6,7-difluoro-3,4-dihydro-1H-quinolin-2-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Aluminium chloride (134 g) is added with vigorous stirring to 3',4'-difluoro-3-chloropropionanilide (67 g) and then, after approximately 2 minutes, 3',4'-difluoro-3-chloropropionanilide (135.9 g) and aluminium chloride (272 g) are added again in small portions in the course of 15 minutes. The temperature rises spontaneously to approximately 60° C. and the reaction mixture becomes liquid. The mixture is then heated to 110° C. in the course of 20 minutes and maintained at between 110° C. and 120° C. for 2 hours. The reaction mixture (at approximately 110° C.) is poured in the course of 10 minutes with vigorous stirring into a mixture of 35% strength hydrochloric acid (840 cc) and crushed ice (1 kg). The temperature is allowed to rise to approximately 20° C. and the product is drained, washed with water (2×600 cc), ethanol (300 cc) at 5° C. and ethyl ether (2×400 cc) at approximately 20° C. 6,7-Difluoro-1,4-dihydrocarbostyril (131.58 g) is obtained in the form of a beige solid, m.p. 216° C., which is used without further treatment for the subsequent steps. rises spontaneously to approximately 60° C. maintained at between 110° C. and 120° C. for 2 hours The reaction mixture (at approximately 110° C.) is poured in the course of 10 minutes to rise to approximately 20° C. washed with water (2×600 cc), ethanol (300 cc) at 5° C. at approximately 20° C

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Phosphoryl chloride (76.9 cc) is added in the course of 30 minutes, with stirring and at between 10° and 15° C. to a mixture of trichloromethane (800 cc) and dimethylformamide (74.35 cc), and the mixture is stirred for 1 hour at a temperature in the region of 20° C. To the solution obtained, 6,7-difluoro-3,4-dihydrocarbostyril (65.8 g) is added in the course of 10 minutes at approximately 20° C. with vigorous stirring. The suspension obtained is heated to a temperature in the region of 60° C. and maintained at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of ice (500 g) and water (500 cc) is added with vigorous stirring. The solid obtained is drained at approximately 5° C. and washed with water (3×300 cc) at 5° C. The wet product obtained and sodium acetate (60 g) are added simultaneously in the course of 1 hour to water (1.5 liters) at 90° C., so as to maintain the pH at approximately 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to approximately 50° C. and the product is drained at this temperature and washed with water (3×300 cc) at approximately 20° C. 2-Chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline 70.18 g) is obtained in the form of a yellow solid, m.p. 260° C., which is used without further treatment for the subsequent steps. To the solution obtained The suspension obtained is heated to a temperature in the region of 60° C. maintained at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added with vigorous stirring The solid obtained is drained at approximately 5° C. washed with water (3×300 cc) at 5° C The wet product obtained so as to maintain the pH at approximately 6 The mixture is stirred for a further 30 minutes at 90° C. to fall to approximately 50° C. washed with water (3×300 cc) at approximately 20° C

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: 76.9 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 800 cm3 of trichloromethane and 74.35 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril are added in the course of 10 minutes, at about 20° C., with vigorous stirring, to the solution obtained. The solution obtained is heated to a temperature close to 60° C. and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 500 g of ice and 500 cm3 of water is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 3 times 300 cm3 of water at 5° C. The moist product obtained and 60 g of sodium acetate are added simultaneously, in the course of 1 hour, to 1.5 liters of water at 90° C., in such a way as to keep the pH at about 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 300 cm3 of water at about 20° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C., which is used in this form for the subsequent steps. close to 20° C obtained The solution obtained is heated to a temperature close to 60° C. kept at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added, with vigorous stirring The solid obtained is drained at about 5° C. washed with 3 times 300 cm3 of water at 5° C The moist product obtained The mixture is stirred for a further 30 minutes at 90° C. to fall to about 50° C. washed with 3 times 300 cm3 of water at about 20° C

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

実験手順: 76.9 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 800 cm3 of trichloromethane and 74.35 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril are added in the course of 10 minutes, at about 20° C., with vigorous stirring, to the solution obtained. The suspension obtained is heated to a temperature close to 60° C. and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 500 g of ice and 500 cm3 of water is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 3 times 300 cm3 of water at 5° C. The moist product obtained and 60 g of sodium acetate are added simultaneously, in the course of 1 hour, to 1.5 liters of water at 90° C., in such a way as to keep the pH at about 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 300 cm3 of water at about 20° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C., which is used in this form for the subsequent steps. close to 20° C obtained The suspension obtained is heated to a temperature close to 60° C. kept at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added, with vigorous stirring The solid obtained is drained at about 5° C. washed with 3 times 300 cm3 of water at 5° C The moist product obtained The mixture is stirred for a further 30 minutes at 90° C. to fall to about 50° C. washed with 3 times 300 cm3 of water at about 20° C

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

実験手順: 76.9 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 800 cm3Of trichloromethane and 74.35 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril are added in the course of 10 minutes, at about 20° C., with vigorous stirring, to the solution obtained The solution obtained is heated to a temperature close to 60° C. and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 500 g of ice and 500 cm3 of water is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 3 times 300 cm3 of water at 5° C. The moist product obtained and 60 g of sodium acetate are added simultaneously, in the course of 1 hour, to 1.5 liters of water at 90° C., in such a way as to maintain the pH at about 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 300 cm3 of water at about 20° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C., which is used in this form for the subsequent steps. close to 20° C obtained The solution obtained is heated to a temperature close to 60° C. kept at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added, with vigorous stirring The solid obtained is drained at about 5° C. washed with 3 times 300 cm3 of water at 5° C The moist product obtained in such a way as to maintain the pH at about 6 The mixture is stirred for a further 30 minutes at 90° C. to fall to about 50° C. washed with 3 times 300 cm3 of water at about 20° C

