ethyl 3-oxo-4-phenylbutanoate

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

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

Procedure: The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylbutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277; Found, 277.

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

Procedure: To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56 mmol) and pyridine (1.3 mL) in CH2Cl2 (20 mL) at 0° C. The solution was stirred for 30 min at 0° C., then allowed to warm slowly to rt and stirred overnight. The reaction mixture was then washed with 10% aqueous HCl (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and heated under reflux conditions for 4 h. The mixture was cooled to rt and then concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (PE/EA=1/4) to afford the title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd for C12H14O3, 207; Found, 207. to warm slowly to rt stirred overnight The reaction mixture was then washed with 10% aqueous HCl (2×10 mL) The organic layer was dried (MgSO4) filtered concentrated under reduced pressure The crude residue was dissolved in EtOH (20 mL) heated under reflux conditions for 4 h The mixture was cooled to rt concentrated under reduced pressure The resulting oil was purified by flash column chromatography (PE/EA=1/4)

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

Procedure: To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56 mmol) and pyridine (1.3 mL) in CH2Cl2 (20 mL) at 0° C. The solution was stirred for 30 min at 0° C., then allowed to warm slowly to rt and stirred overnight. The reaction mixture was then washed with 10% aqueous HCl (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and heated under reflux conditions for 4 h. The mixture was cooled to rt and then concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (PE/EA=1/4) to afford the title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd for C12H14O3, 207; Found, 207. to warm slowly to rt stirred overnight The reaction mixture was then washed with 10% aqueous HCl (2×10 mL) The organic layer was dried (MgSO4) filtered concentrated under reduced pressure The crude residue was dissolved in EtOH (20 mL) heated under reflux conditions for 4 h The mixture was cooled to rt concentrated under reduced pressure The resulting oil was purified by flash column chromatography (PE/EA=1/4)

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

Procedure: To a suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (2.5 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixure was partitoned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil. After stirring at 20° C. for 2 hours The organic layer was separated washed with water and brine dried over magnesium sulfate evaporated The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5)

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

Procedure: To a solution of γ-phenyl acetoacetic acid ethyl ester (2.88 g) in a mixture of acetic acid (30 ml) and water (10 ml) were added sodium acetate (1.83 g) and 1-(4-chlorophenyl)-1-methyl hydrazine hydrochloride (2.73 g) {prepared from 4-chloro-N-methyl-N-nitroso aniline by subjecting to reduction with zinc powder in a mixture of acetic acid and water [m.p.171-174° C.; NMR (200 MHz, DMSO-d6) ppm: 3.14(3H,s), 7.20(2H,d,J=9 Hz), 7.29(2H,d,J=9 Hz)]}. The mixture was stirred for 15 minutes at room temperature, then for 20 minutes at 110° C. The reaction mixture was concentrated, which was dissolved in ethyl acetate. The solution was washed with water, dilute hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate and water, successively, which was then dried, followed by distilling off the solvent. The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=4:1) to give ethyl ester of 5-chloro-1-methyl-3-phenylindole-2-acetic acid as an oily substance (4.34 g). [NMR (200 MHz, CDCl3) ppm: 1.29(3H,t,J=7 Hz), 3.76(3H,s), 3.86(2H,s), 4.24(2H,q,J=7 Hz), 7.17-7.62(8H,m)] for 20 minutes at 110° C The reaction mixture was concentrated which was dissolved in ethyl acetate The solution was washed with water, dilute hydrochloric acid, water an aqueous solution of sodium hydrogencarbonate and water, successively, which was then dried by distilling off the solvent The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=4:1)

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

Procedure: The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylbutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277. Found, 277.

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

Procedure: To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56 mmol) and pyridine (1.3 mL) in CH2Cl2 (20 mL) at 0° C. The solution was stirred for 30 min at 0° C., then allowed to warm slowly to rt and stirred overnight. The reaction mixture was then washed with 10% aqueous HCl (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and heated under reflux conditions for 4 h. The mixture was cooled to rt and then concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (PE/EA=1/4) to afford the title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd for C12H14O3, 207. Found, 207. to warm slowly to rt stirred overnight The reaction mixture was then washed with 10% aqueous HCl (2×10 mL) The organic layer was dried (MgSO4) filtered concentrated under reduced pressure The crude residue was dissolved in EtOH (20 mL) heated under reflux conditions for 4 h The mixture was cooled to rt concentrated under reduced pressure The resulting oil was purified by flash column chromatography (PE/EA=1/4)

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

Procedure: The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4-phenylacetoacetate in the same manner as in Example 1.

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

Procedure: Compound 2a (1.03 g, 5.0 mmol) prepared in Step 1 of Example A-1 was charged in a 25 mL round-bottom flask and dissolved in 6 mL of ethanol. A solution of 2-hydrazinopyridine (0.55 g, 5.0 mmol, manufactured by Aldrich) in 5 mL of ethanol at 50° C. was gradually added thereto over 30 minutes, followed by reaction for 1 hour. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated by evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography [n-Hex/EtOAc=3/1 (v/v)] to afford a compound of 3-benzyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (3a). followed by reaction for 1 hour the reaction solution was concentrated by evaporation extracted with ethyl acetate washed with saturated brine dried over anhydrous sodium sulfate concentrated purified by column chromatography [n-Hex/EtOAc=3/1 (v/v)]

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

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

Procedure: To a solution of γ-phenyl acetoacetic acid ethyl ester (2.88 g) in a mixture of acetic acid (30 ml) and water (10 ml) were added sodium acetate (1.83 g) and 1-(4-chlorophenyl)-1-methyl hydrazine hydrochloride (2.73 g) {prepared from 4-chloro-N-methyl-N-nitroso aniline by subjecting to reduction with zinc powder in a mixture of acetic acid and water [m.p.171°-174° C.; NMR (200 MHz, DMSO-d6) ppm: 3.14(3H,s), 7.20(2H,d,J=9 Hz), 7.29(2H,d,J=9 Hz)]}. The mixture was stirred for 15 minutes at room temperature, then for 20 minutes at 110° C. The reaction mixture was concentrated, which was dissolved in ethyl acetate. The solution was washed with water, dilute hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate and water, successively, which was then dried, followed by distilling off the solvent. The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=4:1) to give ethyl ester of 5-chloro-1-methyl-3-phenylindole-2-acetic acid as an oily substance (4.34 g). [NMR (200 MHz, CDCl3) ppm: 10 1.29(3H,t,J=7 Hz), 3.76(3H,s), 3.86(2H,s), 4.24(2H,q,J=7 Hz), 7.17-7.62(8H,m)] for 20 minutes at 110° C The reaction mixture was concentrated which was dissolved in ethyl acetate The solution was washed with water, dilute hydrochloric acid, water an aqueous solution of sodium hydrogencarbonate and water, successively, which was then dried by distilling off the solvent The residue was purified by means of a silica gel (30 g) column chromatography (hexane-ethyl acetate=4:1)