ethyl 4-(4-fluorophenyl)-3-oxobutanoate

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl )-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in CH2Cl2 (30 mL) was stirred for 1 h at 0° C. and at ambient temp for 2 h. The solution was diluted with CH2Cl2 (40 mL) and the organic phase was washed with 0.1 N HCl and brine, dried over Na2SO4 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (5.3 g, 86.8% yield). the organic phase was washed with 0.1 N HCl and brine dried over Na2SO4 evaporated to dryness refluxed for 2 hours The solution was evaporated the resulting orange oil was left in the freezer overnight to give a yellow solid The crude solid was recrystallized from EtOH

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl )-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl )-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

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

Procedure: A mixed solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (0.95 g), N,N-dimethylformamide dimethylacetal (1.59 g) and toluene (7 ml) was stirred at 100° C. to 105° C. for 14 hours while methanol was distilled off. After cooling to room temperature, the residue was concentrated under reduced pressure. Further, 7 ml of toluene was added and the residue was concentrated to one-third of its volume under reduced pressure. Toluene (3.5 ml) was added to give a solution of ethyl 5-(dimethylamino)-2-[(dimethylamino)methylene]-4-(4-fluorophenyl)-3-oxopent-4-enoate. This solution was cooled to 0° C. to 5° C., trifluoroethyl amine (0.43 ml) and a 4.3 M solution of hydrogen chloride in ethyl acetate (1.57 ml) were added, and the mixture was stirred at 100° C. to 105° C. for three hours. After cooling to room temperature, the layers were separated by adding water, and the organic layer was concentrated to 3.5 ml. Toluene (1.4 ml) was added, followed by stirring at room temperature. The resulting solid was collected by filtration to give 1.07 g of the title compound as a solid. was distilled off the residue was concentrated under reduced pressure Further, 7 ml of toluene was added the residue was concentrated to one-third of its volume under reduced pressure Toluene (3.5 ml) was added

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

Procedure: N,N-Dimethylformamide dimethylacetal (3.6 ml) was added to a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (1200 mg) in n-propyl acetate (13 ml) at room temperature, and the mixture was stirred at 90° C. for four hours. The solvent was distilled off under reduced pressure, and ethanol (18 ml) was added, followed by addition of 2-propylamine (688 μl). After stirring at 60° C. for one hour, 2-propylamine (459 μl) was added and the mixture was further stirred at 60° C. for one hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->80:1 (v/v)] to give 620 mg of the title compound as an oily substance. The solvent was distilled off under reduced pressure, and ethanol (18 ml) was added followed by addition of 2-propylamine (688 μl) After stirring at 60° C. for one hour 2-propylamine (459 μl) was added the mixture was further stirred at 60° C. for one hour The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->80:1 (v/v)]

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

Procedure: N,N-Dimethylformamide dimethylacetal (3.9 ml) was added to a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (1310 mg) in n-butyl acetate (15 ml) at room temperature, and the mixture was stirred at 90° C. for five hours. The solvent was distilled off under reduced pressure, and ethanol (20 ml) was added, followed by addition of ethylamine (2 M solution in THF, 4.4 ml). After stirring at 60° C. for two hours, ethylamine (2 M solution in THF, 3.0 ml) was added and the mixture was further stirred at 60° C. for two hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->70:1 (v/v)] to give 985 mg of the title compound as an oily substance. The solvent was distilled off under reduced pressure, and ethanol (20 ml) was added followed by addition of ethylamine (2 M solution in THF, 4.4 ml) After stirring at 60° C. for two hours ethylamine (2 M solution in THF, 3.0 ml) was added the mixture was further stirred at 60° C. for two hours The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->70:1 (v/v)]

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in CH2Cl2 (30 mL) was stirred for 1 h at 0° C. and at ambient temp for 2 h. The solution was diluted with CH2Cl2 (40 mL) and the organic phase was washed with 0.1 N HCl and brine, dried over Na2SO4 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (5.3 g, 86.8% yield). the organic phase was washed with 0.1 N HCl and brine dried over Na2SO4 evaporated to dryness refluxed for 2 hours The solution was evaporated the resulting orange oil was left in the freezer overnight to give a yellow solid The crude solid was recrystallized from EtOH

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute ethanol (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute ethanol (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+. cooled to room temperature The reaction mixture was heated for an additional hour concentrated in vacuo The residue was treated with 1N HCl until the pH of the reaction The precipitate was collected

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

Procedure: The intermediate, 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8) can be obtained using the chemistry described in Scheme 2. Thus, 2-(4-fluorophenyl)acetyl chloride (10) can be treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) in the presence of pyridine and the resulting adduct can be refluxed in ethanol to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (12). Treatment of intermediate 12 with triazine and sodium ethoxide in ethanol can furnish the requisite ester intermediate, which can be readily hydrolyzed in the presence of sodium hydroxide at elevated temperature to furnish intermediate 8.