Methanol → Clopidogrel

HRID 598050Notes

Reaction equation

HRID 598050 reaction equation
S(=O)(=O)(O)O.[CH3:6][OH:7].S(OC)(OC)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:23](N)=[O:24]>ClCCl.O>[CH3:6][O:7][C:23](=[O:24])[C@@H:22]([N:26]1[CH2:31][CH2:30][C:29]2[S:32][CH:33]=[CH:34][C:28]=2[CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15]

Participants

7

Reactant 4

HCID 887MethanolHCID 1118Sulfuric AcidHCID 6497Dimethyl SulfateHCID 9944392Clopidogrel Impurity 7

Product 1

HCID 60606Clopidogrel

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
45 °C

Procedure

Concentrated sulfuric acid (˜98%; 496 ml; 9.30 mol) was charged into methanol (1.75 l) with sting between 25-38° C. followed by dimethyl sulfate (250 ml; 2.636 mol). The contents were heated to reflux for 3 hours, after which the reaction mixture was cooled to 40-50° C. and (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5yl)acetamide (500 g; 1.55 mol) was charged. The reaction mixture was heated to 65° C. and maintained between 65-66° C. for a period of 60 hours. The reaction mixture was cooled to 25-30° C. and poured into water (10.0 l) with stirring. Dichloromethane (5.0 l) was added, stirred for 1 hour, after which the organic layer was separated. To the aqueous layer dichloromethane (2.5 l) was added and stirred for 1 hour and the separated organic layer was combined with the earlier separated layer and washed with water (2.5 l). 5% (w/v) aqueous sodium bicarbonate solution (2.5 l) was added to this organic layer and stirred for a period of an hour and the separated organic layer was washed with 0.25% sulfuric acid (2.5 l) followed by water (2.5 l) and treated with activated carbon (40.0 g) for a period of 3 hours with stirring. The activated carbon was removed by filtration through a celite bed and the celite bed was washed with dichloromethane (1.0 l). This washing was coupled with the filtrate and the solvent removed under vacuum to yield (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid methyl ester as a pale yellow oil. Yield: 380 g (73.0% by theory). The product was identified by IR spectrum, 1H and 13C NMR investigation.

Workup

  1. customwith sting between 25-38° C.
  2. temperatureThe contents were heated
  3. temperatureto reflux for 3 hours
  4. temperatureThe reaction mixture was heated to 65° C.
  5. temperaturemaintained between 65-66° C. for a period of 60 hours
  6. temperatureThe reaction mixture was cooled to 25-30° C.
  7. stirringstirred for 1 hour
  8. customafter which the organic layer was separated
  9. additionTo the aqueous layer dichloromethane (2.5 l) was added
  10. stirringstirred for 1 hour
  11. customearlier separated layer
  12. washwashed with water (2.5 l)
  13. addition5% (w/v) aqueous sodium bicarbonate solution (2.5 l) was added to this organic layer
  14. stirringstirred for a period of an hour
  15. washthe separated organic layer was washed with 0.25% sulfuric acid (2.5 l)
  16. additiontreated with activated carbon (40.0 g) for a period of 3 hours
  17. stirringwith stirring
  18. customThe activated carbon was removed by filtration through a celite bed
  19. washthe celite bed was washed with dichloromethane (1.0 l)
  20. customthe solvent removed under vacuum

Sources & evidence

ORD record
ord-1eeac41e9b66461da4931435e878c37f
Source dataset
uspto-grants-2011_03
Patent number
US07897613B2

Reaction notes

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