1-(Bis(4-fluorophenyl)methyl)piperazine → (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-one

HRID 990367Notes

Reaction equation

HRID 990367 reaction equation
[CH:1]1([NH:7][C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[N:24]2[CH2:25][CH2:26][N:27]([C:9](=[O:11])[C@@H:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:28][CH2:29]2)=[CH:35][CH:34]=1

Participants

6

Reactant 3

HCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11356330HCID 11356330, compound

Product 1

HCID 57173107(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-oneYield 76%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A suspension of (S)-2-cyclohexylamino-4-methyl-pentanoic acid (0.556 g, 2.62 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.378 g, 1.31 mmol) in dry DMF (7 mL) was treated with Triton® B (2.40 mL, 5.28 mmol, 40 weight percent solution in methanol), a clear solution was obtained. The resulting reaction solution was cooled to 0° C. in an ice-water bath. To this solution was added solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.993 g, 2.62 mmol). After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution. White solid which forms was removed by filtration. The two layers of the filtrate were separated; the organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (30% EtOAc in hexanes) affording 0.48 g (76%) of the pure titled compound as a white foam: mp 45-54° C. APCI-MS m/z 484.4 (MH+).

Workup

  1. customa clear solution was obtained
  2. customThe resulting reaction solution
  3. customthe cooling bath was removed
  4. waitthe stirring was continued at ambient temperature for 30 minutes
  5. waitAfter this period
  6. additionthe reaction mixture was mixed with 60 mL of diethyl ether and 60 mL of saturated aqueous NaHCO3 solution
  7. customWhite solid which forms was removed by filtration
  8. customThe two layers of the filtrate were separated
  9. washthe organic layer was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL)
  10. dry with materialwas dried over Na2SO4
  11. concentrationThe solution was concentrated in vacuo
  12. customaffording a viscous oil
  13. customThe crude product was purified by flash chromatography (30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-679bf3247cff44f9ace5588ced8c5fd8
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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