反应详情

温度

140 °C

A stirred mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1, 150 mg, 0.365 mmol) in iPrOH (0.5 mL) was treated with tert-butyl[3-(trifluoromethylpyrrolidine-3-yl)]carbamate (179 mg, 0.547 mmol) and DIPEA (0.159 mL, 0.912 mmol) were added at RT. The resulting mixture was stirred at 140° C. for 12 h. The solution was diluted in EtOAc (50 mL), washed with a 2 N citric acid solution (20 mL), aq. sat. solution of NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 40 g, DCM/MeOH 95:5). Obtained (R)-tert-butyl (1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(pyrimidin-5-yl)pyridin-2-yl)-3-(trifluoromethyl)pyrrolidin-3-yl)carbamate (137 mg, 0.196 mmol) was suspended in DCM (1 mL) and TFA (0.453 mL, 5.88 mmol) was added at RT. The resulting light yellow solution was stirred for 1.5 h at RT. The RM was diluted with EtOAc (50 mL), then washed with an aq. sat. solution of NaHCO3 and twice with water (2×20 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel, 12 g, DCM/MeOH 95:5). The obtained residue re-suspended in MeOH (2 mL) was stirred at RT for 15 min. The crystals were filtered and washed with MeOH (2 mL) to afford the title product as a white solid. HPLC (Condition 10) tR=5.92 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=529.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-1.85 (m, 1H) 2.02 (s, 1H) 2.24-2.35 (m, 2H) 3.13-3.27 (m, 2H) 3.37-3.52 (m, 2H) 7.35 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.00 Hz, 2H) 8.14 (d, J=2.35 Hz, 1H) 8.81 (d, J=2.35 Hz, 1H) 8.92 (s, 2H) 9.22 (s, 1H) 10.23 (s, 1H).

1. additionwere added at RT
2. washwashed with a 2 N citric acid solution (20 mL), aq. sat. solution of NaHCO3 (20 mL) and brine (20 mL)
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. customthe solvent was evaporated off under reduced pressure
6. customto give the crude product which
7. customwas purified by flash chromatography (RediSep® Silica gel column, 40 g, DCM/MeOH 95:5)
8. stirringThe resulting light yellow solution was stirred for 1.5 h at RT
9. washwashed with an aq. sat. solution of NaHCO3 and twice with water (2×20 mL)
10. extractionThe aqueous phase was extracted with EtOAc (40 mL)
11. dry with materialThe combined organic phases were dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe crude product was purified by flash chromatography (RediSep® Silica gel, 12 g, DCM/MeOH 95:5)
15. stirringwas stirred at RT for 15 min
16. filtrationThe crystals were filtered
17. washwashed with MeOH (2 mL)