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

HRID 990370Notes

Reaction equation

[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]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:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:51][CH:50]=1>CN(C=O)C.C(OCC)C>[F:68][C:65]1[CH:64]=[CH:63][C:62]([CH:55]([C:52]2[CH:53]=[CH:54][C:49]([F:48])=[CH:50][CH:51]=2)[N:56]2[CH2:57][CH2:58][N:59]([C:5](=[O:7])[C@@H:4]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:60][CH2:61]2)=[CH:67][CH:66]=1

Participants

Conditions

Temperature: 0 °C

Procedure

4-Methyl-2-morpholin-4-yl-pentanoic acid (0.200 g, 0.994 mmol, Example 23, 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 (0.346 mL, 1.99 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.379 g, 0.994 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.287 g, 0.994 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 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 (40% EtOAc in hexane) to provide 0.284 g (60%) of the pure titled compound as a white foam; mp 55-63° C. APCI-MS m/z 472.3.0 (MH+).

Workup

customThe resulting reaction mixture
stirringAfter stirring for, sequentially, 10 minutes at 0° C.
custom20 minutes at ambient temperature, reaction mixture
washthe resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL)
dry with materialwas dried over Na2SO4
concentrationThe solution was concentrated in vacuo
customaffording a viscous oil
customThe crude product was further purified by flash chromatography (40% EtOAc in hexane)

Sources & evidence

ORD record: ord-3c5787205eaf43f1bcaa63ecc752b545
Source dataset: uspto-grants-2002_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06458781B1

Reaction notes

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