5-amino-4-fluoro-2-methylphenol

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:

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 4-chloro-7-methoxy-6-methoxycarbonylquinoline (0.252 g, 1 mmol), (prepared as described for the starting material in Example 55), and 2-fluoro-5-hydroxy-4-methylaniline (0.15 g, 1.2 mmol), (prepared as described for the starting material in Example 1), in cyclohexanol (5 ml) containing 1M ethereal hydrogen chloride (1.2 ml) was heated at 100° C. for 2 hours. The mixture was cooled to ambient temperature and diluted with ether. The solid was collected by filtration then absorbed onto silica using methylene chloride/methanol (1/1) containing ammonium hydroxide (1 ml). The product was eluted with methylene chloride/methanol (100/0 increasing to 94:6). Removal of the solvent by evaporation and trituration of the solid with ether followed by collection of the solid by filtration gave 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxy-6-methoxycarbonylquinoline as a cream solid. (195 mg, 54%). (prepared (prepared The mixture was cooled to ambient temperature The solid was collected by filtration then absorbed onto silica containing ammonium hydroxide (1 ml) The product was eluted with methylene chloride/methanol (100/0 increasing to 94:6) Removal of the solvent by evaporation and trituration of the solid with ether followed by collection of the solid by filtration

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

Procedure: A mixture of 2-acetamido-5-chloro-1,8-naphthyridine (357 mg, 1.6 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (200 mg, 1.4 mmol), (prepared as described for the starting material in Example 1), in isopropanol (20 ml) was heated at reflux for 5 hours. The mixture was allowed to cool and the precipitate was collected by filtration, washed with acetone and dried to give 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine hydrochloride (280 mg, 61%). (prepared was heated at reflux for 5 hours to cool the precipitate was collected by filtration washed with acetone dried

Conditions: temp:250.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-((4-cyano-3-(3-morpholinopropoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(2.96 g, 7 mmol) in DOWTHERM A, (trade mark of Fluka Chemie AG), (100 ml) was heated at 250° C. for 30 minutes. The mixture was allowed to cool, hexane was added and the solvent was decanted from the resulting gum. The residue was triturated with hexane to give crude 6-cyano-7-(3-morpholinopropoxy)-1,4-dihydroquinolin-4-one(1.0 g) as a brown solid. A portion of this product (380 mg, 1.3 mmol) was added to thionyl chloride (10 ml)and DMF (0.1 ml) and the mixture was heated at reflux for 3 hours. The volatiles were removed by evaporation and the residue was azeotroped with toluene (×3). 2-Fluoro-5-hydroxy-4-methylaniline (184 mg, 1.3 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was added to the residue, and the mixture was heated at reflux for 3 hours. The mixture was allowed to cool, the solid product was collected by filtration and recrystallised twice from methylene chloride/methanol/ethyl acetate to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropoxy)quinoline (05 mg, 3% overall). to cool the solvent was decanted from the resulting gum The residue was triturated with hexane to give crude 6-cyano-7-(3-morpholinopropoxy)-1,4-dihydroquinolin-4-one(1.0 g) as a brown solid the mixture was heated at reflux for 3 hours The volatiles were removed by evaporation the residue was azeotroped with toluene (×3) was added to the residue the mixture was heated at reflux for 3 hours to cool the solid product was collected by filtration recrystallised twice from methylene chloride/methanol/ethyl acetate

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

Procedure: A mixture of 4-chloro-6-cyano-7-methoxyquinoline hydrochloride (500 mg, 2 mmol), (prepared by an analogous procedure to that described for the starting material in Example 1 but using methanol instead of 2-methoxyethanol), and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was heated at reflux for 4 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline hydrochloride (176 mg, 54%) as a light brown solid. (prepared by an analogous procedure to (prepared was heated at reflux for 4 hours to cool the solid product was 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-dimethoxyquinoline hydrochloride (360 mg, 1.4 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-5-hydroxy-4-methylaniline (212 mg 1.5 mmol), (prepared as described for the starting material in Example 1), in isopropanol (15 ml) was heated at reflux for 3 hours. The mixture was allowed to cool and the solid product was collected by filtration, washed with acetone and dried to give 6,7-dimethoxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline hydrochloride (146 mg, 29%). (prepared (prepared was heated at reflux for 3 hours to cool the solid product was collected by filtration washed with acetone dried

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

Procedure: A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (304 mg, 1 mmol), (prepared as described for the starting material in Example 5), 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (15 ml) was heated at reflux for 15 hours. The precipitate was collected by filtration, washed with isopropanol and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (205 mg, 50%). (prepared was heated at reflux for 15 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: A solution of 4,7-dichloroquinoline (198 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (1 69 mg, 1.2 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (5 ml) containing 5M hydrochloric acid in isopropanol (0.5 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was triturated with ether. The solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline hydrochloride (300 mg, 88%). was heated at reflux for 2 hours The volatiles were removed by evaporation the residue was triturated with ether The solid was collected by filtration washed with isopropanol dried under vacuum