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

Definitions

• the invention concerns new crystalline forms of the hydrobromide of the (alpha S) alpha-(2- chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (thereinafter clopidogrel hydrobromide), which are characterized by X-ray (RTG) diffraction and infrared spectra, and methods of their preparation.
• RTG X-ray
• the respective salt of clopidogrel with camphorsulfonic acid is converted, by a solution of sodium hydrogen carbonate in methylene chloride medium, into an optically active base, which is obtained by evaporation of the solvent.
• the evaporation residue of the active base is converted into the respective salt.
• the hydrobromide is obtained by dissolving the base in diethyl or diisopropyl ether and precipitating drop by drop with 48% hydrobromic acid. Drying the formed precipitate affords crystals with the melting point of 111 °C.
• toxicity of the hydrobromide is also evaluated, which is even somewhat lower than that of the currently used hydrogensulfate.
• LD50 of clopidogrel hydrogen sulfate is 2591 mg and LD 50 of clopidogrel hydrobromide is 4268 g).
• the new crystalline Form I of clopidogrel hydrobromide is characterized by interplanar distances ascertained by X-ray diffraction, d: 4.01 A; 4.39 A and 3.17 A, or by infrared spectrogram with bands at 1743; 1421; 1237, 760 and 728 cm “1 .
• the new crystalline Form II of clopidogrel hydrobromide is characterized by interplanar distances ascertained by X-ray diffraction, d: 4.52 A; 3.83 A; 3.48 A, or by infrared spectrogram with bands at 1754; 1436; 1317 and 1223 cm “1 .
• the new crystalline form III of clopidogrel hydrobromide is characterized by the following peaks ascertained by X-ray diffraction at 20 positions: 7.796 °; 15.380 °; 18.389 °; 19.369 ° and 23.895 °.
• the crystalline Form I can be obtained from a solution of the base in toluene by precipitating with 48% hydrobromic acid. This procedure yields first an oily emulsion of the hydrobromide in toluene, which is, however, with further stirring converted into a crystalline matter. Stirring can be performed at room temperature but it is also possible to decrease the temperature gradually.
• a preferable method of preparation of crystalline form I involves adding a 48% solution of hydrobromic acid in water to a solution of 5 to 15%o of the clopidogrel base in toluene, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.5.
• Form II can be obtained by reaction of a solution of the clopidogrel base in an organic solvent, e.g. ethyl acetate or toluene, with a solution of hydrobromic acid in toluene. Crystalline Form II gradually matures at decreased temperature, i.e. precipitation is performed preferably at temperatures 0 to 30 °C and crystals grow preferably at temperatures lower than 10 °C.
• the method preferably involves using a solution of the clopidogrel base having a concentration 5 to 40 weight % and precipitating it with a solution of hydrogen bromide in toluene of concentrations 5 to 15 weight %, whereas the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.1.
• Form II can be obtained by introducing gaseous hydrogen bromide into a solution of clopidogrel base in an organic solvent, preferably in an aromatic C 6 -C 1 hydrocarbon, for example toluene.
• hydrogen bromide is introduced at a lowered temperature, e.g., -15 °C to 30 °C, more preferably at a temperature lower than 10 °C; at this temperature, in a stirred solution, the crystalline Form II further matures.
• Usual time of stirring is 2 to 8 hours.
• a preferable concentration of the solution of the clopidogrel base is 15 to 40 weight % and the molar ratio of the clopidogrel base and hydrogen bromide is 1 : 0.9 to 1.1.
• Form III can be prepared by a similar method, wherein, however, hydrogen bromide is introduced into a solution of clopidogrel having a concentration lower than 15 %, preferably 1 to 10 %. Hydrogen bromide is again introduced at a lowered temperature, for example -15 °C to 30 °C. Form III matures at a lower temperature by stirring for 2 to 8 hours.
• Form III can be used as an intermediate which is further processed into the pharmaceutically applicable Form II. This can be made by crystallization or precipitating an alcoholic solution of clopidogrel hydrobromide. Alcohols for said solution are selected from the series of -Cs; 2-propanol being preferred. Another less polar solvent can be added to the solution, preferably an ether, ester or ketone. Methyl tert-butyl ether has turned out to be especially preferred. In this manner, Form II can be obtained in an especially high purity.
• Figure 1 shows infrared spectra of clopidogrel hydrobromide Form I.
• Figure 2 shows infrared spectra of clopidogrel hydrobromide Form II.
• Figure 3 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form I.
• Figure 4 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form II.
• Figure 5 shows an X-ray diffraction pattern of clopidogrel hydrobromide Form III.
• the crystals provided the following X-ray diffraction pattern:
• the resulting crystalline product was characterized by an X-ray diffraction pattern as new Form III. HPLC purity more than 99.5 %.
• Clopidogrel hydrobromide of Example 6 (368.5 g) was dissolved while stirring in 2000 ml of 2-propanol at a temperature up to 60 °C. To this solution methyl tert-butyl ether (MTBE) was added (2135 ml) at 45 to 55 °C. The solution was slowly cooled down to room temperature (ca. 2 hrs); crystallization started. After 2 hours, the solution was cooled down to 0 to -5 °C with stirring overnight (18 hrs). The precipitated crystals were sucked off and washed with 500 ml of MTBE.
• MTBE methyl tert-butyl ether

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• 2004
  • 2004-12-21 WO PCT/CZ2004/000089 patent/WO2005068471A1/en not_active Application Discontinuation
  • 2004-12-21 EA EA200601311A patent/EA008972B1/ru not_active IP Right Cessation
  • 2004-12-21 EP EP04802610A patent/EP1713812A1/en not_active Withdrawn

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