Hydrochloric Acid → Imiglitazar

HRID 1836421Notes

Reaction equation

HRID 1836421 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+].[OH-].[Na+]>CN(C)C=O.O1CCCC1.CO>[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

10

Reactant 6

HCID 313Hydrochloric Acid2×HCID 14798Sodium HydroxideHCID 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 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Under a nitrogen atmosphere, sodium hydride (60%; oily; 127 mg) was added 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 addition of 1N hydrochloric acid (5 ml), an aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried (over MgSO4) and concentrated. The residue was subjected to a silica gel column chromatography and an oily product was obtained from an eluate with ethyl acetate-hexane (1:3, volume ratio). This was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), a 1N aqueous solution of sodium hydroxide (5 ml) was added thereto and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 1N hydrochloric acid (5.5 ml) and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried (over MgSO4) and concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (907 mg; yield: 60%). The powder X-ray crystal diffraction pattern is shown in FIG. 1. Melting point: 126-127° C. (decomposition).

Workup

  1. extractionfollowed by extraction with ethyl acetate
  2. washThe ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride
  3. dry with materialdried (over MgSO4)
  4. concentrationconcentrated
  5. customan oily product was obtained from an eluate with ethyl acetate-hexane (1:3, volume ratio)
  6. stirringthe mixture was stirred at room temperature for 1.5 hours
  7. extractionthe mixture was extracted with ethyl acetate
  8. washThe ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride
  9. dry with materialdried (over MgSO4)
  10. concentrationconcentrated
  11. customThe resulting crystals were recrystallized from ethyl acetate-hexane

Sources & evidence

ORD record
ord-a56c680c6cd44a6884454a0c3a59fec1
Source dataset
uspto-grants-2004_08
Patent number
US06777435B1

Reaction notes

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