1,2-Bis(trimethylsiloxy)cyclobutene → 2-((2-Chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

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Reaction Steps

To the stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208) (20 mg, 0.046 mmol) in TIIF (1 ml) was added drop wise a solution of 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (12.75 mg, 0.055 mmol) in MeOH (0.4 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 5 days (converted to clear solution). Solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 30-70% B over 18 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-(1-(2-oxocyclobutyl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.6 mg).

Provenance & Evidence