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

HRID 2405351Notes

Reaction equation

HRID 2405351 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.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].O.Cl>O1CCOCC1.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>[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:29]5[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([F:26])[CH:28]=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 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 27826743-Fluoro-4-methylbenzeneboronic acidHCID 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 682609965-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(3,3'-difluoro-4'-methyl-4-biphenylyl)-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 58%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 11430Potassium CarbonateSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 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), (3-fluoro-4-methylphenyl)boronic acid (0.370 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.012 mmol) in dioxane (2.0 mL) and 2M aq potassium carbonate (0.5 mL) was irradiated in the microwave at 150° C. for 15 min. The reaction mixture was poured into water (50 mL) and the pH was adjusted to 5 with addition of 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (100% ethyl acetate) and then reverse phase HPLC (30-65% acetonitrile/water with 0.1% NH4OH) provided the title compound as a tan solid (58%). MS(ES)+ m/e 439.2 [M+H]+.

Workup

  1. customwas irradiated in the microwave at 150° C. for 15 min
  2. extractionThe aqueous layer was extracted with ethyl acetate (3×50 mL)
  3. dry with materialthe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification of the residue by flash chromatography (100% ethyl acetate)

Sources & evidence

ORD record
ord-d751b67f5e4641d0a816e0d6899ce678
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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