反应详情

A slurry of 2-amino-2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)propane-1,3-diol hydrochloride (0.075 g, 0.15 mmol), N,N-diisopropylethylamine (0.065 mL, 0.37 mmol), and 1,1,1-triethoxyethane (0.041 mL, 0.22 mmol) in 0.75 mL DMF was heated in a sealed tube for 3 h. The brown solution was cooled and partitioned between EA/water, and the organic layer was washed with 1N aq. HCl, sat'd aq. NaHCO3, brine, and dried over sodium sulfate, filtered, and concentrated in vacuo. The HCl layer was neutralized with 1N aq NaOH and extracted with DCM, and the combined organics were dried, and concentrated in vacuo to give additional material, which was combined with the EA extract to give a brown oil. Purification by silica gel chromatography, 12 g, 0-10% MeOH/DCM provided an impure mixture. This was treated with 1.2 mL DCM and 1H-tetrazole 3 wt % solution in ACN (0.82 mL, 0.28 mmol) at 0° C. under nitrogen was added di-tert-butyl diisopropylphosphoramidite (0.087 mL, 0.28 mmol). The reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was cooled to 0° C. and treated with m-CPBA (77% by weight) (0.083 g, 0.37 mmol). The reaction mixture became immediately clear. After 30 min the reaction mixture was quenched with sat'd aq. NaHCO3 and EA. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a yellow oil. The oil was taken up in 2 mL EtOH and 0.5 mL conc HCl was added with rapid stirring at ambient temperature. The reaction was sealed and heated to 80° C. for 20 min and then cooled to ambient temperature. The solvent was removed and the resulting solid was taken up in MeOH and purified by HPLC, 5-100% ACN/TFA in H2O/TFA; The product-containing fractions were combined and concentrated in vacuo to give a white solid, which was sonicated briefly in MeOH, filtered, rinsing with MeOH followed by DCM. The resulting white solid was dried in vacuo to give (rac)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2-(hydroxymethyl)butyl dihydrogen phosphate MS (ESI) m/z: calculated: 543.1; Observed: 544.0 (M++1).

1. temperatureThe brown solution was cooled
2. custompartitioned between EA/water
3. washthe organic layer was washed with 1N aq. HCl
4. dry with materialdried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. extractionextracted with DCM
8. customthe combined organics were dried
9. concentrationconcentrated in vacuo
10. customto give additional material, which
11. extractionextract
12. customto give a brown oil
13. customPurification by silica gel chromatography, 12 g, 0-10% MeOH/DCM
14. customprovided an impure mixture
15. temperaturethe reaction mixture was cooled to 0° C.
16. customAfter 30 min the reaction mixture was quenched with sat'd aq. NaHCO3 and EA
17. washThe organic layer was washed with brine
18. dry with materialdried over sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated in vacuo to a yellow oil
21. addition0.5 mL conc HCl was added
22. customThe reaction was sealed
23. temperatureheated to 80° C. for 20 min
24. temperaturecooled to ambient temperature
25. customThe solvent was removed
26. custompurified by HPLC, 5-100% ACN/TFA in H2O/TFA
27. concentrationconcentrated in vacuo
28. customto give a white solid, which
29. filtrationfiltered
30. washrinsing with MeOH
31. customThe resulting white solid was dried in vacuo