Cesium fluoride → HCID 11158169, compound

HRID 1513979Notes

Reaction equation

HRID 1513979 reaction equation
[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1Br)([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[CH2:56]([O:63][C:64]1[CH:65]=[C:66]2[C:71](=[CH:72][CH:73]=1)[C:70]([C:74](=[O:90])[C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][CH2:83][N:84]3[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]3)=[CH:77][CH:76]=1)=[C:69](OS(C(F)(F)F)(=O)=O)[CH:68]=[CH:67]2)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:69]1[CH:68]=[CH:67][C:66]2[C:71](=[CH:72][CH:73]=[C:64]([O:63][CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:65]=2)[C:70]=1[C:74](=[O:90])[C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][CH2:83][N:84]2[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89]2)=[CH:77][CH:76]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 25953Cesium fluorideHCID 75806Tricyclohexylphosphine2×HCID 2733548Bis(pinacolato)diboraneHCID 57552555Trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl esterHCID 57552565HCID 57552565, compound

Product 1

HCID 11158169HCID 11158169, compoundYield 36.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 6342AcetonitrileSolvent

Procedure

Add (2-bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester (1.06 g, 3.67 mmol), bis(pinacolato)diboron (1.03 g, 4.04 mmol), palladium(II) acetate (0.062 g, 0.28 mmol), tricyclohexylphosphine (0.103 g, 0.37 mmol) and acetonitrile (40 mL) to a round bottom flask. Stir at ambient temperature for approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (2.10 g, 13.82 mmol), place the flask in a 90° C. oil bath, and stir for 30-45 minutes. Remove the oil bath and allow the reaction mixture to cool to ambient temperature. To this mixture, add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (0.75 g, 1.22 mmol), palladium(II) acetate (0.062 g, 0.28 mmol), tricyclohexylphosphine (0.103 g, 0.37 mmol) and place the reaction in a 90° C. oil bath. Stir the reaction for 4 hours at 90° C. Cool the reaction to ambient temperature, filter it through a pad of Celite and rinse the pad with ample, hot ethyl acetate. Wash the filtrate with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine; then dry (sodium sulfate) and evaporate it in vacuo. Load the resulting material onto an SCX column. Wash with dichloromethane, 50% dichloro-methane/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% methanol gradient in dichloromethane: followed by a second chromatography 2% of 2N NH3 in methanol/25% THF/hexanes: followed by purification on a Chromatotron; 2% MeOH/dichloromethane) to provide 0.300 g (36%) of the title compound: mass spectrum (ion spray) m/z=675 (M+H).

Workup

  1. dissolutionto dissolve most of the reagents
  2. customRemove the oil bath
  3. temperatureto cool to ambient temperature
  4. customthe reaction in a 90° C. oil bath
  5. stirringStir
  6. customthe reaction for 4 hours at 90° C
  7. temperatureCool
  8. customthe reaction to ambient temperature
  9. filtrationfilter it through a pad of Celite
  10. washrinse the pad with ample, hot ethyl acetate
  11. washWash the filtrate with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine
  12. dry with materialthen dry (sodium sulfate)
  13. customevaporate it in vacuo
  14. washWash with dichloromethane, 50% dichloro-methane/methanol
  15. washelute with ammonia solution (2N NH3 in methanol)
  16. customremove solvent under vacuum
  17. customPurify the resulting residue by flash chromatography (silica gel
  18. customfollowed by purification on a Chromatotron

Sources & evidence

ORD record
ord-d53ebebaeceb4c0da5d303293a96d4ff
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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