反应详情

To a solution of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 0.30 g, 0.65 mmol) in DMF (8 mL) was added caesium carbonate to generate a white suspension. The suspension was stirred at room temperature for 1.5 hr, then (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 3.9 mL of 0.34 M solution in DMF, 1.30 mmol, 2.0 equiv.) was added, and the resulting solution was stirred at 60° C. for 20 h. The resulting suspension was concentrated under reduced pressure and the residue was treated separated between a saturated sodium bicarbonate solution (30 mL) and a 4:1 CH2Cl2/isopropanol solution (30 mL). The aqueous phase was extracted with a 4:1 CH2Cl2/isopropanol solution (30 mL). The combined organic phases were dried (anh. sodium sulfate) and concentrated under reduced pressure. The residue was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 5 min., gradient to 95% CH2Cl2: 5% MeOH over 15 minutes; gradient to 90% CH2Cl2: 10% MeOH over 15 min.; gradient to 80% CH2Cl2: 20% MeOH over 15 min.; and gradient to 75% CH2Cl2: 25% MeOH over 15 min.) to give 7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (0.080 g, 43%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz, 1H), 2.85, (t, J=4.6 Hz, 1H), 3.34-3.40 (br m, 1H), 3.75 (s, 3H), 3.82 (s, 3H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (br t, J=9.7 Hz, 2H), 4.31 (br t, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 7.84 (d, J=9.1 Hz, 1H).

1. stirringthe resulting solution was stirred at 60° C. for 20 h
2. concentrationThe resulting suspension was concentrated under reduced pressure
3. additionthe residue was treated
4. customseparated between a saturated sodium bicarbonate solution (30 mL)
5. extractionThe aqueous phase was extracted with a 4:1 CH2Cl2/isopropanol solution (30 mL)
6. dry with materialThe combined organic phases were dried (anh. sodium sulfate)
7. concentrationconcentrated under reduced pressure
8. customThe residue was purified
9. wait100% CH2Cl2 for 5 min.
10. waitgradient to 95% CH2Cl2: 5% MeOH over 15 minutes
11. waitgradient to 90% CH2Cl2: 10% MeOH over 15 min.
12. waitgradient to 80% CH2Cl2: 20% MeOH over 15 min.