Sulfuric Acid → Clopidogrel bisulfate

HRID 1792125Notes

Reaction equation

HRID 1792125 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:22](=[O:26])(=[O:25])([OH:24])[OH:23].CC(OC)(C)C>C(O)CC>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[OH:25][S:22]([OH:26])(=[O:24])=[O:23]

Participants

5

Reactant 3

HCID 1118Sulfuric AcidHCID 15413tert-Butyl methyl etherHCID 60606Clopidogrel

Product 1

HCID 115366Clopidogrel bisulfateYield 69%

Reagents, catalysts & solvents 1

HCID 10311-PropanolSolvent

Procedure

Clopidogrel base (2.86 g, 1 eq.) was dissolved in 1-Propanol (22.6 mL). Eighty percent aqueous sulfuric acid (0.59 mL, 0.66 eq.) was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 hours. Then, the solution was cooled to room temperature and stirred at this temperature for additional 16 hours. The solvent was evaporated to dryness under reduced pressure to obtain an oily residue. To the residue, MTBE (50 mL) was added and the resulting mixture was stirred at room temperature for 24 hours during which a massive precipitate was formed. The white solid was collected by filtration, washed with MTBE (2×10 mL) and dried at 50° C. in a vacuum oven for 30 hours to obtain 2.58 g (69%) of clopidogrel hydrogensulfate crystal Form VI.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux temperature for 2 hours
  3. customThe solvent was evaporated to dryness under reduced pressure
  4. customto obtain an oily residue
  5. stirringthe resulting mixture was stirred at room temperature for 24 hours during which a massive precipitate
  6. customwas formed
  7. filtrationThe white solid was collected by filtration
  8. washwashed with MTBE (2×10 mL)
  9. customdried at 50° C. in a vacuum oven for 30 hours

Sources & evidence

ORD record
ord-70a1d2b862e2446f9dbfd0405e0a6f96
Source dataset
uspto-grants-2006_07
Patent number
US07074928B2

Reaction notes

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