Cesium carbonate → 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-imidazo[1,2-b]pyridazine

HRID 226009Notes

Reaction equation

HRID 226009 reaction equation
[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[S:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[C:19]=1[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 11776TriphenylphosphineHCID 667212022-Bromo-5-fluoro-3-methylbenzo[b]thiopheneHCID 688412672,6-Dimethyl-8-(pentan-3-yl)imidazo[1,2-b]pyridazine

Product 1

HCID 577525998-(1-Ethyl-propyl)-2,6-dimethyl-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-imidazo[1,2-b]pyridazineYield 65%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (435 mg, 2.0 mmol, 1.0 equiv), 2-bromo-5-fluoro-3-methylbenzo[b]thiophene (564 mg, 2.3 mmol, 1.15 equiv), triphenylphosphine (100 mg, 0.38 mmol, 0.19 equiv), Cs2CO3 (1.37 g, 4.2 mmol, 2.1 equiv) and Pd2 dba3 (88 mg, 0.096 mmol, 0.048 equiv) in DMF (4.5 mL, degassed by sparging with nitrogen for 30 min. prior to use) is heated at 130° C. for 4 hr (magnetically-stirred under an atmosphere of N2). The reaction is cooled and partitioned between MTBE (10 mL) and satd. NH4Cl solution (10 mL). The organic phase is washed with satd. NH4Cl solution (2×5 mL), dried (Na2SO4) and concentrated in vacuo to a brown film, which is adsorbed onto silica gel (1.0 g). Material is flash chromatographed (10 g of silica gel; heptane to 5% EtOAc in heptane to 10% EtOAc in heptane) and fractions containing pure product were combined and concentrated. The residue is stirred in warm heptane (6 mL) for 10 min. then refrigerated at −20° C. for 24 hr. Light yellow crystals are separated, washed with cold heptane and dried. The product is recrystallized from MeOH (3 mL) to provide the title compound as light yellow crystals (453 mg, 65%).

Workup

  1. customdegassed
  2. customby sparging with nitrogen for 30 min.
  3. temperatureThe reaction is cooled
  4. custompartitioned between MTBE (10 mL)
  5. washThe organic phase is washed with satd
  6. dry with materialNH4Cl solution (2×5 mL), dried (Na2SO4)
  7. concentrationconcentrated in vacuo to a brown film, which
  8. customchromatographed (10 g of silica gel; heptane to 5% EtOAc in heptane to 10% EtOAc in heptane) and fractions
  9. additioncontaining pure product
  10. concentrationconcentrated
  11. stirringThe residue is stirred in warm heptane (6 mL) for 10 min.
  12. customLight yellow crystals are separated
  13. washwashed with cold heptane
  14. customdried
  15. customThe product is recrystallized from MeOH (3 mL)

Sources & evidence

ORD record
ord-5e9eb9d45bec41fbbff57f27e06f993e
Source dataset
uspto-grants-2009_07
Patent number
US07557103B2

Reaction notes

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