Hydroxylamine → HCID 136354502, compound

HRID 1161093Notes

Reaction equation

HRID 1161093 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.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

9

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 4

HCID 313Hydrochloric AcidSolventHCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
0 °C

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 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).

Workup

  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

Sources & evidence

ORD record
ord-f76780dc007541aea60e627020a15faa
Source dataset
uspto-grants-2010_10
Patent number
US07816523B2

Reaction notes

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