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

HRID 525235Notes

Reaction equation

HRID 525235 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])=[CH:4][C:3]=1[OH:25].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>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:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[CH:4][C:3]=3[OH:25])=[CH:42][C:38]=2[CH:39]=[CH:40]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 27951905-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuranHCID 710877294-(4-bromo-3-hydroxyphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 682611484-[4-(1-benzofuran-5-yl)-3-hydroxyphenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 26.2%

Reagents, catalysts & solvents 1

HCID 178418807HCID 178418807, compoundCatalyst

Conditions

Temperature
100 °C

Procedure

To a microwave vial were added 4-(4-bromo-3-hydroxyphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.172 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (0.26 mmol), Cs2CO3 (0.52 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.00735 mmol). The mixture was purged with nitrogen followed by the addition of 1,4-dioxane (1 mL) and water (0.5 mL). The suspension was heated for 16 h at 100° C., at which point LCMS analysis indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title product as a white solid (20 mg, 26%). MS(ES)+ m/e 445.2 [M+H]+.

Workup

  1. customThe mixture was purged with nitrogen
  2. additionfollowed by the addition of 1,4-dioxane (1 mL) and water (0.5 mL)
  3. customdesired product formation and consumption of starting material
  4. filtrationThe mixture was filtered through a syringe
  5. filtrationfilter
  6. custompurified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA)
  7. customThe desired fractions were collected
  8. additionadded to a separatory funnel
  9. additioncontaining ethyl acetate
  10. extractionThe aqueous phase was extracted with ethyl acetate (3×)
  11. washthe combined organics were washed with brine
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-508d8c1945a145d580c6c5f6dd3573b4
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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