Potassium Carbonate → 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(6-fluoro-2-naphthalenyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 2405447Notes

Reaction equation

HRID 2405447 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([F:60])[CH:56]=2)[CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O1CCOCC1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:50]5[CH:59]=[CH:58][C:57]6[C:52](=[CH:53][CH:54]=[C:55]([F:60])[CH:56]=6)[CH:51]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 3453972-Bromo-6-fluoronaphthaleneHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 673758864-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 682614885-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(6-fluoro-2-naphthalenyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Into a 5 mL microwaveable vial was placed 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol), bis(pinacolato)diboron (0.244 mmol), potassium acetate (0.977 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.024 mmol), and 1,4-dioxane (2 mL). The vial was capped and the contents were purged with nitrogen. The solution stirred at 100° C. for 16 h. LCMS analysis displayed boronic ester intermediate present (boronic ester cleavage to acid also observed on LCMS) as well as a small amount of bromide starting material. The reaction was cooled to room temperature. Added to the vial was 2-bromo-6-fluoronaphthalene (0.244 mmol) and 2M aq potassium carbonate (1 mL). The vial was capped, purged with nitrogen, and stirred at 100° C. for 1 h. The solution was cooled to room temperature, whereby the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (2 mL). All dioxane filtrates were combined and concentrated in vacuo. Reverse phase HPLC (30-80% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (21 mg, 17%). MS(ES)+ m/e 475.1 [M+H]+.

Workup

  1. customThe vial was capped
  2. customthe contents were purged with nitrogen
  3. temperatureThe reaction was cooled to room temperature
  4. additionAdded to the vial
  5. customThe vial was capped
  6. custompurged with nitrogen
  7. stirringstirred at 100° C. for 1 h
  8. temperatureThe solution was cooled to room temperature
  9. customwhereby the dioxane layer separated from the aqueous layer
  10. customThe dioxane layer was removed via pipette
  11. washThe plug was washed with dioxane (2 mL)
  12. concentrationconcentrated in vacuo
  13. customin purifying the title compound (21 mg, 17%)

Sources & evidence

ORD record
ord-839f64f72c5e4b59b93149554a90f90e
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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