WO2004048385A2 - A process for the preparation of crystalline form 1 or clopidogrel hydrogen sulfate - Google Patents
A process for the preparation of crystalline form 1 or clopidogrel hydrogen sulfate Download PDFInfo
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- WO2004048385A2 WO2004048385A2 PCT/PL2003/000130 PL0300130W WO2004048385A2 WO 2004048385 A2 WO2004048385 A2 WO 2004048385A2 PL 0300130 W PL0300130 W PL 0300130W WO 2004048385 A2 WO2004048385 A2 WO 2004048385A2
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- 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
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- the present invention relates to a process for the preparation of crystalline Form 1 of clopidogrel hydrogen sulfate or methyl (S) -(+) - ⁇ - (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate hydrogen sulfate.
- Clopidogrel hydrogen sulfate is an antithrombotic agent, known from the disclosure of EP 0281459 Bl .
- EP 0281459 Bl the method of preparation of the pharmacologically preferred dextrorotatory isomer of this compound was also disclosed.
- the method consisted in reacting methyl ⁇ - (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate with an optically active acid, such as 10-L-camphorsulfonic acid and successively crystallizing the salt thus formed, until a product showing a constant value of optical rotatory power was obtained, followed by base-mediated liberation from its salt of the dextrorotatory free base isomer, methyl (S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate, which was then converted to its hydrogen sulfate salt by reacting with concentrated sulfuric acid.
- Acetone was the solvent used for both the crystallization of the 10-camphorsulfonic acid salt and the conversion of the free base to the hydrogen sulfate salt.
- the experimental examples of this patent application include the procedure for the preparation of amorphous ( S) -clopidogrel hydrogen sulfate at about 0-5°C, at a high dilution (about 3% of free base/ 1 L of solvent) , and after 1-5 hours after the dropwise addition of sulfuric acid has been completed.
- the amorphous (S) -clopidogrel hydrogen sulfate was thermodynamically stable in the solid state.
- a crystalline form of (S) -clopidogrel hydrogen sulfate is defined as essentially pure, when the crystalline form is free from other forms detectable by the spectral methods typically used, which corresponds to the content of less than 5%, and preferably less than 2% of other forms.
- the crystalline (S) -clopidogrel hydrogen sulfate obtained according to the process of the present invention is characterized based on an analysis of the infrared spectrum, X-ray powder diffractogram and of differential scanning calorimetry results.
- the Fourier-transform infrared (FT-IR) spectrum of Form 1 was obtained using the compressed KBr disk technique, on a Perkin Elmer 1725X spectrometer, in the range 4000cm “1 - 400cm “1 , and with a resolution of 4cm “1 .
- the spectrum is substantially different from the spectrum of Form 2 disclosed in the patent US 6429210 Bl, and from the spectrum of amorphous form known from PL 355814 in the entire spectral range 4000 - 400 cm "1 , as is illustrated in Figures .
- FT-IR spectra (KBr disk) : a comparison of characteristic bands, differentiating Form 1 from Form 2 and from amorphic (S) -clopidogrel hydrogen sulfate.
- Fig.2 presents X-ray powder diffractograms of crystalline Forms 1 and 2, and of amorphous (S) -clopidogrel hydrogen sulfate.
- the diffraction profiles are presented in the form of relative CuK ⁇ diffraction line intensity as a function of the deflection angle ⁇ and the interlattice distance d, and were obtained on a Rigaku MINI FLEX diffractometer, within the 2 ⁇ angle range 3 - 40°, at scanning speed of 0.5 deg/min and with counting interval of 0.03 deg.
- a comparison of peak position and intensity of main diffraction lines for crystalline Forms 1 and 2 is presented in Table 2. Table 2
- Fig.3 illustrates a comparison of DSC curves of crystalline Forms 1 and 2 and of amorphous (S) -clopidogrel hydrogen sulfate.
- the curves were obtained by the differential scanning calorimetry method, using a Mettler Toledo DSC 822 apparatus, in an aluminum cup, in the temperature range 40-200°C, in the dynamic segment at the rate of heating 10°C/min.
- the dynamic measurement segment was preceded with an isothermal segment (40°C for 3 minutes) .
- the curves for crystalline Forms 1 and 2 show characteristic endothermic peaks corresponding to the melting of crystalline substances, while the curve for the amorphous substance shows a broad, diluted endothermic signal corresponding to a small enthalpic effect, changing into a curve characteristic of substance decomposition.
