反应详情

A solution of 2,2-dimethylpropionic acid 2-[(S)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester (583 mg, 0.95 mmol), in aqueous 6M HCl (20 mL) was refluxed for 30 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane. The fractions containing product were purified by column chromatography (C18, gradient 2-40% MeOH in 0.5% TFA/H2O) then loaded in dioxane onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane then the product eluted with 10% 880 NH3 in dioxane. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded 278 as a colourless solid (85.8 mg, 21%). LCMS (Method K): RT 2.05 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.29 (1H, s), 8.09 (1H, s), 7.58 (1H, dd, J=9.0, 5.0 Hz), 7.50 (1H, dd, J=9.6, 2.3 Hz), 7.00 (1H, dt, J=9.3, 2.3 Hz), 5.97 (1H, bs), 4.80-4.71 (1H, m), 3.41-3.39 (2H, m), 3.15-3.10 (1H, m), 2.92 (1H, bd, J=11.3 Hz), 2.81 (1H, t, J=11.0 Hz), 2.53-2.21 (4H, m), 2.01-1.97 (1H, m), 1.92-1.86 (1H, m), 1.80 (3H, d, J=6.9 Hz), 1.78-1.70 (1H, m)

1. customvolatiles were removed under reduced pressure
2. washThe cartridge was washed with dioxane/water (1:1)
3. washdioxane and the product eluted with 10% 880 NH3 in dioxane
4. additionThe fractions containing product
5. customwere purified by column chromatography (C18, gradient 2-40% MeOH in 0.5% TFA/H2O)
6. washThe cartridge was washed with dioxane
7. washthe product eluted with 10% 880 NH3 in dioxane
8. customFurther purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM)