Hydroxyamine hydrochloride → 4-((S)-4-((R)-1-Phenylethyl)morpholin-2-yl)benzonitrile

HRID 1896166Notes

Reaction equation

HRID 1896166 reaction equation
[C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29]O>C(O)C>[C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:29])=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

5

Reactant 3

HCID 443297Hydroxyamine hydrochlorideHCID 517045Sodium AcetateHCID 593177364-[(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl]benzaldehyde2×

Product 1

HCID 509925234-((S)-4-((R)-1-Phenylethyl)morpholin-2-yl)benzonitrileYield 86%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of crude 4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl) benzaldehyde (intermediate 14, 55.1 g) in ethanol (280 ml) was added sodium acetate (30.0 g, 365 mmol) and hydroxylamine hydrochloride (25.4 g, 365 mmol) at room temperature. After a reflux for 2 hours, the mixture was partitioned between water and dichloromethane, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was then added with acetic acid (140 ml) and acetic anhydride (140 ml). After the mixture was refluxed for 2 hours, the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1) to afford 4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)benzonitrile (intermediate 15, 45.7 g, 86% from intermediate 13)

Workup

  1. temperatureAfter a reflux for 2 hours
  2. customthe mixture was partitioned between water and dichloromethane
  3. washthe organic layer was washed with water and brine
  4. dry with materialdried over sodium sulfate
  5. customThe solvent was evaporated under reduced pressure
  6. additionThe residue was then added with acetic acid (140 ml) and acetic anhydride (140 ml)
  7. temperatureAfter the mixture was refluxed for 2 hours
  8. customthe solvent was removed under reduced pressure
  9. customThe residue was partitioned between water and chloroform
  10. washThe organic layer was washed with aqueous sodium hydrogen carbonate
  11. dry with materialdried over sodium sulfate
  12. customthe solvent was removed under reduced pressure
  13. customThe residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1)

Sources & evidence

ORD record
ord-80e3fb2336f7443895669d71478637e5
Source dataset
uspto-grants-2013_08
Patent number
US08518939B2

Reaction notes

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