Diisopropylethylamine → (S)-4-Methyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl)-amide

HRID 990356Notes

Reaction equation

HRID 990356 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:61][CH2:62][CH2:63][NH2:64])=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[CH2:61][CH2:62][CH2:63][NH:64][C:12]([C@@H:11]([NH:10][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:56][CH:55]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9390592(S)-[(4-methyl-piperazine-1-carbonyl)-amino]-4-methyl-pentanoic acidHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 18418679HCID 18418679, compound

Product 1

HCID 54304940(S)-4-Methyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl)-amideYield 73.1%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.644 mL, 3.70 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.367 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to afford 0.45 g (73%) of the pure titled compound as a white foam; mp 73-91° C. APCI-MS m/z 501.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 10 minutes at 0° C.
  3. custom20 minutes at ambient temperature, reaction mixture
  4. washthe resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL)
  5. dry with materialwas dried over Na2SO4
  6. concentrationThe solution was concentrated in vacuo
  7. customaffording an viscous oil
  8. customThe crude product was further purified by flash chromatography (20% MeOH in EtOAc)

Sources & evidence

ORD record
ord-69f96db623f04f6baf94a0478cb89db5
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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