Hydrochloric Acid → N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide

HRID 417113

Reaction equation

HRID 417113 reaction equation
C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.[CH3:18][O:19][C:20]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:21]=1[C:22](O)=O.[CH2:31]([N+:38]#[C-])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.[C:41](=[O:44])(O)[O-].[Na+]>CO.O1CCOCC1>[CH2:31]([NH:38][C:41](=[O:44])[CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[N:7]1[C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[N:16]=[C:22]1[C:21]1[C:20]([O:19][CH3:18])=[N:28][C:27]([O:29][CH3:30])=[CH:26][CH:25]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 82558Benzyl isocyanideHCID 516892Sodium BicarbonateHCID 8531782,6-Dimethoxypyridine-3-carboxylic acidHCID 66619231tert-Butyl (2-amino-4,5-difluorophenyl)carbamate

Product 1

HCID 66619365N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) 2,6-dimethoxynicotinic acid commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a 1M hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant. Off-white foam (72%). MS (Turbo Spray) m/z=521.5 [M+H].

Workup

  1. addition5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added
  2. customFrom the clear, light brown and slightly warm solution a suspension formed within a few minutes
  3. stirringAfter stirring for 20 h
  4. stirringThe resulting solution was stirred at room temperature for 29 h
  5. customthe layers were separated
  6. extractionThe aqueous layer was extracted three times with ethyl acetate
  7. washThe combined organic layers were washed with water and brine
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. additiontreated with silica gel
  11. customevaporated to dryness
  12. customThe resulting solid was purified by silica gel chromatography
  13. washeluting with n-heptane:tert-butyl methyl ether (1:1) as eluant

Sources & evidence

ORD record
ord-1f2f3970a14c4845a55fef69b3612914
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Linked notes

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