Cesium fluoride → HCID 67415632, compound

HRID 2099369Notes

Reaction equation

HRID 2099369 reaction equation
[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F-].[Cs+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

5

Reactant 3

HCID 25953Cesium fluoride2×HCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 136383504HCID 136383504, compound

Product 1

HCID 67415632HCID 67415632, compoundYield 96%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
60 °C

Procedure

4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and EtOAc (2×50 ml). The organics were combined, dried over MgSO4 and evaporated. The resulting product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503.

Workup

  1. temperatureheating
  2. waitwas continued at 60° C. for a further 18 hours
  3. customThe solvent was evaporated
  4. customthe residue was partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and EtOAc (2×50 ml)
  5. dry with materialdried over MgSO4
  6. customevaporated
  7. customThe resulting product was then purified by column chromatography
  8. washeluting
  9. temperaturewith increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100)
  10. additionThe fractions containing the desired product
  11. customevaporated under vacuum

Sources & evidence

ORD record
ord-13c3872cba1c4f378eb838f62f8a63f0
Source dataset
uspto-grants-2009_08
Patent number
US07569577B2

Reaction notes

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