- Form 1 is characterized by a higher melting point than Form 2, however, the enthalpy of fusion determined for Form 1 is smaller than the corresponding value obtained for Form 2. Melting points and enthalpies of fusion for both crystalline forms are presented in Table 3.
- the corresponding melting point value was determined using two methods: as an "extrapolated peak” temperature, which is the projection on the extrapolated baseline of the intersection of the tangents to the melting peak curve, and as an "onset” value, which corresponds to the intersection between the extrapolated baseline and the tangent to the ascending slope of the melting peak curve.
- Table 3 A comparison of melting points and heats of fusion for crystalline Forms 1 and 2.
- an essentially pure crystalline form of (S) -clopidogrel hydrogen sulfate is obtained by precipitating the salt formed from the optically active free base methyl ( S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] yridine- 5-acetate and concentrated sulfuric acid, with a precipitating solvent.
- Suitable precipitating solvents according to the process of the present invention are aliphatic and cyclic ethers, preferably 1, 2-dimethoxyethane, 1, 2-diethoxyethane, t-butyl methyl ether, bis (2-ethoxyethyl) ether, and dioxane, and also isobutyl methyl ketone.
- variable A the reaction of the optically active free base methyl (S) - (+) - - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate with concentrated sulfuric acid is carried out directly in the precipitating solvent, such that the (S) -clopidogrel hydrogen sulfate formed precipitates during the dropwise addition of sulfuric acid.
- the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl ( S) - (+) - - (2-chlorophenyl) - 4, 5, 6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate in the precipitating solvent, b) bringing the solution thus obtained to the temperature of 0-30 °C, preferably to 0-5 °C, c) dropwise addition of sulfuric acid to this solution, d) stirring the suspension thus formed at 0-30 °C, during over 10 hours, e) isolation of the precipitate from the reaction mixture ,, and f) drying the precipitate.
- the optically active free base methyl ( S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate is dissolved in a solvent chosen from among C ⁇ _ 3 aliphatic alcohols, followed by a slow addition of concentrated sulfuric acid to the solution thus obtained, and only after the dropwise addition of the acid has been completed, the precipitating solvent is added, which causes the (S) -clopidogrel hydrogen sulfate to precipitate out of the solution.
- the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl (£>) - (+) - - (2-chlorophenyl) - 4 , 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine-5-acetate in a solvent capable of dissolving the free base, b) bringing the solution thus obtained to the temperature of 0-30°C, preferably to 0-5°C, c) dropwise addition of sulfuric acid to this solution, d) dropwise addition of the precipitating solvent to the solution, to which sulfuric acid has already been added, e) stirring the suspension of the precipitate thus formed at 0-30°C, during over 10 hours, f) isolation of the precipitate from the reaction mixture, and g) drying the precipitate.
- Suitable solvents capable of dissolving the free base, are aliphatic alcohols such as ethanol, isopropanol and methoxyethanol .
- the clopidogrel free base methyl (S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate
- a weak base such as sodium bicarbonate, ammonium carbonate or potassium carbonate
- the organic phase is washed with water and concentrated under reduced pressure, which affords the dextroratatory clopidogrel free base.
- the free base is dissolved in an organic solvent or directly in the selected precipitating solvent.
- it is essential to select a suitable initial concentration of the clopidogrel free base in a solvent.
- Beneficial results are obtained when using at least 1 weight part of (S) - clopidogrel free base per 3 volume parts of the solvent.
- the upper level of free base concentration is limited only by technical capabilities to obtain a homogenous precipitate of the product, by the ease of isolation of the precipitate and the ease of excessive acid removal by washing the precipitate.
- the suspension of (S) -clopidogrel hydrogen sulfate precipitate in a solvent is stirred for at least 10 more hours, at the temperature in the range from 0 to 30°C, after which (S) -clopidogrel hydrogen sulfate precipitate is isolated on a typical way, for example by filtration or decantation, washed with the precipitating solvent and the wet product is subjected to drying, first in air, at room temperature, and then under vacuum at temperatures below 50°C.
- the process of the present invention provides essentially pure Form 1 of (S) -clopidogrel hydrogen sulfate, containing less than 5%, preferably less than 2% of crystalline Form 2.
- the (S) -clopidogrel hydrogen sulfate prepared in crystalline Form 1 according to the process of the present invention is characterized by high enentiomeric purity - the content of the S isomer is in excess of 99%.
