Cesium carbonate → 5-Bromo-3-(5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one

HRID 1919160Notes

Reaction equation

HRID 1919160 reaction equation
[F:1][CH2:2][CH:3]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:4]1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=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:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:5]3[CH2:6][CH2:7][N:8]([CH3:9])[CH:3]([CH2:2][F:1])[CH2:4]3)=[CH:15][N:14]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 36143503,5-Dibromo-1-methylpyridin-2(1H)-oneHCID 580442115-(3-(Fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-amine

Product 1

HCID 580437315-Bromo-3-(5-(3-(fluoromethyl)-4-methylpiperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-oneYield 53.6%

Reagents, catalysts & solvents 2

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

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 336f (crude, 14.1 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.5 g, 16.9 mmol), and cesium carbonate (11.5 g, 35.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (820 mg, 1.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (645 mg, 0.7 mmol) were added. After three cycles of vacuum/argon flash, the reaction mixture was heated at reflux for 15 h. The reaction was cooled to room temperature, filtered and concentrated to afford a black solid, which was purified by column chromatography eluting with methylene chloride/methanol (from 100:1 to 50:1) to afford 336g as a yellow solid (3.1 g, 50%). MS: [M+H]+ 410.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting solution for 30 min
  4. temperatureAfter three cycles of vacuum/argon flash, the reaction mixture was heated
  5. temperatureat reflux for 15 h
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford a black solid, which
  9. customwas purified by column chromatography
  10. washeluting with methylene chloride/methanol (from 100:1 to 50:1)

Sources & evidence

ORD record
ord-636a042ece02447bafc4bfd9ad86f689
Source dataset
uspto-grants-2013_12
Patent number
US08618107B2

Reaction notes

Loading…