Diisopropylethylamine → (S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentan-1-one

HRID 990369Notes

Reaction equation

HRID 990369 reaction equation
[CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[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:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[N:58]2[CH2:59][CH2:60][N:61]([C:5](=[O:7])[C@@H:4]([N:8]([CH3:15])[CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH2:3][CH:2]([CH3:1])[CH3:16])[CH2:62][CH2:63]2)=[CH:69][CH:68]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 15458710(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid

Product 1

HCID 53891263(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentan-1-oneYield 75%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.200 g, 0.873 mmol, Example 27, Step A) 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 (0.304 mL, 1.75 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.331 g, 0.873 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.252 g, 0.873 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 50 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 (50% EtOAc in hexane) to provide 0.326 g (75%) of the pure titled compound as a white foam: mp 56-65° C. APCI-MS m/z 500.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 15 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 (50% EtOAc in hexane)

Sources & evidence

ORD record
ord-e599feca927f47e9a8ccf7091f77f28f
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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