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

実験手順: A reaction flask was charged with 6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%). 1H NMR (CD3OD) δ 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H). was added by stirring at rt for 20 h The reaction mixture was quenched with water the product extracted into Et2O The combined organic layers were washed with aqueous 4% MgSO4 dried over Na2SO4 filtered concentrated The product was purified by flash CC (SiO2; DCM)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Aluminium chloride (134 g) is added with vigorous stirring to 3',4'-difluoro-3-chloropropionanilide (67 g) and then, after approximately 2 minutes, 3',4'-difluoro-3-chloropropionanilide (135.9 g) and aluminium chloride (272 g) are added again in small portions in the course of 15 minutes. The temperature rises spontaneously to approximately 60° C. and the reaction mixture becomes liquid. The mixture is then heated to 110° C. in the course of 20 minutes and maintained at between 110° C. and 120° C. for 2 hours. The reaction mixture (at approximately 110° C.) is poured in the course of 10 minutes with vigorous stirring into a mixture of 35% strength hydrochloric acid (840 cc) and crushed ice (1 kg). The temperature is allowed to rise to approximately 20° C. and the product is drained, washed with water (2×600 cc), ethanol (300 cc) at 5° C. and ethyl ether (2×400 cc) at approximately 20° C. 6,7-Difluoro-1,4-dihydrocarbostyril (131.58 g) is obtained in the form of a beige solid, m.p. 216° C., which is used without further treatment for the subsequent steps. rises spontaneously to approximately 60° C. maintained at between 110° C. and 120° C. for 2 hours The reaction mixture (at approximately 110° C.) is poured in the course of 10 minutes to rise to approximately 20° C. washed with water (2×600 cc), ethanol (300 cc) at 5° C. at approximately 20° C

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Phosphoryl chloride (76.9 cc) is added in the course of 30 minutes, with stirring and at between 10° and 15° C. to a mixture of trichloromethane (800 cc) and dimethylformamide (74.35 cc), and the mixture is stirred for 1 hour at a temperature in the region of 20° C. To the solution obtained, 6,7-difluoro-3,4-dihydrocarbostyril (65.8 g) is added in the course of 10 minutes at approximately 20° C. with vigorous stirring. The suspension obtained is heated to a temperature in the region of 60° C. and maintained at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of ice (500 g) and water (500 cc) is added with vigorous stirring. The solid obtained is drained at approximately 5° C. and washed with water (3×300 cc) at 5° C. The wet product obtained and sodium acetate (60 g) are added simultaneously in the course of 1 hour to water (1.5 liters) at 90° C., so as to maintain the pH at approximately 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to approximately 50° C. and the product is drained at this temperature and washed with water (3×300 cc) at approximately 20° C. 2-Chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline 70.18 g) is obtained in the form of a yellow solid, m.p. 260° C., which is used without further treatment for the subsequent steps. To the solution obtained The suspension obtained is heated to a temperature in the region of 60° C. maintained at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added with vigorous stirring The solid obtained is drained at approximately 5° C. washed with water (3×300 cc) at 5° C The wet product obtained so as to maintain the pH at approximately 6 The mixture is stirred for a further 30 minutes at 90° C. to fall to approximately 50° C. washed with water (3×300 cc) at approximately 20° C

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Phosphoryl chloride (76.9 cc) is added in the course of 30 minutes, with stirring and at between 10° and 15° C. to a mixture of trichloromethane (800 cc) and dimethylformamide (74.35 cc), and the mixture is stirred for 1 hour at a temperature in the region of 20° C. To the solution obtained, 6,7-difluoro-3,4-dihydrocarbostyril (65.8 g) is added in the course of 10 minutes at approximately 20° C. with vigorous stirring. The suspension obtained is heated to a temperature in the region of 60° C. and maintained at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of ice (500 g) and water (500 cc) is added with vigorous stirring. The solid obtained is drained at approximately 5° C. and washed with water (3×300 cc) at 5° C. The wet product obtained and sodium acetate (60 g) are added simultaneously in the course of 1 hour to water (1.5 liters) at 90° C., so as to maintain the pH at approximately 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to approximately 50° C. and the product is drained at this temperature and washed with water (3×300 cc) at approximately 20° C. 2-Chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline 70.18 g) is obtained in the form of a yellow solid, m.p. 260° C., which is used without further treatment for the subsequent steps. To the solution obtained The suspension obtained is heated to a temperature in the region of 60° C. maintained at this temperature for 2 hours The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained is added with vigorous stirring The solid obtained is drained at approximately 5° C. washed with water (3×300 cc) at 5° C The wet product obtained so as to maintain the pH at approximately 6 The mixture is stirred for a further 30 minutes at 90° C. to fall to approximately 50° C. washed with water (3×300 cc) at approximately 20° C

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

実験手順: A reaction flask was charged with 6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%). 1H NMR (CD3OD) δ 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H). was added by stirring at rt for 20 h The reaction mixture was quenched with water the product extracted into Et2O The combined organic layers were washed with aqueous 4% MgSO4 dried over Na2SO4 filtered concentrated The product was purified by flash CC (SiO2; DCM)