Hydroxylamine → HCID 136354502, compound

HRID 1161109Notes

Reaction equation

HRID 1161109 reaction equation
NO.[C:3]([C:6]1[CH:35]=[CH:34][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:14][CH:13]=2)=[C:8]([CH2:36][CH2:37][CH3:38])[C:7]=1[OH:39])(=[O:5])[CH3:4].[N:40]1C=CC=CC=1.Cl[C:47]([O:49]CC(CC)CCCC)=[O:48]>C(O)C.O1CCCC1.Cl.CO.O>[C:3]([C:6]1[CH:35]=[CH:34][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH:20]=[C:21]([C:22]4[NH:40][C:47](=[O:48])[O:49][N:23]=4)[CH:24]=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)=[C:8]([CH2:36][CH2:37][CH3:38])[C:7]=1[OH:39])(=[O:5])[CH3:4]

Participants

10

Reactant 4

HCID 787HydroxylamineHCID 1049PyridineHCID 627832-Ethylhexyl chloroformateHCID 666996043-[[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile

Product 1

HCID 136354502HCID 136354502, compoundYield 2.4%

Reagents, catalysts & solvents 5

HCID 313Hydrochloric AcidSolventHCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-b1765ffc31f44d3fa3803cedad98038e
Source dataset
uspto-grants-2010_10
Patent number
US07816523B2

Reaction notes

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