Diisopropylethylamine → N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide

Participants

Reaction Conditions

Reaction Steps

A suspension of the above crude 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid and 4-(oxetan-3-yl)benzene-1,2-diamine (0.135 g, 0.822 mmol) in methylene chloride (8.0 mL) was treated with N,N-diisopropylethylamine (0.716 mL, 4.11 mmol) and cooled to −5° C. (ice/brine). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [HATU] (0.469 g, 1.23 mmol) was added and the reaction mixture was stirred for 5.25 h, warming to 15° C.; HPLC/LC MS indicated complete conversion. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2 (15 mL) and water (7.5 mL). The separated aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown-purple semi-opaque oil/foam. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded both amide regioisomers of the title compound (0.45 g, 82%) as a semi-opaque pink foam: MS (ESI+) for C30H40N8O5 m/z 593.3 (M+H)+; MS (ESI−) for C30H40N8O5 m/z 591.3 (M−H)− and 637.4 (M+HCO2)−; HPLC purity 90% (ret. time, 2.097 min).

Provenance & Evidence