Diisopropylethylamine → (s)-4-Phenyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide

HRID 990372Notes

Reaction equation

HRID 990372 reaction equation
[CH3:1][CH:2]([CH3:23])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.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.[F:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]([C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)[N:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[CH:60][CH:59]=1>CN(C=O)C.C(OCC)C>[F:77][C:74]1[CH:73]=[CH:72][C:71]([CH:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[N:65]2[CH2:66][CH2:67][N:68]([C:5]([C@@H:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH2:3][CH:2]([CH3:1])[CH3:23])=[O:7])[CH2:69][CH2:70]2)=[CH:76][CH:75]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 664093HCID 664093, compoundHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 12017813(s)-4-Phenyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amideYield 76%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-4-Methyl-2-[(4-phenyl-piperazine-1-carbonyl)-amino]pentanoic acid (0.300 g, 0.939 mmol, Example 17, Step B) 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 (0.327 mL, 1.88 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.356 g, 0.939 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.271 g, 0.939 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 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 a viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane, then 60% EtOAc in hexane) to provide 0.42 g (76%) of the pure titled compound as a light yellow foam: mp 83-91 ° C. APCI-MS m/z 590.4 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 10 minutes at 0° C.
  3. custom40 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 a viscous oil
  8. customThe crude product was further purified by flash chromatography (40% EtOAc in hexane

Sources & evidence

ORD record
ord-92b02269f92849bc810d3f6248cc65d0
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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