2-Aminopyridine → 6-Chloro-2-methyl-4-(pyridin-2-ylamino)pyridazin-3(2H)-one

HRID 872154Notes

Reaction equation

HRID 872154 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[N:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:15][C:13]1[CH:14]=[C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1

Participants

9

Reactant 4

HCID 104392-AminopyridineHCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-one

Product 1

HCID 666099546-Chloro-2-methyl-4-(pyridin-2-ylamino)pyridazin-3(2H)-oneYield 92.3%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 2-aminopyridine (500 mg, 5.31 mmol), 103a (1.19 g, 5.31 mmol), cesium carbonate (5.19 g, 15.9 mmol), and 1,4-dioxane (75 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (261 mg, 0.451 mmol) and tris(dibenzylideneacetone)dipalladium(0) (243 mg, 0.266 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (350 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methanol (30 mL) to afford a 92% yield (1.16 g) of 104a as an off-white solid: mp 201-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.38 (m, 2H), 7.75 (m, 1H), 7.54 (d, 1H, J=8.1 Hz), 7.03 (m, 1H), 3.67 (s, 3H); MS (ESI+) m/z 237.0 (M+H).

Workup

  1. customA 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. temperaturethe reaction mixture was heated
  4. temperatureat reflux for 3 h
  5. customThe organic layer was separated
  6. extractionthe aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL)
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was triturated with methanol (30 mL)

Sources & evidence

ORD record
ord-cb536923211c4afb8f9f98a7861eee2a
Source dataset
uspto-grants-2015_03
Patent number
US08975260B2

Reaction notes

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