3-Bromobenzonitrile → 3-[(1-Benzyl-piperidin-4-yl)-(4-diisopropylcarbamoyl-phenyl)-amino]benzamide

HRID 456852Notes

Reaction equation

HRID 456852 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-:73])C.[Na+].[CH:76]([N:79]([CH:89]([CH3:91])[CH3:90])[C:80](=[O:88])[C:81]1[CH:86]=[CH:85][C:84](Br)=[CH:83][CH:82]=1)([CH3:78])[CH3:77]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:84]2[CH:85]=[CH:86][C:81]([C:80](=[O:88])[N:79]([CH:89]([CH3:91])[CH3:90])[CH:76]([CH3:78])[CH3:77])=[CH:82][CH:83]=2)[C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([NH2:6])=[O:73])[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

11

Reactant 5

HCID 233813-BromobenzonitrileHCID 4158521-Benzyl-4-piperidylamineHCID 634876Binap, (A+-)-HCID 36169884-Bromo-N,N-diisopropylbenzamideHCID 23676156Sodium t-butoxide2×

Product 1

HCID 102078323-[(1-Benzyl-piperidin-4-yl)-(4-diisopropylcarbamoyl-phenyl)-amino]benzamide

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 1.07 g of 3-bromobenzonitrile (5.88 mmol) in 15 ml dry toluene was added 1.2 mL of 4-amino-N-benzyl piperidine (5.89 mmol), 293 mg racemic BINAP (0.47 mmol), 215 mg tris(dibenzylideneacetone)dipalladium(0) (0.23 mmol) and 790 mg sodium tert butoxide (8.23 mmol). The reaction was heated at 80° C. under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature and 2.34 g of N,N-diisopropyl-4-bromobenzamide (8.24 mmol) and 790 mg of sodium tert butoxide (8.23 mmol) were added and the reaction heated to reflux. After 20 hours the solution was cooled to room temperature and the reaction diluted with ethyl acetate (50 ml) and water (30 ml) was added, filtered through celite and then the organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 2% dichloromethane in methanol rising to 5% methanol in dichloromethane. The residue was repurified by flash chromatography, eluting 10% hexanes 90% ethyl acetate to yield an orange foam (2.20 g, 4.45 mmol; 76%). The material was found to be >94% pure by HPLC (LUNA 30–80% acetonitrile).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. temperaturethe reaction heated to reflux
  3. temperatureAfter 20 hours the solution was cooled to room temperature
  4. additionwas added
  5. filtrationfiltered through celite
  6. customthe organic layer was separated
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by flash chromatography
  11. washeluting 2% dichloromethane in methanol rising to 5% methanol in dichloromethane
  12. customThe residue was repurified by flash chromatography
  13. washeluting 10% hexanes 90% ethyl acetate
  14. customto yield an orange foam (2.20 g, 4.45 mmol; 76%)

Sources & evidence

ORD record
ord-8984dbd76a35438ebe8e1d3ef83f7b27
Source dataset
uspto-grants-2007_03
Patent number
US07186733B2

Reaction notes

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