A process for preparing clopidogrel or a salt thereof.
Description
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a schematic representation of processes of the present invention.
Claims
1. A process for preparing clopidogrel or a salt thereof, comprising reacting racemic methyl alpha-amino-(2-chlorophenyl)acetate with L-(+)-tartaric acid, separating a formed tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate from a reaction mixture, and heating a reaction mixture to form racemic methyl alpha-amino-(2-chlorophenyl)acetate.
2. The process of claim 1, wherein a starting material methyl α-amino-(2-chlorophenyl)acetic acid is prepared by reacting DL-2-chlorophenylglycine with methanol in the presence of sulfuric acid.
3. The process of claim 1, wherein reacting with L-(+)-tartaric acid occurs in the presence of a solvent consisting essentially of methanol.
4. The process of claim 1, wherein heating a reaction mixture is carried out at temperatures about 30° C. to about 100° C.
5. The process of claim 1, wherein formed racemic methyl alpha-amino-(2-chlorophenyl)acetate is reacted with additional L-(+)-tartaric acid to form a tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate.
6. The process of claim 1, further comprising reacting a tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate with a base to form S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate, which is reacted with 2-thienyl-p-toluenesulfonate to form a reaction product, and further reacting a reaction product with formaldehyde to form clopidogrel.
7. The process of claim 6, wherein 2-thienyl-p-toluenesulfonate is prepared by reacting thiophene-2-ethanol with a p-toluene sulfonyl halide, in a solvent comprising toluene.
8. The process of claim 6, wherein a base comprises sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.
9. The process of claim 6, wherein formaldehyde is used in the form of an aqueous solution having a concentration about 40 percent by weight, in a volume about 3 L to about 15 L per kg of S-(+)-methyl α-(2-thienylethylamino)-(2-chlorophenyl)acetate.
10. The process of claim 6, further comprising reacting clopidogrel with sulfuric acid to form clopidogrel hydrogen sulfate.
11. The process of claim 10, wherein clopidogrel hydrogen sulfate has crystalline Form I.
12. The process of claim 10, wherein clopidogrel hydrogen sulfate has crystalline Form II.
13. A continuous process for preparing clopidogrel or a salt thereof, comprising reacting racemic methyl alpha-amino-(2-chlorophenyl)acetate with L-(+)-tartaric acid, separating a formed tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate from a reaction mixture, heating a reaction mixture to form racemic methyl alpha-amino-(2-chlorophenyl)acetate, and reacting formed racemic methyl alpha-amino-(2-chlorophenyl)acetate with additional L-(+)-tartaric acid to form a tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate.
14. The process of claim 13, wherein reacting with L-(+)-tartaric acid occurs in the presence of a solvent consisting essentially of methanol.
15. The process of claim 13, wherein heating a reaction mixture is carried out at temperatures about 30° C. to about 100° C.
16. The process of claim 13, further comprising reacting a tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate with a base to form S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate, which is reacted with 2-thienyl-p-toluenesulfonate to form a reaction product, and further reacting a reaction product with formaldehyde to form clopidogrel.
17. The process of claim 16, wherein 2-thienyl-p-toluenesulfonate is prepared by reacting thiophene-2-ethanol with a p-toluene sulfonyl halide, in a solvent comprising toluene or dichloromethane.
18. A process for preparing 2-thienyl-p-toluenesulfonate, comprising reacting thiophene-2-ethanol with a p-toluene sulfonyl halide, in a solvent comprising toluene or dichloromethane.
19. The process of claim 18, wherein reacting is conducted in the presence of a base.
20. The process of claim 18, wherein reacting is conducted in the presence of triethylamine.
Patent Application
20070225320
