Sulfuric Acid → Clopidogrel

HRID 988859Notes

Reaction equation

HRID 988859 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].OS(O)(=O)=O.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]

Participants

5

Reactant 3

HCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 9944392Clopidogrel Impurity 7

Product 1

HCID 60606Clopidogrel

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
-15 °C

Procedure

5 g of (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 50 ml methanol and the solution was cooled till −15° C. 15 mL (0.28 mol) of conc. H2SO4 (98%) was added dropwise in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was gradually increased, and stirred at 31° C. for 30 min, and then refluxed at 70° C. for 21 hrs. The solvent was distilled off under reduced pressure and to the residue 50 mL of water was added and stirred for 30 min followed by cooling to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The yield was 3.8 g of crude product purified by column, using hexane:ethyl acetate (9:1) as eluent.

Workup

  1. temperaturemaintaining the temperature till −15° C
  2. additionAfter the completion of addition the reaction mixture
  3. temperaturewas gradually increased
  4. temperaturerefluxed at 70° C. for 21 hrs
  5. distillationThe solvent was distilled off under reduced pressure and to the residue 50 mL of water
  6. additionwas added
  7. stirringstirred for 30 min
  8. temperatureby cooling to −5° C
  9. customThe pH of reaction mixture
  10. extractionThe residue was extracted with 100 mL ethyl acetate
  11. dry with materialThe organic layer was dried over anhydrous Na2SO4
  12. customevaporated under vacuum
  13. customThe yield was 3.8 g of crude product purified by column

Sources & evidence

ORD record
ord-8eed692f58fb49e38486c50a391b5254
Source dataset
uspto-grants-2003_10
Patent number
US06635763B2

Reaction notes

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