反应详情

温度

2.5 °C

To a stirred, cold (0-5° C.) solution of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxamide (300 g, 1.54 mol, in anhydrous tetrahydrofuran (3.0 L) under a nitrogen atmosphere is added slowly, in portions, lithium aluminum hydride (pellets, 30 g, 0.79 mol) over a period of 0.5 hours. After stirring for 5 hours at 0-5° C. the reaction is quenched by slowly adding saturated sodium sulfate solution (75 mL) to the stirred reaction mixture maintained at 5-15° C. Magnesium sulfate (70 g) is added and the mixture is stirred for 15 minutes. The mixture is then filtered and the filter pad is washed with tetrahydrofuran (1.0 L). The solvent is removed by evaporation at 20-70° C. under diminished pressure to provide a tan-colored oil. The oil is diluted with dichloromethane (1.0 L) and the solution is washed with 1.5 N hydrochloric acid (350 mL). The organic layer is separated and concentrated under aspirator vacuum at 20-70° C. to an oil. Fresh dichloromethane (1.00 L) and water (1.50 L) containing dissolved sodium hydrogensulfite (220 g) are added to the oil. The mixture is stirred for 15 minutes and the phases are separated. The aqueous phase is washed with dichloromethane (2×300 mL). Dichloromethane (1.0 L) and 10 N sodium hydroxide (220 mL) are added (with cooling) to the aqueous phase and the mixture is stirred for 10 minutes The lower organic phase is separated and washed with water (500 mL). The dichloromethane extract is evaporated under diminished pressure at 20-70° C. to give an oil, which crystallizes on cooling, to provide 140.1 g (67%) of 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carbaldehyde, as a white, crystalline solid having, m.p 40-42° C., 1H NMR (300 MHz, CDCl3) 2.67-2.75 (m, 2H), 2.95 (t, 2H, J=7.3 Hz), 4.22 (t, 2H, J=7.3 Hz), 6.52 (s, 1H), 9.89 (s, 1H) and HPLC-MS purity, 99.86% at 12.9 minutes:

1. customis quenched by slowly adding saturated sodium sulfate solution (75 mL) to the stirred reaction mixture
2. temperaturemaintained at 5-15° C
3. additionMagnesium sulfate (70 g) is added
4. stirringthe mixture is stirred for 15 minutes
5. filtrationThe mixture is then filtered
6. washthe filter pad is washed with tetrahydrofuran (1.0 L)
7. customThe solvent is removed by evaporation at 20-70° C. under diminished pressure
8. customto provide a tan-colored oil
9. washthe solution is washed with 1.5 N hydrochloric acid (350 mL)
10. customThe organic layer is separated
11. concentrationconcentrated under aspirator vacuum at 20-70° C. to an oil
12. additionFresh dichloromethane (1.00 L) and water (1.50 L) containing
13. dissolutiondissolved sodium hydrogensulfite (220 g)
14. additionare added to the oil
15. stirringThe mixture is stirred for 15 minutes
16. customthe phases are separated
17. washThe aqueous phase is washed with dichloromethane (2×300 mL)
18. additionDichloromethane (1.0 L) and 10 N sodium hydroxide (220 mL) are added
19. temperature(with cooling) to the aqueous phase
20. stirringthe mixture is stirred for 10 minutes The lower organic phase
21. customis separated
22. washwashed with water (500 mL)
23. extractionThe dichloromethane extract
24. customis evaporated under diminished pressure at 20-70° C.
25. customto give an oil, which
26. customcrystallizes
27. temperatureon cooling