1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide

HRID 1093862Notes

Reaction equation

HRID 1093862 reaction equation
CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65]>CN(C=O)C.O>[F:50][C:51]1[CH:63]=[CH:62][C:54]([O:55][CH:56]2[CH2:61][CH2:60][N:59]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]3[N:18]=[CH:17][N:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:20]=3)=[O:22])[CH2:58][CH2:57]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 66591819[(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acidHCID 665920874-(4-Fluoro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride

Product 1

HCID 665915241-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amideYield 49%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (97 mg, 0.75 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (61 mg, 0.25 mmol) in DMF (2 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol). After 2 minutes of stirring, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) to afford 59.3 mg (49% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 491, 96%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (m, 1H), 8.3 (m, 1H), 8.05 (m, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.4 (m, 4H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.4 (b, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at ambient temperature overnight
  3. extractionextracted with ethyl acetate
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue obtained
  7. customwas purified by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent)

Sources & evidence

ORD record
ord-140c0f8b7e4d4e0fb302f8ab09ee77ae
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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