Potassium Carbonate → 2-Ethyl-5-(6-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)aniline

HRID 539814Notes

Reaction equation

HRID 539814 reaction equation
Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:24][CH3:25])=[C:15]([NH:17]C(=O)C(C)(C)C)[CH:16]=3)[N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[C:35]([C:40]([F:43])([F:42])[F:41])=[N:36][CH:37]=[CH:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)C>[CH2:24]([C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[C:35]([C:40]([F:43])([F:42])[F:41])=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:7][N:6]3[CH:8]=2)=[CH:16][C:15]=1[NH2:17])[CH3:25]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 569244343-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridineHCID 86667863N-(5-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylphenyl)pivalamide

Product 1

HCID 575162302-Ethyl-5-(6-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)anilineYield 75.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
60 °C

Procedure

A 250 mL flask is charged with N-(5-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylphenyl)pivalamide (2.45 g, 0.00686 mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (2.34 g, 0.00857 mol), K2CO3 (2.37 g, 0.0171 mol), palladium(II)acetate (0.154 g, 0.686 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.563 g, 0.00137 mol), isopropanol:water (150 mL, 3:1). The mixture is stirred and heated at 60° C. for 6 hr. The mixture is concentrated to dryness, crude product taken up in EtOAc (100 mL), washed with water (50 mL), organic collected and concentrated onto celite and purified by silica gel chromatography (0-75% EtOAc in CH2Cl2). Intermediate is taken up in EtOH (100 mL) and conc. HCl (90 mL) is added. The reaction mixture is heated to reflux for 18 hrs. Reaction is concentrated, taken up in EtOAc (100 mL), washed with 100 mL Sat. NaHCO3. Compound is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (1.98 g, 75% over two steps). LCMS m/z=384.4, 385.4 [M+H]+, tR=2.59 min.

Workup

  1. concentrationThe mixture is concentrated to dryness, crude product
  2. washwashed with water (50 mL)
  3. customorganic collected
  4. concentrationconcentrated onto celite
  5. custompurified by silica gel chromatography (0-75% EtOAc in CH2Cl2)
  6. additionconc. HCl (90 mL) is added
  7. temperatureThe reaction mixture is heated
  8. temperatureto reflux for 18 hrs
  9. customReaction
  10. concentrationis concentrated
  11. washwashed with 100 mL Sat. NaHCO3
  12. concentrationCompound is concentrated onto celite
  13. custompurified by silica gel chromatography (0-100% EtOAc in CH2Cl2)

Sources & evidence

ORD record
ord-c4e0c7d017914ea0ae73634ee98535a4
Source dataset
uspto-grants-2014_10
Patent number
US08871767B2

Reaction notes

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