Diisopropylethylamine → 4-(1-{2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionyl}-piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile

HRID 511136Notes

Reaction equation

HRID 511136 reaction equation
[CH3:1][C@@H:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:3](O)=[O:4].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.[NH:56]1[CH2:61][CH2:60][CH:59]([NH:62][C:63]2[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[C:65]([C:71]([F:74])([F:73])[F:72])[CH:64]=2)[CH2:58][CH2:57]1>CN(C)C=O.ClCCl.O1CCCC1>[CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:3]([N:56]1[CH2:61][CH2:60][CH:59]([NH:62][C:63]2[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[C:65]([C:71]([F:72])([F:73])[F:74])[CH:64]=2)[CH2:58][CH2:57]1)=[O:4]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 43345818N-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amineHCID 58576422(S)-2-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid

Product 1

HCID 585764544-(1-{2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionyl}-piperidin-4-ylamino)-2-trifluoromethyl-benzonitrileYield 100%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionic acid (57 mg; 0.18 mmol, prepared in accordance with Example 67), diisopropylethyl amine (140 μL; 0.8 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (65 mg; 0.17 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 of 4-(Piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile (50 mg; 0.17 mmol) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 1 hour at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. Upon addition of acetonitrile to the residue obtained a precipitation is observed. The precipitate is filtered, washed with acetonitrile (2×3 mL) and dried under high vacuum to afford the desired product (98 mg; 0.17 mmol). The structure was confirmed using Protocol II-B. Calculated mass=568; observed mass=568; HPLC retention time=4.812 min.

Workup

  1. stirringthe reaction is then stirred for 1 hour at room temperature
  2. washthe organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL)
  3. dry with materialis dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. additionUpon addition of acetonitrile to the residue
  6. customobtained
  7. customa precipitation
  8. filtrationThe precipitate is filtered
  9. washwashed with acetonitrile (2×3 mL)
  10. customdried under high vacuum

Sources & evidence

ORD record
ord-b9d3a46783b942edae5262d85c1ca7ba
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

Loading…