FIELD OF INVENTION
The present invention relates to a simple and efficient process for the preparation of amorphous clopidogrel hydrogen sulfate. More particularly, the present invention relates to industrially efficient process for the preparation of pure amorphous methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of the formula I:
(Formula I Removed)
BACKGROUND OF THE INVENTION
Clopidogrel hydrogen sulfate of formula I is a known blood platelet aggregation inhibitory and antithrombotic pharmaceutical active ingredient and is chemically known as methyl (+)-(S)-a-(o-chlorophenyl)-6. 7-dihydrothieno [3,2-c] pyridine-5(4H)-acetate hydrogen sulfate.
(Formula I Removed)
Its platelet inhibiting activity makes it an effective drug for reducing the incidence of ischemic strokes, heart attack due to vascular diseases such as atherosclerosis.
Clopidogrel or its salts were first disclosed in US patent 4,529,596 as racemic mixture. US patent 4,847,265 reports the formation of (S)-(+)-clopidogrel hydrogen sulfate for the first time, whereby resolution is earned out using 10-L-camphorsulfonic acid in acetone followed by successive crystallization of the salt until a product was obtained in sufficient enantiomeric purity followed by release of dextro rotatory isomer from its salt by a base. The above process leads to the formation of dextro rotatory isomer of clopidogrel hydrogen sulfate in crystalline form which was later named as Form I. This patent was however, completely silent in disclosing the crystal form of the product.
US patent 6,429,210 discloses form II of clopidogrel hydrogen sulfate which is characterized by its melting range, infrared spectrum and powdered X-ray diffraction pattern. Tt is also described that the two crystalline polymorphic forms I and IT differed in their stability, physical properties, spectral characteristics and their method of preparation, however, both the polymorphs have similar bioavailability, as shown in their bioequivalence in healthy human volunteers. According to above patent, both polymorphs, namely Form I and form II are prepared from same solvent i.e. acetone under different reaction conditions.
US patent 6,767,913 discloses crystalline forms III, IV and V and amorphous form of clopidogrel hydrogen sulfate and processes for preparing the same. Amorphous form of clopidogrel hydrogen sulfate is prepared by dissolving clopidogrel hydrogen sulfate in an alcohol selected from the group consisting of methanol and ethanol followed by addition of ether as an anti solvent. Alternatively amorphous clopidogrel hydrogen sulfate is prepared by dissolving clopidogrel base in acetone, treated with sulfuric acid and refluxed, thereafter solvent is distilled out completely to obtain amorphous product.
WO 2005/063708 A2 discloses processes for the preparation of hydrated form of amorphous clopidogrel hydrogen sulfate by treating clopidogrel base with sulfuric acid in suitable solvent like alcohols, tetrahydrofuran, dimethylformamide etc and water, removing the solvent and isolating the amorphous form by adding antisolvent like pentane, hexane. heptane, cyclohexane, pet ether or mixture thereof.
WO 2005/104663 A2 discloses processes for the preparation of form I and form II of clopidogrel hydrogen sulfate by using ethyl acetate under different crystallization temperature. Form I is prepared by dissolving clopidogrel base in ethyl acetate and treated with sulfuric acid at 18-20°C and maintaining the reaction temperature at 28-3()°C for 7-8 hours. Form II is prepared by dissolving clopidogrel base in ethyl acetate and cooling the reaction mass to 5-10°C, treated with sulfuric acid at same temperature and maintaining the reaction temperature at 10-15°C for 8-12 hours.
In our co-pending application 1075/DEL/2006, we have discussed the method for the preparation of Form I of clopidogrel hydrogen sulphate from clopidogrel base using sulfuric acid in the presence of ketonic and halogenated solvents and seeds of form I of clopidogrel hydrogen sulphate.
US patent Application 2006/0100231 Al disclose processes for the preparation of the amorphous clopidogrel hydrogen sulfate by dissolving clopidogrel base in methanol or ethanol or mixture thereof, acidifying it with sulfuric acid and subsequently slowly removing the solvent.
PCT Application No. 2005/003138 A2 discloses a process for the preparation of amorphous clopidogrel hydrogen sulfate which comprises dissolving clopidogrel base in acetone or dichloromethane, adding sulfuric acid or a mixture of sulfuric acid and diisopropyl ether, cyclohexane or ethyl acetate to the mixture, adding the obtained
mixture containing clopidogrel hydrogen sulfate to the above solvent, and filtering, optionally washing and drying the obtained precipitate.
So it is evident from the prior art that same solvent can give different polymorphs under different experimental conditions. 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 supersaturation and promote crystallization. The most notable variables of composition and processing are solvent/solvent combinations, degree of supersaturation, pH value, heating rate, cooling rate, etc. Various polymorphs of clopidogrel hydrogen sulfate have been disclosed in different patents/applications that are discussed above.
Tt has been found that known crystalline salts of clopidogrel have exhibited certain disadvantages, in particular in terms of their low solubility and in connection with the pharmaceutical formulation thereof. It has been observed that the problems coupled with the known crystalline forms of clopidogrel can be abridged, or overcome by using amorphous clopidogrel. Amorphous form of clopidogrel hydrogen sulfate has been found to be non-hygroscopic, possesses good dissolution characteristics and adequate stability over the time.
Most of the prior art methods for the preparation of amorphous clopidogrel hydrogen sulfate involve the use of ether solvents which are usually not recommended at industrial scale. However, there still remains a need for novel and modified process of preparing pure amorphous clopidogrel hydrogen sulfate which will be suitable for large-scale preparation, in terms of simplicity, chemical yield, and purity of the product.
