反应详情

To a solution of compound 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (55 mg, 0.10 mmol, 1 equiv.) in THF/H2O (1.0 mL/1.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.30 mmol, 1 equiv.). The resulting mixture was stirred overnight at room temperature. Upon completion, the reaction was diluted with CH2Cl, (5 mL) and water (5 mL). The aqueous layer was adjusted with 1 N HCl to about pH3 and extracted with CH2Cl2 (5 mL×3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was used for the next step without further purification. To a solution of the above acid in DMF (2 mL) was added 1-methylpiperidin-4-amine (25 μL, 0.20 mmol, 2 equiv.), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (95 mg, 0.25 mmol, 2.5 equiv.) and DIEA (52 μL, 0.30 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for overnight. After removal of the solvent, the residue was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. Removal of solvent under vacuum afforded crude product 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide 46 mg. It was used for next step without further purification. LC-MS (M+H): 645.22

1. extractionextracted with CH2Cl2 (5 mL×3)
2. washThe combined organic layer was washed with brine (20 mL)
3. dry with materialdried over Na2SO4
4. customAfter removal of solvent under vacuum
5. customthe resulting residue was used for the next step without further purification
6. stirringThe reaction mixture was stirred at room temperature for overnight
7. customAfter removal of the solvent
8. additionthe residue was diluted with EtOAc (20 mL)
9. washwashed with water (20 mL) and brine (20 mL)
10. dry with materialThe organic phase was dried over Na2SO4
11. customRemoval of solvent under vacuum