Triethylamine → 4-(Imidazo[1,2-b]pyridazin-6-ylethynyl)aniline

HRID 589897Notes

Reaction equation

HRID 589897 reaction equation
O[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58]([C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)#[CH:59]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CO.C(Cl)Cl>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([C:59]#[C:58][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)=[N:7]2

Participants

11

Reactant 5

HCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 142176Phenyl triflimideHCID 37600254-EthynylanilineHCID 178515753HCID 178515753, compound

Product 1

HCID 1186384084-(Imidazo[1,2-b]pyridazin-6-ylethynyl)aniline

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
60 °C

Procedure

To a stirring mixture of 6-hydroxyimidazo[1,2-b]pyridazine (3.24 g, 24 mmol, 1 eq) in anhydrous DMF (25 mL) under nitrogen atmosphere was added triethylamine (13.4 mL, 4 eq) and N-phenyl-bis(trifluoromethanesulfonimide) (8.47 g, 1 eq). After 18 hours at room temperature, to the reaction was added triphenylphosphine (157 mg, 0.025 eq), bis(triphenylphosphine)palladium(II) dichloride (1.0 g, 0.06 eq), copper(I) iodide (914 mg, 0.2 eq), and a solution of 4-ethynylaniline (4.342 g, 1.5 eq) in DMF (10 mL) under nitrogen atmosphere. The resulting reaction mixture was heated at 60° C. for four hours. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, the residue mixture was subject to a gradient column chromatography (EtOAc-Hex 1:3 to 3:1). The product fractions were collected, concentrated, and the residue was triturated with EtOAc-Hex (1:5) to give the first batch of as a yellow solid in amount of 1.277 g. The brown solid found as a remainder on top of the syringe column was re-subject to another gradient column chromatography (MeOH-DCM 1:200 to 1:30) to give a second batch of 4-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline in amount of 829 mg. The total yield was 2.106 g (37%).

Workup

  1. customThe resulting reaction mixture
  2. temperatureThe reaction was then cooled to room temperature
  3. washwashed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine
  4. dry with materiallastly dried with anhydrous sodium sulfate
  5. customThe upper solution was decanted
  6. concentrationconcentrated
  7. customThe product fractions were collected
  8. concentrationconcentrated
  9. customthe residue was triturated with EtOAc-Hex (1:5)
  10. customto give the first batch of as a yellow solid in amount of 1.277 g

Sources & evidence

ORD record
ord-4e54af6335044566b73d14cb0b9ca142
Source dataset
uspto-grants-2016_01
Patent number
US09233968B1

Reaction notes

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