FIELD OF INVENTION
The present invention relates to a novel process for the preparation of Form I of Clopidogrel hydrogen sulfate. More particularly, the present invention relates to polymorphic Form I of methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5(4H)-acetate hydrogen sulfate of the Formula I
Formula I
(Formula Removed)
BACKGROUND OF THE INVENTION
Clopidogrel chemically known as methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5(4H)-acetate, has the following structural formula:
(Formula Removed)
Clopidogrel is a known blood platelet aggregation inhibitory and antithrombotic pharmaceutical active ingredient. Platelet inhibiting activity of Clopidogrel makes it an effective drug for reducing the incidence of ischemic strokes, heart attack due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation,
Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attack.
(+) Clopidogrel was first disclosed in U.S. Patent 4,529,596 which discloses a racemic mixture of clopidogrel and process for preparing such a mixture by the reaction of thienopyridine derivative with a chloro compound in solvents like dimethyl formamide, alcohols and ethyl acetate in the presence of metal carbonates.
U.S. Patent 4,847,265 reports the formation of (S)-(+)-Clopidogrel hydrogen sulfate for the first time, with melting point of 184 °C, but was however, completely silent in disclosing the crystal form of the product.
U.S. Patents 4,847,265; 5,132,435; 6,258,961; 6,215,005; and 6,180, 793, which are hereby incorporated by reference in their entirety, describe the methods that can be used to prepare clopidogrel hydrogen sulfate.
Active pharmaceutical ingredients and their salts are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process. A large number of factors can influence crystal nucleation and growth during this process, including the composition, the crystallization medium and the processes used to generate super saturation and promote crystallization. The most notable variables of composition and processing are solvent/solvent combinations, degree of super saturation, pH value, heating rate, cooling rate, etc. Various polymorphs of Clopidogrel hydrogen suifate have been disclosed in different patents that are referred herein.
US patent 6,429,210, (referred herein as '210), discloses two polymorphs of Clopidogrel hydrogen sulfate referred to as Form I and Form II. The patent '210
identified that the precipitation method described in US 4,847,265 has lead to crystalline Form I. The '210 also deals with a new crystalline form II of Clopidogrel hydrogen sulfate. According to '210 patent both polymorphs were prepared from same solvent viz; acetone.
US patent application 2003/0114479 discloses crystalline forms III, IV and V and amorphous form of Clopidogrel hydrogen sulfate.
PCT application WO 2004/020443 discloses process for the preparation of crystalline forms I of Clopidogrel hydrogen sulfate. According to this patent application, a process is claimed to produce Form I consistently by forming hydrogen sulfate salt of Clopidogrel from a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixture of alcohols and esters. The process involves dissolving Clopidogrel base in solvents like isopropyl alcohol and/or butyl acetate, cooling the mixture, adding sulfuric acid and inoculating the mixture with Form I of Clopidogrel hydrogen sulfate and stirring the crystallized mixture precisely at a temperature between-5 and +15°C to get crystals of Clopidogrel in Form I. In another process variant, the Clopidogrel hydrogen sulfate was directly dissolved at reflux in the above mentioned solvents and crystallized under cooling.
Although the process mentioned in the above patent application works in butyl acetate, which is known to have hazardous properties (affects central nervous system and exposure limit is 150 ppm), but fails to give pure Form I in other industrially friendly solvents like ethyl acetate under the specified conditions. As the Form I is thermodynamically unstable, the process variant of dissolving Clopidogrel hydrogen sulfate salt in solvents at higher temperature and cooling to precipitate Form I resulted in Form II or Form IV or their mixture with Form I.
PCT publication WO 2004/048385 discloses process for preparation of crystalline Form I of Clopidogrel hydrogen sulfate by reacting (S)-(+)Clopidogrel base with concentrated sulfuric acid and the product is precipitated using solvent such as aliphatic or cyclic ethers or isobutyl methyl ketone.
