Tetraethyltin → 2-(Difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-4-(methylthio)quinazoline

HRID 473187Notes

Reaction equation

HRID 473187 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].[CH2:24]([Sn](CC)(CC)CC)[CH3:25].[Li+].[Cl-]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[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]([CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

6

Reactant 3

HCID 11704TetraethyltinHCID 433294Lithium ChlorideHCID 666094698-Bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline

Product 1

HCID 666095022-(Difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-4-(methylthio)quinazolineYield 73.7%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
135 °C

Procedure

To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (300 mg, 0.75 mmol), bis(tri-tert-butylphosphine)palladium (38 mg, 0.075 mmol), tetraethyltin (0.295 mL, 1.5 mmol), and LiCl (95 mg, 2.25 mmol) was added DMF (15 mL). The reaction vessel was evacuated and flushed with argon (2×). The mixture was then heated in a microwave synthesizer at 135° C. for 30 min. The mixture was partitioned between EtOAc and saturated aq sodium bicarbonate and the organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-4-(methylthio)quinazoline (193 mg, 73%) as a white solid. LC-MS (ESI) m/z 350 (M+H)+.

Workup

  1. customThe reaction vessel was evacuated
  2. customflushed with argon (2×)
  3. customThe mixture was partitioned between EtOAc and saturated aq sodium bicarbonate
  4. customthe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure onto Celite
  8. customThe mixture was purified by silica gel chromatography
  9. washeluting with 0-10% EtOAc/hexanes

Sources & evidence

ORD record
ord-ba75f8f51b434f6fb068a37afaaaf1d6
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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