反应详情

温度

110 °C

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 63 mg, 0.156 mmol), (3S,4S)-4-(dimethylamino) pyrrolidin-3-ol (50.8 mg, 0.250 mmol) and DIPEA (0.191 mL, 1.094 mmol) and iPrOH (1 mL) in a sealed vial was heated at 110° C. for 4 h The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min) followed by preparative HPLC (Condition 10). Fractions containing 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 DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white foam. HPLC (Condition 7) tR=5.71 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=493 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.95-3.03 (m, 1H) 3.16-3.26 (m, 2H) 3.34-3.46 (m, 2H) 4.00-4.13 (m, 1H) 4.97-5.13 (m, 1H) 6.33-6.45 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, J=9.40 Hz, 3H) 8.04 (s, 1H) 8.68-8.81 (m, 1H) 10.20 (s, 1H) 12.88-13.16 (m, 1H).

1. extractionextracted with EtOAc
2. washThe combined extracts were washed with brine (10 mL)
3. dry with materialdried over Na2SO4
4. customthe solvent was evaporated off under reduced pressure
5. customto give a crude product which
6. customwas purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min)
7. additionFractions containing product
8. additiontreated with sat. aq. Na2CO3
9. customthe MeCN was evaporated off under reduced pressure
10. customto give an aq. residue which
11. extractionwas extracted with DCM
12. dry with materialThe combined extracts were dried over Na2SO4
13. customthe solvent was evaporated off under reduced pressure