4-bromo-2-N-methylbenzene-1,2-diamine

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: An orange solution consisting of 5-bromo-N-methyl-2-nitroaniline (1-2, 10.5 g, 45.4 mmol) in Acetic acid (200 ml) was treated with Zinc dust (8.92 g, 136 mmol, 3.0 eq), generating a mild exotherm. The cloudy maroon reaction mixture was capped and stirred for 20 min. The reaction was >80% complete, so an additional amount of Zinc dust (1.0 g, 16 mmol, 0.35 eq) was added and the reaction was stirred for 15 min. LC/MS showed complete reduction, so the reaction mixture was filtered through Celite and washed with MeOH. The residual filtrate was concentrated in vacuo, then partitioned between EtOAc (2×300 ml) and saturated aqueous NaHCO3 (350 ml). The combined organic layers were dried over Na2SO4 and concentrated, affording the title compound, 4-bromo-N2-methylbenzene-1,2-diamine (1-3), as a brown solid with >90% purity. LRMS m/z: Calc'd for C7H9BrN2 (M+H) 202.1, found 202.8. The cloudy maroon reaction mixture was capped the reaction was stirred for 15 min so the reaction mixture was filtered through Celite washed with MeOH The residual filtrate was concentrated in vacuo partitioned between EtOAc (2×300 ml) and saturated aqueous NaHCO3 (350 ml) The combined organic layers were dried over Na2SO4 concentrated

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a round bottom flask was added 4-bromo-N2-methylbenzene-1,2-diamine (1-2) (9.07 g, 45.1 mmol), sulfamide (8.84 g, 92 mmol), and finally anhydrous pyridine (75 mL). The reaction mixture was then heated to 125° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 14 hours. The crude reaction mixture was then allowed to cool to room temperature, suspended in ethyl acetate and added 6N HCl until pH <3. Crude mixture was then filtered. Filtrate organics were separated, then washed with 6N HCl twice dried over sodium sulfate, filtered, and concentrated to give 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3). HRMS (M+H)+: observed=262.9486, calculated=262.9484. cooled reflux condenser The crude reaction mixture to cool to room temperature Crude mixture was then filtered Filtrate organics were separated washed with 6N HCl twice dried over sodium sulfate filtered concentrated

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a round bottom flask was added 4-bromo-N2-methylbenzene-1,2-diamine (1-2) (9.07 g, 45.1 mmol), sulfamide (8.84 g, 92 mmol), and finally anhydrous pyridine (75 mL). The reaction mixture was then heated to 125° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 14 hours. The crude reaction mixture was then allowed to cool to room temperature, suspended in ethyl acetate and added 6N HCl until pH <3. Crude mixture was then filtered. Filtrate organics were separated, then washed with 6N HCl twice dried over sodium sulfate, filtered, and concentrated to give 6-bromo-1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3). HRMS (M+H)+: observed=262.9486, calculated=262.9484. cooled reflux condenser The crude reaction mixture to cool to room temperature Crude mixture was then filtered Filtrate organics were separated washed with 6N HCl twice dried over sodium sulfate filtered concentrated

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 5-bromo-N-methyl-2-nitroaniline (1-1) (12.4 g, 53.7 mmol) in 1,4 Dioxane (100 mL) at 0° C. was added powdered zinc (17.6 g, 269 mmol), followed by dropwise addition of glacial acetic acid (15.0 mL, 262 mmol). The reaction mixture was then permitted to warm to room temperature, sonicated for a few minutes, then permitted to stir at room temperature overnight, then heated to 90° C. in a hot oil bath for four hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate, cooled to 0° C. and neutralized with 6N NaOH while stirring until slightly basic. Crude mixture was then filtered. Filtrate organics were separated, then washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-N2-methylbenzene-1,2-diamine (1-2) as a black oil. MS (M)+: observed=200.9, calculated=201.06. sonicated for a few minutes heated to 90° C. in a hot oil bath for four hours The crude reaction mixture was then cooled to room temperature while stirring until slightly basic Crude mixture was then filtered Filtrate organics were separated washed with a saturated solution of sodium bicarbonate brine, dried over sodium sulfate filtered concentrated

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 5-bromo-N-methyl-2-nitroaniline (1-1) (12.4 g, 53.7 mmol) in 1,4 Dioxane (100 mL) at 0° C. was added powdered zinc (17.6 g, 269 mmol), followed by dropwise addition of glacial acetic acid (15.0 mL, 262 mmol). The reaction mixture was then permitted to warm to room temperature, sonicated for a few minutes, then permitted to stir at room temperature overnight, then heated to 90° C. in a hot oil bath for four hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate, cooled to 0° C. and neutralized with 6N NaOH while stirring until slightly basic. Crude mixture was then filtered. Filtrate organics were separated, then washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-N2-methylbenzene-1,2-diamine (1-2) as a black oil. MS (M)+: observed=200.9, calculated=201.06. sonicated for a few minutes heated to 90° C. in a hot oil bath for four hours The crude reaction mixture was then cooled to room temperature while stirring until slightly basic Crude mixture was then filtered Filtrate organics were separated washed with a saturated solution of sodium bicarbonate brine, dried over sodium sulfate filtered concentrated

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

実験手順: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (554 mg) was added to a solution of 4-bromo-N2-methylbenzene-1,2-diamine (279 mg), diisopropylethylamine (0.727 mL) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 mL) at room temperature. The mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 80° C. for 1 hr. After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80 mg) as a pale brown solid. the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and brine dried over magnesium sulfate concentrated in vacuo The obtained residue was dissolved in acetic acid (5 mL) the mixture was stirred at 80° C. for 1 hr After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and brine dried over magnesium sulfate concentrated in vacuo The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate)

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

実験手順: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (554 mg) was added to a solution of 4-bromo-N2-methylbenzene-1,2-diamine (279 mg), diisopropylethylamine (0.727 mL) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 mL) at room temperature. The mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 80° C. for 1 hr. After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80 mg) as a pale brown solid. the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and brine dried over magnesium sulfate concentrated in vacuo The obtained residue was dissolved in acetic acid (5 mL) the mixture was stirred at 80° C. for 1 hr After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and brine dried over magnesium sulfate concentrated in vacuo The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate)

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 stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C., and the mixture was allowed to warm to room temperature for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with DCM. The mixture was washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.7 g) as an off-white solid. The mixture was concentrated in vacuo diluted with DCM The mixture was washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine successively dried over Na2SO4 concentrated in vacuo purified by column chromatography (hexane/EtOAc)

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 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH4Cl (100 ml), saturated NaHCO3 (60 ml), water (100 ml) and brine (100 ml). The DCM layer was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid. The mixture was then concentrated in vacuo the residue was diluted with DCM (200 ml) washed with saturated NH4Cl (100 ml), saturated NaHCO3 (60 ml), water (100 ml) and brine (100 ml) The DCM layer was then dried over Na2SO4 concentrated in vacuo The residue was purified by silica gel column chromatography (hexane/EtOAc)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The mixture of 5-bromo-N1-methylbenzene-1,2-diamine (300 mg) and TFA (10 ml) was stirred at 90° C. overnight. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The precipitate was collected by filtration, washed with IPE/hexane and dried in vacuo to give the title compound (265 mg) as a purple solid. The mixture was quenched with saturated NaHCO3 solution extracted with EtOAc The organic layer was separated washed with water and brine dried over MgSO4 concentrated in vacuo The precipitate was collected by filtration washed with IPE/hexane dried in vacuo