反应详情

温度

100 °C

A mixture of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, Example 208D (in 12163-US-psp), (25 mg, 0.045 mmol), 2-chloro-n-methylacetamide (97 mg, 0.090 mmol), sodium iodide (13.53 mg, 0.090 mmol) and Et3N (0.024 mL, 0.135 mmol) in DMF (1.2 mL) in a microwave vial was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Removal of the solvent followed by silica gel chromatography eluting with DCM containing 0 to 2% MeOH to afford the PMB-protected product which was dissolved in DCM (0.7 ml), and TFA (0.7 ml) and anisole (0.025 mL, 0.226 mmol) were added. The resulting mixture was heated at 50° C. for 3 h. After removal of solvent the residue was taken in MeOH/DCM and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount (5 CV) of mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents to afford 2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-N-methylacetamide (15.6 mg).

1. washwashed with water, brine
2. dry with materialdried over Na2SO4
3. customRemoval of the solvent
4. washeluting with DCM containing 0 to 2% MeOH
5. customto afford the PMB-protected product which
6. temperatureThe resulting mixture was heated at 50° C. for 3 h
7. customAfter removal of solvent the residue
8. additionmixed-mode polymer
9. washThis was washed with methanol and product
10. washwas eluted with large amount (5 CV) of mixture of 2 N solution of ammonia in methanol and DCM (1:1)
11. customRemoval of the solvents