Dimethylformamide → 2-[[2-(dimethylcarbamoylamino)pyridin-4-yl]methylamino]-N-(2-methylindazol-6-yl)benzamide

HRID 600675

Reaktionsgleichung

Reaktionsgleichung von HRID 600675
Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:34])[C:31]([NH2:33])=[O:32].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:29][N:30]([CH3:34])[C:31](=[O:32])[NH:33][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1

Komponenten

8

Edukt 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 11737N,N-DimethylureaHCID 231189722-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

Produkt 1

HCID 115540512-[[2-(dimethylcarbamoylamino)pyridin-4-yl]methylamino]-N-(2-methylindazol-6-yl)benzamideAusbeute 71,3 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)KatalysatorHCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (110 mg, 0.25 mmol, prepared as detailed infra in Example 4A) and 1,1-dimethylurea (114 mg, 1.3 mmol) were suspended in dioxane (3 mL) under a nitrogen atmosphere and treated consecutively with DMF (1 mL), cesium carbonate (98 mg, 0.3 mmol), Pd2 dba3 (5 mg, 0.005 mmol) and Xantphos (9 mg, 0.015 mmol). The reaction mixture was flushed with nitrogen and heated for 5 hours at 110° C. (bath temperature). On cooling the reaction was concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica get (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5) to give 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide (79 mg, 71%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.15 (1H, s), 8.80 (1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.82 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.22-7.32 (2H, m), 6.95 (1H, d), 6.68 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 2.91 (6H, s); m/z (ES+) 444 [M+H]+, 223; Mp. 184° C.

Aufarbeitung

  1. customThe reaction mixture was flushed with nitrogen
  2. temperatureOn cooling the reaction
  3. concentrationwas concentrated in vacuo
  4. customThe residue was partitioned between CH2Cl2 and water
  5. washThe organic phase was washed with brine
  6. customdried
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography on Isolute® flash silica
  10. customget
  11. wash(Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 95:5)

Quellen und Nachweise

ORD-Eintrag
ord-9aa0692e81b44ed48cd76252abdcead7
Quelldatensatz
uspto-grants-2011_03
Patentnummer
US07902229B2

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