Cesium carbonate → 4-(2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one

HRID 473200Notes

Reaction equation

HRID 473200 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.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][C:67]1=[O:72].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]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C:67]3=[O:72])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 669533-MorpholinoneHCID 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 666104604-(2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-oneYield 57.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (336 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (144 mg, 0.25 mmol), morpholin-3-one (102 mg, 1 mmol) and Cs2CO3 (383 mg, 1.18 mmol) was added dioxane (5 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 100° C. overnight. The mixture was diluted with MeOH and DCM and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one (203 mg, 57%) as a mixture which was used without further purification. LC-MS (ESI) m/z 421 (M+H)+.

Workup

  1. customThe reaction vessel was evacuated
  2. customflushed with argon (3×)
  3. additionThe mixture was diluted with MeOH and DCM
  4. concentrationconcentrated under reduced pressure onto Celite
  5. customThe mixture was purified by silica gel chromatography
  6. washeluting with 0-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-7a51c97d94d94335b199e355342bb9b9
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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