Potassium Phosphate, Tribasic → 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)-N-(oxetan-3-yl)quinazoline-8-carboxamide

HRID 473206Notes

Reaction equation

HRID 473206 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)C2C3[O:43][C:42]4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O:66]1[CH2:69][CH:68]([NH2:70])[CH2:67]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[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:42]([NH:70][CH:68]3[CH2:69][O:66][CH2:67]3)=[O:43])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 98339233-OxetanamineHCID 666094698-Bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline

Product 1

HCID 666103252-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)-N-(oxetan-3-yl)quinazoline-8-carboxamideYield 266.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °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), palladium acetate (6 mg, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg, 0.05 mmol), oxetan-3-amine (55 mg, 0.75 mmol) and K3PO4 (320 mg, 1.5 mmol) was added toluene (2 mL). The vial was evacuated and flushed with carbon monoxide (2×) and the mixture was heated at 110° C. overnight under an atmosphere of carbon monoxide. The mixture was diluted with DCM/MeOH and concentrated under reduced pressure onto Celite. The residue was purified by silica gel chromatography eluting with 10-100% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)-N-(oxetan-3-yl)quinazoline-8-carboxamide (56 mg, 26%). LC-MS (ESI) m/z 421 (M+H)+.

Workup

  1. customThe vial was evacuated
  2. customflushed with carbon monoxide (2×)
  3. additionThe mixture was diluted with DCM/MeOH
  4. concentrationconcentrated under reduced pressure onto Celite
  5. customThe residue was purified by silica gel chromatography
  6. washeluting with 10-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-28eb8dc552b449a88083d3772cb8802a
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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