Acetone → Clopidogrel bisulfate

HRID 253071Notes

Reaction equation

HRID 253071 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])([OH:25])(=[O:24])=[O:23].[K+].CC(C)=O>O>[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 180AcetoneHCID 60606ClopidogrelHCID 516920Potassium bisulfate

Product 1

HCID 115366Clopidogrel bisulfateYield 42%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a stirred suspension of clopidogrel base (3.83 g, 0.0119 mole) in water (3 mL) was added potassium hydrogen sulfate (1.62 g, 0.0119 mole) at 25-30° C. The reaction mixture was stirred for 15 minutes and acetone (25 mL) was added, further stirred for 30 minutes and filtered. The filtrate was distilled at 50-55° C. under reduce pressure (5-10 mm). Benzene (10 mL) was added to the reaction mixture and distilled at 90-95° C., di-isopropyl ether (20 mL) was added and stirred at 25-30° C. for 1 hour and filtered. The semi sold material was dissolved in dichloromethane (25 mL) and distilled under reduced pressure (5-10 mm) to give clopidogrel hydrogen sulfate (2.1 g). The amorphous form was similarly characterized by XRD, DSC, IR, chemical purity (HPLC)>99% and chiral purity (chiral HPLC) 99.5% (e.e.), % water 3.0, m.p. 94-98° C. (softens).

Workup

  1. stirringfurther stirred for 30 minutes
  2. filtrationfiltered
  3. distillationThe filtrate was distilled at 50-55° C.
  4. additionBenzene (10 mL) was added to the reaction mixture
  5. distillationdistilled at 90-95° C.
  6. additiondi-isopropyl ether (20 mL) was added
  7. stirringstirred at 25-30° C. for 1 hour
  8. filtrationfiltered
  9. dissolutionwas dissolved in dichloromethane (25 mL)
  10. distillationdistilled under reduced pressure (5-10 mm)

Sources & evidence

ORD record
ord-e74c392ef6284cb09d0b8b2e987f8a6f
Source dataset
uspto-grants-2011_01
Patent number
US07872019B2

Reaction notes

Loading…