We have found that the above process does not give pure Form I in isobutyl methyl ketone under specified reaction conditions. There is formation of lumps and it is very difficult to isolate pure Form I of Clopidogrel hydrogen sulfate.
PCT publication WO 2005/003139 discloses process for preparation of Form I of Clopidogrel hydrogen sulfate wherein clopidogrel base is dissolved in solvent such as acetone, methylene chloride or isopropanol and treated with sulfuric acid, thereafter the reaction mixture is added to the suspension of Clopidogrel hydrogen sulfate Form I in di-isopropyl ether.
PCT publication WO 2005/012300 discloses a process for the preparation of Form I of Clopidogrel hydrogen sulfate, by contacting clopidogrel bisulfate with sulfuric acid solution in acetate solvent followed by its isolation.
PCT application WO 2005/100364 discloses process for the preparation of Form I of Clopidogrel hydrogen sulfate, comprising converting clopidogrel salt into its base, said base is brought into dry solution with an organic solvent selected from methyl acetate, ethyl acetate, dichloromethane, or t-butyl methyl ether, followed by reaction with sulfuric acid.
So, it is evident from the prior art that methods to produce Form I of Clopidogrel hydrogen sulfate from different solvents require very specific temperature range and specific conditions for getting reproducible results. Most of the methods are poorly reproducible, necessitating the optimization of experimental conditions along with that
of the selection of solvents. Since Form I is kinetically controlled and Form II is thermodynamically controlled form, minor variation(s) in condition(s) appears to give Form II instead of expected Form I or a mixture of Form I & Form II. Since, Form I of Clopidogrel hydrogen sulfate is used for pharmaceutical formulation; there is an urgent need to develop an efficient process which can give highly pure Form I consistently without contamination of other forms.
Thus the object of present invention is to provide a reliable method for obtaining Form I of Clopidogrel hydrogen sulfate without detectable impurities of Form II or any other form of Clopidogrel hydrogen sulfate.
Main object of present invention to provide a simple and efficient process for the preparation of highly pure Form I of Clopidogrel hydrogen sulfate from clopidogrel base which is viable on industrial scale.
SUMMARY OF THE INVENTION
The present invention describes an improved process for preparation of methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate hydrogen sulfate Form I of the formula I,
Formula I (Formula Removed)
which comprises,
a) dissolving clopidogrel base in a suitable organic solvent;
b) adding halogenated solvent and seeding of Form I of Clopidogrel hydrogen sulfate,
c) cooling the reaction mixture to -10 to 0 °C;
d) adding solution of sulfuric acid in a suitable organic solvent at -10 to 0 °C;
e) stirring the reaction mixture for sufficient time to convert to Form I of Clopidogrel
hydrogen sulfate;
f) isolating Clopidogrel hydrogen sulfate Form I.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a PXRD pattern for Clopidogrel Hydrogen Sulfate Form I Fig. 2 is a DSC thermo gram of Clopidogrel Hydrogen Sulfate Form I
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention describes an improved process for the preparation of highly pure crystalline Form I of Clopidogrel hydrogen sulfate. The process eliminates the problems of prior art and is convenient to operate for regular commercial production.
In one embodiment of the present invention, the Clopidogrel base or Clopidogrel camphor sulphonic acid salt used as the starting materials in the present invention, can be prepared by the methods known in prior art and described herein for reference.
Generally, thieno [3,2-c] pyridine hydrochloride is reacted with a-bromo-(2-chlorophenyl) acetic acid methyl ester in N,N-dimethylformamide at 15-20°C. After completion of the reaction, water is added into the reaction mass and the product is
extracted in methylene chloride which is distilled off to give (+) clopidogrel base as residue. The racemic mixture of clopidogrel so obtained is taken in acetone and 1 (-) camphor sulfonic acid is added and the reaction mass is refluxed for 4 hours. After that the reaction mass is maintained at 40-45°C for 16 hours. Clopidogrel camphor sulfonic acid salt which separates out, is filtered, washed with acetone and dried.
