1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (1-Biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester

HRID 1178159Notes

Reaction equation

HRID 1178159 reaction equation
CCN(C(C)C)C(C)C.[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([CH:16]([N:18]([CH2:26][C:27](O)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:58][C:59]1[CH:60]=[CH:61][C:62]([C:73]([F:76])([F:75])[F:74])=[C:63]([C:65]([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[O:66])[CH:64]=1>CN(C=O)C.O>[C:22]([O:21][C:19](=[O:20])[N:18]([CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[CH3:17])[CH2:26][C:27]([N:70]1[CH2:71][CH2:72][N:67]([C:65](=[O:66])[C:63]2[CH:64]=[C:59]([F:58])[CH:60]=[CH:61][C:62]=2[C:73]([F:76])([F:74])[F:75])[CH2:68][CH2:69]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 59559653[(1-Biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acidHCID 66625607(2-Trifluoromethyl-5-fluoro-phenyl)-piperazin-1-yl-methanone hydrochloride

Product 1

HCID 59559575(1-Biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl esterYield 27.56%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (182 mg, 0.24 mL, 1.4 mmol) was added to a stirred solution of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid (100 mg, 0.28 mmol) in DMF (5 mL). HOBT (42 mg, 0.31 mmol) and EDCI (135 mg, 0.7 mmol) were then added at room temperature. After 2 minutes, (5-Fluoro-2-trifluoromethyl-phenyl)-piperazin-1-yl-methanone hydrochloride salt (105 mg, 0.3 mmol) 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. The resulting residue was purified by column chromatography (using 60-120 silica gel and 30-50% EtOAc in hexane as eluent) to afford 43 mg (27.56% yield) of (1-biphenyl-4-yl-ethyl)-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester, LCMS Purity: 96.02%. 1H NMR (CDCl3): δ 7.78 (t 1H), 7.64-7.5 (s, 4H), 7.5-7.3 (m, 5H), 7.24 (d, 1H), 7.04 (m, 1H), 5.8-5.2 (bd, 2H), 4.0 (s, 1H), 3.8 (s, 3H), 3.6-3.2 (m, 5H), 3.1 (s, 3H), 1.5 (s, 9H).

Workup

  1. extractionthe product was extracted with EtOAc
  2. washthe organic layer was washed with brine
  3. dry with materialThe organic phase was dried over Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue was purified by column chromatography (using 60-120 silica gel and 30-50% EtOAc in hexane as eluent)

Sources & evidence

ORD record
ord-e3a174d798884e94a4be25a49e87e325
Source dataset
uspto-grants-2010_11
Patent number
US07842696B2

Reaction notes

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