Sulfuric Acid → Clopidogrel

HRID 1591934Notes

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

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 US patent application 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 US 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. US patent application 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 US patent application 2003/0114479 discloses the preparation method of Clopidogrel hydrogen sulfate Form-I using different combinations of alcohol and ether in 56-88% yield.

Workup

customThese polymorphs are prepared
distillationExcess of acetone is distilled
filtrationfollowed by filtration

Sources & evidence

ORD record: ord-2cc5dff628fd40e3904952f7b9b8ca0a
Source dataset: uspto-grants-2007_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07291735B2

Reaction notes

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