Potassium Carbonate → 4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylsulfanyl}-benzoic acid methyl ester

HRID 417165Notes

Reaction equation

HRID 417165 reaction equation
[SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([CH:30]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:31]OC3C=CC=CC=3F)[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:31][CH:30]([N:29]2[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=[C:25]2[C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[CH:11][CH:10]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 237573Methyl 4-sulfanylbenzoateHCID 461844412-(4-Chloro-phenyl)-1-[1-cyclohexyl-2-(2-fluoro-phenoxy)-ethyl]-5,6-difluoro-1H-benzoimidazole

Product 1

HCID 666193434-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylsulfanyl}-benzoic acid methyl esterYield 65%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 74 mg (0.44 mmol) methyl 4-mercaptobenzoate in 3 ml N,N-dimethylformamide was added 61 mg (0.44 mmol) potassium carbonate at 0° C. The reaction mixture was stirred for 15 min. and then 200 mg (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 34, intermediate) was added at the same temperature. The cooling bath was removed and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was poured on 10% aqueous 30 ml citric acid and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 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 70:30) to give the desired compound as a colorless solid (65%). MS (Turbo Spray) m/z=541.2 [M+H].

Workup

  1. customThe cooling bath was removed
  2. stirringthe reaction mixture stirred for 18 hours at room temperature
  3. additionThe reaction mixture was poured on 10% aqueous 30 ml citric acid and 30 ml ethyl acetate
  4. customthe layers were separated
  5. extractionThe aqueous layer was extracted a second time with 30 ml ethyl acetate
  6. washThe combined organic layers were washed with 30 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 70:30)

Sources & evidence

ORD record
ord-f8ffa32bd1ce4279841018904f4d70a8
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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