ethyl 2,4-dioxo-5-phenoxypentanoate

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

Procedure: The compound was prepared from 3-phenoxy-butan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

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

Procedure: The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

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

Procedure: The compound was prepared from 1-(3-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol) in EtOH (3 mL). The mixture was stirred at 80° C. for 16 hours and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil. the solvent was evaporated in vacuo The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80) The desired fractions were collected the solvents evaporated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol) in EtOH (3 mL). The mixture was stirred at 80° C. for 16 hours and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil. the solvent was evaporated in vacuo The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80) The desired fractions were collected the solvents evaporated in vacuo

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

Procedure: Sodium (6.74 g, 293 mmol) was added to EtOH (808 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 mL, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.9 g, 54% yield) as an oil. was completely dissolved Then the mixture was stirred at room temperature for 16 hours the solvent was evaporated in vacuo The residue was dissolved in H2O extracted with DCM The organic layer was separated dried (Na2SO4) filtered the solvents evaporated in vacuo The crude product was purified by open column chromatography (silica; DCM)

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

Procedure: Sodium (6.74 g, 293 mmol) was added to EtOH (808 mL) at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 mL, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.9 g, 54% yield) as an oil. was completely dissolved Then the mixture was stirred at room temperature for 16 hours the solvent was evaporated in vacuo The residue was dissolved in H2O extracted with DCM The organic layer was separated dried (Na2SO4) filtered the solvents evaporated in vacuo The crude product was purified by open column chromatography (silica; DCM)

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

Procedure: The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 3 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 4 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrazine hydrate (0.27 mL, 2.76 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (0.69 g, 2.76 mmol in EtOH (3 mL)). The mixture was stirred at 80° C. overnight. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in AcOEt 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.66 g, 98% yield) as a yellow oil. The solvent was evaporated in vacuo The crude product was purified by flash column chromatography (silica; DCM in AcOEt 0/100 to 20/80) The desired fractions were collected the solvents evaporated in vacuo

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

Procedure: Sodium (6.74 g, 293 mmol) was added to EtOH at 0° C. The mixture was stirred at 0° C. until the sodium was completely dissolved. Then phenoxy-2-propanone (53 mL, 266 mmol) was added dropwise. The mixture was stirred at 0° C. for 10 minutes and then diethyl oxalate (36 g, 266 mmol) was added. Then the mixture was stirred at room temperature for 16 hours and the solvent was evaporated in vacuo. The residue was dissolved in H2O and the mixture was acidified with a 1M solution of HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; DCM) to yield 2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester (35.85 g, 54% yield) as an oil. was completely dissolved Then the mixture was stirred at room temperature for 16 hours the solvent was evaporated in vacuo The residue was dissolved in H2O extracted with DCM The organic layer was separated dried (Na2SO4) filtered the solvents evaporated in vacuo The crude product was purified by open column chromatography (silica; DCM)

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

Procedure: The compound was prepared from 3-phenoxy-butan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).

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

Procedure: The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).