- the crystalline Form 1 of (S) -clopidogrel hydrogen sulfate prepared according to the process of the present invention may be used as the active pharmaceutical ingredient for manufacturing of pharmaceuticals which find application in the treatment and prevention of thrombosis, by acting as a platelet aggregation inhibitor and an anticoagulant .
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Abstract
The crystalline Form 1 of methyl (S)-clopidogrel hydrogen sulfate is prepared by precipitating the salt formed in the reaction of the optically active base, methyl (S) - (+) -α- (2-chlorophenyl) -4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridine-5-acetate with concentrated sulfuric acid, using a precipitating solvent selected from a group comprising aliphatic and cyclic ethers and isobutyl methyl ketone. Methyl (S) - (+) -α- (2-chlorophenyl) -4,5,6,7- tetrahydrothieno[3,2-c]pyridine-5-acetate hydrogen sulfate is useful in the treatment and prevention of thrombosis, by acting as a platelet aggregation inhibitor and an anticoagulant.
Description
A PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM 1 OF CLOPIDOGREL HYDROGEN SULFATE
The present invention relates to a process for the preparation of crystalline Form 1 of clopidogrel hydrogen sulfate or methyl (S) -(+) -α- (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate hydrogen sulfate.
Clopidogrel hydrogen sulfate is an antithrombotic agent, known from the disclosure of EP 0281459 Bl . In EP 0281459 Bl the method of preparation of the pharmacologically preferred dextrorotatory isomer of this compound was also disclosed. The method consisted in reacting methyl α- (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate with an optically active acid, such as 10-L-camphorsulfonic acid and successively crystallizing the salt thus formed, until a product showing a constant value of optical rotatory power was obtained, followed by base-mediated liberation from its salt of the dextrorotatory free base isomer, methyl (S) - (+) -α- (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate, which was then converted to its hydrogen sulfate salt by reacting with concentrated sulfuric acid. Acetone was the solvent used for both the crystallization of the 10-camphorsulfonic acid salt and the conversion of the free base to the hydrogen sulfate salt.
According to the examples of the patent EP 0281459 Bl, (S) -
clopidogrel hydrogen sulfate is thus isolated in a pure crystalline form, melting at 184 °C and having optical rotatory power in methanol [α] D= +55.10°.
According to the teachings of the patent US 6429210 Bl, the crystalline form thus obtained is described as Form 1. Patent US 6429210 Bl also disclosed that the mother liquors remaining after crystallization of Form 1 of (S) - clopidogrel hydrogen sulfate after a period of 3-6 months yield another crystalline form of (S) -clopidogrel hydrogen sulfate, described as Form 2. Another method for Form 2 formation, disclosed in US 6429210 Bl, requires the use of acetone as the crystallization solvent and seeding the crystallizing mixture with seed crystals of Form 2 of (S) - clopidogrel hydrogen sulfate. Upon a systematic experimental study of the polymorphism phenomena shown by (S) -clopidogrel hydrogen sulfate, it has now been determined that, independent of the way on which (S) -clopidogrel is transformed into the hydrogen sulfate salt, said salt crystallizes from an acetone solution always in the crystalline Form 2, which precipitates out of such solution immediately after an equimolar amount of sulfuric acid has been added, and without a need for a 3-6 months waiting period.
It has also been observed that upon the clopidogrel salt formation from (S) -clopidogrel free base and sulfuric acid in an acetone solution according to the conditions
described in US 6429210 Bl, a substantial loss of enantiomeric purity of (S) -clopidogrel hydrogen sulfate occurs. On the basis of these observations, it has been determined that the use of acetone as the solvent not only leads to the spontaneous formation of Form 2, but it can be associated with deterioration of the optical purity of the end product, which is a serious limitation of the method.
Thus, a need clearly exists in the art for such conditions for the preparation of crystalline (S) - clopidogrel hydrogen sulfate, which give consistently repeatable results and which afford (S) -clopidogrel hydrogen sulfate in the well defined crystalline Form 1, and in high enantiomeric purity.
