Sulfuric Acid → Clopidogrel

HRID 1455485Notes

Reaction equation

HRID 1455485 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].OS(O)(=O)=O.S(=O)(=O)(O)O>CC(C)=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[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4]

Participants

4

Reactant 2

HCID 1118Sulfuric AcidHCID 115366Clopidogrel bisulfate2×

Product 1

HCID 60606Clopidogrel

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
2.5 °C

Procedure

Clopidogrel bisulfate Form I and II was first time disclosed in International Publication No. WO 99/65915, though Form-I is originally disclosed in EP 281459. U.S. Pat. Nos. 6,429,210; 6,504,030 and U.S. patent application Ser. No. 2002/019829 A1 disclose the manufacturing process of Clopidogrel hydrogen sulfate Form-I and II. These polymorphs are prepared by dissolving Clopidogrel camphor sulfate in acetone followed by addition of conc. sulfuric acid at an ambient temperature. Excess of acetone is distilled and residue is cooled down to 0-5° C. followed by filtration to get Clopidogrel Form-I. The Form-II of Clopidogrel is obtained from residual mother liquor after 3-6 months period. These U.S. patents does not disclose a process for the manufacture of Form-I only and hence, there is huge loss in the yield of Clopidogrel hydrogen sulfate Form-I. U.S. patent application Ser. No. 2003/0114479 discloses the manufacturing processes for Clopidogrel hydrogen sulfate Form-I, II, III, IV, V and amorphous forms. The application also claims the preparation of Clopidogrel hydrogen sulfate Form-I from amorphous Clopidogrel hydrogen sulfate. Specification of the U.S. patent application Ser. No. 2003/0114479 discloses the preparation method of Clopidogrel hydrogen sulfate Form-I using different combinations of alcohol and ether in 56-88% yield.

Workup

  1. customThese polymorphs are prepared
  2. distillationExcess of acetone is distilled
  3. filtrationfollowed by filtration

Sources & evidence

ORD record
ord-7e69021a81cf4f94a45ebeefa2689fc4
Source dataset
uspto-grants-2009_01
Patent number
US07482453B2

Reaction notes

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