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

HRID 417158Notes

Reaction equation

HRID 417158 reaction equation
[CH2:1]([NH:8][C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:44]([O-])=[O:45].[Na+]>>[CH2:1]([N:8]([N:44]=[O:45])[C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 4

HCID 176Acetic AcidHCID 7918Acetic AnhydrideHCID 23668193Sodium NitriteHCID 66619256N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamide

Product 1

HCID 86639903N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamideYield 53%

Conditions

Temperature
0 °C

Procedure

To a ice-cold solution of 13.15 g (29.1 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamide in 95 ml (1.659 mol) acetic acid and 199.7 ml (3.52 Mol) acetic anhydride were added in portions over 60 min. 10.04 g (145 mmol) sodium nitrite. The reaction mixture was stirred for 1 h at 0° C., then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 with solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give the desired compound as a light yellow solid (53%). MS (Turbo Spray): m/z=481.1 [M+H].

Workup

  1. customat room temperature
  2. customovernight
  3. customThe mixture was evaporated
  4. extractionThe aqueous layer was extracted twice with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated to dryness
  9. customThe residue was purified by silica gel column chromatography
  10. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50)

Sources & evidence

ORD record
ord-376eaea4fc61496ba4755df65e695e1f
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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