Cesium fluoride → HCID 68523549, compound

HRID 1948944Notes

Reaction equation

HRID 1948944 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][CH2:33][C@@H:32](OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:31]1)=[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[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:34]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 86600825HCID 86600825, compound

Product 1

HCID 68523549HCID 68523549, compoundYield 95%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (2.0 g; prepared as described in Example 22-preparation of starting materials), tert-butyl-3-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (2.4 g) and cesium fluoride (2.9 g) in dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was evaporated under vacuum and partitioned between methylene chloride and water. The solutions were filtered to remove insoluble solids and the methylene chloride was washed with water, saturated brine and adsorbed onto silica. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 96/4). The fractions containing the required product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yloxy]-7-methoxyquinazoline as a yellow foam (2.9 g, 95%); 1H NMR Spectrum: (DMSO-d6) 1.40 (s, 9H), 2.00-2.32 (m, 2H), 3.20-3.55 (m, 3H), 3.69 (dd, 1H), 3.92 (s, 3H), 5.00-5.20 (m, 1H), 7.20 (s, 1H), 7.20-7.32 (m, 1H), 7.40-7.57 (m, 2H), 7.80 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 489.

Workup

  1. customThe reaction mixture was evaporated under vacuum
  2. custompartitioned between methylene chloride and water
  3. filtrationThe solutions were filtered
  4. customto remove insoluble solids
  5. washthe methylene chloride was washed with water, saturated brine
  6. customThe product was then purified by column chromatography on silica eluting
  7. temperaturewith increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 96/4)
  8. additionThe fractions containing the required product
  9. customevaporated under vacuum

Sources & evidence

ORD record
ord-7ca5af8e59fd4eb09cbdc6e3f6db07f5
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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