# US 2014/0155351 A1 · Process for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0155351 A1 - Document ID: US20140155351A1 - Status: Published application - Kind: A1 - Application number: 14/123,109 - Filed: 2012-06-21 - Published: 2014-06-05 - Earliest claimed: 2011-06-22 - Assignees: Yichang Changjiang Pharmaceutical Co., Ltd; Sunshine Lake Pharma Co., Ltd. - Inventors: Lijun Li; Hailong Wang; Zhongqing Wang - Web page: https://patentgrep.com/patent/US20140155351A1 ## CPC - C07F 7/188: {by reactions involving the formation of Si-O linkages} - A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors - C07D 495/04: Ortho-condensed systems - C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)} - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract 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. ## Claims ### Claim 1 A method for preparing prasugrel comprising acetylating a compound of formula (III): with an acetylating agent in a solvent and in the presence of a base, wherein the solvent has a boiling point of less than 80° C. and an oral median lethal dose (LD50) higher than 2500 mg/Kg, wherein the compound of Formula (III) is prepared by the steps of condensing a compound of Formula (IV) with a compound of Formula (V) or a salt thereof to form a product, and purifying the product; wherein the purifying step is recrystallizing the compound of Formula (III) with a mixture of acetone and water, and wherein R is a hydroxy protecting group selected from p-toluenesulfonyl, methanesulfonyl, or a silyl having the following formula: wherein each of R1, R2 and R3 is independently C1-C10 alkyl. ### Claim 2 (depends on 1) The method of claim 1, wherein the solvent is acetone, methyl ethyl ketone or a combination thereof. ### Claim 3 (depends on 1) The method of claim 1, wherein the acetylating agent is acetyl chloride, acetyl bromide, acetic anhydride or a combination thereof. ### Claim 4 (depends on 1) The method of claim 1, wherein the base is a tertiary amine, a secondary amine, diethylamine, triethylamine or a combination thereof. ### Claim 5 (depends on 1) The method of claim 1, wherein the acetylating reaction is carried out in the presence of an acetylation catalyst, wherein the acetylation catalyst is a 4-dialkylaminopyridine. ### Claim 6 (canceled) ### Claim 7 (canceled) ### Claim 8 (depends on 1) The method of claim 1, wherein the volume ratio of the acetone and water is from 0.5:1 to 3:1, or from 0.8:1 to 2.5:1, or from 0.9:1 to 2.1:1, or from 0.9:1 to 1.1:1, or from 1.9:1 to 2.1:1, or from 1:1, or 2:1. ### Claim 9 A crystalline form of prasugrel hydrochloride, wherein the crystalline form is form H1 or form H3, wherein c) form H1 has 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; or d) form H3 has 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. ### Claim 10 (depends on 9) The crystalline form of claim 9, 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. ### Claim 11 (depends on 9) The crystalline form of claim 9, wherein the crystalline form is form H3 having 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. ### Claim 12 A method for preparing crystalline form of prasugrel hydrochloride 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. ### Claim 13 (depends on 12) The method of claim 12, 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. ### Claim 14 (depends on 12) The method of claim 12, wherein the good solvent is acetic acid, and the anti-solvent is an ester solvent or ethyl acetate. ### Claim 15 (depends on 12) The method of claim 12, wherein the good solvent is acetic acid, and the anti-solvent is an aromatic hydrocarbon solvent or toluene. ### Claim 16 (canceled) ### Claim 17 (depends on 12) The method of claim 12, wherein the good solvent is acetic acid, and the anti-solvent is an ether solvent or methyl tert-butyl ether. ### Claim 18 (canceled) ### Claim 19 (depends on 9) 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 9. ### Claim 20 (depends on 5) The method of claim 5, wherein the alkyl is C1-C6 alkyl or methyl.