The teachings of the Polish patent application PL 355814 (not published in the date of the filing the present patent application) disclosed that when the reaction of methyl (S) - (+) -α- (2-chlorophenyl) -4,5,6, 7-tetrahydro- thieno [3 , 2-c]pyridine-5-acetate with concentrated sulfuric acid was carried out in t-butyl methyl ether (MTBE) , optionally in the presence of a small amount of isopropyl alcohol, an amorphous form of (S) -clopidogrel hydrogen sulfate was obtained. The experimental examples of this patent application include the procedure for the preparation of amorphous ( S) -clopidogrel hydrogen sulfate at about 0-5°C, at a high dilution (about 3% of free base/ 1 L of solvent) , and after 1-5 hours after the dropwise
addition of sulfuric acid has been completed. The amorphous (S) -clopidogrel hydrogen sulfate was thermodynamically stable in the solid state.
Unexpectedly, it has now been determined that the solid, amorphous (S) -clopidogrel hydrogen sulfate, when left in the solution from which it precipitated, undergoes a thermodynamically driven crystalline form change, affording the crystalline Form 1.
Moreover, it has now been determined that by applying a higher concentration of the optically active free base in a given solvent system and/or by stirring the suspension of said precipitating ( S) -clopidogrel salt in a given solvent or solvent mixture, for a substantially longer time, the Form 1 of (S) -clopidogrel hydrogen sulfate, essentially free from other crystalline forms and from the amorphous salt, is obtained.
It is assumed for the purpose of the present invention that a crystalline form of (S) -clopidogrel hydrogen sulfate is defined as essentially pure, when the crystalline form is free from other forms detectable by the spectral methods typically used, which corresponds to the content of less than 5%, and preferably less than 2% of other forms.
The crystalline (S) -clopidogrel hydrogen sulfate obtained according to the process of the present invention is characterized based on an analysis of the infrared
spectrum, X-ray powder diffractogram and of differential scanning calorimetry results.
The Fourier-transform infrared (FT-IR) spectrum of Form 1 was obtained using the compressed KBr disk technique, on a Perkin Elmer 1725X spectrometer, in the range 4000cm"1 - 400cm"1, and with a resolution of 4cm"1. The spectrum is substantially different from the spectrum of Form 2 disclosed in the patent US 6429210 Bl, and from the spectrum of amorphous form known from PL 355814 in the entire spectral range 4000 - 400 cm"1, as is illustrated in Figures .
Table 1. FT-IR spectra (KBr disk) : a comparison of characteristic bands, differentiating Form 1 from Form 2 and from amorphic (S) -clopidogrel hydrogen sulfate.
A comparison of the infrared spectra of: the crystalline Form 1 obtained according to the process of the
present invention, of Form 2 and of amorphous (S) - clopidogrel hydrogen sulfate is illustrated in Fig.l.
Fig.2 presents X-ray powder diffractograms of crystalline Forms 1 and 2, and of amorphous (S) -clopidogrel hydrogen sulfate. The diffraction profiles are presented in the form of relative CuKα diffraction line intensity as a function of the deflection angle θ and the interlattice distance d, and were obtained on a Rigaku MINI FLEX diffractometer, within the 2θ angle range 3 - 40°, at scanning speed of 0.5 deg/min and with counting interval of 0.03 deg. A comparison of peak position and intensity of main diffraction lines for crystalline Forms 1 and 2 is presented in Table 2. Table 2
According to the process of the present invention, an essentially pure crystalline form of (S) -clopidogrel hydrogen sulfate is obtained by precipitating the salt formed from the optically active free base methyl ( S) - (+) - α- (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] yridine- 5-acetate and concentrated sulfuric acid, with a precipitating solvent.
Suitable precipitating solvents according to the process of the present invention are aliphatic and cyclic ethers, preferably 1, 2-dimethoxyethane, 1, 2-diethoxyethane, t-butyl methyl ether, bis (2-ethoxyethyl) ether, and dioxane, and also isobutyl methyl ketone.
In one embodiment of the present invention (variation A) , the reaction of the optically active free base methyl (S) - (+) - - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2-
c]pyridine-5-acetate with concentrated sulfuric acid is carried out directly in the precipitating solvent, such that the (S) -clopidogrel hydrogen sulfate formed precipitates during the dropwise addition of sulfuric acid. According to this embodiment of the present invention, the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl ( S) - (+) - - (2-chlorophenyl) - 4, 5, 6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate in the precipitating solvent, b) bringing the solution thus obtained to the temperature of 0-30 °C, preferably to 0-5 °C, c) dropwise addition of sulfuric acid to this solution, d) stirring the suspension thus formed at 0-30 °C, during over 10 hours, e) isolation of the precipitate from the reaction mixture ,, and f) drying the precipitate. According to another embodiment of the present invention (variation B) , the optically active free base methyl ( S) - (+) -α- (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate is dissolved in a solvent chosen from among Cι_3 aliphatic alcohols, followed by a slow addition of concentrated sulfuric acid to the solution thus obtained, and only after the dropwise addition of the
acid has been completed, the precipitating solvent is added, which causes the (S) -clopidogrel hydrogen sulfate to precipitate out of the solution.
