4-chloro-2,6-difluoroaniline

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: Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184 mg, 0.61 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200 mg, 1.22 mmol) in the presence of sodium hydride (60%, 87 mg, 1.4 mmol) in DMF (8 ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212 mg, 74%).

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

実験手順: Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184 mg, 0.61 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200 mg, 1.22 mmol) in the presence of sodium hydride (60%, 87 mg, 1.4 mmol) in DMF (8 ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212 mg, 74%).

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

実験手順: Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (246 mg, 0.764 mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline (250 mg, 1.53 mmol), (see WO 97/30035 Example 15), in DMF (9 ml) and in the presence of sodium hydride (60%, 76.5 mg, 1.9 mmol) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (210 mg, 61%). (prepared

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 24.0 g (147 mmol) of 4-chloro-2,6-difluoroaniline and 22.9 g of 1,2-propanediol was placed in a round bottom flask and heated to 35° C. with stirring. A mixture of 14.5 g (49 mmol) of 88 percent purity 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine with 29.1 g of dichloromethane was prepared and was added in 1 mL shots over a 4 hour period. The resulting mixture was heated another 4 hours and was then stirred overnight at ambient temperature. It was then cooled to about 20° C. and filtered, collecting the solids present. The solids were slurried in 30 mL of a 1:1 mix of 2-propanol and water, collected by filtration, washed with 2×30 mL of 2-propanol, and air dried to obtain 14.8 g (75 percent of theory) of the title compound as a white powder of 98 percent purity melting at 203-204° C. was placed in a round bottom flask was prepared was added in 1 mL shots over a 4 hour period The resulting mixture was heated another 4 hours was then stirred overnight at ambient temperature It was then cooled to about 20° C. filtered collecting the solids present mix of 2-propanol and water collected by filtration washed with 2×30 mL of 2-propanol, and air dried

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 24.0 g (147 mmol) of 4-chloro-2,6-difluoroaniline and 22.9 g of 1,2-propanediol was placed in a round bottom flask and heated to 35° C. with stirring. A mixture of 14.5 g (49 mmol) of 88 percent purity 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine with 29.1 g of dichloromethane was prepared and was added in 1 mL shots over a 4 hour period. The resulting mixture was heated another 4 hours and was then stirred overnight at ambient temperature. It was then cooled to about 20° C. and filtered, collecting the solids present. The solids were slurried in 30 mL of a 1:1 mix of 2-propanol and water, collected by filtration, washed with 2×30 mL of 2-propanol, and air dried to obtain 14.8 g (75 percent of theory) of the title compound as a white powder of 98 percent purity melting at 203-204° C. was placed in a round bottom flask was prepared was added in 1 mL shots over a 4 hour period The resulting mixture was heated another 4 hours was then stirred overnight at ambient temperature It was then cooled to about 20° C. filtered collecting the solids present mix of 2-propanol and water collected by filtration washed with 2×30 mL of 2-propanol, and air dried

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

実験手順: Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184 mg, 0.61 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200 mg, 1.22 mmol) in the presence of sodium hydride (60%, 87 mg, 1.4 mmol) in DMF (8 ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212 mg, 74%).

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

実験手順: Using an analogous procedure to that described for the preparation of the starting material in Example 9, 7-benzyloxy-4-chloro-6-methoxyquinazoline (184 mg, 0.61 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was reacted with 4-chloro-2,6-difluoroaniline (200 mg, 1.22 mmol) in the presence of sodium hydride (60%, 87 mg, 1.4 mmol) in DMF (8 ml) to give 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (212 mg, 74%).

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

実験手順: Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (246 mg, 0.764 mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline (250 mg, 1.53 mmol), (see WO 97/30035 Example 15), in DMF (9 ml) and in the presence of sodium hydride (60%, 76.5 mg, 1.9 mmol) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (210 mg, 61%). (prepared

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: 40 g of 4-chloro-2,6-difluoroaniline were dissolved in 300 ml of absolute toluene. With stirring, 100 ml of trichloromethyl chloroformate were added dropwise at 20° C. The mixture was slowly heated to reflux. After three and half hours, the mixture was concentrated and the resulting isocyanate was used directly for the synthesis of intermediate 3. The mixture was slowly heated to reflux After three and half hours, the mixture was concentrated the resulting isocyanate was used directly for the synthesis of intermediate 3

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 35.5 g of 2,6-difluoroaniline were mixed with 200 ml of concentrated acetic acid, and the mixture was heated to 80° C. 42.4 g of sulfuryl chloride were mixed with approximately the same amount of concentrated acetic acid, and the mixture was added dropwise to the heated solution. The mixture was then heated at reflux for six hours. After cooling, the solution was concentrated under reduced pressure and the residue was stirred with water and pentane. The solid residue was filtered off and washed with water. The resulting solid was admixed with 200 ml of concentrated hydrochloric acid and heated at reflux for two hours. After cooling, the solution was carefully made slightly alkaline using aqueous sodium hydroxide solution, and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phase was dried over sodium sulfate and freed from the solvent. Yield: 40 g; the mixture was added dropwise to the heated solution The mixture was then heated at reflux for six hours After cooling the solution was concentrated under reduced pressure The solid residue was filtered off washed with water heated at reflux for two hours After cooling the mixture was extracted three times with 100 ml of ethyl acetate each time The organic phase was dried over sodium sulfate