Dimethylacetamide → 6-cyano-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide

HRID 85469Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 85469
Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30](C)C(=O)C.C([O-])(O)=O.[Na+]>O.[C-]#N.[Zn+2].[C-]#N.[Zn].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].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>[C:29]([C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1)#[N:30]

Komponenten

9

Edukt 3

HCID 31374DimethylacetamideHCID 516892Sodium BicarbonateHCID 545970746-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1H-indazole-4-carboxamide

Produkt 1

HCID 545972996-cyano-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 11186Zinc cyanide (Zn(CN)2)KatalysatorHCID 23994ZincKatalysatorHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)KatalysatorHCID 178418807HCID 178418807, VerbindungKatalysatorHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
135 °C

Versuchsvorschrift

To 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.25 g, 0.564 mmol), zinc cyanide (0.066 g, 0.564 mmol), zinc (7.37 mg, 0.113 mmol), and dppf (0.063 g, 0.113 mmol) was added N,N-Dimethylacetamide (DMA) (5.0 mL). The suspension was stirred with degassing under nitrogen for 5 min. Next added PdCl2(dppf)-CH2Cl2 adduct (0.046 g, 0.056 mmol). The reaction contents were sealed and stirred with heating at 135° C. (heat block) for 16 h. The reaction mixture was allowed to cool to RT, diluted with 80 mL of water, and adjusted to pH˜8 with sat NaHCO3. The contents were stirred for 30 min, filtered, and the filter cake was washed with water. The collected solid was dried under hi vacuum for 4 h. The crude product was dissolved in DCM/MeOH followed by addition of silica gel, and concentrated in vacuo to dryness. The contents were purified by silica gel chromatography (dry loaded; eluent: 2-65% gradient of 10% methanol in dichloromethane and dichloromethane). The product was concentrated from MTBE and dried in hi-vac oven for 6 h at 45° C. to afford the title compound as 0.190 g (85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.75 (m, 2H) 1.83-1.93 (m, 2H) 1.94-2.06 (m, 2H) 2.10-2.19 (m, 5H) 2.21 (s, 3H) 4.35 (d, J=4.80 Hz, 2H) 5.31 (t, J=7.07 Hz, 1H) 5.89 (s, 1H) 7.91 (d, J=1.26 Hz, 1H) 8.51 (s, 1H) 8.60 (s, 1H) 8.66 (t, J=4.93 Hz, 1H) 11.54 (s, 1H); LC-MS (ES) m/z=390.2 [M+H]+

Aufarbeitung

  1. additionTo 20 mL microwave vial containing
  2. customwith degassing under nitrogen for 5 min
  3. customThe reaction contents
  4. customwere sealed
  5. stirringstirred
  6. temperature(heat block) for 16 h
  7. temperatureto cool to RT
  8. stirringThe contents were stirred for 30 min
  9. filtrationfiltered
  10. washthe filter cake was washed with water
  11. customThe collected solid was dried under hi vacuum for 4 h
  12. dissolutionThe crude product was dissolved in DCM/MeOH
  13. additionfollowed by addition of silica gel
  14. concentrationconcentrated in vacuo to dryness
  15. customThe contents were purified by silica gel chromatography (dry loaded; eluent: 2-65% gradient of 10% methanol in dichloromethane and dichloromethane)
  16. concentrationThe product was concentrated from MTBE
  17. customdried in hi-vac oven for 6 h at 45° C.

Quellen und Nachweise

ORD-Eintrag
ord-582e43d7a88045e99efcc88bcbb5461b
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846935B2

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