Picolinic acid → c-Met inhibitor 1

HRID 2386592Notes

Reaction equation

HRID 2386592 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.N1C=CC=CC=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[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 1018Picolinic acidHCID 10796Cesium carbonateHCID 401540075-iodo-2-methyl-2H-indazoleHCID 178480034HCID 178480034, compound

Product 1

HCID 56650915c-Met inhibitor 1Yield 87.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

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 (50 g, 268 mmol) in DMF (750 mL) is added 5-iodo-2-methyl-2H-indazole (55.5 g, 215.1 mmol), 2-Pyridinecarboxylic Acid (5.5 g, 44.7 mmoles), Copper (I) Iodide (4 g, 21.0 mmoles), and Cesium Carbonate (212.5 g, 652.2 moles). The mixture is under N2 and stirred at 100° C. for 10 hours. The reaction mixture is then cooled to room temperature and poured into water (2000 mL). After stirring at room temperature for 30 min, the mixture is extracted with a mixed solvent (2 L×2, CHCl3/IPA=3/1). The combined organic layer is then washed four times with mixed solution (25% NH4OH(aq)/brine=¼; 800 mL), sat. LiCl(aq) (1 L), sat. brine (1.5 L×2), and dry over Na2SO4. The organic solution is concentrated under reduced pressure to give a brown crude solid product. The crude product is triturated with ethyl acetate (800 mL) at room temperature for 3 hours and the pure product is collected by filtration to afford the title compound (68 g, 87.2%) as a white solid. MS (m/z): 363.0 (M+H).

Workup

  1. temperatureThe reaction mixture is then cooled to room temperature
  2. stirringAfter stirring at room temperature for 30 min
  3. extractionthe mixture is extracted with a mixed solvent (2 L×2, CHCl3/IPA=3/1)
  4. washThe combined organic layer is then washed four times with mixed solution (25% NH4OH(aq)/brine=¼; 800 mL), sat. LiCl(aq) (1 L), sat. brine (1.5 L×2)
  5. dry with materialdry over Na2SO4
  6. concentrationThe organic solution is concentrated under reduced pressure
  7. customto give a brown crude solid product
  8. customThe crude product is triturated with ethyl acetate (800 mL) at room temperature for 3 hours
  9. filtrationthe pure product is collected by filtration

Sources & evidence

ORD record
ord-491a521bd8ec47b9b449df26bee9bbd2
Source dataset
uspto-grants-2012_09
Patent number
US08268836B2

Reaction notes

Loading…