1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 2',6'-Difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide

HRID 1177909Notes

Reaction equation

HRID 1177909 reaction equation
CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:56]2[C:57]([F:61])=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[CH:67][CH:66]=1)=[O:69]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 53271592',6'-Difluorobiphenyl-4-carboxylic acidHCID 669531782-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride

Product 1

HCID 251667082',6'-Difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amideYield 36%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (198.6 mg, 0.26 mL, 1.5 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (144.1 mg, 0.4 mmol) in DMF (4 mL). HOBT (50.7 mg, 0.37 mmol) and EDCI (163.6 mg, 0.85 mmol) were then added at room temperature. After 2 minutes, 2′,6′-difluoro-biphenyl-4-carboxylic acid (80 mg, 0.34 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 65 mg (35.8% yield) of 2′,6′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 82.25%. 1H NMR (DMSO-d6): δ 8.8-8.7 (t, 1H), 8.0 (d, 2H), 7.9-7.7 (m, 2H), 7.7-7.6 (m, 1H), 7.6-7.5 (m, 4H), 7.3-7.2 (m, 2H), 4.2 (dd, 2H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 3H), 3.2-3.1 (m, 2H).

Workup

  1. additionwas added
  2. extractionthe product was extracted with EtOAc
  3. washthe organic layer was washed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customto get the residue
  7. customThe obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent)

Sources & evidence

ORD record
ord-e82e3aea24d4420bb1869f67d56b82a5
Source dataset
uspto-grants-2010_11
Patent number
US07842696B2

Reaction notes

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