ethyl 3-(4-fluoroanilino)-3-oxopropanoate

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

Procedure: Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mol) of 4-fluoroaniline, 4.05 grams (0.04 mole) of triethylamine and 200 milliliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mol) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few milliliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42° C. and a white precipitate of triethylamine hydrochloride separate therefrom. The mixture was then stirred at ambient temperature for about 2 hours and the triethylamine hydrochloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallization from ethyl acetate-cyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluorophenyl)amino]-3-oxopropanoate having a melting point of 68° C-71° C. Into a nitrogen-purged reaction flask with good stirring at room temperature rose to 42° C. a white precipitate of triethylamine hydrochloride separate The mixture was then stirred at ambient temperature for about 2 hours the triethylamine hydrochloride filtered off washed with solvent dried to give 5.2 grams (0.04 mole) The filtrate was freed of solvent on a rotary evaporator the resulting purple solid dissolved in methylene chloride which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters) dried over magnesium sulfate and solvent vacuum to give a crude solid product Recrystallization from ethyl acetate-cyclohexane

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

Procedure: Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mol) of 4-fluoroaniline, 4.05 grams (0.04 mole) of triethylamine and 200 milliliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mol) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few milliliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42° C. and a white precipitate of triethylamine hydrochloride separate therefrom. The mixture was then stirred at ambient temperature for about 2 hours and the triethylamine hydrochloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallization from ethyl acetate-cyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluorophenyl)amino]-3-oxopropanoate having a melting point of 68° C-71° C. Into a nitrogen-purged reaction flask with good stirring at room temperature rose to 42° C. a white precipitate of triethylamine hydrochloride separate The mixture was then stirred at ambient temperature for about 2 hours the triethylamine hydrochloride filtered off washed with solvent dried to give 5.2 grams (0.04 mole) The filtrate was freed of solvent on a rotary evaporator the resulting purple solid dissolved in methylene chloride which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters) dried over magnesium sulfate and solvent vacuum to give a crude solid product Recrystallization from ethyl acetate-cyclohexane

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

Procedure: Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mole) of 4-fluoroaniline, 4.05 grams (0.04 mole) of triethylamine and 200 milliliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mole) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few milliliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42° C. and a white precipitate of triethylamine hydrochloride separated therefrom. The mixture was then stirred at ambient temperature for about 2 hours and the triethylamine hydrochloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallization from ethyl acetatecyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluorophenyl)amino]-3-oxopropanoate having a melting point of 68° C.-71° C. Elemental analysis of the product indicated the following: Into a nitrogen-purged reaction flask with good stirring at room temperature rose to 42° C. a white precipitate of triethylamine hydrochloride separated The mixture was then stirred at ambient temperature for about 2 hours the triethylamine hydrochloride filtered off washed with solvent dried to give 5.2 grams (0.04 mole) The filtrate was freed of solvent on a rotary evaporator the resulting purple solid dissolved in methylene chloride which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters) dried over magnesium sulfate and solvent vacuum to give a crude solid product Recrystallization from ethyl acetatecyclohexane

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

Procedure: To a 4-necked 3 L round bottom flask, is added EtOH (1500 mL), ethyl 3-(4-fluorophenylamino)-3-oxopropanoate (139 g, 617 mmol), sodium ethoxide (65.6 g, 925 mmol) and 4-methoxy-3-buten-2-one (103 g, 925 mmol). The mixture is refluxed for 3 hours. After the solution is cooled to RT, the reaction mixture is concentrated under reduced pressure to remove the EtOH. The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL). The aqueous phase is extracted with DCM (3×500 mL). The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour. After filtration and washing with EtOAc (50 mL), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid is obtained as a yellow solid (85.3 g, 56% yield). MS (m/z): 248 (M+H). The mixture is refluxed for 3 hours the reaction mixture is concentrated under reduced pressure to remove the EtOH The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL) The aqueous phase is extracted with DCM (3×500 mL) The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL) dried over anhydrous Na2SO4 concentrated under reduced pressure The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour After filtration washing with EtOAc (50 mL)

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

Procedure: To a 4-necked 3 L round bottom flask, is added EtOH (1500 mL), ethyl 3-(4-fluorophenylamino)-3-oxopropanoate (139 g, 617 mmol), sodium ethoxide (65.6 g, 925 mmol) and 4-methoxy-3-buten-2-one (103 g, 925 mmol). The mixture is refluxed for 3 hours. After the solution is cooled to RT, the reaction mixture is concentrated under reduced pressure to remove the EtOH. The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL). The aqueous phase is extracted with DCM (3×500 mL). The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour. After filtration and washing with EtOAc (50 mL), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid is obtained as a yellow solid (85.3 g, 56% yield). MS (m/z): 248 (M+H). The mixture is refluxed for 3 hours the reaction mixture is concentrated under reduced pressure to remove the EtOH The residue is diluted with DCM (700 mL) and 1 M HCl (1500 mL) The aqueous phase is extracted with DCM (3×500 mL) The combined organic extracts are washed with saturated aqueous sodium chloride (1000 mL) dried over anhydrous Na2SO4 concentrated under reduced pressure The residue is triturated with EtOAc (150 mL) at RT (10-15° C.) for 1 hour After filtration washing with EtOAc (50 mL)

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

Procedure: Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mol) of 4-fluoroaniline, 4.05 grams (0.04 mole) of triethylamine and 200 milliliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mol) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few milliliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42° C. and a white precipitate of triethylamine hydrochloride separate therefrom. The mixture was then stirred at ambient temperature for about 2 hours and the triethylamine hydrochloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallization from ethyl acetate-cyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluorophenyl)amino]-3-oxopropanoate having a melting point of 68° C-71° C. Into a nitrogen-purged reaction flask with good stirring at room temperature rose to 42° C. a white precipitate of triethylamine hydrochloride separate The mixture was then stirred at ambient temperature for about 2 hours the triethylamine hydrochloride filtered off washed with solvent dried to give 5.2 grams (0.04 mole) The filtrate was freed of solvent on a rotary evaporator the resulting purple solid dissolved in methylene chloride which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters) dried over magnesium sulfate and solvent vacuum to give a crude solid product Recrystallization from ethyl acetate-cyclohexane

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

Procedure: Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mole) of 4-fluoroaniline, 4.05 grams (0.04 mole) of triethylamine and 200 milliliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mole) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few milliliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42° C. and a white precipitate of triethylamine hydrochloride separated therefrom. The mixture was then stirred at ambient temperature for about 2 hours and the triethylamine hydrochloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallization from ethyl acetatecyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluorophenyl)amino]-3-oxopropanoate having a melting point of 68° C.-71° C. Elemental analysis of the product indicated the following: Into a nitrogen-purged reaction flask with good stirring at room temperature rose to 42° C. a white precipitate of triethylamine hydrochloride separated The mixture was then stirred at ambient temperature for about 2 hours the triethylamine hydrochloride filtered off washed with solvent dried to give 5.2 grams (0.04 mole) The filtrate was freed of solvent on a rotary evaporator the resulting purple solid dissolved in methylene chloride which solution was washed in succession with 2N HCl (3×75 milliliters), and water (2×75 milliliters) dried over magnesium sulfate and solvent vacuum to give a crude solid product Recrystallization from ethyl acetatecyclohexane