1-Hydroxybenzotriazole → N-biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-propionamide

HRID 1093826Notes

Reaction equation

HRID 1093826 reaction equation
CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]1[CH:54]=[C:55]([CH:63]=[C:64]([F:67])[C:65]=1[F:66])[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[N:60]2[CH2:61][CH2:62][CH:57]([O:56][C:55]3[CH:54]=[C:53]([F:52])[C:65]([F:66])=[C:64]([F:67])[CH:63]=3)[CH2:58][CH2:59]2)=[CH:14][CH:15]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 55049154N-biphenyl-4-yl-malonamic acidHCID 66591659HCID 66591659, compound

Product 1

HCID 57874399N-biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-propionamideYield 17%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of N-biphenyl-4-yl-malonamic acid (100 mg, 0.4 mmol) in DMF (2.0 mL) followed by HOBt (81 mg, 0.6 mmol) and EDCI.HCl (114 mg, 0.6 mmol). After 2 minutes of stirring, 4-(3,4,5-trifluoro-phenoxy)-piperidine hydrochloride (100 mg, 0.4 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated. The remaining residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 30 mg (17% Yield) of N-biphenyl-4-yl-3-oxo-3-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-propionamide. LC/MS [M+H]+: 469.17, 98.06%, 1H NMR (300 MHz, DMSO-d6): δ7.6 (m, 6H), 7.4 (m, 2H), 7.3 (m, 1H), 7.1 (m, 2H), 4.6 (m, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.5 (m, 1H).

Workup

  1. additionwas added
  2. stirringstirring
  3. waitwas continued at ambient temperature overnight
  4. extractionextracted with ethylacetate
  5. washwashed with brine
  6. concentrationconcentrated
  7. customThe remaining residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3)

Sources & evidence

ORD record
ord-1536a4705bfb4ec5a7dd8684840fcea3
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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