Hydrochloric Acid → Imiglitazar

HRID 584408Notes

Reaction equation

HRID 584408 reaction equation
[H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:3]/[N:4]=[C:5](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:39][CH:38]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 109469404-(4-Chloromethylphenoxy)methyl-5-methyl-2-phenyloxazoleHCID 12137371methyl (4E)-4-hydroxyimino-4-phenylbutanoate

Product 1

HCID 9890879ImiglitazarYield 60.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of methyl E-4-hydroxyimino-4-phenylbutyrate (661 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at room temperature for 1.5 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (907 mg, yield 60%) as colorless crystals. m.p. 126-127° C. (decomposition)

Workup

  1. additionwas added
  2. extractionthe mixture was extracted with ethyl acetate
  3. washThe ethyl acetate layer was washed with saturated aqueous sodium chloride
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto obtain an oil from a fraction
  7. washeluted with ethyl acetate-hexane (1:3
  8. dissolutionThis oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml)
  9. additionwas added
  10. stirringthe mixture was stirred at room temperature for 1.5 hours
  11. addition1N HCl (5.5 ml) was added to the reaction mixture
  12. extractionthe mixture was extracted with ethyl acetate
  13. washThe ethyl acetate layer was washed with saturated aqueous sodium chloride
  14. dry with materialdried (MgSO4)
  15. concentrationconcentrated
  16. customThe residual crystal was recrystallized from ethyl acetate-hexane

Sources & evidence

ORD record
ord-011ba0c26da846d89bf0ab2e9aef4e7b
Source dataset
uspto-grants-2005_08
Patent number
US06924300B2

Reaction notes

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