反应详情

A mixture of 25 g of benzylpiperazine (1) and 10 g of 2-fluorobenzaldehyde (2) were allowed to react in refluxing dioxane/water (1:2, 90 mL total volume) for 24 hours in the presence of 17 g K2CO3. The resultant reaction mixture was allowed to cool to room temperature, was extracted with methylene chloride and the organic layer was then washed with water, 5% hydrochloric acid, brine, and was then dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (5:1 hexanes-ethyl acetate) afforded 20 g of the benzaldehyde 3 in 89% yield; MS (AP/CI) observed: 281.1 (M+H)+ (100%). The benzaldehyde 3 (8 g) was subsequently allowed to react with 7.3 g of 1-acetyl-pyrrolidin-2-one (4) in the presence of 4.6 g of NaH (60% in mineral oil) at 0° C. for 1 hour followed by warming to room temperature and stirring for 2 hours. After quenching carefully with methanol at 0° C., the solvent was removed in vacuo, the residue was diluted with water, was extracted with methylene chloride and the organic extracts were washed with brine and were dried over magnesium sulfate and were filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40:1 chloroform-methanol) to provide 7.9 g of 3-[2-(4-benzyl -piperazin-1-yl)-benzylidene]-pyrrolidin-2-one (5) in 80% yield; MS (AP/CI) observed: 348.1 (M+H)+, 100%. Hydrogenation of 6.3 g of 5 with 1.5 g of Pd/C in 100 mL of methanol under 50 p.s.i. of pressure at 60° C. provided 3.8 g (82% yield) of 3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (6) following filtration, removal of solvent in vacuo, and purification by silica gel chromatography (30:1:0.3 chloroform-methanol-ammonium hydroxide); MS (AP/CI) observed: 260.1 (M+H)+, 100%.