Clopidogrel camphor sulfonic acid salt obtained is purified in acetone at reflux temperature followed by cooling to 20-25°C. The crystallized product is filtered, washed with acetone and dried. Quantity of N,.N-dimethylformamide was 4.8 times that of thieno [3,2-c] pyridine hydrochloride in the above said reaction of thieno [3,2-c] pyridine hydrochloride with a-bromo-(2-chlorophenyl) acetic acid methyl ester. (+) Clopidogrel camphor sulfonic acid salt is then basified with aqueous sodium bicarbonate and extracted in methylene chloride which is distilled off to get (+) clopidogrel base as residue.
In another embodiment of the present invention, Clopidogrel base formed by above process is converted to crystalline Form I of Clopidogrel hydrogen sulfate by taking clopidogrel base in a suitable organic solvent followed by addition of halogenated solvent at -10 to 0 °C. This is followed by addition of sulfuric acid in a suitable solvent and isolation of the required product in high yield.
Preferably, clopidogrel base is taken in suitable organic solvent and halogenated solvent is added to it at ambient temperature. The solution is stirred to get a clear solution which is cooled to -10 to 0 °C.
In a preferred embodiment, Clopidogrel base is taken in suitable organic solvent at ambient temperature followed by cooling to -10 to 0 °C. To the cooled solution, halogenated hydrocarbon is added. Thus, cooling the reaction mixture before or after
the addition of the halogenated solvent does not affect the course of reaction and in any way does not limit the scope of invention.
In a preferred embodiment, suitable organic solvent is selected from ketonic and aliphatic hydrocarbon solvent. Preferably, the ketonic solvent is selected of a group of solvents which have the ability to dissolve Clopidogrel base completely thus includes methyl isobutyl ketone. The aliphatic hydrocarbon solvent can be selected from amongst n-hexane and n-heptane. Halogenated solvent referred herein is selected from methylene dichloride, chloroform, carbontetrachloride, ethylene dichloride. Preferably, methylene chloride is used.
The reaction mixture is seeded with crystalline Form I of Clopidogrel hydrogen sulfate while maintaining the temperature at -10 to 0 °C. Seeding of polymorph Form I is essential for the preparation of pure Form I of Clopidogrel hydrogen sulfate.
Thereafter reaction mixture is treated with a solution of sulfuric acid in a suitable organic solvent preferably ketonic solvent or aliphatic hydrocarbon at a temperature of -10 to 0°C. The solution of sulfuric acid in organic solvent is prepared by dropwise addition of sulfuric acid in organic solvent at -10 to 0 °C.
According to the present invention, it is advantageous to add halogenated solvent to the reaction mixture before adding sulfuric acid because addition of halogenated solvent makes the reaction mixture free flowing without any lumps.
The resulting reaction mixture is stirred further at temperature below 0°C for about two to six hours followed by increase in temperature slowly in about more than six hours to 15-20°C.. The reaction mixture is again stirred for additional eight to twelve hours at 15-20°C to prepare pure Form I.
Thereafter pure product is recovered by filtration at 15-20°C and further dried to remove solvents in a vacuum tray drier. The Clopidogrel hydrogen sulfate Form I so obtained, is highly pure without detectable impurities of Form II of Clopidogrel hydrogen sulfate or any other Form in X-ray diffraction pattern.
Advantages of the present invention
1) The invention provides an efficient method for the preparation of Clopidogrel
hydrogen sulfate Form I which is highly pure and free from any other polymorph
of Clopidogrel hydrogen sulfate
2) The process consistently produces Clopidogrel hydrogen sulfate Form I having
allowable level of impurities and residual solvents.
3) The present invention provides a simple and efficient process for the preparation
of Clopidogrel hydrogen sulfate from clopidogrel base or clopidogrel camphor
sulfonic acid salt which is viable on an industrial scale.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the presentinvention.
