3-methylcyclopentane-1,2-dione

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30. is refluxed for 2 h The mixture is then cooled extracted with ethyl acetate Pooled extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30. is refluxed for 2 h The mixture is then cooled extracted with ethyl acetate Pooled extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30. is refluxed for 2 h The mixture is then cooled extracted with ethyl acetate Pooled extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the Compound of Example 3 (500 mg, 2.36 mmol), 3-methyl-1,2-cyclopentanedione (350 mg, 3.11 mmol), acetic acid (0.18 mL, 3.11 mmol) in ethanol (10 mL) was refluxed for 8 h. The reaction mixture was evaporated, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 85:15, affording the title product as a brown solid. was refluxed for 8 h The reaction mixture was evaporated poured into water extracted with EtOAc The combined organic layers were washed with brine dried on Na2SO4 evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 85:15

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30. is refluxed for 2 h The mixture is then cooled extracted with ethyl acetate Pooled extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5)