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WO2011069473A1 - A method for the preparation of prasugrel hydrochloride in polymorphous form b - Google Patents

A method for the preparation of prasugrel hydrochloride in polymorphous form b Download PDF

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WO2011069473A1
WO2011069473A1 PCT/CZ2010/000126 CZ2010000126W WO2011069473A1 WO 2011069473 A1 WO2011069473 A1 WO 2011069473A1 CZ 2010000126 W CZ2010000126 W CZ 2010000126W WO 2011069473 A1 WO2011069473 A1 WO 2011069473A1
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prasugrel
hydrochloride
solvent
hydrogen chloride
dissolved
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Inventor
Hana Stepankova
Katerina Kaminska
Josef Hajicek
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Zentiva KS
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Zentiva KS
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    • 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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  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to a 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 (prasugrel hydrochloride) in crystalline form B, wherein prasugrel base of formula II is dissolved or suspended in an organic solvent and reacted with hydrogen chloride dissolved in an organic solvent or in water at a temperature in the range of -20 °C to 75°C and crystallized, optionally after addition of a co-solvent.

Description

A method for the preparation of prasugrel hydrochloride in polymorphous form B
Technical Field 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.
Figure imgf000003_0001
(I)
Background Art Prasugrel, a method for the preparation thereof, as well as its use as an anti-aggregation substance in patients with a risk of vessel clogging by a blood clot, was first described in the patent no. EP 0 542 411.
The patent of the Sankyo Company no. EP 1 298 132 describes prasugrel hydrochloride and maleate. Prasugrel hydrochloride, referred to as crystal A here, was prepared by reaction of the base in acetone with 36% hydrochloric acid at 25 °C. Crystals of prasugrel hydrochloride with the melting point of 133 to 136 °C were obtained. By reacting again with 36% hydrochloric acid in the same solvent but at an increased temperature (40 °C), hydrochloride referred to as crystal Bl with the melting point of 166 to 174 °C was obtained. The same procedure; however, after inoculation with crystal Bl, provided hydrochloride with the melting point of 165 to 178 °C, crystal B2 here.
Another patent application of Sankyo, EP 2 003 136, characterizes 2 crystalline forms of prasugrel hydrochloride with physical and analytical methods. Form B of the hydrochloride in accordance with this application is prepared as in the previous case from the base in acetone by addition of 36% HCl at an increased temperature (52 °C here) and after inoculation. At the same time, this application also refers to a polymorphous form of prasugrel base.
The general patent application of Sandoz no. WO 2008/000418 describes preparation of various hydrochlorides of pharmaceutically active substances by means of in situ generated HCl from trialkyl silyl chlorides. Form B of prasugrel hydrochloride was also prepared by this method and characterized with physical and analytical methods.
The newly published application no. WO 2009/062044 (Reddy Laboratories) describes new crystalline forms C, D, E of prasugrel hydrochloride, as well as its amorphous form. Form C in accordance with this patent was produced by conversion of the prasugrel base with aqueous hydrochloric acid in 2-butanol at 40 °C or 28 °C. Form D was prepared by a reaction of the base dissolved in i-propylalcohol with HCl in the same solvent at 40 °C.
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 patent application no. WO 2009/066326 of MSM Laboratories describes prasugrel fumarate, benzene sulphonate, p-roluene sulphonate and malate.
Helm published the patent application no. WO 2009/098142, which encompasses salts of alkyl sulfonic and aryl sulfonic acids with improved chemical stability. Disclosure of Invention
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.
Figure imgf000004_0001
(I) The manufacturing method of prasugrel hydrochloride, form B, according to this invention leads to a high yield of the product with a pure polymorphous form with high chemical purity.
Detailed description of the invention
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
Figure imgf000005_0001
