反应详情

To a solution of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (333 mg, 0.648 mmol) in anhydrous DMF (4.0 mL) under nitrogen at room temperature was added (4aR,7S,8R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (196 mg, 0.777 mmol) and cesium carbonate (633 mg, 1.943 mmol). After stirring at room temperature for 1.5 h, the mixture was poured into water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resultant orange film was dissolved in formic acid (3.6 mL) and saturated aqueous potassium hydrogen sulfate (0.8 mL) was added. After stirring at room temperature for 72 hours, the mixture was warmed to 50° C. for 3.5 h, and then allowed to cool to room temperature. The mixture was slowly poured into saturated aqueous sodium bicarbonate (80 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant brown oil was dissolved in methanol (10 mL) and THF (3 mL). 1N aqueous lithium hydroxide (5 mL) was added and the mixture was stirred at room temperature. After 30 minutes, the mixture was poured into saturated aqueous sodium bicarbonate (80 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant beige solid film was chromatographed using a Gilson™ reverse phase preparatory HPLC eluted with MeCN/water/TFA. The slower eluting isomeric product fractions were poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resultant clear oil was dissolved in MeCN and water, frozen at −78° C., then lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C24H22ClN3O5 467.12, observed m/e: 468.17 (M+H)+ (Rt 1.92/4 min). 1H NMR δ (ppm)(DMSO-d6): 7.91 (s, 1H), 7.77-7.73 (m, 6H), 7.49 (t, J=8.0 Hz, 2H), 7.39 (t, J=7.5 Hz, 1H), 5.44 (br s, 1H), 5.26 (d, J=5.5 Hz, 1H), 4.91 (m, 1H), 4.59 (t, J=5.5 Hz, 1H), 4.18 (q, J=5.5 Hz, 1H), 3.69 (dd, J=11.0 Hz, 6.0 Hz, 1H), 3.55 (t, J=9.0 Hz, 1H), 3.45 (m, 1H), 3.29 (t, J=10.5 Hz, 1H), 3.21 (m, 1H), 3.15 (m, 1H).

1. extractionextracted with ethyl acetate (2×70 mL)
2. washThe combined organic layers were washed with brine
3. dry with materialdried over sodium sulfate
4. concentrationconcentrated under reduced pressure
5. dissolutionThe resultant orange film was dissolved in formic acid (3.6 mL)
6. additionsaturated aqueous potassium hydrogen sulfate (0.8 mL) was added
7. stirringAfter stirring at room temperature for 72 hours
8. temperaturethe mixture was warmed to 50° C. for 3.5 h
9. temperatureto cool to room temperature
10. additionThe mixture was slowly poured into saturated aqueous sodium bicarbonate (80 mL)
11. extractionextracted with ethyl acetate (2×100 mL)
12. washThe combined organic layers were washed with brine (60 mL)
13. dry with materialdried over sodium sulfate
14. concentrationconcentrated under reduced pressure
15. dissolutionThe resultant brown oil was dissolved in methanol (10 mL)
16. addition1N aqueous lithium hydroxide (5 mL) was added
17. stirringthe mixture was stirred at room temperature
18. waitAfter 30 minutes
19. additionthe mixture was poured into saturated aqueous sodium bicarbonate (80 mL)
20. extractionextracted with ethyl acetate (2×100 mL)
21. washThe combined organic layers were washed with brine (60 mL)
22. dry with materialdried over sodium sulfate
23. concentrationconcentrated under reduced pressure
24. customThe resultant beige solid film was chromatographed
25. washeluted with MeCN/water/TFA
26. washThe slower eluting isomeric product fractions
27. additionwere poured into saturated sodium bicarbonate
28. extractionextracted with ethyl acetate
29. washThe organic layer was washed with brine
30. dry with materialdried over sodium sulfate
31. concentrationconcentrated under reduced pressure
32. dissolutionThe resultant clear oil was dissolved in MeCN
33. temperaturewater, frozen at −78° C.