1,2-Dimethoxyethane → 2-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazine

HRID 1803873Notes

Reaction equation

HRID 1803873 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2I)=[CH:4][CH:3]=1.C(COC)OC.C(=O)(O)[O-].[Na+].[N:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 516892Sodium BicarbonateHCID 2734379(Pyridin-4-yl)boronic acid2×HCID 594069722-(4-Fluorophenyl)-3-iodo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

Product 1

HCID 251443712-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-3-pyrid-4-ylimidazo[1,2-b]pyridazineYield 100.6%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2.80 g (6.40 mmol) of 2-(4-fluorophenyl)-3-iodo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in 200 mL of a mixture of dimethoxyethane and water (9:1), are added 1.36 g (12.8 mmol) of sodium bicarbonate and 0.95 g (7.7 mmol) of (pyrid-4-yl)boronic acid. After sparging with a stream of argon for a few moments, 0.21 g (0.26 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) is added and the reaction mixture is refluxed under argon for 18 hours. A further 0.95 g (7.7 mmol) of (pyrid-4-yl)boronic acid, 0.21 g (0.26 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and 10 mL of water are then added. Heating is continued for 24 hours. The solvent is then evaporated off under reduced pressure and the brown residue is triturated with aqueous 3N hydrochloric acid and then filtered on a Büchner funnel. The aqueous phase is washed twice with diethyl ether and then cautiously neutralized, using aqueous ammonia diluted with ice, to basic pH. The product is extracted with chloroform, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give 2.5 g of a yellowish powder.

Workup

  1. additionis added
  2. temperaturethe reaction mixture is refluxed under argon for 18 hours
  3. temperatureHeating
  4. customThe solvent is then evaporated off under reduced pressure
  5. customthe brown residue is triturated with aqueous 3N hydrochloric acid
  6. filtrationfiltered on a Büchner funnel
  7. washThe aqueous phase is washed twice with diethyl ether
  8. additiondiluted with ice, to basic pH
  9. extractionThe product is extracted with chloroform
  10. dry with materialthe organic phase is dried over sodium sulfate
  11. filtrationfiltered
  12. customthe solvent is evaporated off

Sources & evidence

ORD record
ord-b798b205f4cd4860b320e408358b2702
Source dataset
uspto-grants-2013_01
Patent number
US08354405B2

Reaction notes

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