1-Hydroxybenzotriazole → {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester

HRID 227149Notes

Reaction equation

HRID 227149 reaction equation
[I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C@@H:9]([NH2:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:20]([O:24][C:25](=[O:26])[NH:27][C@H:28]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][CH:37]=1)[C:29](=[O:30])[NH:17][C@H:9]([C:7]1[NH:6][C:5]2[CH:18]=[CH:19][C:2]([I:1])=[CH:3][C:4]=2[N:8]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:22])([CH3:23])[CH3:21]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66815165(R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acidHCID 178511763HCID 178511763, compound

Product 1

HCID 178450554{(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl esterYield 83%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylamine (161 mg, 0.44 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (179 mg, 0.49 mmol) (prepared as described below), N,N-diisopropylethylamine (310 μL, 1.77 mmol), N-hydroxybenzotriazole (72 mg, 0.53 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (202 mg, 0.53 mmol) and a catalytic amount of dimethyl-pyridin-4yl-amine. The mixture was stirred under an atmosphere of nitrogen with warming to room temperature over 3 hours. The reaction was poured into ice/water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 35% v/v ethyl acetate/hexanes to give {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (260 mg, 83%).

Workup

  1. extractionextracted with ethyl acetate (2×20 mL)
  2. washwashed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by chromatography over silica gel gradient
  7. washeluted with 20 to 35% v/v ethyl acetate/hexanes

Sources & evidence

ORD record
ord-2c8528283eb14d82be6097fee6c82b82
Source dataset
uspto-grants-2009_07
Patent number
US07557221B2

Reaction notes

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