Cesium fluoride → HCID 60036687, compound

HRID 1948923Notes

Reaction equation

HRID 1948923 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]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:32][C@H:31]1[C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[O:29])([CH3:26])([CH3:25])[CH3:24].[F-].[Cs+]>CN(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:17][CH3:18])=[C:13]([O:16][C@@H:33]3[CH2:34][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@H:31]([C:48](=[O:52])[N:49]([CH3:50])[CH3:51])[CH2:32]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

5

Reactant 3

HCID 25953Cesium fluorideHCID 574768684-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-olHCID 60036699HCID 60036699, compound

Product 1

HCID 60036687HCID 60036687, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Dimethylformamide (8 ml) was added to 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (0.489 g; prepared as described in the starting materials for Example 22), (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine (0.678 g) and cesium fluoride (0.697 g). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol and adsorbed onto silica. The product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated. The residue was re-purified by column chromatography eluting with increasingly polar mixtures of ethyl acetate/methanol (100/0 to 92/8). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless gum which crystallised on standing (0.36 g); 1H NMR Spectrum: (DMSO d6 @ 373K) 1.41 (s, 9H), 1.99 (m, 1H), 2.92-3.03 (m, 7H); 3.44 (m, 1H), 3.96 (s 3H), 4.14 (m, 1H), 4.70 (t, 1H), 5.10 (m, 1H), 7.22-7.30 (m, 2H), 7.44 (t, 1H), 7.62 (t, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 560.

Workup

  1. customprepared
  2. customThe reaction mixture was evaporated under vacuum
  3. dissolutionthe residue dissolved in methylene chloride/methanol
  4. customThe product was then purified by column chromatography
  5. washeluting
  6. temperaturewith increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10)
  7. additionThe fractions containing the expected product
  8. customevaporated
  9. customThe residue was re-purified by column chromatography
  10. washeluting
  11. temperaturewith increasingly polar mixtures of ethyl acetate/methanol (100/0 to 92/8)
  12. additionThe fractions containing the required product
  13. customevaporated under vacuum

Sources & evidence

ORD record
ord-65ce9a8f79234fbc85fe5fcc99417aac
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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