反应详情

温度

-20 °C

A mixture of tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.673 g, 1.280 mmol) in THF (15 mL) under inert atmosphere was treated with a solution of 5-fluoro-6-methoxypyridin-3-amine (0.364 g, 2.56 mmol) in THF (10 mL) via syringe. The mixture was chilled to −20° C. in a diluted dry ice/acetone bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 3.84 mL, 3.84 mmol) was added slowly via syringe into the reaction mixture. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere for 1 h. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with 100% ethyl acetate to give tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.459 g, 0.709 mmol, 55.3% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.61 (s, 1H) 9.65 (t, J=1.96 Hz, 1H) 8.31 (dd, J=12.52, 2.35 Hz, 1H) 8.18-8.23 (m, 2H) 8.03 (d, J=2.35 Hz, 1H) 5.80 (dd, J=10.47, 2.05 Hz, 1H) 3.96 (s, 3H) 3.76 (s, 1H) 3.55 (d, J=6.85 Hz, 1H) 3.36 (s, 4H) 2.85 (s, 3H) 2.40 (d, J=3.33 Hz, 4H) 2.07 (s, 1H) 2.02 (s, 1H) 1.97 (s, 1H) 1.54-1.81 (m, 2H) 1.41 (d, J=6.65 Hz, 3H) 1.36 (s, 9H) 1.19 (s, 1H) 0.90 (d, J=6.65 Hz, 1H). m/z (ESI, +ve ion) 648.2 (M+H)+.

1. additionAfter the addition
2. customthe ice bath was removed
3. additionThe mixture was diluted with chloroform (20 mL) and water (10 mL)
4. extractionThe organic layer was extracted with chloroform (3×10 mL)
5. dry with materialThe combined organic extracts were dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. custompurified by chromatography through a silica-gel column (80 g)
9. washeluting with 100% ethyl acetate