Dimethylformamide → t-Butyl 4'-[[3(R)-[[3-[2(R)-benzyloxypropyl]amino-3-methyl-1-oxobutyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylate

HRID 1755790Notes

Reaction equation

HRID 1755790 reaction equation
[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][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])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:36]1[CH:37]=[C:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:40][CH:41]=1.[CH3:55]N(C)C=O>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][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[N:19]([CH2:55][C:45]2[CH:44]=[CH:43][C:42]([C:39]3[C:38]([C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[CH:37][CH:36]=[CH:41][CH:40]=3)=[CH:47][CH:46]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 4

HCID 6228Dimethylformamide2×HCID 24758Sodium hydrideHCID 186514253-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamideHCID 19036077HCID 19036077, compound2×

Product 1

HCID 22855160t-Butyl 4'-[[3(R)-[[3-[2(R)-benzyloxypropyl]amino-3-methyl-1-oxobutyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylateYield 92%

Procedure

To a solution of 600 mg(1.42 mmol) of 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (Step C) in 10 mL of N,N-dimethylformamide at 0° C. under nitrogen was added 59.5 mg(1.49 mmol) of 60% sodium hydride/oil dispersion. After stirring for 5 minutes, a solution of 450 mg (1.49 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 4 mL of dimethylformamide was added dropwise via cannula. The flask originally containing the t-butyl 4-bromomethyl-1,1'-biphenyl-2-carboxylate was rinsed with 2 mL dimethylformamide which was added to the reaction mixture. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 300 mL of ethyl acetate and washed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine, dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by column flash chromatography on silica gel eluting with chloroform/10% ammonium hydroxide in methanol (93/7) to give 900 mg (92%) of the product. 1H NMR (200MHz, CD3OD): δ1.10 (s, 3H), 1.12 (s, 9H), 1.15 (s, 3H), 1.25 (d, 7 Hz, 3H), 2.15-2.70 (m, 7H), 3.84 (q, 6 Hz, 1H), 4.48-4.68 (m, 3H), 4.82 (d, 15 Hz, 1H), 5.31 (d, 15 Hz, 1H), 7.08-7.48 (m, 16H), 7.7 (dd; 2, 7 Hz; 1H). FAB-MS: calculated for C43H51N3O5 689; found 690 (M+H,70%).

Workup

  1. washwas rinsed with 2 mL dimethylformamide which
  2. additionwas added to the reaction mixture
  3. stirringstirred for 1.5 hours
  4. additionThe reaction mixture was diluted with 300 mL of ethyl acetate
  5. washwashed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customthe solvents removed under vacuum
  9. customThe residue was purified by column flash chromatography on silica gel eluting with chloroform/10% ammonium hydroxide in methanol (93/7)

Sources & evidence

ORD record
ord-7ed0e1fefd9a4191952b9aaae281b225
Source dataset
uspto-grants-1995_08
Patent number
US05438136

Reaction notes

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