Cesium carbonate → 4-[5-chloro-2-fluoro-4-(7-quinolinyl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525229Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 525229
Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=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>[Cl:8][C:7]1[C:2]([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)=[CH:3][C:4]([F:26])=[C:5]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:25])[CH:6]=1

Komponenten

5

Edukt 3

HCID 10796Cesium carbonateHCID 592961167-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)QuinolineHCID 710870634-(4-bromo-5-chloro-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Produkt 1

HCID 682613774-[5-chloro-2-fluoro-4-(7-quinolinyl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneAusbeute 33 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 178418807HCID 178418807, VerbindungKatalysator

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a microwave vial were added 4-(4-bromo-5-chloro-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.124 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.16 mmol), cesium carbonate (0.37 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0062 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated for 15 h at 100° C. Analysis by LCMS 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, and concentrated to afford the title product as an off-white solid (20 mg, 33%). MS(ES)+ m/e 492.2, 494.0 [M+H]+.

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag
ord-2e366af757e14f119205e52578c5cb37
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09340529B2

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