Hydrogen Peroxide → Cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid

HRID 1161308Notes

Reaction equation

HRID 1161308 reaction equation
C(N[C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)C1C=CC=CC=1.N([O-])=[O:40].[Na+].[Li+].[OH-].OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:32]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]([OH:40])=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1

Participants

7

Reactant 4

HCID 784Hydrogen PeroxideHCID 3939Lithium HydroxideHCID 23668193Sodium NitriteHCID 66619365N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide

Product 1

HCID 66619285Cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acidYield 57.6%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 7918Acetic AnhydrideSolvent

Procedure

To a solution of N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide (3.50 g, 6.72 mmol, 1.0 equiv) in a mixture of acetic acid (25 mL) and acetic acid anhydride (50 mL) was added at 0° C. in several small portions sodium nitrite (10.20 g, 147.91 mmol, 22.0 equiv) within 1 h. The reaction mixture was stirred overnight allowing to warm up to rt. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was taken up in a mixture of THF:water (3:1, 40 mL) and a pre-prepared solution of LiOH (1.61 g, 67.23 mmol, 10.0 equiv) in hydrogen peroxide (15.24 g, 13.73 mL, 134.46 mmol, 20.0 equiv; 30% solution in water) was added and stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of 1 M HCl and the aqueous layer extracted with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. Purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol yielded 1.67 g (57%) of the title compound. MS (ES+): 432 (M+H).

Workup

  1. concentrationThe solution was concentrated by evaporation under reduced pressure
  2. additionthe pH adjusted to 9 by addition of a solution of 1 M NaHCO3
  3. extractionthe aqueous layer extracted with diethyl ether
  4. dry with materialThe combined organic phases were dried over MgSO4
  5. concentrationconcentrated by evaporation under reduced pressure
  6. additionThe crude material was taken up in a mixture of THF:water (3:1, 40 mL)
  7. stirringstirred at rt for 30 min
  8. concentrationThe solution was concentrated by evaporation under reduced pressure
  9. additionthe pH adjusted to 4 by addition of 1 M HCl
  10. extractionthe aqueous layer extracted with diethyl ether
  11. dry with materialThe combined organic phases were dried over MgSO4
  12. concentrationconcentrated by evaporation under reduced pressure
  13. customPurification by silica column chromatography
  14. washeluting with a gradient of dichloromethane/methanol

Sources & evidence

ORD record
ord-1a43f74bea4a47babf906760daef6f94
Source dataset
uspto-grants-2010_10
Patent number
US07816540B2

Reaction notes

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