1-Hydroxybenzotriazole → 5-Phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide

HRID 1093587Notes

Reaction equation

HRID 1093587 reaction equation
[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1>CN(C=O)C.O>[O:18]=[C:16]([N:52]1[CH2:53][CH2:54][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:66])([F:67])[F:68])[CH2:56][CH2:57]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)=[O:13]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 433543392-[(5-Phenyl-1,2-oxazol-3-yl)formamido]acetic acidHCID 66591440Piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride

Product 1

HCID 578745095-Phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amideYield 60.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.0685 g, 0.00024 mol) in DMF (2 mL) was added DIPEA (0.173 g, 0.00134 mol), HOBt (0.045 g, 0.00034 mol) and EDCI.HCl (0.064 g, 0.00034 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.068 g, 0.00024 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (35% ethyl acetate in hexane) to afford 0.0684 g (60%) of 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide. LCMS: 473.17 (M+1)+, 97.41%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.94 (m, 2H), 7.52 (m, 3H), 7.38 (m, 3H), 6.98 (d, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.4 (m, 2H).

Workup

  1. extractionthe product was extracted with ethyl acetate
  2. customThe ethyl acetate layer was collected
  3. washwashed with brine solution
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe resulting residue was purified by column chromatography

Sources & evidence

ORD record
ord-d798256611a84d569298d79e1f208e7c
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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