Hydrochloric Acid → 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 2405372Notes

Reaction equation

HRID 2405372 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[O:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][CH:14]5[CH2:17][N:16]([C:18]([CH:20]6[CH2:22][CH2:21]6)=[O:19])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:23])=[CH:4][CH:3]=3)=[CH:40][C:36]=2[CH:37]=[CH:38]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 27951905-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran2×HCID 67355143HCID 67355143, compound

Product 1

HCID 673761624-[4-(1-benzofuran-5-yl)phenyl]-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 40.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (83 mg, 0.220 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.5 mL, 1.00 mmol) was stirred at 100° C. in an oil bath for 22 h. Additional 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol) were added and the reaction mixture was heated at 100° C. in an oil bath for 20 h. The reaction was cooled to room temperature, poured into water (50 mL), and adjusted to pH˜4.5 with 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate, then 0-10% methanol/ethyl acetate) followed by a second purification by reverse phase HPLC (20-70% acetonitrile/water+0.1% NH4OH) provided the title compound as an ivory solid (37 mg, 38%). MS(ES)+ m/e 415.2 [M+H]+.

Workup

  1. customIn a microwave vial purged with nitrogen
  2. temperaturethe reaction mixture was heated at 100° C. in an oil bath for 20 h
  3. temperatureThe reaction was cooled to room temperature
  4. extractionThe aqueous layer was extracted with ethyl acetate (3×50 mL)
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification of the residue by flash chromatography (ethyl acetate
  9. custom0-10% methanol/ethyl acetate) followed by a second purification by reverse phase HPLC (20-70% acetonitrile/water+0.1% NH4OH)

Sources & evidence

ORD record
ord-8b709cb4e7884089b50b790af97cb9c3
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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