4-Fluorobenzonitrile → (-)-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-1,1-dimethyl-ethoxy}-benzonitrile

HRID 417118Notes

Reaction equation

HRID 417118 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:17])([OH:16])[CH3:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.F[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:15])([CH3:17])[O:16][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 145174-FluorobenzonitrileHCID 3251421Potassium bis(trimethylsilyl)amideHCID 666192681-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol

Product 1

HCID 66619524(-)-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-1,1-dimethyl-ethoxy}-benzonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1.0 g (2.39 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol and 0.289 g (2.39 mmol) 4-fluorobenzonitrile (commercially available) in 10 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 4.77 ml (2.39 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and the reaction stirred at room temperature for 5 days. The yellow suspension was poured onto 10% aqueous ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The compound was purified twice by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting first with n-heptane for 5 min, then with a gradient of dichloromethane:ethyl acetate (100:0 to 90:10). Colorless foam (40%). MS (Turbo Spray): m/z=520.2 [M+H].

Workup

  1. customThe cooling bath was removed
  2. additionThe yellow suspension was poured onto 10% aqueous ammonium chloride solution
  3. customthe phases were separated
  4. extractionThe aqueous layer was extracted three times with ethyl acetate
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated
  9. customThe compound was purified twice by silica gel chromatography
  10. washeluting first with n-heptane for 5 min

Sources & evidence

ORD record
ord-c1476a2400c948078f7c9a8b6076cf3a
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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