Sodium Bicarbonate → N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-4-carboxamide

HRID 85427Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 85427
Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[CH:3]=1)=[O:15]

Komponenten

6

Edukt 3

HCID 516892Sodium BicarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 545964906-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

Produkt 1

HCID 54596626N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-4-carboxamideAusbeute 77,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 218864351,4-Dioxane--water (1/1)Lösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (82 mg, 0.4 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (10.8 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (66.4 mg, 0.79 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. The mixture was evaporated, DCM/MeOH (1:1) was added, and the contents pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes, it was sonicated, and the solids that precipitated were filtered. Acetonitrile was added, solids that precipitated were filtered, and further washed with acetonitrile/ether (2:8) and dried to afford the title compound as an off-white solid (84 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.48 (t, J=4.93 Hz, 1H) 8.31 (s, 1H) 8.26 (s, 1H) 8.04 (s, 1H) 8.03 (s, 1H) 7.81 (d, J=1.01 Hz, 1H) 5.90 (s, 1H) 5.06 (quin, J=6.57 Hz, 1H) 4.39 (s, 1H) 4.38 (s, 1H) 3.90 (s, 3H) 2.23 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.48 (s, 3H); LC-MS (ES) m/z=419.0

Aufarbeitung

  1. customIn a 25 mL sealable tube under nitrogen were combined
  2. customthe resulting mixture was degassed with nitrogen for 10 min
  3. customthe vessel was sealed
  4. customThe mixture was evaporated
  5. additionDCM/MeOH (1:1) was added
  6. customthe contents pre-absorbed on silica gel
  7. custompurified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH)
  8. customwas sonicated
  9. customthe solids that precipitated
  10. filtrationwere filtered
  11. additionAcetonitrile was added
  12. customsolids that precipitated
  13. filtrationwere filtered
  14. washfurther washed with acetonitrile/ether (2:8)
  15. customdried

Quellen und Nachweise

ORD-Eintrag
ord-8f3e9de92f1d4b33abb71b0648c6ead9
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846935B2

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