Hydrochloric Acid → 4-[3-fluoro-3'-(methyloxy)-4-biphenylyl]-5-{[(3S)-1-propanoyl-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 2405446Notes

Reaction equation

HRID 2405446 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH2:37]C.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH2:36][CH3:37])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 62324Propionyl chloride2×HCID 673772131,1-dimethylethyl (3S)-3-({4-[3-fluoro-3'-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate

Product 1

HCID 673766094-[3-fluoro-3'-(methyloxy)-4-biphenylyl]-5-{[(3S)-1-propanoyl-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 312751,4-DioxaneSolvent

Procedure

Into a 4 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-3′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.226 mmol). Added to the vial was 4N HCl in dioxane (2.0 mL). The vial was capped and the solution was stirred at room temperature for 2 h. The solution was concentrated in vacuo. Into the vial were place dichloromethane (1 mL) and N,N-diisopropylethylamine (0.14 mL). The solution was cooled in an ice bath. Into a separate vial, propanoyl chloride (0.217 mmol) was taken up in dichloromethane (1 mL) and then 0.5 ml, of this solution was added to the cold reaction. The vial was capped and stirred for 1 h, allowing the ice bath to slowly warm to room temperature. Since it was determined that the reaction was not complete, additional 0.10 mL of propanoyl chloride solution in dichloromethane was added to the reaction. After 1 h, the reaction was complete. Dichloromethane (1 mL) and saturated aq NH4Cl were added to the reaction. The vial was lightly agitated and the liquid phases were allowed to separate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (21 mg, 21%). MS(ES)+ m/e 424.9 [M+H]+.

Workup

  1. additionAdded to the vial
  2. customThe vial was capped
  3. concentrationThe solution was concentrated in vacuo
  4. temperatureThe solution was cooled in an ice bath
  5. addition0.5 ml, of this solution was added to the cold reaction
  6. customThe vial was capped
  7. stirringstirred for 1 h
  8. temperatureto slowly warm to room temperature
  9. waitAfter 1 h
  10. stirringThe vial was lightly agitated
  11. customto separate
  12. customThe organic layer was separated
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customin purifying the title compound (21 mg, 21%)

Sources & evidence

ORD record
ord-6e5b3a7b296b4e2fa9670bc6291ebacc
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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