Hydrochloric Acid → Imiglitazar

HRID 1836422Notes

Reaction equation

HRID 1836422 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 86%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Under a nitrogen atmosphere, sodium hydride (60%; oily; 3.00 g) was added to a solution of methyl (E)-4-hydroxyimino-4-phenylbutyrate (15.5 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (23.5 g) in N,N-dimethylformamide (100 ml) at 0° C. and the mixture was stirred for 2 hours. This was neutralized with 1N hydrochloric acid, aqueous solution of sodium bicarbonate was added thereto 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 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 (100 ml)-methanol (50 ml), a 2N aqueous solution of sodium hydroxide (50 ml) was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid and 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 (24.5 g; yield: 86%). Melting point: 126-127° C. A part (500 mg) of the crystals was dissolved in ethanol (5 ml) with heating and cooled at 0° C. The precipitating crystals were collected to give crystals (466 mg) showing a powder X-ray crystal diffraction pattern as given in FIG. 2. Melting point: 137-138° C.

Workup

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

Sources & evidence

ORD record
ord-3311fee7192a456ba20195e9c93cea41
Source dataset
uspto-grants-2004_08
Patent number
US06777435B1

Reaction notes

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