Pyridine → Nitazoxanide Impurity

HRID 341263Notes

Reaction equation

HRID 341263 reaction equation
[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[NH2:34]>C(OCC)(=O)C.O.CCOCC>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:9])[NH:34][C:30]1[S:29][CH:33]=[CH:32][N:31]=1)(=[O:3])[CH3:2]

Participants

9

Reactant 5

HCID 1049PyridineHCID 21552-AminothiazoleHCID 2244AspirinHCID 24386Thionyl ChlorideHCID 516892Sodium Bicarbonate

Product 1

HCID 3363745Nitazoxanide ImpurityYield 52%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
0 °C

Procedure

2-(Acetyloxy)-benzoic acid (500, 1.80 g, 10.0 mmol) was placed in a 250 mL round bottom flask equipped with a stirbar, vacuum adapter and septum. Ether (100 mL) and pyridine (1.00 mL, 12.4 mmol) were added to create a clear, colorless solution, which was cooled to zero in an ice bath before thionyl chloride (875 μL, 12.0 mmol) was added dropwise over ca. 30 sec. A thick white precipitate formed upon the addition of each drop. The reaction mixture was stirred for 90 minutes at 0° C. before being filtered through paper, and removing the solvents in vacuo. Sodium bicarbonate (3.42 g, 40.7 mmol) and 1,3-thiazol-2-amine (1.00 g, 10.0 mmol) were weighed into a 250 mL round bottom flask and water (30 mL) and ethyl acetate (30 mL) were added to form a colorless biphase, which was stirred rapidly. The crude acid chloride was suspended in ethyl acetate (10 mL) and added dropwise to the rapidly stirring biphase. The resulting biphase was capped lightly and stirred rapidly at room temperature for 2 hours. The biphase layers were separated, and the aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated to give 501 (1.36 g, 52%) as a colorless powder, which was used without purification.

Workup

  1. customequipped with a stirbar, vacuum adapter and septum
  2. additionwas added dropwise over ca. 30 sec
  3. customA thick white precipitate formed upon the addition of each drop
  4. filtrationbefore being filtered through paper
  5. customremoving the solvents in vacuo
  6. customto form a colorless biphase, which
  7. stirringwas stirred rapidly
  8. additionadded dropwise to the
  9. stirringrapidly stirring biphase
  10. customThe resulting biphase was capped lightly
  11. stirringstirred rapidly at room temperature for 2 hours
  12. customThe biphase layers were separated
  13. extractionthe aqueous was extracted twice with ethyl acetate
  14. washThe combined organics were washed with brine
  15. dry with materialdried with MgSO4
  16. filtrationfiltered
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-12b1cf4b5daf4612ac466f6699854b25
Source dataset
uspto-grants-2014_11
Patent number
US08895752B2

Reaction notes

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