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

HRID 511106Notes

Reaction equation

HRID 511106 reaction equation
[Li+].[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O-])=[O:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=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+:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[CH:64][C:63]=1[C:75]([F:78])([F:77])[F:76])([O-:61])=[O:60]>CN(C)C=O.ClCCl.O1CCCC1>[N+:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:70][CH2:71][N:72]([C:18](=[O:19])[CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:24])([F:2])[F:23])=[CH:22][CH:21]=4)[CH2:11][CH2:12]3)[CH2:73][CH2:74]2)=[CH:64][C:63]=1[C:75]([F:78])([F:76])[F:77])([O-:61])=[O:60]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 585769023-[4-(4-Trifluoromethyl-benzyloxy)-piperidin-1-yl]-propionic acid lithium saltHCID 66671805(4-Nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride

Product 1

HCID 585767501-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-trifluoromethyl-benzyloxy)-piperidin-1-yl]-propan-1-one

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

3-[4-(4-Trifluoromethyl-benzyloxy)-piperidin-1-yl]-propionic acid lithium salt (130 mg; 0.36 mmol, prepared in accordance with Example 56), diisopropylethyl amine (87 μL; 0.50 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (132 mg; 0.35 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-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (15 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 105 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (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 (96 mg; 0.16 mmol). The structure was confirmed using Protocol I-B. Calculated mass=603; observed mass=603; HPLC retention time=5.038 min.

Workup

  1. stirringthe reaction is then stirred for 105 minutes at room temperature
  2. washthe organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (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-f3e19197a5404bddab066af59bfc5053
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

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