Pyridine → HCID 59003137, compound

HRID 2353885Notes

Reaction equation

HRID 2353885 reaction equation
[C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:10]([C:9]([F:8])([F:41])[F:42])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2)(=[O:3])[CH3:2]

Participants

5

Reactant 3

HCID 1049PyridineHCID 7918Acetic AnhydrideHCID 86616067HCID 86616067, compound

Product 1

HCID 59003137HCID 59003137, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Add 3,5-bis(trifluoromethyl)benzylamine (1.49 g, 6.13 mmol) followed by titanium isopropoxide (1.60 mL, 5.47 mmol) to a solution of tert-butyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (1.49 g, 4.38 mmol) in tetrahydrofuran (17.5 mL) at room temperature under nitrogen and stir the solution for 14 h. Dilute the reaction with methanol (35 mL) and slowly add sodium borohydride (0.248 g, 6.57 mmol) to the reaction and stir at room temperature for 3 h. Add 2 N NaOH (20 mL) and water (20 mL) to the reaction and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate (3×75 mL). Separate the filtrate and wash the organic layer with brine (25 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (6.0 mL, 64.0 mmol) dropwise to a suspension of tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.42 g, 4.26 mmol) and pyridine (5.2 mL, 64.0 mmol) in dichloromethane (17 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with 2 M potassium hydrogen sulfate and saturated aqueous sodium bicarbonate (25 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid.

Workup

  1. additionAfter the addition
  2. customremove the cooling bath
  3. temperaturewarm
  4. customthe reaction to room temperature
  5. washwash with 2 M potassium hydrogen sulfate and saturated aqueous sodium bicarbonate (25 mL each)
  6. dry with materialDry the organic layer over sodium sulfate
  7. filtrationfilter
  8. customremove the solvent under reduced pressure
  9. customPurify the residue
  10. washeluting with hexanes/ethyl acetate (60:40)

Sources & evidence

ORD record
ord-cac195caba324023a7e99e5f26fef8ca
Source dataset
uspto-grants-2010_07
Patent number
US07749992B2

Reaction notes

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