Diisopropylethylamine → 6-(3,3-Difluoropyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Temperatur

140 °C

6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) was suspended in iPrOH (0.5 mL). 3,3-Difluoropyrrolidine hydrochloride (72.7 mg, 0.507 mmol) and DIPEA (0.177 mL, 1.013 mmol) were added at RT. The light brown solution was stirred at 140° C. for 23 h. The RM was diluted with EtOAc (50 mL) and washed with a 2 N citric acid solution (20 mL) and water (3×20 mL). The combined aq. phases were extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to give the crude material that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3). The resulting product was dissolved in MeOH (2 mL). The resulting white suspension was stirred at RT for 15 min then filtered. The solid was washed with MeOH (5 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.017 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=466.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.04 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=13.10 Hz, 2H) 7.37 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, 2H) 8.15-8.19 (m, 1H) 8.82-8.85 (m, 1H) 8.94 (d, J=0.78 Hz, 2H) 9.23 (s, 1H) 10.27 (s, 1H).

1. washwashed with a 2 N citric acid solution (20 mL) and water (3×20 mL)
2. extractionThe combined aq. phases were extracted with EtOAc
3. dry with materialthe combined extracts were dried over Na2SO4
4. filtrationfiltered
5. customthe solvent was evaporated off under reduced pressure
6. customto give the crude material that
7. customwas purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3)
8. dissolutionThe resulting product was dissolved in MeOH (2 mL)
9. stirringThe resulting white suspension was stirred at RT for 15 min
10. filtrationthen filtered
11. washThe solid was washed with MeOH (5 mL)
12. customdried

ORD-Eintrag

ord-dbda38f6074c4c7dbb2972d924861663

Quelldatensatz

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09278981B2