6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one

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:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsily)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsily)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e. the mixture was placed in an oil bath On heating a red-brown homogeneous solution was obtained within 5 minutes continued for another 30 minutes The flask was cooled to ambient temperature the reaction was quenched with water (125 ml) Ethyl acetate (100 ml) was added the material was transferred to a separatory funnel The organic phase was collected the aqueous phase was back extracted with ethyl acetate (2×70 ml) The combined organic phases were dried over magnesium sulfate filtered concentrated in vacuo The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane

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

実験手順: To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsily)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsily)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e. the mixture was placed in an oil bath On heating a red-brown homogeneous solution was obtained within 5 minutes continued for another 30 minutes The flask was cooled to ambient temperature the reaction was quenched with water (125 ml) Ethyl acetate (100 ml) was added the material was transferred to a separatory funnel The organic phase was collected the aqueous phase was back extracted with ethyl acetate (2×70 ml) The combined organic phases were dried over magnesium sulfate filtered concentrated in vacuo The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane

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

実験手順: A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer, was charged with 5,7-difluoro-2,3-dihydro-1H-indene-1-one (10 g, 59.4 mmol) followed by dry dichloromethane (100 ml) and methanesulfonic acid (71.3 ml, 1.1 mol). The reaction was cooled to 0° C. (ice bath) and to this was added sodium azide (5.41 g; 83.2 mmol) in 4 equal portions over 20 minutes. The reaction was stirred at 0° C. for 2 hours and then a 20% aqueous solution of sodium hydroxide (175 ml) was added over 30 minutes with vigorous stirring. After complete addition the mixture was transferred to a separatory funnel and the methylene chloride phase was isolated. This was shaken with an equal volume of 50% diluted brine solution. The organic phase was collected and the aqueous phases were back extracted with dichloromethane (2×80 ml). The organic phases were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified via HPLC on silica gel, eluting with 40% to 95% ethyl acetate/hexanes to provide the desired product as a white solid (8.364 g). (M+H)+=184 m/e. A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer After complete addition the mixture was transferred to a separatory funnel The organic phase was collected the aqueous phases were back extracted with dichloromethane (2×80 ml) dried (magnesium sulfate) filtered concentrated in vacuo The crude residue was purified via HPLC on silica gel eluting with 40% to 95% ethyl acetate/hexanes

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

実験手順: To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsilyl)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsilyl)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e. the mixture was placed in an oil bath On heating a red-brown homogeneous solution was obtained within 5 minutes continued for another 30 minutes The flask was cooled to ambient temperature the reaction was quenched with water (125 ml) Ethyl acetate (100 ml) was added the material was transferred to a separatory funnel The organic phase was collected the aqueous phase was back extracted with ethyl acetate (2×70 ml) The combined organic phases were dried over magnesium sulfate filtered concentrated in vacuo The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane

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

実験手順: A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer, was charged with 5,7-difluoro-2,3-dihydro-1H-indene-1-one (10 g, 59.4 mmol) followed by dry dichloromethane (100 ml) and methanesulfonic acid (71.3 ml, 1.1 mol). The reaction was cooled to 0° C. (ice bath) and to this was added sodium azide (5.41 g; 83.2 mmol) in 4 equal portions over 20 minutes. The reaction was stirred at 0° C. for 2 hours and then a 20% aqueous solution of sodium hydroxide (175 ml) was added over 30 minutes with vigorous stirring. After complete addition the mixture was transferred to a separatory funnel and the methylene chloride phase was isolated. This was shaken with an equal volume of 50% diluted brine solution. The organic phase was collected and the aqueous phases were back extracted with dichloromethane (2×80 ml). The organic phases were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified via HPLC on silica gel, eluting with 40% to 95% ethyl acetate/hexanes to provide the desired product as a white solid (8.364 g). (M+H)+=184 m/e. A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer After complete addition the mixture was transferred to a separatory funnel The organic phase was collected the aqueous phases were back extracted with dichloromethane (2×80 ml) dried (magnesium sulfate) filtered concentrated in vacuo The crude residue was purified via HPLC on silica gel eluting with 40% to 95% ethyl acetate/hexanes

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

実験手順: To a flask containing a solution of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one (4 g, 21.8 mmol) and isobutyronitrile (6.04 g, 87.4 mmol) in dry tetrahydrofuran (45 ml) was added a solution of potassium bis(trimethylsily)amide (50.4 ml, 0.91M in tetrahydrofuran) and the mixture was placed in an oil bath and heated to 70° C. On heating a red-brown homogeneous solution was obtained within 5 minutes. After 1 hour at 70° C., additional potassium bis(trimethylsily)amide (5 ml of 0.91 M) was added and was stirring continued for another 30 minutes. The flask was cooled to ambient temperature and the reaction was quenched with water (125 ml). Ethyl acetate (100 ml) was added and the material was transferred to a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×70 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane to provide a semi-pure component (710 mg, 33% purity) as well as pure product as a white powder (316 mg). (M+H)+=233 m/e. the mixture was placed in an oil bath On heating a red-brown homogeneous solution was obtained within 5 minutes continued for another 30 minutes The flask was cooled to ambient temperature the reaction was quenched with water (125 ml) Ethyl acetate (100 ml) was added the material was transferred to a separatory funnel The organic phase was collected the aqueous phase was back extracted with ethyl acetate (2×70 ml) The combined organic phases were dried over magnesium sulfate filtered concentrated in vacuo The residue was purified by chromatography on silica gel eluting with 100% dichloromethane to 3% methanol/dichloromethane

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

実験手順: A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer, was charged with 5,7-difluoro-2,3-dihydro-1H-indene-1-one (10 g, 59.4 mmol) followed by dry dichloromethane (100 ml) and methanesulfonic acid (71.3 ml, 1.1 mol). The reaction was cooled to 0° C. (ice bath) and to this was added sodium azide (5.41 g; 83.2 mmol) in 4 equal portions over 20 minutes. The reaction was stirred at 0° C. for 2 hours and then a 20% aqueous solution of sodium hydroxide (175 ml) was added over 30 minutes with vigorous stirring. After complete addition the mixture was transferred to a separatory funnel and the methylene chloride phase was isolated. This was shaken with an equal volume of 50% diluted brine solution. The organic phase was collected and the aqueous phases were back extracted with dichloromethane (2×80 ml). The organic phases were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified via HPLC on silica gel, eluting with 40% to 95% ethyl acetate/hexanes to provide the desired product as a white solid (8.364 g). (M+H)+=184 m/e. A 1000 ml 3-neck round bottom flask, fitted with an overhead stirrer After complete addition the mixture was transferred to a separatory funnel The organic phase was collected the aqueous phases were back extracted with dichloromethane (2×80 ml) dried (magnesium sulfate) filtered concentrated in vacuo The crude residue was purified via HPLC on silica gel eluting with 40% to 95% ethyl acetate/hexanes