反应详情

温度

0 °C

Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,756,382, Example 192) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 45 minutes and then allowed to warm to ambient temperature. After 5 hours the reaction mixture was concentrated under reduced pressure and the residue was allowed to stand over the weekend. The residue was diluted with methanol (20 mL) and then heated to 50° C. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred for about 2.5 hours. The mixture was made basic with aqueous sodium hydroxide and then extracted with ethyl acetate (×2). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 400 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}isoquinoline-3-carboxamide as a white solid, mp 245-246° C. Anal calcd for C25H24N6O2: % C, 67.73; % H, 5.59; % N, 18.80. Found: % C, 67.38; % H, 5.54; % N, 18.84.

1. temperaturea chilled
2. temperatureto warm to ambient temperature
3. concentrationAfter 5 hours the reaction mixture was concentrated under reduced pressure
4. additionThe residue was diluted with methanol (20 mL)
5. temperatureheated to 50° C
6. additionHydrochloric acid (about 10 mL of 6 N) was added
7. stirringthe mixture was stirred for about 2.5 hours
8. extractionextracted with ethyl acetate (×2)
9. dry with materialThe combined extracts were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. customto provide a yellow solid
13. customThis material was purified by prep HPLC (COMBIFLASH system
14. washeluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide
15. customwith a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid
16. temperatureto cool
17. customthe solvent was decanted
18. customThe resulting material was dried under vacuum