According to this another embodiment of the present invention, the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl (£>) - (+) - - (2-chlorophenyl) - 4 , 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine-5-acetate in a solvent capable of dissolving the free base, b) bringing the solution thus obtained to the temperature of 0-30°C, preferably to 0-5°C, c) dropwise addition of sulfuric acid to this solution, d) dropwise addition of the precipitating solvent to the solution, to which sulfuric acid has already been added, e) stirring the suspension of the precipitate thus formed at 0-30°C, during over 10 hours, f) isolation of the precipitate from the reaction mixture, and g) drying the precipitate.
Suitable solvents, capable of dissolving the free base, are aliphatic alcohols such as ethanol, isopropanol and methoxyethanol . According to both aforementioned embodiments of the present invention, the clopidogrel free base, methyl (S) -
(+) -α- (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate, is obtained on the way known in the art, that is from 10-camphorsulfonic acid salt of methyl (S) - (+) -α- (2-chlorophenyl) -4,5,6,7- tetrahydrothieno [3, 2-c] pyridine-5-acetate under the action of an aqueous solution of a weak base, such as sodium bicarbonate, ammonium carbonate or potassium carbonate, in the presence of on organic, water-immiscible solvent such as dichloro ethane, at the temperature 5-20°C. The organic phase is washed with water and concentrated under reduced pressure, which affords the dextroratatory clopidogrel free base. Before the reaction with sulfuric acid is carried out, the free base is dissolved in an organic solvent or directly in the selected precipitating solvent. In order to prepare well-shaped crystals of Form 1 according to the process of the present invention, it is essential to select a suitable initial concentration of the clopidogrel free base in a solvent. Beneficial results are obtained when using at least 1 weight part of (S) - clopidogrel free base per 3 volume parts of the solvent.
The upper level of free base concentration is limited only by technical capabilities to obtain a homogenous precipitate of the product, by the ease of isolation of the precipitate and the ease of excessive acid removal by washing the precipitate.
According to the process of the present invention, after the dropwise addition of sulfuric acid has been completed, optionally followed by addition of the precipitating solvent, the suspension of (S) -clopidogrel hydrogen sulfate precipitate in a solvent is stirred for at least 10 more hours, at the temperature in the range from 0 to 30°C, after which (S) -clopidogrel hydrogen sulfate precipitate is isolated on a typical way, for example by filtration or decantation, washed with the precipitating solvent and the wet product is subjected to drying, first in air, at room temperature, and then under vacuum at temperatures below 50°C.
Examples of organic solvent/precipitating solvent combinations used to prepare Form 1 of (S) -clopidogrel hydrogen sulfate (according to the process of the invention) are included in Table 4.
Table 4. Parameters for the production of Form 1 of (S) clopidogrel hydrogen sulfate.
* A - the free base was dissolved in a precipitating solvent ;
B - the free base was dissolved in an organic solvent (1) and a precipitating solvent (2) was added after the hydrogen sulfate salt was formed.
The process of the present invention provides essentially pure Form 1 of (S) -clopidogrel hydrogen
sulfate, containing less than 5%, preferably less than 2% of crystalline Form 2. The (S) -clopidogrel hydrogen sulfate prepared in crystalline Form 1 according to the process of the present invention, is characterized by high enentiomeric purity - the content of the S isomer is in excess of 99%.
The crystalline Form 1 of (S) -clopidogrel hydrogen sulfate prepared according to the process of the present invention may be used as the active pharmaceutical ingredient for manufacturing of pharmaceuticals which find application in the treatment and prevention of thrombosis, by acting as a platelet aggregation inhibitor and an anticoagulant .
