反应详情

温度

0 °C

A suspension of NaH (720 mg; 60 wt %; 432 mg NaH contained; 17.99 mmol) in DMF (9 mL) at 0° C. was treated with a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g; 13.84 mmol) in DMF (9 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was treated with a solution of 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (2.499 g; 15.22 mmol) in DMF (10 mL). The reaction was stirred at 0° C. for 45 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried over sodium sulfate, filtered and evaporated to a residue. The residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane). The fractions containing the desired product were combined and evaporated to a white solid. Crystalline solid was also recovered from the chromatography fractions. The solid isolated from chromatography was recrystallized from EtOH/heptane. The solid (4 g) was suspended in EtOH (150 ml), then heated until completely dissolved, allowed to cool to RT and heptane (100 ml) was added. The mixture was aged at RT overnight, cooled to 0° C. for 5 minutes and filtered to provide the title compound). LCMS: calc. 425.17 obs: 426.09 (M+1). 1H NMR (CDCl3): δ 8.48 (d, 1H), 8.20 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDCl3), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2O), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), −0.08 (q, 1H).

1. stirringThe reaction was stirred at 0° C. for 45 minutes
2. temperatureto warm to room temperature
3. stirringstirred overnight
4. customThe reaction was quenched with saturated aqueous NH4Cl
5. customthe mixture partitioned between ethyl acetate and water
6. washThe organic layer was washed twice more with water
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. customevaporated to a residue
10. customThe residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane)
11. additionThe fractions containing the desired product
12. customevaporated to a white solid
13. customCrystalline solid was also recovered from the chromatography fractions
14. customThe solid isolated from chromatography
15. customwas recrystallized from EtOH/heptane
16. temperatureheated
17. dissolutionuntil completely dissolved
18. temperatureto cool to RT
19. additionheptane (100 ml) was added
20. waitThe mixture was aged at RT overnight
21. temperaturecooled to 0° C. for 5 minutes
22. filtrationfiltered