反应详情

温度

100 °C

A mixture of (S)-1-[1-(tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethylamine from Example 18 (295 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (400 mg, 1.68 mmol) and DIPEA (0.38 mL, 2.16 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 16 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. Purification by Isolute® SCX-2 was repeated a second time and then the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 128 as a white solid (310 mg, 71%). LCMS: RT 2.42 and 2.46 min [M+H]+ 364.0. 1H NMR (DMSO, 400 MHz): δ 8.38-7.88 (3H, m), 7.80 (1H, t, J=8.38 Hz), 7.65-7.54 (1H, m), 7.21-7.09 (2H, m), 5.95 (1H, br), 4.71-4.57 (1H, m), 4.14-4.04 (1H, m), 4.00-3.86 (1H, m), 3.83-3.71 (1H, m), 3.55-3.43 (1H, m), 3.16 (0.5H, d, J=4.68 Hz), 2.56-2.43 (0.5H, m), 2.36-2.23 (0.5H, m), 2.02 (0.5H, br), 1.83-1.72 (4H, m), 1.56 (0.5H, bd, J=13.68 Hz), 1.24-1.08 (0.5H, m). Signals split due to presence of rotamers/tautomers

1. temperatureAfter cooling to RT
2. customvolatiles were removed under reduced pressure
3. washwas washed with MeOH
4. washthe product eluted with 2M NH3/MeOH
5. additionThe product containing fractions
6. concentrationconcentrated in vacuo
7. customPurification by Isolute® SCX-2
8. customthe resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM)