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

HRID 2405325Notes

Reaction equation

HRID 2405325 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.FC(F)(F)S(O[C:39]1[CH:47]=[CH:46][C:42]2[CH:43]=[CH:44][O:45][C:41]=2[CH:40]=1)(=O)=O.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>[O:45]1[C:41]2[CH:40]=[C:39]([C:21]3[CH:22]=[CH:23][C:18]([N:13]4[C:12]([CH2:11][C@@H:8]5[CH2:9][CH2:10][N:6]([C:4]([CH:1]6[CH2:3][CH2:2]6)=[O:5])[CH2:7]5)=[N:16][NH:15][C:14]4=[O:17])=[CH:19][CH:20]=3)[CH:47]=[CH:46][C:42]=2[CH:43]=[CH:44]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 11357589Benzofuran-6-YL trifluoromethanesulfonateHCID 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 682611264-[4-(1-benzofuran-6-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 16.2%

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-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.235 mmol) in dioxane (1.5 mL) was treated with 1-benzofuran-6-yl trifluoromethanesulfonate (0.230 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (11.5 mg), and 2M aq potassium carbonate (0.705 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 flash chromatography (0-8% methanol/dichloromethane), followed by purification by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-45% acetonitrile w/0.1% TFA/water w/0.1% TFA). The combined product fractions were neutralized with the addition of saturated aqueous sodium bicarbonate, concentrated under reduced pressure, and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as an off-white amorphous solid (16 mg, 15% yield). MS(ES)+ m/e 428.9 [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 flash chromatography (0-8% methanol/dichloromethane)
  10. customfollowed by purification by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-45% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  11. additionThe combined product fractions were neutralized with the addition of saturated aqueous sodium bicarbonate
  12. concentrationconcentrated under reduced pressure
  13. extractionextracted with dichloromethane
  14. dry with materialThe combined organic layers were dried over magnesium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-87ac5b6f83d2497988a6e4d371c95a53
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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