Sulfuric Acid → Clopidogrel hydrogen sulfate

HRID 988860Notes

Reaction equation

HRID 988860 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH: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].[OH:21][S:22]([OH:25])(=[O:24])=[O:23].[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[S:22](=[O:23])(=[O:21])([OH:25])[OH:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH: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 113128242-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide

Product 1

HCID 16757820Clopidogrel hydrogen sulfate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
67.5 °C

Procedure

5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 20 ml methanol and the solution warmed to 65 to 70° C. 15 mL (0.28 mol) of chilled conc. H2SO4 (98%, −15° C.) was added slowly in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was heated at 70° C. for 16 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 combined eluent was evaporated at reduced pressure to yield 2.8 g of crude product purified by column chromatography, using hexane:ethyl acetate (9:1) as eluent to give 2 g of titled compound (1) and 1 g of the starting material (S)-(+)-(II).

Workup

  1. temperaturemaintaining the temperature till −15° C
  2. additionAfter the completion of addition the reaction mixture
  3. temperaturewas heated at 70° C. for 16 hrs
  4. distillationThe solvent was distilled off under reduced pressure and to the residue 50 mL of water
  5. additionwas added
  6. temperatureby cooling to −5° C
  7. customThe pH of reaction mixture
  8. extractionThe residue was extracted with 100 mL ethyl acetate
  9. dry with materialThe organic layer was dried over anhydrous Na2SO4
  10. customevaporated under vacuum
  11. customThe combined eluent was evaporated at reduced pressure
  12. customto yield 2.8 g of crude product
  13. custompurified by column chromatography

Sources & evidence

ORD record
ord-5d64ce4c40b749eaa836be3b00b58b69
Source dataset
uspto-grants-2003_10
Patent number
US06635763B2

Reaction notes

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