反应详情

To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.171 mmol) and (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.047 g, 0.205 mmol) in DMF (2 mL) was added sodium hydride (10.26 mg, 0.257 mmol) and the mixture was stirred at rt. After stirring for 4 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The amber oil was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV). The resulting impure amber oil (11.4 mg, 0.017 mmol) was taken up in DCE (4 mL). Hoveyda-Grubbs catalyst 2nd generation (2.72 mg, 4.34 μmol) then copper(I) iodide (3.31 mg, 0.017 mmol) were added and the mixture was stirred at 90° C. After 3 h, the mixture was cooled to rt and filtered and concentrated. The residue was purified by prep HPLC to give ethyl (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16,22-octaen-3-yl]acetate (3.0 mg, 4.57 μmol, 27% yield). LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.

1. stirringAfter stirring for 4 h
2. washwashed with 1N HCl
3. dry with materialThe organic phase was dried (Na2SO4)
4. filtrationfiltered
5. concentrationconcentrated
6. customThe amber oil was purified by flash chromatography (Biotage; 10% MeOH/DCM; 10 CV)
7. stirringthe mixture was stirred at 90° C
8. temperaturethe mixture was cooled to rt
9. filtrationfiltered
10. concentrationconcentrated
11. customThe residue was purified by prep HPLC