反应详情

温度

0 °C

Add hydroxylamine (50% solution in water, 0.128 mL, 2.09 mmol) to a solution of 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (950 mg, 1.90 mmol) in ethanol (20 mL) and stir. Heat the solution to reflux for 3 hours. Cool the reaction to ambient temperature and concentrate to dryness. Dissolve the resulting residue in tetrahydrofuran (20 mL) and cool to 0° C. Add pyridine (226 mg, 2.85 mmol) and 2-ethylhexyl chloroformate (403 mg, 2.09 mmol) and stir. After 30 minutes, add water (50 mL) and extract with ethyl acetate. Combine the organic extracts, dry with sodium sulfate, filter and concentrate to dryness. Dissolve the resulting residue in xylenes (20 mL) and heat to 130° C. After 4 hours, cool to ambient temperature and concentrate under reduced pressure to dryness. Purify the resulting residue by flash chromatography eluting with acetone:acetic acid:hexanes (25%:1%:74%) to give a white solid. Dissolve the solid in a solution of 1% aqueous hydrochloric acid:methanol, and stir. After 1 hour, concentrate under reduced pressure to dryness. Purify the resulting residue by reverse phase chromatography eluting with methanol:acetic acid:water to yield the title compound as a white solid (22 mg, 2.4%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.48 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d, 1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (m, 4H), 7.49 (t, 1H), 7.63 (m, 2H), 7.79 (d, 1H), 7.89 (s, 1H), 12.83 (s, 1H), 12.96 (bs, 1H); MS (esi negative) m/z (rel intensity) 473 (100).

1. temperatureHeat the solution
2. temperatureto reflux for 3 hours
3. temperatureCool
4. customthe reaction to ambient temperature
5. concentrationconcentrate to dryness
6. dissolutionDissolve the resulting residue in tetrahydrofuran (20 mL)
7. extractionextract with ethyl acetate
8. dry with materialdry with sodium sulfate
9. filtrationfilter
10. concentrationconcentrate to dryness
11. dissolutionDissolve the resulting residue in xylenes (20 mL)
12. temperatureheat to 130° C
13. waitAfter 4 hours
14. temperaturecool to ambient temperature
15. concentrationconcentrate under reduced pressure to dryness
16. customPurify the resulting residue by flash chromatography
17. washeluting with acetone
18. customacetic acid:hexanes (25%:1%:74%) to give a white solid
19. waitAfter 1 hour
20. concentrationconcentrate under reduced pressure to dryness
21. customPurify the resulting residue by reverse phase chromatography
22. washeluting with methanol