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3,5-Bis(trifluoromethyl)benzylamine → (+/-)-t-Butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate

HRID 2353963
Notes
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Reaction equation

HRID 2353963 reaction equation
[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C:27](=O)[C:26]2[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH4-].[Na+]>CO.O.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[C:26]2[CH:32]=[C:33]([C:36]([F:39])([F:37])[F:38])[CH:34]=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:18])[CH3:19]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 5210993,5-Bis(trifluoromethyl)benzylamineHCID 4311764Sodium borohydrideHCID 686786965-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86616081(+/-)-t-Butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 11026
Titanium isopropoxide
Catalyst
HCID 887MethanolSolvent
HCID 962WaterSolvent
HCID 8857Ethyl AcetateSolvent

Procedure

Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at room temperature overnight. Dilute the mixture with 5 mL of Methanol and add sodium borohydride (0.8 mmol). Stir the suspension at room temperature for 30 min then dilute with water (20 mL) and ethyl acetate (20 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×20 mL). Separate the organics, dry over sodium sulfate, and filter. Remove the solvent under vacuum to afford (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate crude (0.2 g, MS (ES+): 557 (M+H)). Without further purification, add acetyl chloride (0.8 mmol) and pyridine (0.8 mmol) to a solution of (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in dichloromethane. After stirring for 2 h remove solvent under vacuum and chromatograph over silica gel using ethyl acetate/hexane (5-40%) to elute. This affords the title compound as an oil (0.2 g, 83%) which foams under vacuum: MS (ES−): 597 (M−H).

Workup

  1. stirringStir the suspension at room temperature for 30 min
  2. filtrationFilter the resulting emulsion through celite
  3. washwash with ethyl acetate (3×20 mL)
  4. customSeparate the organics,
  5. dry with materialdry over sodium sulfate
  6. filtrationfilter
  7. customRemove the solvent under vacuum

Sources & evidence

ORD record
ord-5b74781093d54dd18638cf7f9e0ca76f
Source dataset
uspto-grants-2010_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07749992B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes