Water → [2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cycloheptyl-acetic acid ethyl ester

HRID 417142Notes

Reaction equation

HRID 417142 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:38])[CH:29](Br)[CH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:26].O>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([O:27][C:28](=[O:38])[CH:29]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:26]

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonate3×HCID 609805362-(4-Chloro-phenyl)-5,6-difluoro-1H-benzoimidazoleHCID 86639900Bromo-cycloheptyl-acetic acid ethyl ester3×

Product 1

HCID 66619224[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cycloheptyl-acetic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2.2 g (8.31 mmol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 1, intermediate a) in 22 ml N,N-dimethyl formamide was added 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester. The reaction mixture was stirred at 100° C. for 1 hour. Then, 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added. Stirring was continued at 100° C. for another 6 hours. Another 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added and the reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured on 200 ml water and 200 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 200 ml ethyl acetate. The organic layers were washed with 200 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (63%). MS (Turbo Spray): m/z=447.2 [M+H].

Workup

  1. stirringStirring
  2. waitwas continued at 100° C. for another 6 hours
  3. stirringthe reaction mixture was stirred at 100° C. for 18 hours
  4. customthe layers were separated
  5. extractionThe aqueous layer was extracted a second time with 200 ml ethyl acetate
  6. washThe organic layers were washed with 200 ml brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under vacuum
  10. customThe residue was purified by silica gel chromatography
  11. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40)

Sources & evidence

ORD record
ord-a0158b43fc4746f4a4da043538889681
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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