1-Hydroxybenzotriazole → N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide

HRID 1665599Notes

Reaction equation

C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53](=[O:60])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:46][CH:45]=1>CN(C=O)C.O>[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:45]=[CH:46][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53]([N:54]2[CH2:55][CH2:56][N:57]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:21]=3[F:20])[CH2:58][CH2:59]2)=[O:60])=[CH:48][CH:49]=1

Participants

Conditions

Temperature: 10 °C

Procedure

HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2,5-difluorobenzoic acid (34 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to 36 mg (37%) of N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 464.17 (M+1)+, 97.6%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.34 (t, 1H), 7.12 (m, 3H), 3.85 (d, 3H), 3.7 (m, 3H), 3.55 (d, 2H), 3.4 (m, 2H).

Workup

additionwere added
filtrationThe resulting precipitate was filtered
custompurified by column chromatography

Sources & evidence

ORD record: ord-54557f37fdb848f797fec0dc6d2bc302
Source dataset: uspto-grants-2011_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08039463B2

Reaction notes

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