乐伐替尼杂质24

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

实验步骤: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

实验步骤: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

实验步骤: 7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (30.0 g) and tetrabutylammonium chloride (13.9 g) were dissolved in acetone (400 ml), and the solution was stirred at room temperature. A solution of 4-amino-3-chlorophenol hydrochloride (36.0 g) in a 20% aqueous sodium hydroxide solution (64 ml) was added thereto. The mixture was then heated under reflux for 3 hr. The reaction solution was cooled to room temperature, and chloroform and water were added to the cooled reaction solution, followed by extraction with chloroform. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. Next, sodium sulfate was removed, and the solvent was then removed by distillation. The residue was washed with methanol, and the washed solid was subjected to evaporation to dryness in vacuo through a vacuum pump to give 36.6 g (yield 90%) of the title compound. The mixture was then heated under reflux for 3 hr The reaction solution was cooled to room temperature followed by extraction with chloroform The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine was then dried over anhydrous sodium sulfate Next, sodium sulfate was removed the solvent was then removed by distillation The residue was washed with methanol the washed solid was subjected to evaporation to dryness in vacuo through a vacuum pump

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60 wt %, 5.80 g) was added to dimethyl sulfoxide (40 ml). The mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-3-chlorophenol hydrochloride (13.05 g) was added thereto. The mixture was stirred at room temperature for 10 min. 4-Chloro-6,7-dimethoxyquinazoline (8.14 g), which is a chloroquinazoline derivative synthesized by a conventional method as described, for example, in J. Am. Chem. Soc., 68, 1299 (1946) or J. Am. Chem. Soc., 68, 1305 (1946), was then added thereto. The mixture was stirred at 110° C. for 30 min. Water was then added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 9.13 g (yield 76%) of the title compound. was then cooled to room temperature The mixture was stirred at room temperature for 10 min synthesized by a conventional method , 68, 1305 (1946), was then added The mixture was stirred at 110° C. for 30 min followed by extraction with chloroform The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension The precipitated crystal was collected by suction filtration

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60 wt %, 320 mg) was added to dimethyl sulfoxide (3.6 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-3-chlorophenol hydrochloride (720 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (600 mg) was then added thereto, and the mixture was stirred at 105° C. for 22 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 533 mg (yield 66%) of the title compound. was then cooled to room temperature the mixture was stirred at room temperature for 10 min the mixture was stirred at 105° C. for 22 hr followed by extraction with chloroform The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension The precipitated crystal was collected by suction filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.89 g (yield 60%) of the title compound. was then cooled to room temperature the mixture was stirred at room temperature for 10 min the mixture was stirred at 100° C. overnight followed by extraction with chloroform The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue The precipitated crystal was collected by suction filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (0.80 g, yield 60%). the mixture was stirred at room temperature for 10 min the mixture was stirred at 100° C. overnight the mixture was extracted with chloroform The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure Methanol was added to the residue the precipitated crystal was collected by suction filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (0.80 g, yield 60%). the mixture was stirred at room temperature for 10 min the mixture was stirred at 100° C. overnight the mixture was extracted with chloroform The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution was dried over anhydrous sodium sulfate The solvent was removed by distillation under the reduced pressure Methanol was added to the residue the precipitated crystal was collected by suction filtration

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

实验步骤: To a solution of 0.90 g (0.005 mol) of 4-amino-3-chlorophenol hydrochloride in 8 ml of water and 2 ml of 20% aqueous ammonia is added a solution of 1.23 g (0.005 mol) of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 10 ml of acetone. 17 ml of 6% aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 6 hours 30 minutes. After 12 hours at 6° C., the precipitate formed is filtered off and dried. The product is purified on a column of silica (eluent: 100% dichloromethane and then dichloromethane/methanol up to 10% methanol). 0.01 g of 2-(2-chloro-4-hydroxyphenylamino)-5-[(2-hydroxyethyl)methylamino][1,4]benzoquinone (compound 4) is obtained. After 12 hours at 6° C. the precipitate formed is filtered off dried The product is purified on a column of silica (eluent

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

实验步骤: To a solution of 0.90 g (0.005 mol) of 4-amino-3-chlorophenol hydrochloride in 8 ml of water and 2 ml of 20% aqueous ammonia is added a solution of 1.23 g (0.005 mol) of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 10 ml of acetone. 17 ml of 6% aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 6 hours 30 minutes. After 12 hours at 6° C., the precipitate formed is filtered off and dried. The product is purified on a column of silica (eluent: 100% dichloromethane and then dichloromethane/methanol up to 10% methanol). 0.01 g of 2-(2-chloro-4-hydroxyphenylamino)-5-[(2-hydroxyethyl)methylamino][1,4]benzoquinone (compound 4) is obtained. After 12 hours at 6° C. the precipitate formed is filtered off dried The product is purified on a column of silica (eluent

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

实验步骤: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portion wise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying

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

实验步骤: Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portion wise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS (H2O-GC/MS): m/e 186 (100). to gentle reflux for 12 hours cooled the resulting mixture was extracted with ethyl acetate (2×500 mL) The extracts were washed with brine dried over magnesium sulfate filtered evaporated The resulting solid was triturated with warm ether filtration and vacuum drying