反应详情

温度

-15 °C

Biphenyl-2-ylcarbamic acid 1-{3-[3-(3-hydroxylpropyl)-2-oxoimidazolidin-1-yl]propyl}piperidin-4-yl ester (5.2 g, 10.8 mmol, 1.0 eq; prepared as described in Preparation 4) was dissolved in DCM (120 mL) and cooled to −15° C. DMSO (7.6 mL, 108.3 mmol, 10 eq) was added, followed by DIPEA (9.4 mL, 54.1 mmol, 5 eq). After 5 minutes of stirring, pyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid. The reaction was stirred for two hours, during which it was permitted to warm slowly to 0° C. After the complete conversion of the starting material, the organic solution was transferred to a separatory funnel and washed with saturated solution of sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate, and filtered. To the filtrate was added anhydrous MeOH (120 mL), and cooled to 0° C. for 15 minutes. p-Hydroxybenzylamine-hydrobromide (4.18 g, 20.5 mmol, 1.9 eq) was added as a solid and the reaction was stirred for 30 minutes at 0° C. Solid Na(OAc)3BH (6.86 g, 32.4 mmol, 3.0 eq) was added in one portion, and the reaction was removed from the ice bath and stirred for 1 hour. Aqueous HCl (1N, 500 mL) was added to the reaction, and the solution was transferred to a separatory funnel. The DCM layer was removed and EtOAc (300 mL) was added. The layers were well mixed and separated. Solid NaOH was added to the aqueous acid layer to adjust the pH to 12-14. The aqueous base layer was then extracted with EtOAc (2×250 mL). The extracted organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated to yield 5.6 g (88% yield crude, over two steps). The crude material was dissolved in DCM (˜1 g/50 mL) and with vigorous stirring was added 0.5 M NaH2PO4 (3×250 mL). The acidic washes were combined and brought to pH=6.5 using 6N NaOH. The aqueous layer was then washed using DCM (300 mL). The aqueous layer was then removed and brought to pH=˜11 using 6N NaOH. The aqueous layer was extracted with EtOAc (3×250 mL). The extracted organic layers were combined, washed with water (2×200 ml) and saturated brine (250 mL), and dried over sodium sulfate. The drying agent was removed via filtration and the organic solution was concentrated. The final purification was conducted via silica gel chromatography (eluent: 11% MeOH in DCM with 1% NH3(25% aq)) to afford the title compound (2.5 g, 4.32 mmol, 40% yield). MS m/z: [M+H+] calcd for C34H43N5O4, 586.3; found, 586.4.

1. additionpyridine-sulfur trioxide complex (8.6 g, 54.1 mmol, 5 eq) was added in one portion as a solid
2. stirringThe reaction was stirred for two hours, during which it
3. temperatureto warm slowly to 0° C
4. customAfter the complete conversion of the starting material, the organic solution was transferred to a separatory funnel
5. washwashed with saturated solution of sodium bicarbonate and brine
6. dry with materialThe organic phase was then dried over anhydrous sodium sulfate
7. filtrationfiltered
8. additionTo the filtrate was added anhydrous MeOH (120 mL)
9. temperaturecooled to 0° C. for 15 minutes
10. stirringthe reaction was stirred for 30 minutes at 0° C
11. customthe reaction was removed from the ice bath
12. stirringstirred for 1 hour
13. additionAqueous HCl (1N, 500 mL) was added to the reaction
14. customthe solution was transferred to a separatory funnel
15. customThe DCM layer was removed
16. additionEtOAc (300 mL) was added
17. additionThe layers were well mixed
18. customseparated
19. additionSolid NaOH was added to the aqueous acid layer
20. extractionThe aqueous base layer was then extracted with EtOAc (2×250 mL)
21. washwashed with saturated brine
22. dry with materialdried over sodium sulfate
23. customThe drying agent was removed via filtration
24. concentrationthe organic solution was concentrated
25. customto yield 5.6 g (88% yield crude, over two steps)
26. stirringwith vigorous stirring
27. washThe aqueous layer was then washed
28. customThe aqueous layer was then removed
29. extractionThe aqueous layer was extracted with EtOAc (3×250 mL)
30. washwashed with water (2×200 ml) and saturated brine (250 mL)
31. dry with materialdried over sodium sulfate
32. customThe drying agent was removed via filtration
33. concentrationthe organic solution was concentrated
34. customThe final purification