Bromide ion → 4'-[[2,3,4,5-Tetrahydro-3(R)-[[3-methyl-1-oxo-3-[[(benzyloxy)carbonyl]amino] butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl]-[1,1'-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester

HRID 1591471Notes

Reaction equation

HRID 1591471 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:36]=1.[Br-]>CN(C)C=O>[CH3:53][C:50]([O:49][C:47]([C:42]1[C:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([CH3:30])([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH3:29])[C:18]3=[O:28])=[CH:40][CH:39]=2)=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:48])([CH3:51])[CH3:52]

Participants

6

Reactant 4

HCID 259Bromide ionHCID 24758Sodium hydrideHCID 9906257tert-Butyl 4'-(bromomethyl)biphenyl-2-carboxylateHCID 105735633-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide

Product 1

HCID 228551634'-[[2,3,4,5-Tetrahydro-3(R)-[[3-methyl-1-oxo-3-[[(benzyloxy)carbonyl]amino] butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl]-[1,1'-biphenyl]-2-carboxylic acid 1,1-dimethylethyl esterYield 96%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 1.22 g (3.0 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 10 mL of dry dimethylformamide under nitrogen was added 131.6 mg (3.29 mmol) of 60% sodium hydride in oil. After stirring for 20 minutes, a solution of 1.14 g (3.29 mmol) of t-butyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared according to the procedure of D. J. Carini, et. al. EPO publication 324,377) in 2.5 mL of dimethylformamide was added by cannula. The flask which originally contained the bromide was rinsed with 2.5 mL dimethylformamide which was added to the reaction mixture. After stirring at room temperature for 2 hours, the reaction was diluted with 400 mL of ethyl acetate, washed with 100 mL of water and 100 mL of brine. The organic layer was 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 (55:45) to afford 1.74 g (96%) of the product as a white foam. 1H NMR (200MHz, CDCl3): 1.15 (s,9H), 1.45 (s,3H), 1.48 (s,3H), 1.76 (m,1H), 2.35-2.62 (m,5H), 4.48 (m,1H), 4.79 (d,14 Hz,1H), 5.04 (t,12 Hz,2H), 5.35 (d,14 Hz,1H), 6.70 (d,6 Hz,1H), 7.10-7.45 (m,17H), 7.72 (m,1H). FAB-MS: calculated for C41H45N3O6 675; found 683 (M+Li).

Workup

  1. washwas rinsed with 2.5 mL dimethylformamide which
  2. additionwas added to the reaction mixture
  3. stirringAfter stirring at room temperature for 2 hours
  4. additionthe reaction was diluted with 400 mL of ethyl acetate
  5. washwashed with 100 mL of water and 100 mL of brine
  6. dry with materialThe organic layer was dried over magnesium sulfate
  7. filtrationfiltered
  8. customthe solvent removed under vacuum
  9. customThe residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45)

Sources & evidence

ORD record
ord-d576a815223d4ea99824129b15e8c72a
Source dataset
uspto-grants-1993_04
Patent number
US05206235

Reaction notes

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