Beta-Propiolactone → 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamide

Participants

Reaction Steps

4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.073 mmol, Example 563) was taken up in MeOH (0.2 mL) and THF (0.2 mL) and oxetan-3-one (9.38 μl, 0.146 mmol) and trimethyl orthoformate (0.081 mL, 0.731 mmol) were added. The reaction was stirred at room temperature for 3 h. Next, sodium cyanoborohydride (9.19 mg, 0.146 mmol) and one drop of AcOH were added and the reaction was stirred at room temperature overnight. Only a trace of product detected by LCMS, so an additional 2 eq. each of oxetanone and NaCNBH3 were added, and the reaction was heated at 50° C. for 8 h. The reaction was cooled to room temperature and an additional 2 eq. each of oxetanone and reducing agent were added. The reaction was stirred at room temperature over the weekend. An additional 2 eq. each of oxetanone and NaCNBH3 were added, along with 1 drop of AcOH, and the reaction was heated at 50° C. for 6 h. The reaction was cooled to room temperature and water was added; a yellow solid crashed out. The solid was collected by filtration and purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethyl-1-(oxetan-3-yl)piperazine-2-carboxamide (1.9 mg).

Provenance & Evidence