1,4-Dioxane → 2-Bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone

HRID 869141Notes

Reaction equation

HRID 869141 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[O:20]1CCO[CH2:22][CH2:21]1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.C1C(=O)N([Br:51])C(=O)C1>[Cl-].[Na+].O.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>[Br:51][CH2:22][C:21]([C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][CH:3]=1)=[O:20]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 67184N-bromobutanimideHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 866861256-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine

Product 1

HCID 866861262-Bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
150 °C

Procedure

6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (300 mg, 1.1 mmol, 1.0 equiv) and dioxane (5 mL) were added to a microwave vial and sonication was applied until the mixture was homogeneous. Tributyl(1-ethoxyvinyl)stannane (475 μL, 1.4 mmol, 1.3 equiv) and trans-dichlorobis(triphenylphosphine)palladium (30 mg, 0.04 mmol, 0.03 equiv) were then added, and the reaction was heated in a microwave reactor at 150° C. for 20 min. The reaction was concentrated, dissolved in EtOAc (25 mL), and mixed with 2.0 M potassium fluoride (5 mL). The mixture was filtered through celite, and then washed with water, dried over Na2SO4, filtered, and concentrated. The crude solid was redissolved in 50% THF/water (4 mL), followed by the addition of NBS (300 mg, 1.7 mmol, 1.5 equiv). The reaction mixture was stirred for 1 h and then diluted with brine (20 mL) and ethyl acetate (20 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a brown oil that was purified by silica gel chromatography (0-100% EtOAC/hexanes) to afford 270 mg of 2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone as an orange oil.

Workup

  1. customsonication
  2. concentrationThe reaction was concentrated
  3. dissolutiondissolved in EtOAc (25 mL)
  4. additionmixed with 2.0 M potassium fluoride (5 mL)
  5. filtrationThe mixture was filtered through celite
  6. washwashed with water
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. dissolutionThe crude solid was redissolved in 50% THF/water (4 mL)
  11. customAfter transferring to a separatory funnel
  12. stirringshaking
  13. customthe organic layer was separated from the aqueous layer
  14. dry with materialThe organic layer was then dried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customto give a brown oil that
  18. customwas purified by silica gel chromatography (0-100% EtOAC/hexanes)

Sources & evidence

ORD record
ord-37aa8b1789a54f8fa45041d8ebd26feb
Source dataset
uspto-grants-2015_03
Patent number
US08969346B2

Reaction notes

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