反应详情

To a solution of 1,2,4-triazole (167 mg, 2.417 mmol) in anhydrous pyridine (1.5 mL) was added phosphorous oxychloride (POCl3) (75 μL, 0.806 mmol) and stirred at rt for 15 min. To this mixture was added dropwise a solution of 5-(3-benzyloxy-phenyl)-7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (100 mg, 0.269 mmol) in anhydrous pyridine (2.5 mL) over a 3.5 min period and stirred at rt for an additional 3 h. The reaction was cooled to 0° C. and quenched with 2M NH3 in i-PrOH (10 mL ) and stirred for an additional 30 min at rt. The mixture was filtered through a fritted funnel and the filtrate was concentrated in vacuo, partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined CHCl3 fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3] resulting in a dark brown oil which was crystallized from EtOAc/hexanes to obtain the title compound as a light tan solid. 1H NMR (CDCl3, 400 MHz) δ 1.95-2.08 (m, 1H), 2.09-2.22 (m, 1H), 2.39-2.50 (m, 2H), 2.59-2.72 (m, 2H), 4.14 (quint, J=8.4 Hz, 1H), 5.16 (s, 2H), 5.57 (brs, 2H), 7.02-7.09 (m, 1H), 7.22-7.28 (m, 3H), 7.31-7.50 (m, 5H), 7.85 (s, 1H); MS (ES+): m/z 372.1 (100) [MH+]; HPLC: tR=3.05 min (MicromassZQ, nonpolar—5 min).

1. stirringstirred at rt for an additional 3 h
2. temperatureThe reaction was cooled to 0° C.
3. customquenched with 2M NH3 in i-PrOH (10 mL )
4. stirringstirred for an additional 30 min at rt
5. filtrationThe mixture was filtered through a fritted funnel
6. concentrationthe filtrate was concentrated in vacuo
7. custompartitioned between CHCl3 and H2O
8. customseparated
9. extractionThe aqueous layer was re-extracted with CHCl3 (3×)
10. washthe combined CHCl3 fractions were washed with brine (1×)
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customthe crude material was chromatographed on silica gel [eluting with 2% MEOH in CHCl3]
15. customresulting in a dark brown oil which
16. customwas crystallized from EtOAc/hexanes