which comprises a process in which the base of prasugrel of formula II is dissolved or suspended in an organic solvent and reacted with hydrogen chloride, dissolved in an organic solvent or in water at a temperature of the solvent in the range of -20 °C to 75 °C, and further crystallized at the same temperature and/or after addition of a co-solvent or after cooling. The resulting product is separated and dried.
Figure imgf000005_0002
(II)
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. To the solution or suspension 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. For the preparation of 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.
It is suitable, in some embodiments, to add a co-solvent after the reaction with hydrogen chloride, which co-solvent can be an acetic acid ester, especially ethyl or i-propyl acetate. After addition of hydrogen chloride it is also suitable to inoculate the reaction mixture with crystals of the hydrochloride of form B.
In accordance with this invention 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%.
In a preferable embodiment of this invention 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. In addition, 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.
Figure imgf000006_0001
Brief Description of Drawings
Figure la - X-ray powder diffraction pattern of prasugrel hydrochloride of form A
Figure lb - DSC record of prasugrel hydrochloride of form A
Figure 2a - X-ray powder diffraction pattern of prasugrel hydrochloride of form B Figure 2b - DSC record of prasugrel hydrochloride of form B Specific working examples Melting points were measured on a Kofler block.
Samples of the prasugrel salts in the examples below were evaluated with the X-ray diffraction analysis by means of the following procedure:
The diffraction pattern was produced on an X'PERT PRO MPD PANalytical powder diffractometer with a graphite monochromator, used radiation CuKa (λ= 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 to 40° 2Θ, increment size: 0.01° 2Θ at the dwell on reflection of 50s; the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. 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
Temperature programme:
1 ) 1 minute at 50 °C
2) 50 to 200 °C at the rate of 10°C/minute (except prasugrel HCL 50 to 250 °C at the rate of l0 °C/min).
Carrier gas: N2 20 ml/min.
Samples of prasugrel and its salts in the following examples were evaluated with HPLC by means of the following procedure:
The HPLC determination was performed in an octadecyl column (250x4.6 mm; 5 μηι) at the temperature of 30 °C with UV detection at 228 nm. Gradient elution with a phosphate buffer (0.01 M KH2P04 pH 2.2) with acetonitrile at the flow rate of 1.0 ml/min with the following gradient: 0 min 80 % of the buffer; 40 min 10 % of the buffer (linear gradient); 45 min 10 % of the buffer, was used for the separation. The equilibration time of the column was 10 minutes. The injected volume was 10 μΐ. 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. Example 1
Preparation of prasugrel hydrochloride of form B
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. To this solution 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. 1.28 g of prasugrel hydrochloride of form B was obtained (88.1 %) with the melt, point = 165.8 to 168.2 °C. HPLC: purity 99.8%; content of the compound of formula III 0.1%.
X-ray analysis
Table 2: Characteristic peaks of prasugrel hydrochloride of form B
Figure imgf000008_0001
The X-ray powder diffraction pattern is presented in fig. 2a, the DSC record is in fig. 2b in the annex. Example 2
Preparation of prasugrel hydrochloride of form B
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. To the prasugrel solution 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. By 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 3
Preparation of prasugrel hydrochloride of form B
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
Preparation of prasugrel hydrochloride of form A
Prasugrel base (2.55 g; 6.82 mmol) is dissolved in ethyl methyl ketone (25) ml at a temperature of up to 35 °C and cooled down in a water + ice bath to 0 °C. Under stirring and at the temperature of 0°C A solution of HC1 in ethanol (1.45 ml containing 0.237 g HC1) is added dropwise to this solution under stirring at the temperature 0 °C. The reaction mixture was stirred at the temperature of 0 °C for 1 hour. The separated crystalline substance was aspirated and dried freely in air. 2.26 g of prasugrel hydrochloride of form A (80.7%) were obtained with the melt, point = 122 to 124 °C. HPLC: purity 99.3%. X-ray analysis
Table 1 : Characteristic peaks of prasugrel hydrochloride of form A
Figure imgf000010_0001
The X-ray powder diffraction pattern is presented in fig. la, the DSC record is in fig. lb in annex.

