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

HRID 2405385

Reaction equation

HRID 2405385 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][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[CH:37][C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=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:35]5[CH:36]=[CH:37][C:38]6[O:42][CH2:41][CH2:40][C:39]=6[CH:43]=5)=[CH:20][C:19]=4[F:33])[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 27761595-Bromo-2,3-dihydro-1-benzofuranHCID 67376890HCID 67376890, compound

Product 1

HCID 673756505-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(2,3-dihydro-1-benzofuran-5-yl)-2-fluorophenyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 29%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.351 mmol) in dioxane (1.5 mL) was treated with 5-bromo-2,3-dihydro-1-benzofuran (0.319 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (18 mg), and 2M aq potassium carbonate (0.956 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. 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 organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound (29%). MS(ES)+ m/e 449.0 [M+H]+.

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additionwas diluted with water (50 mL)
  5. extractionwas extracted with dichloromethane
  6. dry with materialThe organic layer was dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH)

Sources & evidence

ORD record
ord-aca2cc8fffde4a649616596ff89d049c
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Linked notes

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