3,4,5-Trifluorobenzonitrile → (+)-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-1,1-dimethyl-ethoxy}-3,5-difluoro-benzonitrile

HRID 417129Notes

Reaction equation

HRID 417129 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:28])([O:16]C3C=CC(C4NN=NN=4)=CC=3)[CH3:15])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:45]#[N:46].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:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14]([CH3:15])([CH3:28])[O:16][C:49]3[C:48]([F:51])=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=3[F:41])[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 5938143,4,5-TrifluorobenzonitrileHCID 3251421Potassium bis(trimethylsilyl)amideHCID 178458272HCID 178458272, compound2×

Product 1

HCID 66619407(+)-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-1,1-dimethyl-ethoxy}-3,5-difluoro-benzonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 0.10 g (0.24 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol (Example 88, intermediate b) and 38 mg (0.24 mmol) 3,4,5-trifluorobenzonitrile in 2 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 0.53 ml (0.26 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and stirring was continued for 18 h. The reaction mixture was poured onto aqueous saturated 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 residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane for 5 min., then with a gradient of dichloromethane:ethyl acetate (100:0 to 95:5). Light brown foam (45%). MS (Turbo Spray): m/z=556.2 [M+H].

Workup

  1. customThe cooling bath was removed
  2. additionThe reaction mixture was poured onto aqueous saturated 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 residue was purified by silica gel chromatography
  10. washeluting with n-heptane for 5 min.

Sources & evidence

ORD record
ord-d82505e749984c868b9a2126965c90f0
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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