Diisopropylethylamine → 3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-propan-1-one

HRID 511110Notes

Reaction equation

HRID 511110 reaction equation
[Li+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:20])[C:17]([O-:19])=O)[CH2:11][CH2:10]2)=[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+:55]([C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)=[CH:60][C:59]=1[C:71]([F:74])([F:73])[F:72])([O-:57])=[O:56]>CN(C)C=O.ClCCl.O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH3:20])[C:17]([N:68]3[CH2:69][CH2:70][CH:65]([NH:64][C:61]4[CH:62]=[CH:63][C:58]([N+:55]([O-:57])=[O:56])=[C:59]([C:71]([F:72])([F:73])[F:74])[CH:60]=4)[CH2:66][CH2:67]3)=[O:19])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 585764403-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium saltHCID 66671805(4-Nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride

Product 1

HCID 585769113-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-propan-1-one

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium salt (62 mg; 0.22 mmol, prepared in accordance with Example 60), diisopropylethyl amine (87 μL; 0.50 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (76 mg; 0.20 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 (63 mg; 0.20 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 60 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 (47 mg; 0.08 mmol). The structure was confirmed using Protocol I-A. Calculated mass=554; observed mass=554; HPLC retention time=3.45 min.

Workup

  1. stirringthe reaction is then stirred for 60 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-0b5da39c048c4866a88bfac98981fa8c
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

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