5-amino-2-bromo-4-fluorophenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.9 mmol), (prepared as described for the starting material in Example 2), and 4-bromo-2-fluoro-5-hydroxyaniline (206 mg, 1 mmol), as described in EP 61741 A2), in 2-pentanol (8 ml) was heated at reflux for 4 hours. The precipitate was collected by filtration, washed with isopropanol, followed by ether, and dried under vacuum to give 4-(4-bromo-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline (225 mg, 58%). (prepared was heated at reflux for 4 hours The precipitate was collected by filtration washed with isopropanol dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1M Ethereal hydrogen chloride (0.34 ml, 0.34 mmol) was added to 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (115 mg, 0.34 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (61 mg, 0.38 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) and the mixture was heated at reflux for 90 minutes and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration. The impure solid was treated with methylene chloride/methanol/ammonia (100/8/1) (5 ml), and water was added. The reprecipitated product was collected by filtration and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (32%). the mixture was heated at reflux for 90 minutes to cool the solid product collected by filtration The impure solid was treated with methylene chloride/methanol/ammonia (100/8/1) (5 ml), and water was added The reprecipitated product was collected by filtration dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1M Ethereal hydrogen chloride (0.34 ml, 0.34 mmol) was added to 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (115 mg, 0.34 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (61 mg, 0.38 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) and the mixture was heated at reflux for 90 minutes and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration. The impure solid was treated with methylene chloride/methanol/ammonia (100/8/1) (5 ml), and water was added. The reprecipitated product was collected by filtration and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (32%). the mixture was heated at reflux for 90 minutes to cool the solid product collected by filtration The impure solid was treated with methylene chloride/methanol/ammonia (100/8/1) (5 ml), and water was added The reprecipitated product was collected by filtration dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1M Ethereal hydrogen chloride (0.72 ml, 0.72 mmol) was added to 4-chloro-6-methoxy-7-(2-morpholinoethoxy)quinazoline (210 mg, 0.65 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (115 mg, 0.71 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) and the mixture heated at reflux for 2 hours and then allowed to cool. The mixture was diluted with acetone and the precipitated product collected by filtration. The impure product was dissolved in methylene chloride/ammonia (100/1) and methanol, the insolubles removed by filtration and the volatiles were removed from the filtrate by evaporation. The solid residue was washed with water and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-morpholinoethoxy)quinazoline (60 mg, 21%). the mixture heated at reflux for 2 hours to cool the precipitated product collected by filtration The impure product was dissolved in methylene chloride/ammonia (100/1) methanol, the insolubles removed by filtration the volatiles were removed from the filtrate by evaporation The solid residue was washed with water dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (260 mg, 0.90 mmol), thionyl chloride (5 ml) and DMF (2 drops) was heated at reflux for 45 minutes and allowed to cool. The excess thionyl chloride was removed by evaporation, and the residue azeotroped with toluene. A solution of 4-chloro-2-fluoro-5-hydroxyaniline (160 mg, 1.0 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) was added to the residue and the mixture was heated at reflux for 1 hour and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline hydrochloride(381 mg, 83%). was heated at reflux for 45 minutes to cool The excess thionyl chloride was removed by evaporation the residue azeotroped with toluene the mixture was heated at reflux for 1 hour to cool the solid product collected by filtration washed with acetone dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (260 mg, 0.90 mmol), thionyl chloride (5 ml) and DMF (2 drops) was heated at reflux for 45 minutes and allowed to cool. The excess thionyl chloride was removed by evaporation, and the residue azeotroped with toluene. A solution of 4-chloro-2-fluoro-5-hydroxyaniline (160 mg, 1.0 mmol), (as described in EP 61741 A2), in isopropanol (5 ml) was added to the residue and the mixture was heated at reflux for 1 hour and then allowed to cool. The mixture was diluted with acetone, and the solid product collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline hydrochloride(381 mg, 83%). was heated at reflux for 45 minutes to cool The excess thionyl chloride was removed by evaporation the residue azeotroped with toluene the mixture was heated at reflux for 1 hour to cool the solid product collected by filtration washed with acetone dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.1 g, 8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2-fluoro-5-hydroxyaniline (1.43 g, 8.9 mmol), (as described in EP 61741 A2), in isopropanol (150 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (1.45 g, 47%). (prepared was heated at reflux for 2 hours to cool the solid product collected by filtration washed with isopropanol dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (2.1 g, 8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2-fluoro-5-hydroxyaniline (1.43 g, 8.9 mmol), (as described in EP 61741 A2), in isopropanol (150 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (1.45 g, 47%). (prepared was heated at reflux for 2 hours to cool the solid product collected by filtration washed with isopropanol dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Isopropanolic hydrogen chloride (0.1 ml of a 5M solution) was added to a solution of 4-chloro-6,7-dimethoxyquinazoline (202 mg, 0.9 mmol) and 4-bromo-2-fluoro-5-hydroxyaniline (as described in EP 61741 A2) (206 mg, 1 mmol) in 2-butanol (8 ml). The mixture was heated at reflux for 45 minutes, then allowed to cool. The precipitated product was collected by filtration, washed with 2-butanol, and then with ether, and dried under vacuum to give 4-(4-bromo-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride hydrate (340 mg, 87%) as a white solid. The mixture was heated at reflux for 45 minutes to cool The precipitated product was collected by filtration washed with 2-butanol with ether, and dried under vacuum