Examples
Example 1
Step-1
(+) Clopidogrel Camphor Sulfonic Acid Salt
N.N-Dimethylformamide (4.80 L) was cooled to 15-20°C and added to triethylamine (1.261) and thieno[3,2-c]pyridine hydrochloride (1.0kg) under stirring. To the reaction
mass a-bromo-2-chlorophenyl acetic acid methyl ester (1.65 kg) was added slowly followed by stirring for 30 minutes at 15-20°C. It was followed by addition of water (4.0 1) and methylene chloride (4.0 1). The layers were separated and methylene chloride was distilled out under reduced pressure to afford (+) clopidogrel free base as residue (1.83 kg). The racemic mixture of clopidogrel so obtained was taken in acetone and 1 (-) camphor sulfonic acid (1.21 kg) was added. The reaction mass was refluxed for 4 hours and maintained at 40-45°C for 16 hours. Clopidogrel camphor sulfonic acid salt obtained was purified in 21 volumes of acetone at reflux temperature followed by cooling to 20-25°C. The crystallized product was filtered, washed with acetone and dried to afford the title compound.
Step- II Clopidogrel base
The (+) Clopidogrel camphor sulfonic acid salt obtained in above step (0.84kg), was basified with aqueous sodium bicarbonate (0.42kg) using methylene chloride (5.04L) as reaction medium. The product was extracted with methylene chloride. Methylene chloride was distilled off to afford 0.5kg of the title compound.
Example 2
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel base (28 g) was dissolved in methyl isobutyl ketone (345 ml) at room temperature. To this solution, chloroform (4.5 ml) and seed of Clopidogrel Form I (5.6 g) were added and the reaction mixture was cooled to -10 to -5 °C. To the reaction mass, a cooled solution of sulfuric acid (7.2 g) in methyl isobutyl ketone (173 ml) was added drop wise maintaining temperature below 0 °C under inert atmosphere. . The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 15-17°C slowly and stirring was
continued for further 10 hours. The product was filtered, washed with methyl isobutyl ketone and dried to obtain the title compound. The powdered X-ray diffraction pattern shown in Fig 1 indicated that the material obtained is Form I of Clopidogrel hydrogen sulfate.
Example 3
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel base (28 g) was dissolved in methyl isobutyl ketone (345 ml) at room temperature. To this solution, carbon tetrachloride (4.5 ml) was added and the reaction mixture was seeded with Clopidogrel Form I (5.6 g). The solution was cooled to -10 to -5 °C. To the reaction mass, a cooled solution of sulfuric acid (7.2 g) in methyl isobutyl ketone (173 ml) was added drop wise under inert atmosphere at -10 to -5 °C. The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 16-18°C slowly and stirring was continued for further 10 hours. The product was filtered, washed with methyl isobutyl ketone and dried to obtain the title compound.
Example 4
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel base (28 g) was dissolved in methyl isobutyl ketone (345 ml) at room temperature and the solution was cooled to -10 to 0 °C. To this solution, ethylene dichloride (4.5 ml) was added and the reaction mixture was seeded with Clopidogrel Form I (5.6 g). To the reaction mass, a cooled solution of sulfuric acid (7.2 g) in methyl isobutyl ketone (173 ml) was added drop wise under inert atmosphere at -10 to -5 °C. The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 16-18°C slowly and stirring was
continued for further 10 hours. The product was filtered, washed with methyl isobutyl ketone and dried to obtain the title compound.
Example 5
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel base (15 g) was dissolved in n-hexane (185 ml) at room temperature and the solution was cooled to -10 to -5 °C. To this solution, methylene chloride (2.5 ml) was added and the reaction mixture was seeded with Clopidogrel Form I (3.0 g). To the reaction mass, a cooled solution of sulfuric acid (7.2 g) in n-hexane (93 ml) was added drop wise under inert atmosphere at -10 to -5 °C. The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 16-18°C slowly and stirring was continued for further 10 hours. The product was filtered, washed with n-hexane and dried to obtain the title compound.
