4-fluoro-3-methoxyaniline

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:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) with ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate synthesized from ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (2.8 g) in accordance with a method known per se in the art dissolved therein. The reaction mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (2.7 g) and N,N-dimethylformamide (6 ml) were added to the residue, followed by stirring at 90° C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (80 ml) and distilled water (300 ml) were added to the reaction mixture, thereby conducting liquid separation. A chloroform layer was washed twice with distilled water (300 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.98 g) as a colorless powder. dissolved The reaction mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (2.7 g) and N,N-dimethylformamide (6 ml) were added to the residue to cool chloroform (80 ml) and distilled water (300 ml) were added to the reaction mixture liquid separation A chloroform layer was washed twice with distilled water (300 ml) dried over anhydrous magnesium sulfate concentrated under reduced pressure Deposits were dispersed in ethanol collected by filtration washed with ethanol and diisopropyl ether in that order

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Difluoroaniline (2.6 g) was added to a 28% methanol solution of sodium methoxide, and the mixture was heated for 2 days at about 60° C. and for 4 days at 110° C. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml). A chloroform layer was washed with distilled water (20 ml) and then dried over anhydrous magnesium sulfate. The dry chloroform layer was concentrated under reduced pressure to obtain the title compound (2.8 g) as a dark brown oil. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml) A chloroform layer was washed with distilled water (20 ml) dried over anhydrous magnesium sulfate The dry chloroform layer was concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-methylbenzoyl)acrylate synthesized from ethyl 2,4,5-trifluoro-3-methylbenzoylacetate (2.6 g) in accordance with a method known per se in the art. The mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (3.0 g) and N,N-dimethylformamide (7 ml) were added to the residue, followed by stirring at 90° C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (100 ml) and distilled water (250 ml) were added to the mixture, thereby conducting liquid separation. A chloroform layer was then washed twice with distilled water (250 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.59 g) as a colorless powder. The mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (3.0 g) and N,N-dimethylformamide (7 ml) were added to the residue to cool chloroform (100 ml) and distilled water (250 ml) were added to the mixture liquid separation A chloroform layer was then washed twice with distilled water (250 ml) dried over anhydrous magnesium sulfate concentrated under reduced pressure Deposits were dispersed in ethanol collected by filtration washed with ethanol and diisopropyl ether in that order

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

Procedure: To 4-fluoro-3-methoxyaniline (4.0 g, 28 mmol) refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (4.0 g, 57 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The organic phase was extracted with DCM. The combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to provide 6-fluoro-7-methoxy-2-methylquinoline (5.2 g, 96% yield) as a dark brown paste. The reaction was heated to reflux for 2 hours then cooled The organic phase was extracted with DCM The combined organic phases dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in refluxing 6N HCl (20 mL) was added dropwise (E)-but-2-enal (0.99 g, 14 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-methoxy-2-methylquinoline as a brown solid. the reaction was heated to reflux for 2 hours After cooling extracted with DCM The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of 4-fluoro-3-(methyloxy)aniline (25.0 g, 177 mmol) in ethanol (300 mL) was added 3-(trifluoromethyl)benzaldehyde (30.8 g, 177 mmol) dropwise. The mixture was stirred at reflux for 1 h, and 2-oxobutanoic acid (18.08 g, 177 mmol) was added portionwise. The reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The solid precipitate was collected by filtration, washed with ethanol, and air dried to give 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (29.1 g, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ14.34 (br. s., 1H), 7.94-7.98 (m, 2H), 7.88 (d, J=7.78 Hz, 1H), 7.77 (t, J=7.65 Hz, 1H), 7.71 (d, J=8.53 Hz, 1H), 7.54 (d, J=12.05 Hz, 1H), 4.03 (s, 3H), 2.38 (s, 3H); MS (m/z) 380.1 (M+H+). at reflux for 1 h The reaction mixture was stirred at reflux for an additional 3 h stirred overnight The solid precipitate was collected by filtration washed with ethanol, and air dried

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

Procedure: To a solution of 4-fluoro-3-(methyloxy)aniline (25.0 g, 177 mmol) in ethanol (300 mL) was added 3-(trifluoromethyl)benzaldehyde (30.8 g, 177 mmol) dropwise. The mixture was stirred at reflux for 1 h, and 2-oxobutanoic acid (18.08 g, 177 mmol) was added portionwise. The reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The solid precipitate was collected by filtration, washed with ethanol, and air dried to give 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (29.1 g, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ14.34 (br. s., 1H), 7.94-7.98 (m, 2H), 7.88 (d, J=7.78 Hz, 1H), 7.77 (t, J=7.65 Hz, 1H), 7.71 (d, J=8.53 Hz, 1H), 7.54 (d, J=12.05 Hz, 1H), 4.03 (s, 3H), 2.38 (s, 3H); MS (m/z) 380.1 (M+H+). at reflux for 1 h The reaction mixture was stirred at reflux for an additional 3 h stirred overnight The solid precipitate was collected by filtration washed with ethanol, and air dried