Acetic Acid → [2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-(4,4-difluoro-cyclohexyl)-acetic acid

HRID 417146Notes

Reaction equation

HRID 417146 reaction equation
C(N(N=O)[C:9](=[O:37])[CH:10]([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:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:47])C>O1CCCC1.O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:20]2[N:19]([CH:10]([CH:11]3[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:9]([OH:47])=[O:37])[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:35][CH:34]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 784Hydrogen PeroxideHCID 168937Lithium hydroxide, monohydrateHCID 86639901N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide

Product 1

HCID 66619456[2-(4-Chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-(4,4-difluoro-cyclohexyl)-acetic acidYield 49%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 3.05 g (5.46 mmol) N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 15 ml tetrahydrofuran and 10 ml water were added dropwise over 5 min. a solution of 2.29 g (54.57 mmol) lithium hydroxide monohydrate in 11.14 ml (109 mmol) 30% hydrogen peroxide solution and 10 ml water. The reaction mixture turned into a turbid solution and became slightly warm (cooled temporarily using an ice-bath). After stirring for 2 h the pH was adjusted to pH 4 using 12.48 ml (218 mmol) acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated. The remaining yellow foam was treated with 100 ml tert-butyl methylether and the resulting light yellow suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum to give a first batch of compound (yellow solid). The mother liquor was purified on a preparative HPLC system (Phenomenex Gemini column) eluting with a gradient of acetonitrile and water. to give another batch of compound (colorless solid). Overall yield 49%. MS (Turbo Spray): m/z=441.3 [M+H].

Workup

  1. temperaturebecame slightly warm (
  2. temperaturecooled temporarily
  3. extractionThe resulting light yellow solution was extracted three times with ethyl acetate
  4. washThe combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. additionThe remaining yellow foam was treated with 100 ml tert-butyl methylether
  9. filtrationthe resulting light yellow suspension was filtered
  10. washwashed with tert-butyl methyl ether
  11. customdried under high vacuum
  12. customto give a first batch of compound (yellow solid)
  13. customThe mother liquor was purified on a preparative HPLC system (Phenomenex Gemini column)
  14. washeluting with a gradient of acetonitrile and water
  15. customto give another batch of compound (colorless solid)

Sources & evidence

ORD record
ord-65c777efd8134af88c4d2b3b148e082f
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

Loading…