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

HRID 1665597
Notes
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Reaction equation

HRID 1665597 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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27332744-Chloro-2,5-difluorobenzoic acidHCID 66625265N-Biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride

Product 1

HCID 44230807
N-biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide
Yield 24.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

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

  1. additionwere added
  2. filtrationThe resulting precipitate was filtered
  3. 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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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes