Cesium carbonate → 6-chloro-4-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-one

HRID 337310Notes

Reaction equation

HRID 337310 reaction equation
[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2].Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH: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>ClCCl.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.[Pd].O1CCOCC1>[Cl:20][C:18]1[CH:19]=[C:14]([NH:12][C:10]2[CH:11]=[C:5]3[CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7][N:6]3[N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[N:17]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 580439485-Ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amineHCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-one

Product 1

HCID 667432696-chloro-4-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2-methyl-2H-pyridazin-3-oneYield 76.7%

Reagents, catalysts & solvents 4

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

In a 250 mL round-bottomed flask, 5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (350 mg, 2.11 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (471 mg, 2.11 mmol, Eq: 1.00), cesium carbonate (2.4 g, 7.37 mmol, Eq: 3.50) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (183 mg, 316 μmol, Eq: 0.15) were combined with dioxane (40 ml) and the reaction mixture was flushed with argon. Then bis(dibenzylideneacetone)palladium (90.8 mg, 158 μmol, Eq: 0.075) was added and the reaction mixture was heated at 90° C. for 18 hr. After cooling to room temperature it was diluted with 50 mL dichloromethane and water. The aqueous layer was back-extracted with DCM (2×25 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 3% MeOH in DCM). The pure fractions were triturated with EtOAc. Mixed fractions and filtrate were purified by chromatography to afford pure product, which was combined with the triturated solid to afford the desired product (500 mg). (M+H)+=309 m/e.

Workup

  1. customthe reaction mixture was flushed with argon
  2. temperatureAfter cooling to room temperature it
  3. extractionThe aqueous layer was back-extracted with DCM (2×25 mL)
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by flash chromatography (silica gel, 40 g, 0% to 3% MeOH in DCM)
  7. customThe pure fractions were triturated with EtOAc
  8. customMixed fractions and filtrate were purified by chromatography
  9. customto afford pure product, which

Sources & evidence

ORD record
ord-b50cc56872c9465e969b2cc839b9af73
Source dataset
uspto-grants-2014_11
Patent number
US08889682B2

Reaction notes

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