Acetic Acid → ethyl 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)amino)cyclobutyl)propanoate

Participants

Reaction Steps

A mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.50 g, 1.6 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.27 g, 1.6 mmol) in methanol (10 mL) was treated with acetic acid (0.09 mL, 2 mmol) at rt and the flask was evacuated and flushed with nitrogen (×3). The reaction mixture was treated at rt with sodium cyanoborohydride (0.26 g, 4.1 mmol), which afforded instant gas evolution and a nearly colorless, clear solution in a few minutes. The reaction mixture was stirred for 1 h at rt; HPLC/LC MS indicated a ˜2:1 mixture of product to starting amine. At 1.5 h additional ethyl 3-(3-oxocyclobutyl)propanoate (66 mg, 0.39 mmol) in MeOH (1.0 mL) was added and the reaction mixture was stirred at rt for 30 min; HPLC/LC MS indicated ˜70% conversion and some dialkylation. At 2 h 15 min water (4.0 mL) was added and the mixture was concentrated in vacuo. The residual aqueous layer was diluted with saturated aqueous sodium bicarbonate (10 mL, to pH 9) and extracted with CH2Cl2 (3×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford the reductive amination product as a white foam, which was carried on without further purification: MS (ESI+) for C22H32N6O5 m/z 461.1 (M+H)+, 483.1 (M+Na)+.

Provenance & Evidence