Chloroacetonitrile → (4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetonitrile

HRID 525147

Reaction equation

HRID 525147 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]#[N:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]#[N:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1

Participants

5

Reactant 3

HCID 7856ChloroacetonitrileHCID 11430Potassium CarbonateHCID 67376285Gsk2194069

Product 1

HCID 53373411(4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetonitrileYield 48.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (70 mg, 0.51 mmol, 4 eq) and chloroacetonitrile (17 mg, 0.231 mmol, 1.8 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-60% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (29 mg, 48%). MS(ES)+ m/e 468.2 [M+H]+.

Workup

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additionpoured into a mixture of dichloromethane and water
  5. customThe organic layer was separated
  6. washThe aqueous layer was washed with dichloromethane
  7. extractionThe organic extractions
  8. washwashed 3× with a dilute brine solution
  9. customThe organic layer was separated
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-60% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  14. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
  15. extractionextracted with dichloromethane
  16. dry with materialThe organic layer was dried over sodium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f15aca8f33944c3b9601078827aa2011
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Linked notes

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