Cesium fluoride → [6-Benzyloxy-2-(2,4-difluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone

HRID 1513944Notes

Reaction equation

HRID 1513944 reaction equation
[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.[F-].[Cs+].Br[C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=1[F:70]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd].C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[O:35])=[C:14]([C:63]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:64]=1[F:70])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 676741-Bromo-2,4-difluorobenzene3×HCID 2734316Bis(neopentyl glycolato)diboronHCID 57552555Trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester

Product 1

HCID 57552519[6-Benzyloxy-2-(2,4-difluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanoneYield 58.1%

Reagents, catalysts & solvents 2

HCID 2734559Bis(tricyclohexylphosphine) palladium(0)CatalystHCID 6342AcetonitrileSolvent

Procedure

Add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (0.45 g, 0.73 mmol), bis(neopentyl glycolato)diboron (0.18 g, 0.81 mmol), bis(tricyclohexylphosphine)palladium(0) (0.098 g, 0.15 mmol) and acetonitrile (7.5 mL) to a round bottom flask. Stir at ambient temperature for approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (1.00 g, 6.61 mmol), place the flask in a 90° C. oil bath, and stir under nitrogen for 2-3 minutes. Now add 1-bromo-2,4-difluorobenzene (0.174 mL, 1.54 mmol) and stir for 20 minutes. At this time add more 1-bromo-2,4-difluorobenzene (0.06 mL, 0.53 mmol) and continue stirring the reaction for 2 hours at 90° C. At this time add more 1-bromo-2,4-difluorobenzene (0.05 mL, 0.44 mmol) and continue stirring for another 2 hours. Cool the reaction to ambient temperature and then filter it through a pad of Celite. Rinse the pad with ample, hot ethyl acetate. Wash the filtrate in a separatory funnel with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine; then dry (sodium sulfate) and evaporate it in vacuo. Load resulting material onto an SCX column, wash with dichloromethane, 50% dichloromethane/methanol, elute with ammonia solution (2N NH3 in methanol) and remove solvent under vacuum. Purify the resulting residue by flash chromatography (silica gel; 1.5%-3% methanol gradient in dichloromethane) to provide 0.245 g (58%) of the title compound: mass spectrum (ion spray) m/z=578 (M+H).

Workup

  1. dissolutionto dissolve most of the reagents
  2. stirringcontinue stirring
  3. customthe reaction for 2 hours at 90° C
  4. stirringcontinue stirring for another 2 hours
  5. temperatureCool
  6. customthe reaction to ambient temperature
  7. filtrationfilter it through a pad of Celite
  8. washRinse the pad with ample, hot ethyl acetate
  9. washWash the filtrate in a separatory funnel with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine
  10. dry with materialthen dry (sodium sulfate)
  11. customevaporate it in vacuo
  12. customLoad resulting material onto an SCX column
  13. washwash with dichloromethane, 50% dichloromethane/methanol
  14. washelute with ammonia solution (2N NH3 in methanol)
  15. customremove solvent under vacuum
  16. customPurify the resulting residue by flash chromatography (silica gel; 1.5%-3% methanol gradient in dichloromethane)

Sources & evidence

ORD record
ord-efb9870f2eab4b8883e8f748478c8008
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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