Hydrogen Peroxide → Cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid

HRID 1099469Notes

Reaction equation

HRID 1099469 reaction equation
C(N[C:9](=[O:36])[CH:10]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[N:11]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C@H:21]([O:28][CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.N([O-])=[O:38].[Na+].[Li+].[OH-].OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH:30]1([CH:10]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([OH:38])=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1

Participants

7

Reactant 4

HCID 784Hydrogen PeroxideHCID 3939Lithium HydroxideHCID 23668193Sodium NitriteHCID 66810460N-Benzyl-2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide

Product 1

HCID 66810397Cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 7918Acetic AnhydrideSolvent

Procedure

To a solution of N-benzyl-2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide (5.91 g, 12.17 mmol, 1.0 equiv) in a mixture of acetic acid (40 mL) and acetic acid anhydride (80 mL) was added at 0° C. in several small portions sodium nitrite (18.47 g, 267.76 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 (2.91 g, 121.71 mmol, 10.0 equiv) in hydrogen peroxide (2.76 g, 24.84 mL, 243.42 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 acetic acid 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 heptane (+1% acetic acid)/ethyl acetate yielded the title compound as two clean diastereoisomers in 1.52 g (32%, isomer A) and 1.50 g (31%, isomer B) together with a mixed fraction of 0.90 g (19%). Isomer A: MS (ISP): 397.3 [M+H]+. Isomer B: MS (ISP): 397.1 [M+H]+. Mixed fraction: MS (ISP): 397.1 [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 acetic acid
  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 heptane (+1% acetic acid)/ethyl acetate

Sources & evidence

ORD record
ord-9dc75d615e3f46e989a35a53ce622ffe
Source dataset
uspto-grants-2012_03
Patent number
US08143422B2

Reaction notes

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