1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 5-(2-Fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

HRID 1178128Notes

Reaction equation

HRID 1178128 reaction equation
CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[O:21][N:20]=2)=[O:24])[CH2:52][CH2:53]1)=[O:69]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 167823945-(2-Fluorophenyl)-1,2-oxazole-3-carboxylic acidHCID 669531292-Amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]ethanone hydrochloride

Product 1

HCID 595596335-(2-Fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amideYield 32.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (219 mg, 0.29 mL, 1.68 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid (100 mg, 0.48 mmol) in DMF (2 mL). HOBT (68.5 mg, 0.5 mmol) and EDCI (97.2 mg, 0.5 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (100 mg, 0.48 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated. The obtained solid was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in hexane as eluent) to afford 82 mg (32.5% yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.05%. 1H NMR (DMSO-d6): δ 8.8 (t, 1H), 7.9 (m, 2H), 7.4 (m, 5H), 7.2 (d, 1H), 7.2 (d, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.1 (m, 2H).

Workup

  1. filtrationfiltered the solid
  2. customprecipitated
  3. customThe obtained solid was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in hexane as eluent)

Sources & evidence

ORD record
ord-d9cc55adffd544cb920f391705d3757b
Source dataset
uspto-grants-2010_11
Patent number
US07842696B2

Reaction notes

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