反应详情

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 solution to reflux. After 3 hours, cool to ambient temperature and concentrate to give a residue. Dissolve the 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 layers, dry with sodium sulfate filter and concentrate to give a residue. Dissolve the residue in xylenes (20 mL) and heat to 130° C. After 4 hours, cool to ambient temperature and concentrate under reduced pressure to give a residue. Purify the 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 give a residue. Purify the 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 solution to reflux
2. concentrationconcentrate
3. customto give a residue
4. temperaturecool to 0° C
5. waitAfter 30 minutes
6. extractionextract with ethyl acetate
7. dry with materialdry with sodium sulfate
8. filtrationfilter
9. concentrationconcentrate
10. customto give a residue
11. temperatureheat to 130° C
12. waitAfter 4 hours
13. temperaturecool to ambient temperature
14. concentrationconcentrate under reduced pressure
15. customto give a residue
16. customPurify the 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
21. customto give a residue
22. customPurify the residue by reverse phase chromatography
23. washeluting with methanol