3-bromo-4-chloro-N-methoxy-N-methylbenzamide

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:

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: 3-Bromo-4-chloro-N-methoxy-N-methylbenzamide (1.0 mg, 3.8 mmol, 1.0 eq) and 4-chloro phenyl boronic acid (787 mg, 5 mmol, 1.3 eq) was dissolved in toluene and stirred for 10 minutes. The solution was purged with nitrogen for 10 minutes and degassed under vacuum. Tetrakis triphenylphosphinepalladium (223 mg, 0.19 mmol, 0.05 eq) and K2CO3 (696 mg, 5 mmol, 1.3 eq) were added to the reaction. The mixture was refluxed for 12 h under nitrogen and the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired compound (1 g, 90%). 1H NMR (400 MHz, CD3OD) δ 3.37-3.39 (s, 3H), 3.60-3.64 (s, 3H), 7.10-7.13 (t, 1H), 7.25-7.27 (t, 1H), 7.43-7.48 (m, 3H), 7.60-7.63 (m, 3H). MS (ESI): 310.2 (M+). The solution was purged with nitrogen for 10 minutes degassed under vacuum The mixture was refluxed for 12 h under nitrogen the volatiles were removed under reduced pressure The residue was diluted with water extracted with ethyl acetate The organic layer was dried with anhydrous Na2SO4 concentrated under vacuum The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane

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

実験手順: 3-Bromo-4-chlorobenzoic acid (1.0 g, 4.24 mmol, 1.0 eq) was dissolved in dry DMF and stirred for 10 minutes. The solution was cooled to 0° C. and treated with N,O-dimethyl hydroxylamine hydrochloride (0.828 mg, 8.48 mmol, 2.0 eq), 1-hydroxybenzotrizole (860 mg, 6.36 mmol, 1.5 eq), N,N-diisopropyl ethylamine (820 mg, 6.37 mmol, 1.5 eq), and EDC HCl (1.2 g, 6.37 mmol, 1.5 eq). The reaction mixture was stirred for 12 h, evaporated under reduced pressure and diluted with water (25 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired product (1 g, 85%). 1H NMR (400 MHz, CD3OD) δ 3.34 (s, 3H), 3.57 (s, 3H), 7.47-7.49 (d, 1H), 7.71-7.74 (d, 1H), 7.85-7.88 (d, 1H). MS (ESI): 278.2 (M+). The reaction mixture was stirred for 12 h evaporated under reduced pressure diluted with water (25 mL) The aqueous layer was extracted with ethyl acetate The organic layer was dried under anhydrous Na2SO4 concentrated under vacuum The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide 105 (2.04 g, 7.3 mmol), was dissolved in 30 mL of dry THF. The solution was chilled to −5° C. in a salt bath under N2. Via syringe, methylmagnesium bromide (2.7 mL, 8.1 mmol) was added slowly to the solution. The solution was stirred for 2 h at −5° C., and then it was warmed to room temperature where it was stirred for another 1 h. The reaction was quenched with saturated NH4Cl, and it was diluted with ether and water. The organic solution was extracted with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was then filtered through a bed of silica and the filtrate was concentrated to give 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.55 g, 91% yield) as a white solid. it was warmed to room temperature where it was stirred for another 1 h The reaction was quenched with saturated NH4Cl, and it was diluted with ether and water The organic solution was extracted with water and brine The organic phase was dried over MgSO4 filtered concentrated in vacuo The crude material was then filtered through a bed of silica the filtrate was concentrated

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

実験手順: A solution of 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide in 100 ml of anhydrous tetrahydrofuran was added dropwise to 43 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran at below 5° C., and stirred for 1 hour. 100 ml of saturated ammonium chloride solution was then added cautiously followed by 100 ml of a 1M solution of hydrochloric acid and the mixture was extracted twice with 400 ml of diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 6.8 g of 3-bromo-4-chlorobenzaldehyde as a pale yellow solid. the mixture was extracted twice with 400 ml of diethyl ether The combined organic extracts were dried over anhydrous sodium sulphate concentrated under reduced pressure

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 10.0 g of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at 0° C. were added 7.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.5 ml of triethylamine followed by 3.9 g of N,O-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a cream solid. was washed with 200 ml of water The organic solution was dried over anhydrous sodium sulphate concentrated under reduced pressure

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

実験手順: Carbonyldiimidazole (7.2 g, 0.045 mol) was added in portions to a stirred suspension of 3-bromo-4-chlorobenzoic acid (10.0 g, 0.042 mol) in dichloromethane (120 mL). The reaction mixture was stirred at room temperature for 30 minutes then at reflux for 30 minutes. Triethylamine (6.3 mL, 0.045 mol) and N,O-dimethylhydroxylamine hydrochloride (4.2 g, 0.043 mol) were added and the reaction mixture was stirred at room temperature overnight, then diluted with water (75 mL) and the layers separated. The aqueous fraction was extracted with dichloromethane (2×50 mL) and the combined organic extracts were washed with citric acid (10%; 2×50 mL), NaHCO3 (50 mL) and brine (50 mL), dried (sodium sulfate) and concentrated to give 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a colourless oil (9.3 g, 79%). 1H NMR (300 MHz; DMSO-d6) 7.98 (1H, s, Ar), 7.60 (1H, d, J 7.2, Ar), 7.48 (1H, d, J 7.2, Ar), 3.54 (3H, s, Me), 3.36 (3H, s, Me). at reflux for 30 minutes the reaction mixture was stirred at room temperature overnight the layers separated The aqueous fraction was extracted with dichloromethane (2×50 mL) the combined organic extracts were washed with citric acid (10%; 2×50 mL), NaHCO3 (50 mL) and brine (50 mL) dried (sodium sulfate) concentrated

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

実験手順: A solution of 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide in 100 ml of anhydrous tetrahydrofuran was added dropwise to 43 ml of a 1M solution of lithium aluminium hydride in tetrahydrofuran at below 5° C., and stirred for 1 hour. 100 ml of saturated ammonium chloride solution was then added cautiously followed by 100 ml of a 1M solution of hydrochloric acid and the mixture was extracted twice with 400 ml of diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 6.8 g of 3-bromo-4-chlorobenzaldehyde as a pale yellow solid. the mixture was extracted twice with 400 ml of diethyl ether The combined organic extracts were dried over anhydrous sodium sulphate concentrated under reduced pressure

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 10.0 g of 3-bromo-4-chlorobenzoic acid in 275 ml of anhydrous dichloromethane at OOC were added 7.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.5 ml of triethylamine followed by 3.9 g of N,O-dimethylhydroxylamine hydrochloride. After stirring overnight at room temperature the mixture was washed with 200 ml of water and then with 200 ml of a 1M solution of hydrochloric acid. The organic solution was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 10.7 g of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide as a cream solid. was washed with 200 ml of water The organic solution was dried over anhydrous sodium sulphate concentrated under reduced pressure