Isopropyl iodide → 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)(isopropyl)amino)cyclobutyl)propanoate

Participants

Reaction Conditions

Reaction Steps

A solution of the above crude 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 in acetonitrile (30 mL) was treated with potassium carbonate (6.3 g, 46 mmol) and isopropyl iodide (3.9 mL, 39 mmol). The reaction mixture in a sealed tube was heated at 90° C. for 6.5 h; HPLC indicated a 4:1 mixture of product to starting material. The reaction mixture was stirred overnight (17.5 h) at rt, treated with additional isopropyl iodide (2.0 mL, 20 mmol), and heated at 90° C. for 3 h; HPLC/LC MS indicated nearly complete conversion. The reaction mixture was cooled to rt and the solids were removed by vacuum filtration, rinsing with CH3CN, and the filtrate was concentrated in vacuo to afford a dull orange oil with precipitate. Purification by column chromatography (5×14.5 cm silica; 0-10% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.49 g, 15%) as a white foam/colorless oil. The mixed fractions containing product were repurified by column chromatography (4×10.5 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) to afford the title compound (1.66 g, 40%) as a white foam/colorless oil contaminated with the bisreductive amination byproduct from Step 1: MS (ESI+) for C25H38N6O5 m/z 503.2 (M+H)+.

Provenance & Evidence