4-(4-CHLORO-PHENYL)-3-OXO-BUTYRIC ACID ETHYL ESTER

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid. prepared above at room temperature the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours the mixture was stirred The organic layer was washed with an aqueous sodium hydrogencarbonate solution a brine, dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid. prepared above at room temperature the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours the mixture was stirred The organic layer was washed with an aqueous sodium hydrogencarbonate solution a brine, dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(4-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 43% yield from 2-(4-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium nitrite (3.4 g, 50.4 mmol) in water (15 ml) was added dropwise over an hour period to a cooled (0° C.), stirred solution of 2-chloroaniline (6.4 g, 50.4 mmol) in acetic acid (50 ml)/water (7 ml). Then a solution of 4-(4-chloro-phenyl)-3-oxo-butyric acid ethyl ester (10 g, 42 mmol) in acetic acid (30 ml) was added dropwise over a 30-minutes period to produce an orange slurry (20 ml of water added to aid stirring). After an additional hour, the mixture was filtered, solids washed with water and air-dried. Solids slurried in ethanol (75 ml) for 30 minutes, filtered, solids washed with methanol and dried in vacuo to afford the title compound (I-2b) as an orange solid, 11.0 g. to produce After an additional hour the mixture was filtered solids washed with water air-dried filtered solids washed with methanol dried in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium nitrite (3.4 g, 50.4 mmol) in water (15 ml) was added dropwise over an hour period to a cooled (0° C.), stirred solution of 2-chloroaniline (6.4 g, 50.4 mmol) in acetic acid (50 ml)/water (7 ml). Then a solution of 4-(4-chloro-phenyl)-3-oxo-butyric acid ethyl ester (10 g, 42 mmol) in acetic acid (30 ml) was added dropwise over a 30-minutes period to produce an orange slurry (20 ml of water added to aid stirring). After an additional hour, the mixture was filtered, solids washed with water and air-dried. Solids slurried in ethanol (75 ml) for 30 minutes, filtered, solids washed with methanol and dried in vacuo to afford the title compound (I-2b) as an orange solid, 11.0 g. to produce After an additional hour the mixture was filtered solids washed with water air-dried filtered solids washed with methanol dried in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(4-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 43% yield from 2-(4-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid. prepared above at room temperature the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours the mixture was stirred The organic layer was washed with an aqueous sodium hydrogencarbonate solution a brine, dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1)

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 250 mL round bottomed flask, to a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) in methylene chloride (100 mL, 2000 mmol) was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred for 3 h at room temperature. Reaction was quenched via addition of a 10% aqueous solution of NaHSO3 (50 mL), and the resulting biphasic mixture was vigorously stirred for 15 minutes. The reaction mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (5.23 g, yield 97.5%) as a yellow oil that was used without further purification. LC/MS (FA) ES− 317, 319, 321. Reaction was quenched via addition of a 10% aqueous solution of NaHSO3 (50 mL) the resulting biphasic mixture was vigorously stirred for 15 minutes The reaction mixture was transferred to a separatory funnel the layers were separated the aqueous layer was extracted with CH2Cl2 (30 mL) The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL) dried over anhydrous MgSO4 filtered concentrated in vacuo