Water → N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(methyloxy)-3-pyridinyl]-1H-indazole-4-carboxamide

HRID 85524

Reaktionsgleichung

Reaktionsgleichung von HRID 85524
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][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].O>COCCOC.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:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:3]=1)=[O:15]

Komponenten

7

Edukt 4

HCID 962WaterHCID 516892Sodium BicarbonateHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 545964906-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

Produkt 1

HCID 68210278N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(methyloxy)-3-pyridinyl]-1H-indazole-4-carboxamideAusbeute 44,1 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 18180031Water 1,2-dimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °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 (120 mg, 0.29 mmol) and [6-(methyloxy)-3-pyridinyl]boronic acid (66 mg, 0.43 mmol) in DME/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (11.7 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 110° C. for 20 min. Water was added and the solids that precipitated were filtered. DCM was added and it was purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered. DMF was added along with some water and the solids that precipitated were filtered and dried to afford the title compound (57 mg, 43%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.69 (d, J=2.27 Hz, 1H) 8.62 (t, J=4.80 Hz, 1H) 8.39 (s, 1H) 8.22 (dd, J=8.72, 2.65 Hz, 1H) 8.15 (s, 1H) 7.87 (s, 1H) 6.97 (d, J=8.59 Hz, 1H) 5.89 (s, 1H) 5.15 (dt, J=13.07, 6.47 Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 3.92 (s, 3H) 2.22 (s, 3H) 2.12 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H). MS(ES) [M+H]+ 446.1.

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 solids that precipitated
  4. filtrationwere filtered
  5. additionDCM was added
  6. customit was purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH)
  7. customFractions were evaporated
  8. additionEtOAc was added along with some hexanes, it
  9. customwas sonicated
  10. customthe solids that precipitated
  11. filtrationwere filtered
  12. additionDMF was added along with some water
  13. customthe solids that precipitated
  14. filtrationwere filtered
  15. customdried

Quellen und Nachweise

ORD-Eintrag
ord-0ecc8abb336b468fafa00f543dc1faba
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846935B2

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