The present invention is illustrated by the following, non-limiting examples. Example 1 Variation A
To a solution of methyl (S) - (+) -α- (2-chlorophenyl) - 4, 5, 6, 7-tetrahydrothieno [3, 2-c]pyridine-5-acetate (3.25 g, ca. 0.01 mol) in 1, 2-dimethoxyethane (30 mL) , which was cooled to 0°C, concentrated sulfuric acid (1 g) was added dropwise, with stirring while maintaining the temperature of the mixture in the predetermined range 0 - 5°C. After the addition has been completed, the suspension was stirred for another 12 hours. The precipitate was filtered and washed with 1, 2-dimethoxyethane (15 mL) . The wet product
was dried in air, followed by drying in a vacuum oven at the temperature of ca. 40°C, until a constant mass was obtained. This gave the precipitate (3.8 g) ; m.p. 183-6°C (yield ca. 90%). Enantiomeric purity of the product: 99.62%. The identity of the product was determined on the basis of its IR spectrum and its X-ray powder diffraction profile to be the crystalline Form 1 of (S) -clopidogrel hydrogen sulfate. Example 2 Variation B
To a solution of methyl (S) -(+) -α- (2-chlorophenyl) - 4, 5, 6, 7-tetrahydrothieno [3, 2-c]pyridine-5-acetate (3.25 g, ca. 0.01 mol) in ethanol (20 mL) , which was cooled to 0°C, 96% sulfuric acid (1.0 g) was added dropwise, with stirring. The temperature of the mixture was maintained in the range 0 - 5°C. The solution was stirred for 30 minutes, after which time t-butyl methyl ether (30 mL) was added dropwise. Stirring was continued at 0 - 5°, for 10 hours. The precipitate was filtered and washed with t-butyl methyl ether (15 mL) . The wet product was dried in a vacuum oven, at the temperature of 20 - 40°C. This gave the precipitate (3.8 g) ; m.p. 182°C (yield ca. 90%). Enantiomeric purity of the product: 99.12%.
Claims
1. A process for the preparation of crystalline Form 1 of (S) -clopidogrel hydrogen sulfate by reacting the optically active base, methyl (S) - (+) -α- (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate, with concentrated sulfuric acid, characterized in that the salt formed in this reaction is precipitated from the reaction medium with a precipitating solvent. 2. A process according to claim 1, characterized in that the precipitating solvent is selected from a group comprising aliphatic or cyclic ethers, preferably 1,
2- dimethoxyethane, 1, -diethoxyethane, t-butyl methyl ether, bis (2-ethoxyethyl) ether and dioxane or their mixtures, and isobutyl methyl ketone.
3. A process according to claim 1, characterized in that the optically active base, methyl ( S) - (+) -α- (2- chlorophenyl) -4,5,6, 7-tetrahydrothieno [3, 2-c] pyridine-5- acetate, is dissolved directly in the precipitating solvent, followed by a dropwise addition of concentrated sulfuric acid, which is accompanied by salt precipitation during the addition of the acid.
4. A process according to claim 1, characterized in that methyl ( S) - (+) -α- (2-chlorophenyl) -4,5,6,7- tetrahydrothieno [3 , 2-c]pyridine-5-acetate is dissolved in an organic solvent, followed by a slow addition of concentrated sulfuric acid, and after the dropwise addition of the acid to the reaction mixture has been completed, a precipitating solvent is added.
5. A process according to claim 4, characterized in that methyl (-?)-(+) - - (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c]pyridine-5-acetate is dissolved in a Cχ.3 aliphatic alcohol.
6. A process according to claim 3 or 4, characterized in that the initial concentration of methyl (S) - (+) -α- (2- chlorophenyl) -4, 5, 6, 7-tetrahydrothieno [3 , 2-c]pyridine-5- acetate is at least 1 weight part per 3 volume parts of the solvent .
