4-chloro-N-methoxy-N-methylbutanamide

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF (50 ml) was cooled to −50° C., to it was added isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added drop wise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.60-7.53 (1H, m), 7.26-7.09 (2H, m), 3.70 (2H, t), 3.22-3.14 (2H, m), 2.28-2.16 (2H, m). The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: Pyridine (101.28 g, 106.6 mL, 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. MS (ESI): m/z 166.1 (M+H). was stirred continuously at 0° C. for 2 h the organic layer was washed with water The organic layer was separated dried over anhydrous sodium sulphate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. was stirred continuously at 0° C. for 2 h the organic layer was washed with water The organic layer was separated dried over anhydrous sodium sulphate concentrated under reduced pressure

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

実験手順: A solution of 10.2 mL (13.9 g; 72 mmol) 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78° C. as 35.8 mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran was added dropwise. After 15 minutes at -78° C., a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 mL of anhydrous tetrahydrofuran was added dropwise over 25-30 minutes. The resulting solution was maintained at -78° C. for 45 minutes and then warmed briefly to room temperature. The reaction was quenched by addition of 40 mL of 2 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue afforded 8.91 g (70%) of an oil, which had satisfactory purity by 1H NMR (CDCl3). was added dropwise warmed briefly to room temperature The reaction was quenched by addition of 40 mL of 2 N hydrochloric acid partitioned between ethyl acetate and water The organic phase was washed with saturated aqueous sodium bicarbonate solution The organic solution was dried over sodium sulfate filtered concentrated in vacuo

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. was stirred continuously at 0° C. for 2 h the organic layer was washed with water The organic layer was separated dried over anhydrous sodium sulphate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: Pyridine (101.28 g, 106.6 mL 1281.79 mmol) was added to a solution of N,O-dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800 mL) at 0° C. and stirring was continued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0° C. for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 79 g of the title compound as a pale brown liquid. was stirred continuously at 0° C. for 2 h the organic layer was washed with water The organic layer was separated dried over anhydrous sodium sulphate concentrated under reduced pressure

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of the product from Step 1 (3.01 g, 18.1 mmol) in MeCN (40 mL), was added K2CO3 (10 g, 72.4 mmol) and morpholine (1.58 mL, 18.1 mmol). This mixture was then heated to 105° C. in a sealed tube for overnight. The reaction mixture then diluted with MeCN (50 mL), then filtered and concentrated. Residue was taken up in Et2O (100 mL), washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (1.73 g, 44%), which was used directly to next step without further purification. MS (ES+) m/e 217 [M+H]+. filtered concentrated washed with brine 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 solution of 4-chlorobutanoyl chloride (5.64 g, 40.0 mmol) and a N,O-dimethylhydroxylamine hydrochloride (3.91 g, 40.0 mmol) in CH2Cl2 (80 mL) at 0° C., was added pyridine (7.2 ml, 88.0 mmol) in CH2Cl2 (30 mL). This mixture was kept stirring at 0° C. for 1 h, then warmed to rt. The reaction mixture then diluted with Et2O (200 mL), washed with saturated 1N HCl (2×), saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (6.28 g, 95%). MS (ES+) m/e 166 [M+H]+. warmed to rt washed with saturated 1N HCl (2×), saturated NaHCO3 solution and brine dried over Na2SO4 filtered concentrated