反应详情

温度

-15 °C

To a -15° C. solution of phosgene (4.50 mmol, 2.30 mL; 1.9M solution in toluene) in dry tetrahydrofuran (8 mL) is added neat triethylamine (4.50 mmol, 0.450 g; 0.620 mL) and the resulting suspension is stirred at -15° C. for 10 minutes. To this suspension is added 3-picolylamine (4.50 mmol, 0.490 g; 0.460 mL) and triethylamine (4.50 mmol, 0.450 g; 0.620 mL) in dry tetrahydrofuran (10 mL) in one portion and the reaction mixture is stirred at -15° C. for 30 minutes. Subsequently, 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (3.0 mmol, 0.870 g) in dry tetrahydrofuran (7 mL) is added at -15° C. and the reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (20 mL), the volatiles removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer is dried (Na2SO4) and concentrated in vacuo to give a tan solid. This material is purified by flash chromatography (SiO2 :1) 50% ethyl acetate/hexane; 2) 100% ethyl acetate; 3) 5% methanol/ethyl acetate) to give a mixture of starting material and product which is triturated with ether. The title compound is isolated as a white solid (0.158 g; 12%). Also isolated is a mixture of starting pyridazone and title compound (0.511 g). 1H-NMR (DMSO-d6, 400 MHz) δ8.45 (m, 3H); 7.65 (dt, 1H, J=8.0, 1.6 Hz); 7.22 (ddd, 1H, J=8.0, 5.0, 0.7 Hz); 6.94 (d, 1H, J=2.0 Hz); 6.88 (d, 1H, J=8.0 Hz); 6.82 (dd, 1H, J=8.0, 2.0 Hz); 4.63 (m, 1H); 4.38 (m, 3H); 3.70 (s, 3H); 3.65 (m, 1H); 2.74 (s, 3H); 2.65 (m, 1H); 1.79 (m, 2H); 1.63 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3420, 3320, 2950, 1730, 1715, 1530, 1515, 1235, 1135.

1. stirringthe reaction mixture is stirred at -15° C. for 30 minutes
2. temperatureto warm to room temperature overnight
3. customThe reaction is quenched with water (20 mL)
4. customthe volatiles removed in vacuo
5. customthe residue partitioned between ethyl acetate (150 mL) and water (150 mL)
6. dry with materialThe organic layer is dried (Na2SO4)
7. concentrationconcentrated in vacuo
8. customto give a tan solid
9. customThis material is purified by flash chromatography (SiO2 :1) 50% ethyl acetate/hexane
10. custom3) 5% methanol/ethyl acetate) to give
11. additiona mixture of starting material and product which
12. customis triturated with ether