7. A process according to claim 3 or 4, characterized in that the suspension of the precipitated methyl (S) - (+) - - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] pyridine-5- acetate hydrogen sulfate is further stirred at the temperature 0 - 30°C, for at least 10 hours.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016931A3 (en) * | 2003-08-13 | 2005-04-28 | Krka Torvarna Zdravil D D Novo | Crystallisation of solid forms of clopidogrel addition salts |
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2008019053A2 (en) * | 2006-08-03 | 2008-02-14 | Teva Pharmaceutical Industries Ltd. | Process for preparing clopidogrel bisulphate |
| WO2008118030A1 (en) * | 2007-03-23 | 2008-10-02 | Tomasz Kozluk | Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| EP2114957A2 (en) * | 2007-01-29 | 2009-11-11 | IPCA Laboratories Limited | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| WO2011042804A2 (en) | 2009-10-08 | 2011-04-14 | Jubliant Life Sciences Limited | An improved process for the preparation of clopidogrel hydrogen sulfate form i |
| WO2011051976A2 (en) | 2009-10-30 | 2011-05-05 | Matrix Laboratories Ltd | An improved process for the preparation of clopidogrel bisulfate form i |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| WO2007125544A3 (en) * | 2006-04-27 | 2016-06-09 | Ind-Swift Laboratories Limited | Process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate |
| KR20200099012A (en) | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Methods for preparing clopidogrel bisulphate and pharmaceutical composition comprising the same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281459A1 (en) * | 1987-02-17 | 1988-09-07 | Sanofi | Dextrorotatory enantiomer of alpha-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)(2-chlorophenyl)methyl acetate, process for its preparation and pharmaceutical compositions containing it |
| WO1999065915A1 (en) * | 1998-06-15 | 1999-12-23 | Sanofi-Synthelabo | Polymorphic clopidogrel hydrogenesulphate form |
| WO2003051362A2 (en) * | 2001-12-18 | 2003-06-26 | Teva Pharmaceutical Industries Ltd. | Polymorphs of clopidogrel hydrogensulfate |
-
2003
- 2003-11-26 WO PCT/PL2003/000130 patent/WO2004048385A2/en not_active Application Discontinuation
- 2003-11-26 AU AU2003285841A patent/AU2003285841A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281459A1 (en) * | 1987-02-17 | 1988-09-07 | Sanofi | Dextrorotatory enantiomer of alpha-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)(2-chlorophenyl)methyl acetate, process for its preparation and pharmaceutical compositions containing it |
| WO1999065915A1 (en) * | 1998-06-15 | 1999-12-23 | Sanofi-Synthelabo | Polymorphic clopidogrel hydrogenesulphate form |
| WO2003051362A2 (en) * | 2001-12-18 | 2003-06-26 | Teva Pharmaceutical Industries Ltd. | Polymorphs of clopidogrel hydrogensulfate |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016931A3 (en) * | 2003-08-13 | 2005-04-28 | Krka Torvarna Zdravil D D Novo | Crystallisation of solid forms of clopidogrel addition salts |
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| EA010198B1 (en) * | 2004-04-19 | 2008-06-30 | Крка, Товарна Здравил, Д.Д., Ново Место | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| US7999106B2 (en) | 2004-04-19 | 2011-08-16 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form I |
| WO2007125544A3 (en) * | 2006-04-27 | 2016-06-09 | Ind-Swift Laboratories Limited | Process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate |
| WO2008019053A2 (en) * | 2006-08-03 | 2008-02-14 | Teva Pharmaceutical Industries Ltd. | Process for preparing clopidogrel bisulphate |
| WO2008019053A3 (en) * | 2006-08-03 | 2008-07-03 | Teva Pharma | Process for preparing clopidogrel bisulphate |
| EP2114957A4 (en) * | 2007-01-29 | 2011-06-08 | Ipca Lab Ltd | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| EP2114957A2 (en) * | 2007-01-29 | 2009-11-11 | IPCA Laboratories Limited | Process for preparation of crystalline clopidogrel hydrogen sulphate form i |
| US20100216999A1 (en) * | 2007-03-23 | 2010-08-26 | Tomasz Kozluk | Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate |
| WO2008118030A1 (en) * | 2007-03-23 | 2008-10-02 | Tomasz Kozluk | Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| WO2011042804A2 (en) | 2009-10-08 | 2011-04-14 | Jubliant Life Sciences Limited | An improved process for the preparation of clopidogrel hydrogen sulfate form i |
| WO2011042804A3 (en) * | 2009-10-08 | 2011-07-21 | Jubliant Life Sciences Limited | An improved process for the preparation of clopidogrel hydrogen sulfate form i |
| WO2011051976A2 (en) | 2009-10-30 | 2011-05-05 | Matrix Laboratories Ltd | An improved process for the preparation of clopidogrel bisulfate form i |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| KR20200099012A (en) | 2019-02-13 | 2020-08-21 | 한국바이오켐제약 주식회사 | Methods for preparing clopidogrel bisulphate and pharmaceutical composition comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003285841A8 (en) | 2004-06-18 |
| AU2003285841A1 (en) | 2004-06-18 |
| WO2004048385A3 (en) | 2004-08-05 |
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