4-Bromoaniline → (E)-N-(2-Amino-phenyl)-3-{4-[1-(4-bromo-phenylcarbamoyl)-2-(1-methyl-piperidin-4-yl)-ethyl]phenyl}-acrylamide

HRID 220184Notes

Reaction equation

HRID 220184 reaction equation
C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][CH:31]2CCN(C)CC2)[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=O)(C)(C)C.C[CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:69][C:70]1[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=1.Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:27](=[O:28])[NH:76][C:73]2[CH:74]=[CH:75][C:70]([Br:69])=[CH:71][CH:72]=2)[CH2:30][CH:31]2[CH2:44][CH2:43][N:40]([CH3:39])[CH2:41][CH2:42]2)=[CH:24][CH:25]=1

Participants

8

Reactant 6

HCID 78074-BromoanilineHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21893726Hydrochloride methanolHCID 59238319(E)-2-{4-[2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-3-(1-methyl-piperidin-4-yl)-propionic acid

Product 1

HCID 59238277(E)-N-(2-Amino-phenyl)-3-{4-[1-(4-bromo-phenylcarbamoyl)-2-(1-methyl-piperidin-4-yl)-ethyl]phenyl}-acrylamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-3-(1-methyl-piperidin-4-yl)-propionic acid (2.54 g, 5 mmol), Et3N (1.21 g, 10 mmol), and HATU (3.80 g, 10 mmol) in CH2Cl2 (30 mL) was added 4-bromo-phenylamine (1.29 g, 7.5 mmol). This mixture was stirred overnight at room temperature and then evaporated. The mixture was redissolved in 20 ml of EtOAc and washed with 2N HCl (20 mL×3), brine, 5% NaHCO3 (20 mL×3), brine, dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel using hexane/EtOAc to give a white solid. 1.25 M HCl/MeOH (4 mL) was added to the product. The solution was stirred for 4 h at ambient temperature. After reaction, the solution was neutralized with solid NaHCO3. The final product was obtained by preparative HPLC. MS: calc'd 561 (MH+), exp 561 (MH+). 1H NMR (d6-DMSO, 400 MHz), 10.29 (s, 1H), 9.40 (s, 1H), 7.60-7.51 (m, 5H), 7.49-7.45 (m, 4H), 7.34 (d, 1H, J=7.6 Hz), 6.94-6.85 (m, 2H), 6.75 (d, 1H, J=7.6 Hz), 6.58 (t, 1H, J=7.6 Hz), 4.94 (broad s, 2H), 3.84 (t, 1H, J=7.6 Hz), 2.97 (broad s, 2H), 2.36 (s, 3H), 2.22 (broad s, 2H), 2.07-2.00 (m, 1H), 1.80-1.63 (m, 3H), 1.30-1.24 (m, 3H).

Workup

  1. customevaporated
  2. dissolutionThe mixture was redissolved in 20 ml of EtOAc
  3. washwashed with 2N HCl (20 mL×3), brine, 5% NaHCO3 (20 mL×3), brine
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by column chromatography on silica gel
  8. customto give a white solid
  9. stirringThe solution was stirred for 4 h at ambient temperature
  10. customAfter reaction

Sources & evidence

ORD record
ord-49ada6467d6b45f9b11168f83e8da475
Source dataset
uspto-grants-2012_06
Patent number
US08202866B2

Reaction notes

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