反应详情

温度

90 °C

5-[5-Amino-1-(1,1-diethylethyl)-3-methyl-1H-pyrazol-4-yl]-3-fluoro-2-(methyloxy)phenol (2.2 g, 7.5 mmol.) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (2.23 g, 8.6 mmol.) were taken into acetic acid (25 mL) and the resulting mixture heated to 90° C. over 12 hours. An additional aliquot of benzaldehyde (250 mg) was then added and heating was continued an additional 7 hours. At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. then the mixture was allowed to cool to room temperature. The acetic acid was removed and the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate. The organic layer was then washed once with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products. The desired cyclization isomer was purified by silica gel flash chromatography using 2:1 hexanes ethyl acetate as eluent to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6-fluoro-1-methyl-7-(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-8-ol (1.73 g, 44% yield) as a yellow solid after concentration and drying of the pure fractions in vacuo. 1H NMR (400 MHz, CDCl3): 7.66 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.46-7.34 (m, 5H), 7.07 (d, 1H), 6.54 (s, 1H), 5.25 (S, 2H), 4.03 (d, 3H), 2.80 (s, 3H), 1.83 (s, 9H); MS (EI) for C29H27N3O3FCl: 520 (MH+).

1. temperatureheating
2. customAt this time air was bubbled through the solution at a steady rate
3. temperaturewhile maintaining a temperature of 90° C.
4. temperatureto cool to room temperature
5. customThe acetic acid was removed
6. customthe residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate
7. washThe organic layer was then washed once with brine
8. dry with materialthen dried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. customto give a residue
12. additioncontaining roughly
13. additiona 1:1 mixture of two cyclization products
14. customThe desired cyclization isomer was purified by silica gel flash chromatography