1-Hydroxybenzotriazole → N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide

HRID 554151Notes

Reaction equation

HRID 554151 reaction equation
[CH2:1]([N:3]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH:45][C:5](=[O:7])[C@@H:4]1[CH2:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:3]1[CH2:1][CH3:2]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 1399092-Chloro-4-fluorobenzylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 674615891-Ethyl-4,4-dimethyl-5-oxoproline

Product 1

HCID 67461683N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamideYield 63.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-ethyl-4,4-dimethyl-5-oxoproline (0.130 g, 0.702 mmol, prepared as described below), 1-Hydroxybenzotriazole (0.161 g, 1.053 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.202 g, 1.053 mmol) were dissolved in dichloromethane (5 ml) and stirred for 15 minutes at room temperature. [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.842 mmol) and diisopropylethylamine (0.184 ml, 1.053 mmol) were then added to the mixture and stirring continued overnight at room temperature. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed sequentially with 3N citric acid, water, saturated aqueous sodium carbonate, water (×3), and then brine and dried over anhydrous sodium sulfate. Concentration gave a crude solid which was subsequently purified by mass-directed automated HPLC to give N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (0.146 g) as a solid. LC/MS [M+H]+=327/329, retention time=2.35 minutes.

Workup

  1. stirringstirring continued overnight at room temperature
  2. concentrationThe mixture was then concentrated in vacuo
  3. customthe residue partitioned between ethyl acetate and water
  4. extractionextracted with ethyl acetate
  5. washThe combined organic layers were washed sequentially with 3N citric acid, water, saturated aqueous sodium carbonate, water (×3)
  6. dry with materialbrine and dried over anhydrous sodium sulfate
  7. concentrationConcentration
  8. customgave a crude solid which
  9. customwas subsequently purified

Sources & evidence

ORD record
ord-3cc5790e52d646ac93b9054c917ba56c
Source dataset
uspto-grants-2011_11
Patent number
US08048907B2

Reaction notes

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