Diisopropylethylamine → 1-[4-(4-Nitro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-3-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-propan-1-one

HRID 511096Notes

Reaction equation

HRID 511096 reaction equation
[Li+].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O-])=[O:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:60]([C:63]1[CH:75]=[CH:74][C:66]([O:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:65][C:64]=1[C:76]([F:79])([F:78])[F:77])([O-:62])=[O:61]>CN(C)C=O.ClCCl.O1CCCC1>[N+:60]([C:63]1[CH:75]=[CH:74][C:66]([O:67][CH:68]2[CH2:73][CH2:72][N:71]([C:23](=[O:24])[CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][CH:15]([C:12]4[CH:11]=[CH:10][C:9]([O:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:14][CH:13]=4)[CH2:16][CH2:17]3)[CH2:70][CH2:69]2)=[CH:65][C:64]=1[C:76]([F:79])([F:77])[F:78])([O-:62])=[O:61]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 585767123-[4-(4-Phenoxy-phenyl)-piperidin-1-yl]-propionic acid lithium saltHCID 666717594-(4-Nitro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride

Product 1

HCID 585764001-[4-(4-Nitro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-3-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-propan-1-one

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

3-[4-(4-Phenoxy-phenyl)-piperidin-1-yl]-propionic acid lithium salt (115 mg; 0.36 mmol, prepared in accordance with Example 43), diisopropylethyl amine (124 μL; 0.71 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (117 mg; 0.36 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution 4-(4-nitro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (103 mg; 0.32 mmol, prepared in accordance with Example 44) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (2×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (56 mg; 0.09 mmol). The structure was confirmed using Protocol I-B. Calculated mass=598; observed mass=598; HPLC retention time=5.22 min.

Workup

  1. stirringthe reaction is then stirred for 3 hours at room temperature
  2. washthe organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (2×5 mL)
  3. dry with materialis dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe residue obtained
  6. customis finally purified by preparative HPLC

Sources & evidence

ORD record
ord-270912bd863a4626b1d9b1ef1f6a2e19
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

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