ethyl 2,4-dioxo-4-phenylbutanoate

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

Procedure: A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%. to reflux for 5 hours the product was extracted with ethyl acetate The ethyl acetate layer was collected washed with brine solution dried over sodium concentrated under reduced pressure The resulting residue was purified by column chromatography

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

Procedure: To a stirred solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (3.86 g, 0.01754 mole) in methanol (78 mL) was added hydroxylamine hydrochloride (3.657 g, 0.0526 mole) at ambient temperature. The resulting mixture was then heated to reflux overnight. Volatiles were then removed by evaporation and the resulting residue was diluted with water and the product extracted with chloroform. The chloroform layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 2.8 g (79%) of 5-phenyl-isoxazole-3-carboxylic acid methyl ester. LCMS: 204.06 (M+1)+, 97.58%. To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid methyl ester (2.8 g, 0.01379 mol) in a mixture of THF (10 mL), methanol (10 mL) and H2O (10 mL) was added LiOH.H2O (0.87 g, 0.02073 mol) and the resulting mixture was stirred at ambient temperature for 2.5 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.2 g (85%) of 5-phenyl-isoxazole-3-carboxylic acid. LCMS: 190.04 (M+1)+, 96.4%. The resulting mixture was then heated to reflux overnight Volatiles were then removed by evaporation the resulting residue was diluted with water the product extracted with chloroform The chloroform layer was collected washed with brine solution dried over sodium sulfate concentrated under reduced pressure The resulting residue was purified by column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of acetophenone (5 g, 0.0416 mole), diethyl oxalate (7.23 g, 0.0416 mole) in DMF (40 mL) was cooled to 0° C. for 10 minutes. NaH (60% w/w dispersion in oil) (2.0 g, 0.083 mole) was then added, and the resulting mixture was stirred at the same temperature for 30 minutes, then stirred at ambient temperature for 1 hour. The mixture was then heated at 50° C. for 30 minutes. The reaction mixture was quenched with iced water, acidified with aqueous 2.4N HCl solution and the resulting precipitate was isolated by filtration and dried to afford 3.8 g (42%) of 2,4-dioxo-4-phenyl-butyric acid ethyl ester. LCMS: 221.07 (M+1)+, 85.2%. stirred at ambient temperature for 1 hour The reaction mixture was quenched with iced water the resulting precipitate was isolated by filtration dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of acetophenone (5 g, 0.0416 mole), diethyl oxalate (7.23 g, 0.0416 mole) in DMF (40 mL) was cooled to 0° C. for 10 minutes. NaH (60% w/w dispersion in oil) (2.0 g, 0.083 mole) was then added, and the resulting mixture was stirred at the same temperature for 30 minutes, then stirred at ambient temperature for 1 hour. The mixture was then heated at 50° C. for 30 minutes. The reaction mixture was quenched with iced water, acidified with aqueous 2.4N HCl solution and the resulting precipitate was isolated by filtration and dried to afford 3.8 g (42%) of 2,4-dioxo-4-phenyl-butyric acid ethyl ester. LCMS: 221.07 (M+1)+, 85.2%. stirred at ambient temperature for 1 hour The reaction mixture was quenched with iced water the resulting precipitate was isolated by filtration dried

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

Procedure: The title compound was prepared in the same manner as described for intermediate 61 using ethyl 2,4-dioxo-4-phenylbutanoate (5 g, 22.7 mmol), 1-(1-methylethyl)-1H-pyrazol-5-amine (2.84 g, 22.7 mmol), benzene (70 mL), and acetic Acid (44 mL) The crude product was purified by silica gel chromatography (eluent: 0 to 100% EtOAc/hexanes) to give 6.72 g (95%) as a pale yellow solid. LCMS E-S (M+H)=310.5. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.17-8.28 (m, 3H), 7.49-7.64 (m, 3H), 5.38 (quin, J=6.69 Hz, 1H), 4.49 (q, J=7.07 Hz, 2H), 1.57 (d, J=6.57 Hz, 6H), 1.44 (t, 3H). was purified by silica gel chromatography (eluent: 0 to 100% EtOAc/hexanes) to give 6.72 g (95%) as a pale yellow solid

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

Procedure: In 560 ml of ethanol was dissolved 25 g (1.08 eq.) of sodium and a mixture of 135.6ml (146 g; 1 mol) of diethyl oxalate and 116.7 ml (120 g; 1 mol) of acetophenone was added thereto dropwise at 40° C. One hour later, reflux was begun and it was continued for 30 minutes. The solvent was distilled off. The residue was neutralized with sulfuric acid (55 g/water 200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane 1:1), to give colorless plates. The crystals were recovered by filtration with ethyl acetate/hexane. Yield: 114.6 g. was added dropwise at 40° C One hour later, reflux The solvent was distilled off the mixture was extracted with ethyl acetate The organic layer was washed with water a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate Thereafter, the solvent was distilled off the residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane 1:1) to give colorless plates The crystals were recovered by filtration with ethyl acetate/hexane

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