反应详情

温度

40 °C

A solution of tert-butyl 4-(5-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A11) (112 mg, 0.179 mmol) and LiOH.H2O (90 mg, 2.2 mmol) in THF (7.0 mL), MeOH (7.0 mL) and H2O (2.0 mL) was stirred at 35° C. for 24 hours. Additional LiOH.H2O (45 mg, 1.1 mmol) was added and stirring continued at 35° C. for 16 hours. Further LiOH.H2O (45 mg, 1.07 mmol) was added and stirring was continued at 35° C. for 3 days. The volatiles were removed in vacuo and the residue diluted with EtOAc (20 mL) and aqueous HCl (2 M, 20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organics extracts were washed with brine and dried over MgSO4. The volatiles were removed in vacuo and the residue dissolved in anhydrous THF (9.0 mL) and anhydrous DMF (1.5 mL) then HOBt (48 mg, 0.36 mmol), EDCl.HCl (68 mg, 0.36 mmol) and diisopropylamine (0.310 mL, 2.21 mmol) were added under an atmosphere of nitrogen. After 10 minutes of stirring ammonium carbonate (86 mg, 0.89 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours. The temperature was raised to 40° C. and stirring was continued for a further 24 hours. The volatiles were removed in vacuo before EtOAc (20 mL) and saturated NaHCO3 (20 mL) were added to the residue. After separating the layers, the aqueous phase was extracted with EtOAc (2×20 mL) then the combined organic extracts were washed with brine and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A12 as a white solid (77 mg, 71%); 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.72 (s, 1H), 8.14 (d, J=6.7 Hz, 1H), 7.37-7.26 (m, 4H), 7.26-7.18 (m, 1H), 6.98 (s, 1H), 6.02 (s, 1H), 4.05 (d, J=12.7 Hz, 2H), 3.21-3.07 (m, 4H), 2.87-2.75 (m, 3H), 1.81 (d, J=11.1 Hz, 2H), 1.56 (qd, J=13.0, 4.4 Hz, 2H), 1.47-1.38 (m, 11H), 0.97 (s, 2H). LCMS-A: rt 5.273 min; m/z 611 [M+H]+.

1. stirringstirring
2. waitwas continued at 35° C. for 3 days
3. customThe volatiles were removed in vacuo
4. additionthe residue diluted with EtOAc (20 mL) and aqueous HCl (2 M, 20 mL)
5. customThe layers were separated
6. extractionthe aqueous phase was extracted with EtOAc (2×50 mL)
7. washThe combined organics extracts were washed with brine
8. dry with materialdried over MgSO4
9. customThe volatiles were removed in vacuo
10. dissolutionthe residue dissolved in anhydrous THF (9.0 mL)
11. stirringthe resulting mixture was stirred at room temperature for 16 hours
12. stirringstirring
13. waitwas continued for a further 24 hours
14. customThe volatiles were removed in vacuo before EtOAc (20 mL) and saturated NaHCO3 (20 mL)
15. additionwere added to the residue
16. customAfter separating the layers
17. extractionthe aqueous phase was extracted with EtOAc (2×20 mL)
18. washthe combined organic extracts were washed with brine
19. dry with materialdried over MgSO4
20. customThe volatiles were removed under reduced pressure
21. customthe residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.)