Triethylamine → 4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline

HRID 454073Notes

Reaction equation

HRID 454073 reaction equation
C(N(CC)CC)C.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45](OS(C(F)(F)F)(=O)=O)=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:60]=[CH:59][C:37]([O:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([CH:10]=[CH:9][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:46]([O:49][CH3:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[C:36]([F:61])[CH:35]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15458tert-Butyl acrylateHCID 220308424-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazolineHCID 53436545Diphenylpropyl phosphine

Product 1

HCID 540046344-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazolineYield 49%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
82.5 °C

Procedure

Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition was complete the reaction flask was purged with argon. The mixture was stirred at 80-85° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/ether (95/5). After removal of the solvent under vacuum, the solid was triturated with pentane/ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline (63 mg, 49%).

Workup

  1. additionWhen the addition
  2. customwas purged with argon
  3. temperatureAfter cooling
  4. customthe mixture was partitioned between ethyl acetate and water
  5. customThe organic layer was separated
  6. washwashed with water, brine
  7. dry with materialdried (MgSO4)
  8. customevaporated
  9. customThe residue was purified by column chromatography
  10. washeluting with methylene chloride
  11. customAfter removal of the solvent under vacuum
  12. customthe solid was triturated with pentane/ether
  13. filtrationcollected by filtration
  14. customdried under vacuum

Sources & evidence

ORD record
ord-f761ac4cd2fc46feb2615c682bb5d8f1
Source dataset
uspto-grants-2013_07
Patent number
US08492560B2

Reaction notes

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