Cesium carbonate → 2-((5-Cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Participants

Reaction Conditions

Reaction Steps

2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(60 mg, 0.169 mmol), 3-amino-4-fluoro-5-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)benzonitrile (48 mg, 0.166 mmol), DPPF (6.44 mg, 0.012 mmol), Cs2CO3 (92 mg, 0.282 mmol), Xantphos (9.60 mg, 0.017 mmol), Palladium(II)Acetate (11.17 mg, 0.050 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture was cooled to 25° C., diluted with EtOAc, washed with brine and dried (Na2SO4). The solvents were removed and DCE (1 mL)/TFA (0.5 mL) was added. The reaction stirred 3 h and solvents were removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 50-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((5-cyano-2-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (16.9 mg).

Provenance & Evidence