Acetamide → N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide

HRID 473212Notes

Reaction equation

HRID 473212 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].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.[C:66]([NH2:69])(=[O:68])[CH3:67].C([O-])([O-])=O.[Cs+].[Cs+]>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>[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]([NH:69][C:66](=[O:68])[CH3:67])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

7

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 666094698-Bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline

Product 1

HCID 66609059N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamideYield 48%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (200 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol), acetamide (89 mg, 1.5 mmol) and Cs2CO3 (230 mg, 0.7 mmol) was added dioxane (4 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 90° C. overnight. The mixture was diluted with DCM and concentrated under reduced pressure onto Celite. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide (90 mg, 48%). LC-MS (ESI) m/z 379 (M+H)+.

Workup

  1. customThe reaction vessel was evacuated
  2. customflushed with argon (3×)
  3. additionThe mixture was diluted with DCM
  4. concentrationconcentrated under reduced pressure onto Celite
  5. customThe residue was purified by silica gel chromatography
  6. washeluting with 0-50% EtOAc/hexanes

Sources & evidence

ORD record
ord-f56e3cb025fa4e6da222fc195caa2a4c
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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