Hydrochloric Acid → N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide

HRID 417148

Reaction equation

HRID 417148 reaction equation
C1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2C2C(OC)=NC(OC)=CC=2)[CH2:8][O:9]C2C=CC(C(O)=O)=CN=2)CCCCC1.[F:40][C:41]1([F:48])[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1.[Cl:49][C:50]1[CH:58]=[CH:57][C:53](C(O)=O)=[CH:52][CH:51]=1.[CH2:59]([N+:66]#[C-])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[CH2:59]([NH:66][C:8](=[O:9])[CH:7]([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:53]1[CH:57]=[CH:58][C:50]([Cl:49])=[CH:51][CH:52]=1)[CH:44]1[CH2:45][CH2:46][C:41]([F:48])([F:40])[CH2:42][CH2:43]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1

Participants

9

Reactant 6

HCID 313Hydrochloric Acid2×HCID 63184-Chlorobenzoic AcidHCID 82558Benzyl isocyanideHCID 516892Sodium BicarbonateHCID 157890924,4-DifluorocyclohexanoneHCID 461857196-{2-Cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethoxy}-nicotinic acid2×

Product 1

HCID 66619400N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 312751,4-DioxaneSolvent2×

Procedure

To a solution of 3.8 g (15.56 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 38 ml methanol, 2.54 g (17.12 mmol) 4,4-difluorocyclohexanone (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 2.44 g (15.58 mmol) p-chlorobenzoic acid, followed by an addition of 1.9 ml (15.56 mmol) benzyl isocyanide (commercially available). To the viscous slurry 12 ml methanol were added and the reaction for 22.5 h. Then 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added dropwise over 5 min. After 4.5 h another 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added. After 24 h, the suspension was poured onto 300 ml aqueous saturated sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the 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 a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (76%). MS (Turbo Spray): m/z=530.2 [M+H].

Workup

  1. customthe reaction for 22.5 h
  2. waitAfter 24 h
  3. customthe phases were separated
  4. extractionThe aqueous layer was extracted three times with ethyl acetate
  5. washthe 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 a gradient of heptane:ethyl acetate (100:0 to 50:50)

Sources & evidence

ORD record
ord-2fe0822dc2914dcb89b08bc3b7982ac4
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Linked notes

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