反应详情

温度

110 °C

2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) were added to a vial containing iPrOH (1 mL) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 284.1, 32.5 mg, 0.168 mmol) was added under argon atmosphere. The RM was stirred at 110° C. for 40 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, filtered and the filtrate was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 14). Fractions containing product were treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane. The obtained solid was filtered off, washed with n-hexane and dried to afford the title product as a white solid. HPLC (Condition 10) tR=6.11 min, UPLC-MS (Condition 3) tR=0.86 min, m/z=508.2/510.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63 (br. s, 2H) 2.83-2.90 (m, 1H) 3.03-3.11 (m, 1H) 3.20-3.22 (m, 3H) 3.27-3.35 (m, 2H) 3.48-3.56 (m, 2H) 7.34 (d, J=8.21 Hz, 2H) 7.80-7.90 (m, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.75-8.80 (m, 1H) 10.18 (s, 1H).

1. additionwas added under argon atmosphere
2. extractionextracted with EtOAc
3. washThe combined extracts were washed with brine (10 mL)
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. customthe filtrate was evaporated off under reduced pressure
7. customto give the crude product which
8. customwas purified by preparative HPLC (Condition 14)
9. additionFractions containing product
10. additionwere treated with sat. aq. Na2CO3
11. customthe MeCN was evaporated off under reduced pressure
12. extractionThe aq. phase was extracted with EtOAc
13. dry with materialThe combined organic layers were dried over Na2SO4
14. filtrationfiltered
15. customthe filtrate was evaporated off under reduced pressure
16. customto give a residue which
17. filtrationThe obtained solid was filtered off
18. washwashed with n-hexane
19. customdried