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, 100 mg, 0.248 mmol), β-Alanine ethyl ester hydrochloride (267 mg, 1.736 mmol), DIPEA (0.433 mL, 2.480 mmol) and iPrOH (3 mL) were added to a vial, which was sealed and the RM was stirred at 110° C. for 44 h. The RM was treated with saturated aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 (20 mL) and brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified 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 and EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The resulting ester was dissolved in MeOH (0.5 mL) and THF (1 mL), treated with LiOH.H2O (0.548 mL, 0.548 mmol) and stirred for at RT for 90 min. The RM was acidified with aq. 1 M HCl (4 eq.) and the organic solvents were evaporated off under reduced pressure. The product was filtered off, washed with water and n-hexane and dried to give the title product as a white crystalline solid. HPLC (Condition 7) tR=6.08 min, UPLC-MS (Condition 8) tR=0.98 min, m/z=452 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.62 (t, J=6.45 Hz, 2H) 3.79 (q, J=6.26 Hz, 2H) 6.95 (s, 1H) 7.35 (d, J=8.99 Hz, 2H) 7.85-7.95 (m, J=9.38 Hz, 3H) 8.41 (d, J=1.95 Hz, 1H) 8.67 (d, J=2.35 Hz, 1H) 8.86-9.06 (m, 1H) 10.22 (s, 1H) 12.23 (br. s, 1H) 13.18 (br. s, 1H).

1. additionwere added to a vial, which
2. customwas sealed
3. extractionextracted with EtOAc
4. washThe combined extracts were washed with sat. aq. Na2CO3 (20 mL) and brine (10 mL)
5. dry with materialdried over Na2SO4
6. customthe solvent was evaporated off under reduced pressure
7. customto give a residue which
8. customwas purified by preparative HPLC (Condition 10)
9. additionFractions containing product
10. additiontreated with sat. aq. Na2CO3
11. customthe MeCN was evaporated off under reduced pressure
12. customto give an aq. residue which
13. extractionwas extracted with DCM and EtOAc
14. dry with materialThe combined extracts were dried over Na2SO4
15. customthe solvent was evaporated off under reduced pressure
16. dissolutionThe resulting ester was dissolved in MeOH (0.5 mL)
17. stirringstirred for at RT for 90 min
18. customthe organic solvents were evaporated off under reduced pressure
19. filtrationThe product was filtered off
20. washwashed with water and n-hexane
21. customdried