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

HRID 1161318Notes

Reaction equation

HRID 1161318 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.CN(C)C=O.[CH2:24]([O:26][C:27](=[O:36])[CH:28](Br)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:36])[CH:28]([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:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonate2×HCID 2762757Ethyl 2-bromo-2-cyclohexylacetate3×HCID 609805362-(4-Chloro-phenyl)-5,6-difluoro-1H-benzoimidazole

Product 1

HCID 66619480[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl esterYield 75.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To the solution of 75 g (0.28 mol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole in 750 ml N,N-dimethylformamide 116 g (0.33 mol) cesium carbonate and 88 g (0.35 mol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added. The mixture was heated to 100° C. and after stirring for 90 min. another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 6 h another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 22 h (total reaction time) the reaction mixture was cooled to 30° C. and was poured on 1 L ice water and 2 L ethyl acetate. The phases were separated and the aqueous phase extracted with 500 mL ethyl acetate. The combined organic phases were washed three times with 500 ml ice water and once with brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using n-heptane:ethyl acetate (9:1 v/v) as eluant. The product-containing fractions were pooled and the solvent evaporated until a suspension had formed. The suspension was cooled in an ice bath and filtered to give 92 g (75%) of the desired product as colorless solid.

Workup

  1. additionwere added
  2. temperatureAfter 22 h (total reaction time) the reaction mixture was cooled to 30° C.
  3. customThe phases were separated
  4. extractionthe aqueous phase extracted with 500 mL ethyl acetate
  5. washThe combined organic phases were washed three times with 500 ml ice water
  6. dry with materialonce with brine, dried over magnesium sulfate
  7. filtrationfiltered
  8. additionTo the solution, silica gel was added
  9. customthe solvent evaporated
  10. customwas purified by column chromatography over silica gel
  11. customthe solvent evaporated until a suspension
  12. customhad formed
  13. temperatureThe suspension was cooled in an ice bath
  14. filtrationfiltered

Sources & evidence

ORD record
ord-9264f2f2d2fc47c58ec0282198401640
Source dataset
uspto-grants-2010_10
Patent number
US07816540B2

Reaction notes

Loading…