Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-5-yl)nicotinamide

温度

110 °C

K3PO4 (135 mg, 0.635 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid (112 mg, 0.424 mmol) and Pd(PPh3)4 (12.24 mg, 10.59 mmol) were added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 100 mg, 0.212 mmol) in toluene (2 mL) and the RM was stirred at 110° C. for 2 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with water and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.462 mL, 5.99 mmol) and stirred for 1 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated in DCM/n-hexane, filtered and dried to give the title product as a white solid. HPLC (Condition 5) tR=6.545 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=518.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.95 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.24 (m, 2H) 3.44 (m, 1H) 4.17-4.32 (m, 1H) 4.91 (br. s, 1H) 6.88 (s, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.86 (d, J=9.38 Hz, 2H) 8.12 (s, 1H) 8.81 (s, 1H) 10.17 (s, 1H) 13.94 (s, 1H).

1. filtrationThe RM was filtered through Hyflo®
2. washwashed with water
3. customthe solvent was evaporated off under reduced pressure
4. customto give the crude product which
5. customwas purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6)
6. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
7. stirringstirred for 1 h at RT
8. extractionextracted with EtOAc
9. washThe combined extracts were washed with brine (20 mL)
10. dry with materialdried over Na2SO4
11. customthe solvent was evaporated off under reduced pressure
12. customto give a crude product which
13. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1)
14. additionFractions containing pure product
15. customthe solvent was evaporated off under reduced pressure
16. customto give a residue which
17. customwas triturated in DCM/n-hexane
18. filtrationfiltered
19. customdried

ORDレコード

ord-c546f5afe71148f88fbf600b38e2a0bd

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08829195B2