反应详情

Into a 5 liter four neck round bottom flask equipped with overhead stirring, condenser, thermocouple and nitrogen inlet was charged (3S)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile ((S)-38, 82.3 g, 0.215 mol), acetonitrile (1510 mL), water (135 mL) and solid lithium tetrafluoroborate (LiBF4, 206 g, 2.15 mol, 10.0 equiv). The resulting reaction mixture was warmed to reflux and stirred at reflux for 24-36 h. When HPLC and TLC showed that the reaction was deemed complete, the reaction mixture was cooled to room temperature. An aqueous ammonium hydroxide (NH4OH) solution (20% v/v) was added to the reaction mixture to adjust pH to 9-10. The resulting reaction mixture was stirred at room temperature for 15-24 h. When HPLC and TLC showed the de-protection reaction was deemed complete, the reaction mixture was filtered through a Celite pad to remove the insoluble materials. The Celite pad was washed with ethyl acetate (500 mL). The filtrate was further diluted with ethyl acetate (1 L) before being washed with a 20% sodium chloride (NaCl) aqueous solution (1 L). The aqueous fraction was back extracted with ethyl acetate (2×500 mL). The combined organic fractions were then concentrated under reduced pressure to remove the solvents to generate a thick white slurry. The slurry was treated with water (2 L) and the resulting mixture was stirred at room temperature for 18 hours. The solids were collected by filtration, and the wet cake was washed with methyl tert-butyl lether (MTBE, 500 mL) and heptane (500 mL) before being dried at 50° C. in a vacuum oven to constant weight. The dried, crude product (45 g) was then re-crystallized in ethanol (500 mL) and heptane (350 mL) to afford (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile ((S)-39, 42.8 g, 54.2 g theoretical, 79% yield) as white solids. For (S)-39: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.1 (bs, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.59 (d, 1H, J=3.5 Hz), 6.98 (d, 1H, J=3.5 Hz), 4.98 (m, 1H), 3.19 (d, 2H, J=6.6 Hz), 1.57 (d, 3H, J=6.6 Hz); C13H12N6 (MW, 252.27), LCMS (EI) m/e 253 (M++H).

1. customThe resulting reaction mixture
2. temperaturewas warmed
3. temperatureto reflux
4. temperatureat reflux for 24-36 h
5. customThe resulting reaction mixture
6. stirringwas stirred at room temperature for 15-24 h
7. customthe de-protection reaction
8. filtrationthe reaction mixture was filtered through a Celite pad
9. customto remove the insoluble materials
10. washThe Celite pad was washed with ethyl acetate (500 mL)
11. additionThe filtrate was further diluted with ethyl acetate (1 L)
12. washbefore being washed with a 20% sodium chloride (NaCl) aqueous solution (1 L)
13. extractionThe aqueous fraction was back extracted with ethyl acetate (2×500 mL)
14. concentrationThe combined organic fractions were then concentrated under reduced pressure
15. customto remove the solvents
16. additionThe slurry was treated with water (2 L)
17. stirringthe resulting mixture was stirred at room temperature for 18 hours
18. filtrationThe solids were collected by filtration
19. washthe wet cake was washed with methyl tert-butyl lether (MTBE, 500 mL) and heptane (500 mL)
20. custombefore being dried at 50° C. in a vacuum oven to constant weight
21. customThe dried, crude product (45 g) was then re-crystallized in ethanol (500 mL)