Dimethylformamide → 2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile

HRID 473185Notes

Reaction equation

HRID 473185 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].[CH3:24][N:25](C=O)C>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([C:24]#[N:25])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 666094698-Bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline

Product 1

HCID 666095682-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrileYield 64%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
90 °C

Procedure

To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (300 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (69 mg, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (49 mg, 0.088 mmol), and zinc cyanide (110 mg, 0.93 mmol) was added DMF (6 mL). The reaction flask was evacuated and flushed with argon (3×) and then the mixture was heated at 90° C. overnight. The resulting mixture was partitioned between EtOAc and water and the organic layer was washed with 2N NH4OH (3×) and brine (1×), dried over sodium sulfate, and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel flash chromatography eluting with 0-50% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile (168 mg, 64%). LC-MS (ESI) m/z 347 (M+H)+.

Workup

  1. customThe reaction flask was evacuated
  2. customflushed with argon (3×)
  3. customThe resulting mixture was partitioned between EtOAc and water
  4. washthe organic layer was washed with 2N NH4OH (3×) and brine (1×)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure onto Celite
  7. customThe mixture was purified by silica gel flash chromatography
  8. washeluting with 0-50% EtOAc/hexanes

Sources & evidence

ORD record
ord-5b0f5212bb49404b9ebc174946cda5b6
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

Loading…