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

HRID 417111Notes

Reaction equation

HRID 417111 reaction equation
C(N(N=O)[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.O.[OH-].[Li+].OO.C(O)(=[O:48])C>O1CCCC1.O>[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:38])=[O:48])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 784Hydrogen PeroxideHCID 168937Lithium hydroxide, monohydrateHCID 86639899N-benzyl-N-nitroso-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 acid

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 12.1 g (22.02 mmol) N-benzyl-N-nitroso-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 65 ml tetrahydrofuran and 15 ml water were added dropwise over 20 min. a solution of 9.24 g (220 mmol) lithium hydroxide monohydrate in 45 ml (440 mmol) hydrogen peroxide and 30 ml water. The reaction mixture turned into a turbid solution and a slight temperature raise was observed (cooled temporarily using an ice-bath). After 1 h the pH of the mixture was adjusted to pH 4 using 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, once with water and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 200 ml tert-butyl methyl ether and partially evaporated until a precipitation formed. The suspension was cooled in the refrigerator for 30 min, then the solid was filtered off, washed with 50 ml ice-cold tert-butyl methyl ether and dried in high vacuum. White solid (99%). MS (Turbo Spray): m/z=432.2 [M+H].

Workup

  1. temperaturea slight temperature raise
  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, once with water and once with brine
  5. dry with materialThe solution was dried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. dissolutionThe residue was dissolved in 200 ml tert-butyl methyl ether
  9. custompartially evaporated until a precipitation
  10. customformed
  11. temperatureThe suspension was cooled in the refrigerator for 30 min
  12. filtrationthe solid was filtered off
  13. washwashed with 50 ml ice-cold tert-butyl methyl ether
  14. customdried in high vacuum

Sources & evidence

ORD record
ord-9c2f1b6d1d7f43a287107670cac0681f
Source dataset
uspto-grants-2012_01
Patent number
US08088930B2

Reaction notes

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