Hydrochloric Acid → 2-(4-Chloro-phenyl)-1-[1-cyclohexyl-2-(pyridin-3-yloxy)-ethyl]-5,6-difluoro-1H-benzoimidazole

HRID 417086Notes

Reaction equation

HRID 417086 reaction equation
[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH:12]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:20]2[N:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:31][CH:32]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 79713-HydroxypyridineHCID 24758Sodium hydrideHCID 666193191-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole

Product 1

HCID 461844422-(4-Chloro-phenyl)-1-[1-cyclohexyl-2-(pyridin-3-yloxy)-ethyl]-5,6-difluoro-1H-benzoimidazoleYield 65%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 46 mg (0.48 mmol) 3-hydroxypyridine in 3 mL N,N-dimethylformamide were added 21 mg (0.48 mmol, 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred for 10 min. at room temperature. To this suspension 0.2 g (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) were added and the reaction mixture stirred for 4 days at room temperature. The reaction mixture was poured on 30 mL 1N hydrochloric acid and 30 mL ethyl acetate and the phases separated. The aqueous layer was extracted with 30 mL ethyl acetate. The combined organic layers were washed twice with 30 mL water and once with 30 mL brine, dried over magnesium sulfate, filtered and evaporated. 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) to give the desired compound as white solid (65%). MS (Turbo Spray): m/z=468.2 [M+H].

Workup

  1. stirringthe reaction mixture stirred for 4 days at room temperature
  2. customthe phases separated
  3. extractionThe aqueous layer was extracted with 30 mL ethyl acetate
  4. washThe combined organic layers were washed twice with 30 mL water and once with 30 mL brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40)

Sources & evidence

ORD record
ord-3eb0a542a1cf4b01afc72a42b9600307
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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