Cesium carbonate → 6-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-((2-(trimethyl-silyl)ethoxy)methyl)pyridazin-3(2H)-one

HRID 872183Notes

Reaction equation

HRID 872183 reaction equation
Br[C:2]1[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:18]1([C:21]2[NH:25][N:24]=[C:23]([NH2:26])[CH:22]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.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]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][C:23]2[CH:22]=[C:21]([CH:18]3[CH2:20][CH2:19]3)[NH:25][N:24]=2)[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27580143-cyclopropyl-1H-pyrazol-5-amineHCID 580441204-Bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

Product 1

HCID 666119786-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-((2-(trimethyl-silyl)ethoxy)methyl)pyridazin-3(2H)-oneYield 59.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a mixture of 110a (2.38 g, 7.00 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (905 mg, 7.35 mmol), in 1,4-dioxane (40 mL) in a 100 mL single-neck round-bottomed flask was added cesium carbonate (6.84 g, 21.0 mmol). The mixture was purged with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (641 mg, 0.700 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (688 mg, 1.19 mmol) were then added. The flask was connected to a nitrogen-purged condenser and the mixture was refluxed for 6 h under nitrogen. The mixture was cooled to room temperature and filtered. The filter cake was suspended in ethyl acetate (30 mL) and water (10 mL) and filtered through Celite®. The layers were separated. The combined organic layers were dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient 0 to 50% ethyl acetate in heptane to afford 6-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (111a) (1.58 g, 59%).

Workup

  1. customThe mixture was purged with nitrogen for 30 min
  2. custompurged condenser
  3. temperaturethe mixture was refluxed for 6 h under nitrogen
  4. filtrationfiltered
  5. filtrationwater (10 mL) and filtered through Celite®
  6. customThe layers were separated
  7. dry with materialThe combined organic layers were dried with anhydrous magnesium sulfate
  8. customThe drying agent was removed by filtration
  9. concentrationThe filtrate was concentrated under reduced pressure
  10. customThe residue was purified on silica
  11. washeluted with a gradient 0 to 50% ethyl acetate in heptane

Sources & evidence

ORD record
ord-e6f71daecf55423e989e64cfcb1a0933
Source dataset
uspto-grants-2015_03
Patent number
US08975260B2

Reaction notes

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