Potassium Carbonate → 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4'-(1H-pyrrol-1-yl)-4-biphenylyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525211Notes

Reaction equation

HRID 525211 reaction equation
[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:34]5[CH:35]=[CH:36][C:37]([N:40]6[CH:41]=[CH:42][CH:43]=[CH:44]6)=[CH:38][CH:39]=5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 2724351-(4-bromophenyl)-1H-pyrroleHCID 673756365-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 682611455-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4'-(1H-pyrrol-1-yl)-4-biphenylyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 42%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.252 mmol) in dioxane (1.5 mL) was treated with 1-(4-bromophenyl)-1H-pyrrole (0.252 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.756 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (35-65% acetonitrile/water+0.1% NH4OH). The resulting product was purified by silica gel chromatography (0-8% methanol/dichloromethane) to afford the title compound as an amorphous white solid (42%). MS(ES)+ m/e 454.1 [M+H]+.

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  3. customirradiated in a microwave (Biotage Initiator) at 150° C. for 15 min
  4. additionwas diluted with water (50 mL)
  5. extractionwas extracted with dichloromethane
  6. additionThe resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude residue was purified by reverse phase HPLC (35-65% acetonitrile/water+0.1% NH4OH)
  11. customThe resulting product was purified by silica gel chromatography (0-8% methanol/dichloromethane)

Sources & evidence

ORD record
ord-bba1ecee1c8f40b8934783cc3add308f
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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