Cesium carbonate → 5-Bromo-3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1,6-dimethylpyridin-2(1H)-one

HRID 593158Notes

Reaction equation

HRID 593158 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1.Br[C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>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>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:12]2[CH:13]=[C:7]3[CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9][N:8]3[N:11]=2)[C:17](=[O:25])[N:18]([CH3:24])[C:19]=1[CH3:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 299237793,5-Dibromo-1,6-dimethylpyridin-2(1H)-oneHCID 866839915-(2-Methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine

Product 1

HCID 866845905-Bromo-3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1,6-dimethylpyridin-2(1H)-oneYield 62%

Reagents, catalysts & solvents 2

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

Procedure

A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 327b (392 mg, 2.0 mmol), 327d (562 mg, 2.0 mmol), cesium carbonate (1.30 g, 4.0 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the suspension for 10 minutes, xantphos (115 mg, 0.20 mmol) and tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.10 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×15 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 327e (490 mg, 62%) as a yellow solid. MS-ESI: [M+H]+ 396.2

Workup

  1. customA 100-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter bubbling nitrogen through the suspension for 10 minutes
  3. customflush
  4. temperatureheated
  5. temperatureat reflux for 5 h
  6. filtrationfiltered
  7. washThe solid was washed with dichloromethane (2×15 mL)
  8. concentrationThe combined filtrate was concentrated under reduced pressure
  9. customThe residue was purified by silica-gel column chromatography
  10. washeluting with dichloromethane/methanol (80:1 to 30:1)

Sources & evidence

ORD record
ord-f4ca1436db144555b14bfb8ec010a562
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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