Process for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride
View Patent ↗Disclosed herein are a process or method for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride. The process comprises preparation of prasugrel by acetylation in solvents which have low boiling point and/or low toxicity, and the process not only avoids using solvents which have high boiling point and/or high toxicity such as toluene, acetonitrile and so on, but also resolves the problem about thermal instability of prasugrel, and the loss of prasugrel is reduced, as well as the yield is raised. The yield of prasugrel is higher than 85% and the purity is higher than 99.5%. The process can prepare prasugrel and its pharmaceutically acceptable salts. The novel crystalline forms of prasugrel hydrochloride are crystalline form H1, H2 and H3, and their performance in oral absorbability, activating metabolism and inhibiting platelet aggregation is excellent. They have a low toxicity and good thermal stability, and are applicable to the preparation of a drug for preventing or treating diseases caused by thrombosis or embolism.
1. A crystalline form of prasugrel hydrochloride, wherein the crystalline form is form H1 having an X-ray powder diffraction pattern comprising peaks expressed in degrees 2θ at 14.02, 15.92, 18.56, 23.66, 24.46, 25.92 and 26.62±0.3 degrees.
2. The crystalline form of claim 1 , wherein the crystalline form is form H1 having an X-ray powder diffraction pattern comprising peaks expressed in degrees 2θ at 8.02, 8.46, 10.28, 12.34, 12.88, 13.38, 14.02, 14.36, 15.92, 17.36, 18.56, 18.86, 20.54, 22.04, 23.66, 24.46, 25.92, 26.62, 28.3, 29.46 and 30.7±0.3 degrees.
3. A method for preparing the crystalline form of prasugrel hydrochloride of claim 1 comprising dissolving prasugrel hydrochloride in a good solvent to form a solution; and forming crystals by adding the solution slowly into an anti-solvent, wherein the good solvent is an alcohol solvent, a carboxylic acid solvent or a combination thereof, and the anti-solvent is an ether solvent, an aromatic solvent, an ester solvent or a combination thereof.
4. The method of claim 3 , wherein the good solvent is an alcohol solvent, or methanol, ethanol, n-propanol, isopropanol or n-butanol or a combination thereof, and the anti-solvent is an ester solvent or ethyl acetate.
5. The method of claim 3 , wherein the good solvent is acetic acid, and the anti-solvent is an ester solvent or ethyl acetate.
6. A method for preventing or treating diseases caused by thrombosis or embolism in a patient by administering to the patient a pharmaceutically effective amount of the crystalline form of prasugrel hydrochloride of claim 1 .
7. A crystalline form of prasugrel hydrochloride, wherein the crystalline form is form H3 having an X-ray powder diffraction pattern comprising peaks expressed in degrees 2θ at 13.38, 13.78, 14.34, 16.06, 21.48, 22.06 and 25.66±0.3 degrees.
8. The crystalline form of claim 7 , wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks expressed in degrees 2θ at 7.98, 12.86, 13.38, 13.78, 14.34, 16.06, 17.12, 18.66, 20.52, 21.48, 22.06, 23.70, 25.66, 27.14, 27.64, 28.32 and 29.44±0.3 degrees.
9. A method for preparing the crystalline form of prasugrel hydrochloride of claim 7 comprising dissolving prasugrel hydrochloride in a good solvent to form a solution; and forming crystals by adding the solution slowly into an anti-solvent, wherein the good solvent is an alcohol solvent, a carboxylic acid solvent or a combination thereof, and the anti-solvent is an ether solvent, an aromatic solvent, an ester solvent or a combination thereof.
10. The method of claim 9 , wherein the good solvent is an alcohol solvent, or methanol, ethanol, n-propanol, isopropanol or n-butanol or a combination thereof, and the anti-solvent is an ester solvent or ethyl acetate.
11. The method of claim 9 , wherein the good solvent is acetic acid, and the anti-solvent is an ether solvent or methyl tert-butyl ether.
12. A method for preventing or treating diseases caused by thrombosis or embolism in a patient by administering to the patient a pharmaceutically effective amount of the crystalline form of prasugrel hydrochloride of claim 7 .