Potassium Carbonate → N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide

HRID 539799Notes

Reaction equation

HRID 539799 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](B(O)O)=[N:12][N:11]3[CH:19]=2)=[CH:4][C:3]=1[NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Br[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[C:36]([F:39])([F:38])[F:37].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.C(O)(C)C.O>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([CH:19]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:4]=4)[N:9]=3)[N:12]=2)=[C:29]([C:36]([F:37])([F:38])[F:39])[CH:30]=1)#[N:33]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 108006474-Bromo-3-(trifluoromethyl)benzonitrileHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 680891592-(4-Methyl-3-pivalamidophenyl)imidazo[1,2-b]pyridazin-6-ylboronic acid

Product 1

HCID 57406897N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamideYield 48.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 21889133Propan-2-ol--water (1/1)Solvent

Conditions

Temperature
90 °C

Procedure

A 200 mL flask is charged with 2-(4-methyl-3-pivalamidophenyl)imidazo[1,2-b]pyridazin-6-ylboronic acid (11.4 g, 0.0325 mol), 4-bromo-3-(trifluoromethyl)benzonitrile (10.16 g, 0.04 mol), K2CO3 (8.98 g, 0.065 mol), palladium acetate (0.510 g, 2.28 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (1.868 g, 4.55 mmol) and a solution of isopropanol-water (3:1, 80 mL). The mixture is degassed by bubbling N2 through and heated at 90° C. for 5 hours. The mixture is then cooled and filtered through celite, concentrated and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2). The desired fractions are combined and stirred for 24 hours with QuadraSil MP (a mercaptopropyl bound silica gel, 20 g) to scavenge the palladium, filtered and concentrated to give desired title compound (7.5 g). LCMS (m/z)=478.6 [M+H]+, tR=2.97 min.

Workup

  1. customThe mixture is degassed
  2. customby bubbling N2 through and
  3. temperatureThe mixture is then cooled
  4. filtrationfiltered through celite,
  5. concentrationconcentrated
  6. custompurified by silica gel chromatography (0-100% EtOAc in CH2Cl2)
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-948121cf3db84ae29cbe449ce64a4fc8
Source dataset
uspto-grants-2014_10
Patent number
US08871767B2

Reaction notes

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