ethyl 4-oxo-3-propanoylhexanoate

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

Procedure: By a method analogous to that described in Example 34, 3,5-heptane dione was reacted with bromoacetic acid-ethyl ester to form 3,3-dipropionyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to produce 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid-ethyl ester which was saponified to form the free acid. Obtained was 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid having a melting point of 129°-130° C.

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

Procedure: A mixture of 4-oxo-3-propionyl-hexanoic acid ethyl ester (15 g, 70 mmol) and hydrazine hydrate (3.5 mL, 71 mmol) in absolute ethanol (150 mL) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (methanol in methylene chloride) to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as yellow oil (11 g, 51 mmol). was refluxed for 16 h Solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (methanol in methylene chloride)

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

Procedure: A mixture of 4-oxo-3-propionyl-hexanoic acid ethyl ester (15 g, 70 mmol) and hydrazine hydrate (3.5 mL, 71 mmol) in absolute ethanol (150 mL) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (methanol in methylene chloride) to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as yellow oil (11 g, 51 mmol). was refluxed for 16 h Solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (methanol in methylene chloride)

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

Procedure: To a suspension of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in tetrahydrofuran (100 mL) at 0° C. was added dropwise a solution of heptane-3,5-dione (16.6 g, 130 mmol) in tetrahydrofuran (30 mL). After 15 minutes, bromo-acetic acid ethyl ester (14.4 mL, 130 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 4-oxo-3-propionyl-hexanoic acid ethyl ester (19 g, 68%) as yellow oil. extracted several times with ethyl acetate The combined ethyl acetate layers were washed with water a saturated aqueous solution of sodium chloride, dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in heptane)

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

Procedure: Dissolve heptane-3,5-dione (2.5 g, 19.5 mmol) in dry tetrahydrofuran (10 mL) and add the resulting solution dropwise to a chilled (0° C.) suspension of sodium hydride (0.94 g, 23.4 mmol, 60% dispersion in oil) in tetrahydrofuran (20 mL). Stir at 0° C. for 1 hr., then add bromoacetic acid ethyl ester (2.6 mL, 23.4 mmol) dropwise. Stir for 16 hr. at 0° C. and warm to room temperature. Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate the organic layer and wash with saturated aqueous sodium chloride solution (50 mL), dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give 4-oxo-3-propionyl-hexanoic acid ethyl ester as an oil (3.2 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 4.08 (m, 3H), 2.83 (d, 2H), 2.55 (q, 2H), 1.21 (t, 3H), 1.02 (t, 6H). add the resulting solution dropwise to a chilled Stir for 16 hr at 0° C. and warm to room temperature Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL) Separate the organic layer wash with saturated aqueous sodium chloride solution (50 mL) dry (sodium sulfate) filter concentrate Purify eluting with 10:1 hexanes

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

Procedure: Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H). Concentrate to an oil Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL) Separate the organic layer dry (sodium sulfate) filter concentrate

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

Procedure: Dissolve heptane-3,5-dione (2.5 g, 19.5 mmol) in dry tetrahydrofuran (10 mL) and add the resulting solution dropwise to a chilled (0° C.) suspension of sodium hydride (0.94 g, 23.4 mmol, 60% dispersion in oil) in tetrahydrofuran (20 mL). Stir at 0° C. for 1 hr., then add bromoacetic acid ethyl ester (2.6 mL, 23.4 mmol) dropwise. Stir for 16 hr. at 0° C. and warm to room temperature. Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL). Separate the organic layer and wash with saturated aqueous sodium chloride solution (50 mL), dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give 4-oxo-3-propionyl-hexanoic acid ethyl ester as an oil (3.2 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 4.08 (m, 3H), 2.83 (d, 2H), 2.55 (q, 2H), 1.21 (t, 3H), 1.02 (t, 6H). add the resulting solution dropwise to a chilled Stir for 16 hr at 0° C. and warm to room temperature Partition the reaction mixture between diethyl ether (100 mL) and saturated aqueous ammonium chloride solution (50 mL) Separate the organic layer wash with saturated aqueous sodium chloride solution (50 mL) dry (sodium sulfate) filter concentrate Purify eluting with 10:1 hexanes

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

Procedure: Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H). Concentrate to an oil Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL) Separate the organic layer dry (sodium sulfate) filter concentrate

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

Procedure: A mixture of 4-oxo-3-propionyl-hexanoic acid ethyl ester (15 g, 70 mmol) and hydrazine hydrate (3.5 mL, 71 mmol) in absolute ethanol (150 mL) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (methanol in methylene chloride) to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester as yellow oil (11 g, 51 mmol). was refluxed for 16 h Solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (methanol in methylene chloride)

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

Procedure: To a suspension of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in tetrahydrofuran (100 mL) at 0° C. was added dropwise a solution of heptane-3,5-dione (16.6 g, 130 mmol) in tetrahydrofuran (30 mL). After 15 minutes, bromo-acetic acid ethyl ester (14.4 mL, 130 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 4-oxo-3-propionyl-hexanoic acid ethyl ester (19 g, 68%) as yellow oil. extracted several times with ethyl acetate The combined ethyl acetate layers were washed with water a saturated aqueous solution of sodium chloride, dried over sodium sulfate concentrated under reduced pressure The crude product was purified by silica gel column chromatography (0-30% ethyl acetate in heptane)

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

Procedure: To a solution of 4-oxo-3-propionyl-hexanoic acid ethyl ester (500 mg) (preparation analagous to that of 1,1-dimethylethyl 4-oxo-3-propanoylhexanoate in WO2007/141267) in methanol (20 ml) at room temperature was added [1-(4-bromo-phenyl)-ethyl]-hydrazine (0.75 g). After overnight stirring, water was added and the mixture extracted 3 times with ethyl acetate. The organic layer was separated; washed with water and brine solution, then dried and concentrated to afford 792 mg of the title compound. Retention time HPLC: 1.58 min (Method D), ESI mass spectrum: (Br) [M]+=393/395. the mixture extracted 3 times with ethyl acetate The organic layer was separated washed with water and brine solution dried concentrated

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

Procedure: By a method analogous to that described in Example 34, 3,5-heptane dione was reacted with bromoacetic acid-ethyl ester to form 3,3-dipropionyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to produce 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid-ethyl ester which was saponified to form the free acid. Obtained was 3,5-diethyl-1-phenyl-pyrazol-4-acetic acid having a melting point of 129°-130° C.