Diisopropylethylamine → c-Met inhibitor 1

HRID 2386591Notes

Reaction equation

HRID 2386591 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([SH:16])=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.I[C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:18]4[CH:26]=[CH:25][C:24]5[C:20](=[CH:21][N:22]([CH3:27])[N:23]=5)[CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 401540075-iodo-2-methyl-2H-indazoleHCID 178480034HCID 178480034, compound

Product 1

HCID 56650915c-Met inhibitor 1Yield 52.5%

Reagents, catalysts & solvents 3

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (2.3 g, 10.0 mmol) in DMF (20 mL) is added 5-iodo-2-methyl-2H-indazole (2.6 g, 10.0 mmol), tris(dibenzylideneacetone) dipalladium(0) (460 mg; 502.7 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (580 mg, 1.0 mmol), diisopropylethylamine (4 mL, 22.9 mmol). The mixture is purged with N2 and stirred at 100° C. for 18 h. DMF is removed under vacuum, and the residue is purified by flash column chromatography (Combi-Flash, silica gel) eluting with DCM/methanol (20:1) to give a crude product. The crude product is suspended in 20 mL of DCM to give slurry, and the pure product is collected by filtration to afford the title compound (1.9 g, 52.5%) as a yellow solid. MS (m/z): 363.1 (M+H).

Workup

  1. customThe mixture is purged with N2
  2. customDMF is removed under vacuum
  3. customthe residue is purified by flash column chromatography (Combi-Flash, silica gel)
  4. washeluting with DCM/methanol (20:1)
  5. customto give a crude product
  6. customto give slurry
  7. filtrationthe pure product is collected by filtration

Sources & evidence

ORD record
ord-ea678d841d664d46882c6b3762643dbb
Source dataset
uspto-grants-2012_09
Patent number
US08268836B2

Reaction notes

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