3-氯-2,4-二氟苯胺

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 135 g of tin(II) chloride (dihydrate) was added in small fractions to a stirred suspension of 23 g of 3-chloro-2,4-difluoronitrobenzene in 110 cm3 of a 37% aqueous hydrochloric acid solution and 25 cm'of diethyl ether. After the addition, the mixture was heated for 30 minutes at a temperature in the region of 40° C. After cooling the reaction mass, the mixture was poured over 300 cm3 of water supplemented with 150 g of ice. The mixture was made highly alkaline by addition of caustic soda, and then extracted twice with 250 cm3 of chloroform. The extracts were combined, dried over magnesium sulphate, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 17.4 g of 3-chloro-2,4-difluoroaniline was obtained in the form of a beige solid, which melted at 58° C. After the addition After cooling the reaction mass extracted twice with 250 cm3 of chloroform dried over magnesium sulphate concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 18.9 g of N-bromosuccinimide was gradually added to a stirred solution of 17.4 g of 3-chloro-2,4-difluoroaniline in 150 cm3 of dry dimethylformamide, cooled to a temperature in the region of −20° C., while this temperature was maintained. After stirring for 1 hour, the temperature was brought to the region of 20° C. and then the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C. The residue obtained was supplemented with 400 cm3 of hexane and 200 cm3 of water. The mixture was stirred and the aqueous phase decanted off. The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane. The extracts were combined, washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 19.2 g of 2-bromo-5-chloro-4,6-difluoroaniline was obtained in the form of a white solid, which melted at 62° C. was maintained was brought to the region of 20° C. the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C The residue obtained The mixture was stirred the aqueous phase decanted off The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution After drying over magnesium sulphate the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 135 g of tin(II) chloride (dihydrate) was added in small fractions to a stirred suspension of 23 g of 3-chloro-2,4-difluoronitrobenzene in 110 cm3 of a 37% aqueous hydrochloric acid solution and 25 cm'of diethyl ether. After the addition, the mixture was heated for 30 minutes at a temperature in the region of 40° C. After cooling the reaction mass, the mixture was poured over 300 cm3 of water supplemented with 150 g of ice. The mixture was made highly alkaline by addition of caustic soda, and then extracted twice with 250 cm3 of chloroform. The extracts were combined, dried over magnesium sulphate, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 17.4 g of 3-chloro-2,4-difluoroaniline was obtained in the form of a beige solid, which melted at 58° C. After the addition After cooling the reaction mass extracted twice with 250 cm3 of chloroform dried over magnesium sulphate concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 18.9 g of N-bromosuccinimide was gradually added to a stirred solution of 17.4 g of 3-chloro-2,4-difluoroaniline in 150 cm3 of dry dimethylformamide, cooled to a temperature in the region of −20° C., while this temperature was maintained. After stirring for 1 hour, the temperature was brought to the region of 20° C. and then the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C. The residue obtained was supplemented with 400 cm3 of hexane and 200 cm3 of water. The mixture was stirred and the aqueous phase decanted off. The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane. The extracts were combined, washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 19.2 g of 2-bromo-5-chloro-4,6-difluoroaniline was obtained in the form of a white solid, which melted at 62° C. was maintained was brought to the region of 20° C. the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C The residue obtained The mixture was stirred the aqueous phase decanted off The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution After drying over magnesium sulphate the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Starting material: N4-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3-chloro-2,4-difluoro-aniline; other starting materials were prepared as example 1. other starting materials were prepared as example 1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Starting material: N4-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3-chloro-2,4-difluoro-aniline; other starting materials were prepared as example 1. other starting materials were prepared as example 1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Starting material: N4-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3-chloro-2,4-difluoro-aniline; other starting materials were prepared as example 1. other starting materials were prepared as example 1

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Chloro-2,4-difluoroaniline (1.7 g, 10.1 mmol) and 5N hydrogen chloride in isopropanol (2 ml) were added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (4 g, 10.1 mmol, PCT Int. Appl. WO2003082831, AstraZeneca) in isopropanol (50 ml). The mixture was stirred at 80° C. for 3 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane) to give 4-(3-chloro-2,4-difluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (3.63 g, 85%) as a white solid. After evaporation of the solvents the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane)

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 135 g of tin(II) chloride (dihydrate) was added in small fractions to a stirred suspension of 23 g of 3-chloro-2,4-difluoronitrobenzene in 110 cm3 of a 37% aqueous hydrochloric acid solution and 25 cm'of diethyl ether. After the addition, the mixture was heated for 30 minutes at a temperature in the region of 40° C. After cooling the reaction mass, the mixture was poured over 300 cm3 of water supplemented with 150 g of ice. The mixture was made highly alkaline by addition of caustic soda, and then extracted twice with 250 cm3 of chloroform. The extracts were combined, dried over magnesium sulphate, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 17.4 g of 3-chloro-2,4-difluoroaniline was obtained in the form of a beige solid, which melted at 58° C. After the addition After cooling the reaction mass extracted twice with 250 cm3 of chloroform dried over magnesium sulphate concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C