borane (borane triethylamine complex; 27.6 g; assay 96%; 0.23 mol) was dosed in during 60 min maintaining internal temperature at 15° C. The reaction mass was stirred for another 2 hours allowing the mixture to warm to ambient temperature. Thereafter almost no starting material can be detected by HPLC. The reaction mixture was then added to preheated (85° C.) water (126 g) during 30 min. A steady stream of gas was evolved; at the same time solvent was distilled. Heating was continued and the temperature maintained at 85-90° C. for another 1 hour. Finally gas was no longer produced. The resulting mixture was cooled to 20-25° C. Sodium hydroxide (30% aqueous solution; 56.5 g; 0.42 mol) was carefully added in order to bring pH to 7.2-7.7. The resulting mixture was extracted with tert-butyl methyl ether (125 ml). Phases were allowed to separate. The (lower) aqueous phase was split of. The (upper) organic phase was washed with water (2×100 g) and evaporated. Crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (53.9 g; assay 97.8%; yield 98.0%) was obtained as clear oil. A colourless suspension was obtained The reaction mixture was cooled to 15° C. was dosed in during 60 min maintaining internal temperature at 15° C to warm to ambient temperature The reaction mixture was then added during 30 min at the same time solvent was distilled Heating the temperature maintained at 85-90° C. for another 1 hour no longer produced The resulting mixture was cooled to 20-25° C The resulting mixture was extracted with tert-butyl methyl ether (125 ml) to separate The (lower) aqueous phase was split of The (upper) organic phase was washed with water (2×100 g) evaporated

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

実験手順: To a stirred solution of crude 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P4, (12.3 g, 0.046 mol) in acetic acid (120 ml), sodium cyanoborohydride (6.1 g, 0.097 mol) was added portionwise at 12 to 15° C. The reaction mass was stirred at ambient temperature for 18 hours. TLC confirmed the completion of reaction, then solvent was evaporated under reduced pressure (co-evaporation with toluene twice). The resulting residue was poured on to 1 N sodium hydroxide solution (150 ml) and extracted with dichloromethane (2×100 ml). The combined organic layer was washed with water (2×100 ml) followed by drying over anhydrous sodium sulfate before evaporating the solvent to afford crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 100%). the completion of reaction solvent was evaporated under reduced pressure (co-evaporation with toluene twice) The resulting residue was poured on to 1 N sodium hydroxide solution (150 ml) extracted with dichloromethane (2×100 ml) The combined organic layer was washed with water (2×100 ml) by drying over anhydrous sodium sulfate before evaporating the solvent