Cesium fluoride → HCID 67415632, compound

HRID 1175074Notes

Reaction equation

HRID 1175074 reaction equation
[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH: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]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH: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-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (3, 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 crudes were 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-fluorophenyl)amino]-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)+ 503.08.

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 crudes were 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-741e83daf8dc454ebd359324be4d73c5
Source dataset
uspto-grants-2010_11
Patent number
US07838530B2

Reaction notes

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