Pyrazole → 4-(3-Difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide

HRID 900479Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 900479
Br[C:2]1[CH:10]=[C:9]([N:11]2[C:19]3[CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][C:15](=[O:22])[C:14]=3[C:13]([CH:23]([F:25])[F:24])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC([O-])(C)C.[Na+].[NH2:32][CH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.N1C=CC=N1.[OH-].[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].CS(C)=O.C1(C)C=CC=CC=1>[F:24][CH:23]([F:25])[C:13]1[C:14]2[C:15](=[O:22])[CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][C:19]=2[N:11]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:32][CH:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH:10]=2)[N:12]=1

Komponenten

11

Edukt 5

HCID 1048PyrazoleHCID 14798Sodium HydroxideHCID 418807Tetrahydrothiopyran-4-ylamineHCID 23676156Sodium t-butoxideHCID 669527232-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide

Produkt 1

HCID 441906574-(3-Difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 167845palladium(II) acetateKatalysatorHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)KatalysatorHCID 679Dimethyl SulfoxideLösungsmittelHCID 702EthanolLösungsmittelHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide (300 mg, 0.76 mmol), Pd(OAc)2 (8.7 mg, 5 mol %), DPPF (44.5 mg, 10 mol %) and NaOtBu (153 mg, 1.52 mmol) were added to a microwave vial. Toluene (1 mL) and 4-aminotetrahydrothiopyran (116 mg, 1.3 mol eq) were added and the vial was evacuated and back-filled with N2. The reaction mixture was heated at 120° C. for 15 min (microwave). The reaction mixture was filtered and the solids washed with CH2Cl2. The product was purified using flash chromatography eluting with hexanes and EtOAc. Product was recovered as an off-white solid (70 mg, 21%). The preceding product pyrazole (70 mg, 0.16 mmol) was dissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 65 mL, 2 eq) was added and the reaction mixture was heated at 70° C. for 12 hours. The reaction mixture was washed with H2O and EtOAc. The product was purified using flash chromatography eluting with hexanes and EtOAc. The title compound was obtained as an off-white solid (40 mg, 56% yield), LC/MS (m/z): M+H=449.2.

Aufarbeitung

  1. customthe vial was evacuated
  2. additionback-filled with N2
  3. filtrationThe reaction mixture was filtered
  4. washthe solids washed with CH2Cl2
  5. customThe product was purified
  6. washeluting with hexanes and EtOAc
  7. customProduct was recovered as an off-white solid (70 mg, 21%)
  8. temperaturethe reaction mixture was heated at 70° C. for 12 hours
  9. washThe reaction mixture was washed with H2O and EtOAc
  10. customThe product was purified
  11. washeluting with hexanes and EtOAc

Quellen und Nachweise

ORD-Eintrag
ord-035980dcf9e74d6082f138e0932d9e02
Quelldatensatz
uspto-grants-2008_04
Patentnummer
US07358370B2

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