Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the subject of the invention relates to a new method for the manufacture of 5-[2-cyclopropyl- l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride (of formula I), known under the non-proprietary name prasugrel hydrochloride, in polymorphous form B.
• Form D was obtained by a reaction of the base dissolved in ethyl acetate with HCl in the same solvent at 40 °C.
• the amorphous product was obtained by evaporation of the i-propylalcohol solution of the hydrochloride.
• the subject of the invention provides a new method for the manufacture of 5-[2-cyclopropyl- l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride of formula I, known under the non-proprietary name prasugrel hydrochloride, in polymorphous form B.
• the subject of the invention provides a new method for the manufacture of 5-[2-cyclopropyl- l -(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride (formula I), known under the non-proprietary name prasugrel hydrochloride, in polymorphous form B
• the prasugrel base is dissolved or suspended in an organic solvent, which is selected from the group of acetic acid esters and CI to C5 alcohols or their mixtures.
• an organic solvent which is selected from the group of acetic acid esters and CI to C5 alcohols or their mixtures.
• hydrogen chloride dissolved in a solvent selected from the group of acetic acid esters CI to C5 alcohols and water or their mixtures is added dropwise.
• prasugrel hydrochloride 0.8 to 1.1 hydrogen chloride equivalents are used.
• the reaction and subsequent crystallization is carried out at a temperature in the range of from -20 °C to the boiling point of the solvent.
• a co-solvent after the reaction with hydrogen chloride, which co-solvent can be an acetic acid ester, especially ethyl or i-propyl acetate.
• acetic acid ester especially ethyl or i-propyl acetate.
• prasugrel hydrochloride of form B is prepared in this manner, which is characterized by the X-ray diffraction pattern which is presented in fig. 2a in the annex, and by the DSC record which is presented in fig. 2b in the annex.
• Prasugrel hydrochloride prepared in accordance with this invention is characterized by high chemical purity, higher than 96%.
• prasugrel base is dissolved in ethyl acetate or 2- propyl acetate and reacted with hydrogen chloride in ethanol at the temperature of 25 °C and hydrochloride of form B is obtained in a yield higher than 80% and in a higher chemical purity than 99%.
• the method of this invention has the advantage that the production of the hydrochloride and its crystallization is carried out at a lower temperature of 20 to 25 °C as compared to the hitherto known process of preparation from acetone at 40 °C; in practice, this represents considerable energy savings.
• the method of this invention also minimizes production of the decomposition product of the compound of formula III. Thus, a product with very high purity suitable for pharmaceutical use is obtained in a very high yield.
• the DSC records were measured in a Pyris 1 device (Perkin Elmer). The charge of the sample was 3 to 4 mg, heating rate 10 °C/min
• Carrier gas N 2 20 ml/min.
• the HPLC determination was performed in an octadecyl column (250x4.6 mm; 5 ⁇ ⁇ ⁇ ) at the temperature of 30 °C with UV detection at 228 nm.
• the equilibration time of the column was 10 minutes.
• the injected volume was 10 ⁇ .
• the capacity factor of prasugrel is 4.3.
• the sample was prepared by dissolution of the corresponding substance in acetonitrile to the concentration of 1 mg/ml.
• Prasugrel base (1.324 g; 3.545 mmol) is dissolved in isopropyl acetate (13 ml) at a temperature of up to 45 °C and cooled to the room temperature.
• a solution of HCl in ethanol (0.753 g containing 0.123 g of HCl) is added dropwise under stirring.
• the reaction mixture was stirred at the room temperature for 1 hour.
• the separated crystalline substance was aspirated and dried freely in air.
• HPLC purity 99.8%; content of the compound of formula III 0.1%.
• Prasugrel base (1.430 g, 3.83 mmol) is dissolved in ethyl acetate at 40 °C and left to cool down to the room temperature.
• a 16.3% solution of hydrogen chloride in ethanol (1 equivalent) is added dropwise.
• the solution is inoculated and left to crystallize under stirring at the temperature of 20 to 25 °C for 2 hours.
• Aspiration 1.32 g (84 %) of white crystals of form B are obtained with the melt, point: 165 to 167 °C.
• HPLC purity 99.5 %; content of the compound of formula III 0.1%; X-Ray and DSC are equal to the measurements mentioned in Example 1.
• Example 4 To a suspension of prasugrel base (1.627 g; 4.357 mmol) in ethanol (5 ml) 1 equivalent of HC1 in an ethanol solution is added dropwise; to the resulting solution 28 ml of ethyl acetate are added, the mixture is inoculated with B form crystals and stirred at the room temperature. The separated white crystals are aspirated, producing 1.54 g (86.5%) of prasugrel hydrochloride of form B with the melt, point: 167 to 168 °C. HPLC: 96.4 %; X-Ray and DSC are equal to the measurements mentioned in Example 2.
• Example 4 To a suspension of prasugrel base (1.627 g; 4.357 mmol) in ethanol (5 ml) 1 equivalent of HC1 in an ethanol solution is added dropwise; to the resulting solution 28 ml of ethyl acetate are added, the mixture is inoculated with B form crystals and stirred at the
• the X-ray powder diffraction pattern is presented in fig. la, the DSC record is in fig. lb in annex.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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Cited By (4)

Citations (7)

• 2009
  • 2009-12-09 CZ CZ20090828A patent/CZ2009828A3/cs unknown
• 2010
  • 2010-12-09 WO PCT/CZ2010/000126 patent/WO2011069473A1/en active Application Filing
  • 2010-12-09 EA EA201290481A patent/EA201290481A1/ru unknown

Patent Citations (7)

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