1-Hydroxybenzotriazole → N-biphenyl-4-yl-3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-propionamide

HRID 1093669Notes

Reaction equation

HRID 1093669 reaction equation
[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:64]2[CH2:63][CH2:62][CH:61]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[Br:53])[CH2:66][CH2:65]2)=[O:12])=[CH:5][CH:6]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 55049154N-biphenyl-4-yl-malonamic acidHCID 66545672N-(2-Bromophenyl)piperidin-4-amine dihydrochloride

Product 1

HCID 57874398N-biphenyl-4-yl-3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-propionamideYield 18.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.071 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.089 g, 0.0007 mole), HOBt (0.046 g, 0.00034 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.082 g, 0.00028 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, brine and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.025 g (17%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 492 (M+1)+, 92.2%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 4H), 7.44 (t, 3H), 7.34 (t, 1H), 7.18 (t, 1H), 6.68 (d, 1H), 6.6 (t, 1H), 4.45 (d, 1H), 4.0 (d, 1H), 3.65 (bs, 1H), 3.5 (s, 2H), 3.35 (t, 1H), 3.1 (t, 1H), 2.2 (m, 2H), 1.5 (m, 2H).

Workup

  1. extractionthe product was extracted with ethyl acetate
  2. washThe organic layer was washed with aqueous sodium bicarbonate solution, brine
  3. concentrationconcentrated
  4. customThe resulting residue was purified by column chromatography

Sources & evidence

ORD record
ord-2a895bc9fe12466e8664ccda34f46187
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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