Cesium carbonate → 4-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid

HRID 1472577Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1472577
[Cl:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=1.[C:29](=[O:32])([O-])[O-:30].[Cs+].[Cs+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:29]([OH:30])=[O:32])=[C:4]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:25][C:23]3[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH3:19])[CH:24]=3)[CH:12]=2)[CH:3]=1

Komponenten

8

Edukt 5

HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 1210181-Isopropyl-3-methyl-1H-pyrazol-5-amineHCID 4285986Bis[2-(diphenylphosphino)phenyl] etherHCID 575169164-Chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile

Produkt 1

HCID 667692534-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acidAusbeute 6,6 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A solution of 4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (2.8 g, 9.38 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (1.305 g, 9.38 mmol) and cesium carbonate (9.17 g, 28.1 mmol) in 1,4-dioxane (40 mL) was degassed. DPEPhos (0.404 g, 0.750 mmol) followed by palladium acetate (0.084 g, 0.375 mmol) were added, and the suspension was refluxed overnight. The solid was filtered, the reaction mixture was evaporated. The black oil was purified by flush column chromatography on silica gel (5% EtOAc:DCM). The combined fractions were evaporated. The resulting oil was dissolved in dioxane (20 mL) and sodium hydroxide (20 mL, 20.00 mmol) was added and the reaction mixture was refluxed overnight. The layers were separated and the organic layer was washed with 20 ml of 1 M NaOH. The aqueous layers were combined and washed with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4 and filtered. The solution was evaporated, suspended in acetonitrile and filtered. 4-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (260 mg, 0.619 mmol, 6.60% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 1.91 (s, 1 H) 2.13 (s, 3 H) 4.43 (quin, J=6.57 Hz, 1 H) 5.97 (s, 1 H) 6.78 (s, 1 H) 7.05 (dd, J=8.46, 1.89 Hz, 1 H) 7.48 (d, J=1.77 Hz, 1 H) 7.96 (d, J=8.34 Hz, 1 H) 8.03 (s, 1 H) 8.61 (s, 1 H); HPLC Rt=2.70 min, MS (ESI): 420.1, 422.0 [M+H]+.

Aufarbeitung

  1. additionwere added
  2. temperaturethe suspension was refluxed overnight
  3. filtrationThe solid was filtered
  4. customthe reaction mixture was evaporated
  5. customThe black oil was purified
  6. customby flush column chromatography on silica gel (5% EtOAc:DCM)
  7. customThe combined fractions were evaporated
  8. dissolutionThe resulting oil was dissolved in dioxane (20 mL)
  9. temperaturethe reaction mixture was refluxed overnight
  10. customThe layers were separated
  11. washthe organic layer was washed with 20 ml of 1 M NaOH
  12. washwashed with EtOAc
  13. washThe combined organic layers were washed with water, brine
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. customThe solution was evaporated
  17. filtrationfiltered

Quellen und Nachweise

ORD-Eintrag
ord-7a02d01d3450469f844d49f29ef00be0
Quelldatensatz
uspto-grants-2015_04
Patentnummer
US09012479B2

Notizen zur Reaktion

Wird geladen…