反应详情

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.451 mmol) and PdCl2(PPh3)2 (15.84 mg, 23 μmol) were added to a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 77.1, 110 mg, 0.226 mmol) and Na2CO3 (0.451 mL, 0.903 mmol) in DME (1.5 mL)/EtOH (0.3 mL) in a vial, which was sealed, purged with argon and the RM was subjected to MW irradiation at 125° C. for 30 min. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc). The resulting intermediate was dissolved in DCM (2 mL), treated TFA (0.314 mL, 4.07 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8) to give the title product as a white solid. HPLC (Condition 7) tR=6.105 min, UPLC-MS (Condition 8) tR=0.91 min, m/z=465.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.56 Hz, 2H) 3.24-3.38 (m, 2H) 3.81-3.91 (m, 2H) 4.99 (br.s, 1H) 5.04 (br.s, 1H) 6.26-6.36 (m, 1H) 6.72-6.87 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.47-7.94 (m, 5H) 10.10 (s, 1H) 12.75-13.04 (m, 1H).

1. customwas sealed
2. custompurged with argon
3. customthe RM was subjected to MW irradiation at 125° C. for 30 min
4. filtrationThe RM was filtered through Hyflo®
5. customthe solvent was evaporated off under reduced pressure
6. customto give a residue which
7. customwas purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc)
8. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
9. customThe solvent was evaporated off under reduced pressure
10. customto give a residue which
11. extractionextracted with EtOAc
12. washThe combined extracts were washed with brine
13. dry with materialdried over Na2SO4
14. customthe solvent was evaporated off under reduced pressure
15. customto give the crude product which
16. customwas purified by preparative HPLC (Condition 10)
17. additionFractions containing pure product
18. additiontreated with sat. aq. Na2CO3
19. customthe MeCN was evaporated off under reduced pressure
20. customto give an aq. residue which
21. extractionwas extracted with EtOAc
22. washThe combined extracts were washed with brine
23. dry with materialdried over Na2SO4
24. customthe solvent was evaporated off under reduced pressure
25. customto give a residue which
26. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8)