Acetic Acid → methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate

Participants

Reaction Steps

(R)-methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (44 mg, 0.039 mmol) was dissolved in DMF (2.5 ml) and methanol (1 ml). oxetan-3-amine (20 μl, 0.039 mmol) and trimethyl orthoformate (0.25 ml, 2.262 mmol) were added. Acetic acid (0.05 ml, 0.873 mmol) was added drop wise until pH ˜5. The reaction mixture was stirred at room temperature for 10 minutes. sodium cyanoborohydride (21 mg, 0.334 mmol) was added and stirring at room temperature continued for 1 hour. Formaldehyde (50 μl, 0.672 mmol) and additional sodium cyanoborohydride (21 mg, 0.334 mmol) and acetic acid (0.05 ml, 0.873 mmol) were added and the mixture stirred at room temperature for 3 hours, then evaporated in a nitrogen stream overnight. The crude mixture of the 2 diastereomeric products was dissolved in DMSO, filtered and purified by prep HPLC with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 50-90% B over 30 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 give methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.7 mg) (Example 750) and methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.9 mg) (Example 751)

Provenance & Evidence