Example 6
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel base (20 g) was dissolved in n-heptane (246 ml) at room temperature and the solution was cooled to -10 to -5 °C. To this solution, methylene chloride (3.2 ml) was added and the reaction mixture was seeded with Clopidogrel Form I (4.0 g). To the reaction mass, a cooled solution of sulfuric acid (7.2 g) in n-hexane (93 ml) was added drop wise under inert atmosphere at -10 to -5 °C. The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 17°C slowly and stirring was continued for further 10 hours. The product was filtered, washed with n-heptane and dried to obtain the title compound.
Example 7
Preparation of Clopidogrel Hydrogen Sulfate Form I
Clopidogrel camphor sulphonic acid salt (4.0 kg) was taken in methylene chloride (24.0 1) and the aqueous solution of sodium bicarbonate (2.0 kg) was added. After complete addition the layers were separated and methylene chloride was distilled off to obtain clopidogrel base (2.4 kg) as residue. The residue was dissolved in methyl isobutyl ketone (29.88 1) at room temperature and the solution was cooled to -10 to -5 °C. To this solution, methylene chloride (0.4 1) was added and the reaction mixture was seeded with Clopidogrel Form I (0.48 kg). To the reaction mass, a cooled solution of sulfuric acid (0.64 kg) in methyl isobutyl ketone (15.0 1) was added drop wise under inert atmosphere at -10 to -5 °C. The reaction mixture was stirred at same temperature for 3 hours. Thereafter the temperature of reaction mixture was raised to 17°C slowly and stirring was continued for further 10 hours. The product was filtered, washed with methyl isobutyl ketone and dried to obtain the title compound.

WE CLAIM
1. A process for the preparation of methyl(+)-(S)-α-(ochlorophenyl) 6,6-dihydrothieno[3,2c]pyridine-5(4H)-acetate hydrogen sulfate (Clopidogrel hydrogen sulfate) Form I of formula-I,
Formula I
(Formula Removed)
which comprises,
dissolving clopidogrel base in suitable organic solvent,
adding halogenated solvent and seeding of Form I of Clopidogrel hydrogen
sulfate,
cooling the reaction mixture to -10 to 0 °C,
adding solution of sulfuric acid in suitable organic solvent maintaining the
temperature below 0 °C,
stirring the reaction mixture for sufficient time to convert to Form I of
Clopidogrel hydrogen sulfate,
isolating Clopidogrel hydrogen sulfate Form I.
2. A process according to claim 1 wherein suitable organic solvent is selected from
ketones and aliphatic hydrocarbons.
3. A process according to claim 2 wherein suitable organic solvent is selected from
methyl isobutyl ketone, n-hexane, n-heptane.
4. A process according to claim 1 wherein halogenated solvent is selected from
methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride.
5. A process according to claim 4 wherein halogenated solvent is preferably
methylene chloride.
6. A process according to claim 1 wherein Clopidogrel hydrogen sulfate Form I
having a powder X-ray diffraction pattern as shown in Fig. 1.
7. A process for the preparation of highly pure Clopidogrel hydrogen sulfate
Form I substantially the same as described herein.
8. A process for the preparation of Clopidogrel hydrogen sulfate Form I, which
comprises, suspending clopidogrel camphor sulphonic acid salt in organic
solvent, treating the reaction mass with aqueous solution of sodium bicarbonate,
distilling the organic layer to obtain clopidogrel base as residue, dissolving
clopidogrel base in suitable organic solvent, adding halogenated solvent and
seeding of Form I of Clopidogrel hydrogen sulfate, cooling the reaction mixture
to -10 to 0 °C,adding solution of sulfuric acid in suitable organic solvent
maintaining the temperature below 0 °C,stirring the reaction mixture for
sufficient time to convert to Form I of Clopidogrel hydrogen sulfate, isolating
Clopidogrel hydrogen sulfate Form I.