Diisopropylethylamine → (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-N,N-dimethyl-1-pyrrolidinecarboxamide

HRID 525248Notes

Reaction equation

HRID 525248 reaction equation
Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[C:5]([F:21])[CH:4]=1.CNN(NC)C(Cl)=[O:26].[CH:30]([N:33]([CH2:37]C)[CH:34](C)C)(C)C>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10](=[O:20])[NH:11][N:12]=[C:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:37]([N:33]([CH3:34])[CH3:30])=[O:26])[CH2:16]2)=[C:5]([F:21])[CH:4]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 673755214-(4-bromo-2-fluorophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochlorideHCID 86674832N,N-dimethylaminocarbamoyl chloride3×

Product 1

HCID 67375611(3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-N,N-dimethyl-1-pyrrolidinecarboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Into a 4 mL screwcap vial was placed 4-(4-bromo-2-fluorophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.265 mmol), polystyrene-DIEA (216 mg, 3.68 mmol/g loading, 0.794 mmol) and 2 mL dichloromethane. The contents were lightly swirled. In a separate vial, N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was taken up in 1 mL dichloromethane and added to the starting material dropwise via pipette. The vial was capped and the solution was lightly agitated at room temperature overnight. The reaction had only progressed by 50% via LCMS analysis. Another equivalent of N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was added to the reaction. After 8 h at room temperature, another equivalent of N,N-dimethylaminocarbamoyl chloride (0.265 mmol) was added, as well as N,N-diisopropylethylamine (0.100 mL). After 1 h, the reaction mixture became clear. The solution was filtered to remove the polystyrene-DIEA and then concentrated in vacuo. Reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA) was utilized in purifying the title compound (60 mg, 55%). MS(ES)+ m/e 412.3, 414.1 [M+H]+.

Workup

  1. additionadded to the starting material dropwise via pipette
  2. customThe vial was capped
  3. waitAfter 8 h at room temperature
  4. waitAfter 1 h
  5. filtrationThe solution was filtered
  6. customto remove the polystyrene-DIEA
  7. concentrationconcentrated in vacuo
  8. customin purifying the title compound (60 mg, 55%)

Sources & evidence

ORD record
ord-20205ff469994393acfe886575811d0d
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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