2-(4-benzylpiperazin-1-yl)-6-fluorobenzaldehyde

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Combine 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), 1-benzylpiperazine (7.30 mL, 42.2 mmol) and potassium carbonate (5.83 g, 42.2 mmol) in dry N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. Heat the reaction to 80° C. for 4 hours. Cool the reaction to room temperature (20° C.) and stir overnight. Quench the reaction with water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic extracts, wash with saturated ammonium chloride (4×100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum to provide the crude product as a yellow oil. Purify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40) followed by recrystallization from hot ethyl acetate (50 mL). Collect the crystals by suction filtration and rinse with hexane to yield 5.16 g. Concentrate the mother liquor and recrystallize the solid from ethyl acetate (15 mL). Isolate the crystals as above to yield 1.71 g. Repeat the above process to yield an additional 0.95 g. This provides the 2-fluoro-6-[4-benzylpiperazin-1-yl]-benzaldehyde (7.82 g) as yellow crystals, mp 94°-95° C.; 1H NMR (CDCl3) δ 10.26 (1H,-s), 7.44 (1H, td, J=8.1, 6.3 Hz). 7.34 (4H, m), 7.29 (1H, m), 6.84 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=8.3, 8.0 Hz), 3.59 (2H, s), 3.12 (4H, m), 2.66 (4H, m); 13C NMR (CDCl3) δ 187.63, 187.56, 165.73, 162.27, 155.82, 137.82, 135.62, 135.46, 129.20, 128.27, 127.18, 116.91, 116.82, 114.26, 114.22, 109.38, 109.09, 62.95, 53.51, 52.96; 19F NMR CDCl3) δ -115.94 (m); IR (KBr) 2825, 1690, 1607, 1462, 1005 cm-1 ; EI/MS (70eV) 298(80%), 91(100%). Heat the reaction to 80° C. for 4 hours Cool the reaction to room temperature (20° C.) Quench the reaction with water (100 mL) extract with ethyl acetate (3×100 mL) Combine the organic extracts, wash with saturated ammonium chloride (4×100 mL) dry over anhydrous magnesium sulfate/sodium sulfate filter concentrate under vacuum to provide the crude product as a yellow oil Purify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40) followed by recrystallization from hot ethyl acetate (50 mL) Collect the crystals by suction filtration rinse with hexane to yield 5.16 g Concentrate the mother liquor recrystallize the solid from ethyl acetate (15 mL) Isolate the crystals as above to yield 1.71 g Repeat the above process to yield an additional 0.95 g