1-Hydroxybenzotriazole → N-Acetyl-tyrosinyl-valinyl-(4(R)-allyloxyproline) methyl ester

HRID 2229943Notes

Reaction equation

HRID 2229943 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:7][NH:6]1.[NH:15]([C:35]([CH3:37])=[O:36])[C@H:16]([C:25]([NH:27][C@H:28]([C:32](O)=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:7][N:6]1[C:32](=[O:33])[C@H:28]([CH:29]([CH3:30])[CH3:31])[NH:27][C:25](=[O:26])[C@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[NH:15][C:35](=[O:36])[CH3:37]

Participants

9

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 22875497N-Acetyl-tyrosinyl-valineHCID 668534754(R)-Allyloxyproline methyl ester hydrochloride

Product 1

HCID 67541324N-Acetyl-tyrosinyl-valinyl-(4(R)-allyloxyproline) methyl esterYield 33.5%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

4(R)-Allyloxyproline methyl ester hydrochloride (1.05 g, 4.75 mmol) and N-acetyl-Tyr-Val-OH (1.68 g, 5.21 mmol) were dissolved in 10 ml of a 1:1 mixture of dichloromethane and dimethylformamide and cooled to 0° C. Diisopropylethylamine (1 ml, 5.93 mmol) was added to the cooled mixture followed by the addition of N-hydroxybenzotriazole (0.769 g, 5.69 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18 g, 6.2 mmol). After stirring for 2 hours, the mixture was warmed to room temperature and stirred for 16 hours. The reaction was poured into 150 ml of ethyl acetate and washed with 50 ml each of water, 10% sodium hydrogen sulfate, and 10% sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and evaporated to give a light yellow solid. This was purified by flash chromatography eluting with dichloromethane/methanol/pyridine (100:3:0.5) to give 780 mg of the title compound. 1H NMR (CD3OD) δ7.02-6.96 (2H, d), 6.67-6.63 (2H, d), 5.95-5.85 (1H, m), 5.34-5.27 (1H, d), 5.16-5.13 (1H, d), 4.53-4.38 (3H, m), 4.28-4.22 (1H, m), 4.12-3.97 (3H, m), 3.82-3.73 (1H, m), 3.72 (3H, s), 3.04-2.88 (2H, m), 2.85-2.72 (2H, m), 2.45-2.34 (1H, m), 2.08-1.95 (2H, m), 1.92 (3H, s), 1.00-0.92 (6H, 2×d).

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. stirringstirred for 16 hours
  3. washwashed with 50 ml each of water, 10% sodium hydrogen sulfate, and 10% sodium bicarbonate
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated
  7. customto give a light yellow solid
  8. customThis was purified by flash chromatography
  9. washeluting with dichloromethane/methanol/pyridine (100:3:0.5)

Sources & evidence

ORD record
ord-5d5bd9f036174242b8d56f9e3964f8f3
Source dataset
uspto-grants-2002_07
Patent number
US06420522B1

Reaction notes

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