反应详情

{(S)-1-[7-Cyano-6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethyl}carbamic acid tert-butyl ester (215 mg, 0.54 mmol) was dissolved in HCl in dioxane (4N, 5 mL) and the reaction mixture stirred at RT for 1 hour. The mixture was concentrated in vacuo and the residue dissolved in IPA (5 mL). 6-Chloro-9-(tetrahydropyran-2-yl)-9H-purine (167 mg, 0.70 mmol) and DIPEA (275 μL, 1.61 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give an off white solid LCMS (Method C): RT=2.89 min, [M+H]+=502. The solid was dissolved in HCl in methanol (1.25 M, 5 mL) and the reaction mixture stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to prep. HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 346 as a white solid (66 mg, 29%). 1H NMR 300 MHz δ (d6-DMSO): 12.91 (1H, br s), 8.89-8.46 (2H, m), 8.44-7.85 (5H, m), 7.42 (1H, t, J=9.6 Hz), 5.65-5.37 (1H, m), 1.67 (3H, t, J=6.8 Hz), LCMS (Method K): RT=3.03 min, [M+H]+=418

1. concentrationThe mixture was concentrated in vacuo
2. dissolutionthe residue dissolved in IPA (5 mL)
3. temperaturethe reaction mixture heated at 90° C. for 16 hours
4. concentrationThe reaction mixture was concentrated in vacuo
5. washthe resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc)
6. customto give an off white solid LCMS (Method C)
7. stirringthe reaction mixture stirred at RT for 10 min
8. concentrationThe reaction mixture was concentrated in vacuo