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

HRID 1665597Notes

Reaction equation

C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([F:31])[CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54](=[O:61])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[C:45]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:62])[CH2:53][C:54]([N:55]2[CH2:56][CH2:57][N:58]([C:25](=[O:27])[C:24]3[CH:28]=[C:29]([F:30])[C:21]([Cl:20])=[CH:22][C:23]=3[F:31])[CH2:59][CH2:60]2)=[O:61])=[CH:49][CH:50]=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 4-chloro-2,5-difluoro-benzoic acid (40 mg, 0.21 mmol) in DMF (1 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 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 and 60% ethyl acetate in hexane to afford 24 mg (23%) of N-biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.18 (M+1)+, 97.0%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.52 (m, 6H), 7.49 (t, 2H), 7.35 (t, 1H), 7.25 (t, 1H), 3.7 (m, 3H), 3.56 (d, 3H), 3.55 (d, 2H), 3.4 (m, 2H).

Workup

additionwere added
filtrationThe resulting precipitate was filtered
customthen purified by column chromatography

Sources & evidence

ORD record: ord-3612f2e99f05457bad96913aabd7d6ee
Source dataset: uspto-grants-2011_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08039463B2

Reaction notes

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