Claims

Claims A method for the manufacture of prasugrel hydrochloride of formula I
Figure imgf000011_0001
(I) in crystalline form B, characterized in that prasugrel base of formula II
Figure imgf000011_0002
s dissolved or suspended in an organic solvent and reacted with hydrogen chloride dissolved in an organic solvent or in water, at a temperature in the range of -20 °C to 75 °C and crystallized, optionally after addition of a co-solvent.
The method according to claim 1 , characterized in that prasugrel base is dissolved or suspended in a solvent elected from the group consisting of acetic acid esters and CI to C5 alcohols and their mixtures.
The method according to claims 1 or 2, characterized in that the suspension or solution of prasugrel base is reacted with 0.8 to 1.1 equivalents of hydrogen chloride dissolved in a solvent selected from the group consisting of acetic acid esters, CI to C5 alcohols and water and their mixtures.
4. The method according to claims 1 to 3, characterized in that the reaction with hydrogen chloride and crystallization are carried out at a temperature in the range of from -20 °C to the boiling point of the solvent.
5. The method according to claims 1 to 4, characterized in that the reaction with hydrogen chloride and crystallization are carried out at a temperature of 0 to +30 °C.
6. The method according to claims 1 to 5, characterized in that, after the reaction with hydrogen chloride, an acetic acid ester is added to the mixture as a co-solvent.
7. The method according to claim - Θ 6, characterized in that the acetic acid ester is ethyl or 2-propyl ester of acetic acid.
8. The method according to claims 1 to 7, characterized in that the CI to C5 alcohol is ethanol.
9. The method according to claims 1 to 8, characterized in that prasugrel hydrochloride is obtained in chemical purity (HPLC) higher than 96%.
10. The method according to 1 to 8, characterized in that prasugrel hydrochloride is obtained in chemical purity (HPLC) higher than 99%.
PCT/CZ2010/000126 2009-12-09 2010-12-09 A method for the preparation of prasugrel hydrochloride in polymorphous form b Ceased WO2011069473A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012427A (en) * 2012-11-26 2013-04-03 天津大学 Prasugrel hydrochloride ethanol solvate and preparation method thereof
WO2014092589A1 (en) 2012-12-12 2014-06-19 Instytut Farmaceutyczny Process for preparation of prasugrel hydrochloride polymorphic form b of pharmaceutical purity
CN105601643A (en) * 2015-12-23 2016-05-25 山东鲁抗医药股份有限公司 Preparation method of high-purity prasugrel hydrochloride
CN105669696A (en) * 2014-11-21 2016-06-15 四川海思科制药有限公司 Prasugrel hydrochloride compound

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0542411A2 (en) 1991-09-09 1993-05-19 Sankyo Company Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
EP1298132A1 (en) 2000-07-06 2003-04-02 Sankyo Company, Limited Hydropyridine derivative acid addition salts
WO2008000418A2 (en) 2006-06-27 2008-01-03 Sandoz Ag New method for salt preparation
EP2003136A1 (en) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Process for producing high-purity prasugrel and acid addition salt thereof
WO2009062044A2 (en) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs
WO2009066326A2 (en) 2007-11-19 2009-05-28 Msn Laboratories Limited Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts
WO2009098142A1 (en) 2008-02-06 2009-08-13 Helm Ag Prasugrel salts with improved properties

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0542411A2 (en) 1991-09-09 1993-05-19 Sankyo Company Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
EP1298132A1 (en) 2000-07-06 2003-04-02 Sankyo Company, Limited Hydropyridine derivative acid addition salts
EP2003136A1 (en) 2006-04-06 2008-12-17 Daiichi Sankyo Company, Limited Process for producing high-purity prasugrel and acid addition salt thereof
WO2008000418A2 (en) 2006-06-27 2008-01-03 Sandoz Ag New method for salt preparation
WO2009062044A2 (en) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Processes for the preparation of prasugrel, and its salts and polymorphs
WO2009066326A2 (en) 2007-11-19 2009-05-28 Msn Laboratories Limited Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts
WO2009098142A1 (en) 2008-02-06 2009-08-13 Helm Ag Prasugrel salts with improved properties

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012427A (en) * 2012-11-26 2013-04-03 天津大学 Prasugrel hydrochloride ethanol solvate and preparation method thereof
CN103012427B (en) * 2012-11-26 2015-07-08 天津大学 Prasugrel hydrochloride ethanol solvate and preparation method thereof
WO2014092589A1 (en) 2012-12-12 2014-06-19 Instytut Farmaceutyczny Process for preparation of prasugrel hydrochloride polymorphic form b of pharmaceutical purity
CN105669696A (en) * 2014-11-21 2016-06-15 四川海思科制药有限公司 Prasugrel hydrochloride compound
CN105669696B (en) * 2014-11-21 2019-03-26 四川海思科制药有限公司 A kind of prasugrel hydrochloride compound
CN105601643A (en) * 2015-12-23 2016-05-25 山东鲁抗医药股份有限公司 Preparation method of high-purity prasugrel hydrochloride

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