Cesium carbonate → (+/-)-2-((2-chloro-5-cyano-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Participants

Reaction Conditions

Reaction Steps

A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (60.6 mg, 0.171 mmol), (+/−)-3-amino-4-chloro-5-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzonitrile (50 mg, 0.171 mmol), palladium(II) acetate (10.16 mg, 0.045 mmol), Xantphos (9.88 mg, 0.017 mmol), DPPF (9.47 mg, 0.017 mmol) and cesium carbonate (145 mg, 0.444 mmol) in dioxane (3 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 5 h. The reaction mixture was filtered through a celite pad, the filtrate was concentrated. And the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0.5-5% 2 N ammonia in methanol/dichloromethane). It was further purified by prep-HPLC (Pursuit XRs 10 u C18 column, 30×250 mm, room temperature 13.171 min, 30-100% gradient aqueous methanol over 12 minutes containing 0.1% TFA, 40 ml/min at 254 rinm). (+/−)-2-((2-chloro-5-cyano-3-((7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (57 mg) was obtained as a brown solid.

Provenance & Evidence