Hydrochloric Acid → 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one

HRID 872165Notes

Reaction equation

HRID 872165 reaction equation
Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]2[N:18]=[C:19]([NH2:21])[CH:20]=[C:14]2[CH2:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1COCC1.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>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].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][C:19]2[CH:20]=[C:14]3[CH2:13][N:12]([CH3:11])[CH2:17][CH2:16][N:15]3[N:18]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 2733832Lithium HexamethyldisilazideHCID 580439335-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-amineHCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-one

Product 1

HCID 666346996-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-oneYield 76.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
0 °C

Procedure

A 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 103a (1.90 g, 8.53 mmol), 101l (1.18 g, 7.75 mmol) and 1,4-dioxane (40 mL). The flask was purged with nitrogen and cooled to 0° C. A 1 M solution of lithium hexamethyldisilazide in THF (39 mL, 39.0 mmol) was added. After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (381 mg, 0.659 mmol) and tris(dibenzylideneacetone)dipalladium(0) (355 mg, 0.388 mmol) were added, and the reaction mixture was heated at reflux for 2 h. After this time, the mixture was cooled to room temperature and diluted with water (10 mL). The pH of the solution was adjusted to 7.6 with 2 N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica to afford a 76% yield (1.74 g) of 106f as an off-white solid: mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.72 (s, 1H), 6.00 (s, 1H), 4.04 (t, 2H, J=5.1 Hz), 3.65 (s, 3H), 3.53 (s, 2H), 2.82 (t, 2H, J=5.1 Hz), 2.37 (s, 3H); MS (ESI+) m/z 295.1 (M+H).

Workup

  1. customA 250-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
  2. customThe flask was purged with nitrogen
  3. customAfter bubbling nitrogen through the resulting suspension for 30 min
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 2 h
  6. temperatureAfter this time, the mixture was cooled to room temperature
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was extracted with ethyl acetate (3×40 mL)
  9. dry with materialThe combined organic layers were dried over sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by column chromatography on silica

Sources & evidence

ORD record
ord-4e716720049745abb70596b8c0e17649
Source dataset
uspto-grants-2015_03
Patent number
US08975260B2

Reaction notes

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