Sodium Carbonate → 2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl]amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid

HRID 406982Notes

Reaction equation

HRID 406982 reaction equation
Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([CH:40]([CH3:46])[C:41]([O:43]CC)=[O:42])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.ClCCl>[F:21][C:20]([F:23])([F:22])[CH2:19][NH:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([C:34]4[CH:39]=[CH:38][C:37]([CH:40]([CH3:46])[C:41]([OH:43])=[O:42])=[CH:36][CH:35]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=1)=[O:17]

Participants

10

Reactant 4

HCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 58539349Ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoateHCID 67980496N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N'-(2,2,2-trifluoro ethyl)urea

Product 1

HCID 679802542-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl]amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid

Reagents, catalysts & solvents 5

HCID 962WaterCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (250.0 mg, 0.6050 mmol) (from Example 1, step 4), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (280 mg, 0.91 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol, Aldrich, Cat. No. 379670) and sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (5 mL) and a few drops water was heated at 120° C. overnight under nitrogen. After the reaction was cooled to r.t., 1.0 M sodium hydroxide in water (2.4 mL,) was added to the above mixture. The reaction mixture was heated at 100° C. 2 h., then cooled to r.t. The reaction mixture was diluted with ethyl acetate, and extracted with 1N NaOH aqueous solution twice. The combined aqueous phases were acidified to pH˜2 with 6 M HCl aqueous solution, and then extracted with ethyl acetate twice. The combined organic phases (only the extracted portion with acidic aqueous solution) were washed with brine, dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product. LCMS (M+H)+: m/z=483.1.

Workup

  1. temperatureThe reaction mixture was heated at 100° C
  2. temperature2 h., then cooled to r.t
  3. extractionextracted with 1N NaOH aqueous solution twice
  4. extractionextracted with ethyl acetate twice
  5. washThe combined organic phases (only the extracted portion with acidic aqueous solution) were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationAfter filtration
  8. concentrationthe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-409831dbf10e456c81f513359fe0638f
Source dataset
uspto-grants-2014_06
Patent number
US08754114B2

Reaction notes

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