Hydroxyamine hydrochloride → (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester

HRID 507114Notes

Reaction equation

HRID 507114 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16](=O)[CH2:17][C:18](=O)[CH3:19])[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:47][OH:48].C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([C:33]([F:35])([F:36])[F:34])[CH:24]=2)[C:16]2[O:48][N:47]=[C:18]([CH3:19])[CH:17]=2)[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:42])[F:43])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 443297Hydroxyamine hydrochlorideHCID 517045Sodium AcetateHCID 59432337(S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester

Product 1

HCID 59432319(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl esterYield 17%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of compound (S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (600 mg, 0.916 mmol) in methanol (5 mL) at 0° C., add hydroxylamine hydrochloride (96 mg, 1.37 mmol) and sodium acetate (3 mg, 0.046 mmol). Heat the reaction mixture under reflux for 4 h. Cool and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and brine. Separate the layers and dry the organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (20:1 to 3:1) to afford the title compound as an off-white solid (100 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 1.10-2.10 (m, 16H), 2.21 (s, 3H), 2.54 (s, 3H), 4.22-4.83 (m, 3H), 6.89-6.92 (m, 1H), 7.36-7.89 (m, 4H); ESI MS m/z 652 [C30H30F9N3O3+H]+.

Workup

  1. temperatureHeat the reaction mixture
  2. temperatureunder reflux for 4 h
  3. temperatureCool
  4. customremove the solvents under reduced pressure
  5. additionDilute the residue with ethyl acetate and brine
  6. customSeparate the layers
  7. dry with materialdry the organic phase over sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate under reduced pressure
  10. customPurify the residue by flash chromatography
  11. washeluting with hexanes/ethyl acetate (20:1 to 3:1)

Sources & evidence

ORD record
ord-7eda5defa1b14c308327464286d52e5d
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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