Bromide ion → 3-[[1-[[2'-Cyano-[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]amino]-1,1-dimethyl-3-oxopropylcarbamic acid, 1,1-dimethylethyl ester

HRID 1591470

Reaction equation

HRID 1591470 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:33]=1.[Br-]>CN(C)C=O>[C:44]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:27])[CH3:26])[C:15]2=[O:25])=[CH:37][CH:36]=1)#[N:45]

Participants

6

Reactant 4

HCID 259Bromide ionHCID 24758Sodium hydride2×HCID 15019124'-(Bromomethyl)-2-cyanobiphenylHCID 104746043-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide

Product 1

HCID 571704893-[[1-[[2'-Cyano-[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]amino]-1,1-dimethyl-3-oxopropylcarbamic acid, 1,1-dimethylethyl esterYield 90.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 0.83 g (2.21 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) in 6 mL of dry dimethylformamide at room temperature under nitrogen was added 97 mg of 60% sodium hydride dispersion in oil (58 mg NaH, 2.43 mmol, 1.1 eq). After stirring for 1 hour, a solution of 780 mg (2.88 mmol, 1.3 eq) of 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step C) in 2.0 mL of dimethylformamide was added via cannula. The flask which originally contained the bromide was washed with 1 mL of dry dimethylformamide which was then added to the reaction mixture via cannula. After stirring at room temperature for 3 hours, the reaction was diluted with 200 mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (6:4), to afford 1.13 g (90%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.32 (s,3H), 1.40 (s,12H), 1.85 (m,1H), 2.35-2.70 (m,5H), 4.52 (m,1H), 4.90 (d,12 Hz,1H), 5.21 (d,12 Hz,1H), 6.70 (d,5 Hz,1H), 7.10-7.65 (m,12H), 7.72 (d,6 Hz,1H). FAB-MS: calculated for C34H38N4O4 566; found 567 (M+H).

Workup

  1. washwas washed with 1 mL of dry dimethylformamide which
  2. additionwas then added to the reaction mixture via cannula
  3. stirringAfter stirring at room temperature for 3 hours
  4. additionthe reaction was diluted with 200 mL of ethyl acetate
  5. washwashed with 50 mL of water and 50 mL of brine
  6. customThe organic layer was separated
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. customthe solvent removed under vacuum
  10. customThe residue was purified by flash chromatography on silica gel
  11. washeluting with ethyl acetate/hexane (6:4)

Sources & evidence

ORD record
ord-a186ee16567e410c8bf862a9fcbe60c9
Source dataset
uspto-grants-1993_04
Patent number
US05206235

Linked notes

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