Hydrochloric Acid → Pioglitazone N-Oxide

HRID 1482790Notes

Reaction equation

HRID 1482790 reaction equation
Cl.[CH3:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH:20]3[S:26][C:24](=[O:25])[NH:23][C:21]3=[O:22])=[CH:17][CH:18]=2)=[N:8][CH:9]=1.C(=O)(O)[O-:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O.O.C(Cl)Cl>[O:25]=[C:24]1[NH:23][C:21](=[O:22])[CH:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH3:2])=[CH:9][N+:8]=3[O-:28])=[CH:14][CH:15]=2)[S:26]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 4829PioglitazoneHCID 70297m-Chloroperbenzoic acid2×HCID 516892Sodium Bicarbonate

Product 1

HCID 10690658Pioglitazone N-OxideYield 46.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
10 °C

Procedure

The hydrochloric acid salt of pioglitazone (3 g, 7.64 mmol) was dissolved in N,N-dimethylformamide (DMF, 50 mL) and neutralized by addition of an aqueous solution of sodium bicarbonate (NaHCO3, 0.641 g, 7.64 mmol in 6 mL water). The reaction mixture was diluted with water and the white solid was filtered off. It was rinsed with water and dried under vacuum. The resulting solid was resuspended in dichloromethane (CH2Cl2), and meta-chloroperbenzoic acid (m-CPBA, 50% by weight, 2.64 g, 7.64 mmol) was added to the mixture while maintaining the temperature at about 10° C. The reaction mixture was stirred at room temperature for 2 days, and then one more equivalent of m-CPBA (2.64 g, 7.64 mmol) was added. The reaction mixture was stirred for 2 h, then diluted with CH2Cl2 (50 mL). The organic layer was washed with 10% Na2S2O3 in water/water (2:1 v:v), then with 1:1 v:v 10% NaHCO3 in water/water (1:1 v:v). The resulting organic mixture was dried over sodium sulfate, filtered and solvent evaporated to give the crude N-oxide, which was further purified by flash chromatography on silica gel (gradient elution: CH2Cl2/10% MeOH in CH2Cl2 from 9:1 to 1:1). Fractions containing the pure N-oxide were pooled and evaporated to give the title compound (1.313 g, 3.53 mmol, 46.2% yield). LC/MS: 373 (M+1)

Workup

  1. filtrationthe white solid was filtered off
  2. washIt was rinsed with water
  3. customdried under vacuum
  4. stirringThe reaction mixture was stirred for 2 h
  5. washThe organic layer was washed with 10% Na2S2O3 in water/water (2:1 v:v)
  6. dry with materialThe resulting organic mixture was dried over sodium sulfate
  7. filtrationfiltered
  8. customsolvent evaporated
  9. customto give the crude N-oxide, which
  10. customwas further purified by flash chromatography on silica gel (gradient elution: CH2Cl2/10% MeOH in CH2Cl2 from 9:1 to 1:1)
  11. additionFractions containing the pure N-oxide
  12. customevaporated

Sources & evidence

ORD record
ord-401c26a15128426dbb6de361f6f9f88f
Source dataset
uspto-grants-2016_08
Patent number
US09416117B2

Reaction notes

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