Potassium Carbonate → 3-(4-Chloro-2-fluorobenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine

HRID 597862Notes

Reaction equation

HRID 597862 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:6]([C:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:28][O:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][N:35]2[C:39]([CH3:40])=[CH:38][C:37]([NH2:41])=[N:36]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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].O1CCOCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:8]2[N:6]3[N:7]=[C:2]([NH:41][C:37]4[CH:38]=[C:39]([CH3:40])[N:35]([CH2:34][C:33]5[CH:42]=[CH:43][C:30]([O:29][CH3:28])=[CH:31][CH:32]=5)[N:36]=4)[CH:3]=[C:4]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:5]3=[N:10][C:9]=2[CH3:11])=[C:14]([F:20])[CH:15]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 674274551-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amineHCID 715739154-[[6-Chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl]methyl]morpholine

Product 1

HCID 674350193-(4-Chloro-2-fluorobenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amineYield 86.1%

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

Combine 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholin (0.36 g, 0.88 mmol), 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amine (0.248 g, 1.3 equiv.), potassium carbonate (0.30 g, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.076 g, 0.15 equiv.), water (2 mL), and 1,4-dioxane (20 mL) in a round bottom flask. Degas thoroughly with nitrogen then add bis(dibenzylideneacetone)palladium (0.10 g, 0.2 equiv.). Attach a reflux condenser and place under nitrogen. Heat the reaction at reflux overnight. Pass reaction through a Celite plug. Wash the plug with EA. Transfer to a separatory funnel and wash with water. Wash the organic layer with aqueous sodium chloride, and dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo. Purify on silica gel (EA→10% methanol:EA) to give the title compound (0.447 g, 86%) as a pale yellow solid. LCMS (4 min)=590.2, 591.2, M+1.

Workup

  1. customDegas thoroughly with nitrogen
  2. temperatureHeat
  3. customthe reaction
  4. temperatureat reflux overnight
  5. customPass reaction through a Celite plug
  6. washWash the plug with EA
  7. washTransfer to a separatory funnel and wash with water
  8. washWash the organic layer with aqueous sodium chloride
  9. dry with materialdry over anhydrous magnesium sulfate
  10. filtrationFilter
  11. concentrationconcentrate in vacuo
  12. customPurify on silica gel (EA→10% methanol:EA)

Sources & evidence

ORD record
ord-4492c40f18ff48c3ba42ed913be5582c
Source dataset
uspto-grants-2011_03
Patent number
US07897600B2

Reaction notes

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