The object of the present invention, thus, is to provide industrially advantageous process for the preparation of pure amorphous clopidogrel hydrogen sulfate, unique with respect to its simplicity, cost effectiveness and scalability.
SUMMARY OF THE INVENTION
Accordingly the present invention relates a simple and efficient process for the preparation of the amorphous form of clopidogrel hydrogen sulfate of Formula I,
(Formula I Removed)
which comprises dissolving clopidogrel base in a mixture of ketonic solvent and halogenated solvent, adding a mixture of sulfuric acid with ketonic solvent at low temperature, maintaining the reaction solution below ambient temperature for sufficient time to complete precipitation and isolating the pure amorphous clopidogrel hydrogen sulfate.
Alternatively the present invention relates to an one step process for the preparation of the amorphous form of clopidogrel hydrogen sulfate which comprises dissolving clopidogrel camphor sulfonic acid salt in halogenated solvent, basifying it with a suitable base preferably sodium bicarbonate to yield clopidogrel base, dissolving the clopidogrel base in a mixture of ketonic solvent and halogenated solvent, adding a mixture of sulfuric acid with ketonic solvent at low temperature, maintaining the
reaction solution below ambient temperature for sufficient time to complete precipitation and isolating the pure amorphous clopidogrel hydrogen sulfate.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a powdered X-ray diffraction pattern for amorphous clopidogrel hydrogen sulfate.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention describes modified and novel process for the preparation of pure amorphous clopidogrel hydrogen sulfate. The present invention relates to the synthesis of clopidogrel hydrogen sulfate starting from clopidogrel base. Clopidogrel base is obtained by the methods reported in prior art. Generally, clopidogrel base is taken in a mixture of ketonic solvent and halogenated solvent at ambient temperature. The reaction mixture is cooled and treated with a solution of sulfuric acid in ketonic solvent and stirred for sufficient time to prepare amorphous clopidogrel hydrogen sulfate which is isolated by filtration.
In a preferred embodiment, ketonic solvent is preferably selected from a group of ketonic solvents which have the ability to dissolve clopidogrel base completely thus includes methyl isobutyl ketone. Halogenated solvent referred herein is selected from methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride. It is advantageous to add halogenated solvent in ketonic solvent to avoid lump formation. Addition of halogenated solvent thus makes the solution free flowing without any lumps. The solution of sulfuric acid in ketonic solvent is prepared by drop wise addition of sulfuric acid in ketonic solvent at low temperature.
Preferably clopidogrel base is taken in a mixture of methyl isobutyl ketone and methylene chloride at ambient temperature. The resulting solution is cooled to a temperature of-7 to -2°C. To the chilled reaction mixture, a solution of sulfuric acid in methyl isobutyl ketone is added at a temperature of -7 to -2°C. The resulting reaction mixture is stirred at -7 to -2°C for about two to four hours followed by raising the temperature slowly at 15-20°C, The reaction mixture is stirred for sufficient time to precipitate completely pure amorphous clopidogrel hydrogen sulfate. It usually takes eight to twelve hours at 15-20°C to precipitate amorphous product completely. The product is isolated by well known methods in prior art i.e. by filtration. The filtered product is dried under vacuum to remove solvent and isolate pure amorphous clopidogrel hydrogen sulfate in high yield and purity.
In another embodiment of the present invention discloses a one step process for the preparation of pure amorphous clopidogrel hydrogen sulfate from clopidogrel camphor sulfonic acid salt of formula II:
(Formula II Removed)
Formula II
The clopidogrel camphor sulfonic acid salt, used as the starting material of the present invention, can be prepared by the methods well known in prior art.
Generally, clopidogrel camphor sulfonic acid salt is dissolved in halogenated solvent and treated with a solution of suitable base to hydrolyze the salt. After layer separation, organic solvent is distilled out to obtain clopidogrel base as residue. The
residue is dissolved in a mixture of suitable ketonic and halogenated solvent and cooled to temperature below 0 °C. This is followed by addition of solution of sulfuric acid in ketonic solvent and stirred for sufficient time to complete precipitation of amorphous clopidogrel hydrogen sulfate which is isolated by filtration.
The ketonic solvent is preferably selected from a group of ketonic solvents which have the ability to dissolve clopidogrel base completely thus includes methyl isobutyl ketone. Halogenated solvent referred herein is selected from methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride.
Specifically clopidogrel camphor sulfonic acid salt is prepared by reacting 4,5,6.7-tetrahydrothieno [3,2-c] pyridine hydrochloride with a-bromo-(2-clilorophenyl) acetic acid methyl ester in A^A^dirnethylformamide at 15-20°C. Quantity of AW-dimethyl formamide is preferably taken as 4.8 times of thieno [3,2-c] pyridine hydrochloride. After reaction completion, 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 separated is filtered, washed with acetone, and dried. Optionally clopidogrel camphor sulfonic acid salt obtained is purified in acetone at reflux followed by cooling to 20-25°C. (+) Clopidogrel camphor sulfonic acid salt is then taken in methylene chloride and basified with aqueous sodium bicarbonate and extracted in methylene chloride which is distilled off to get (+) clopidogrel base as residue. Preferably clopidogrel base is taken in a mixture of methyl isobutyl ketone and methylene chloride at ambient temperature. The resulting solution is cooled to temperature of-7 to -2°C. To the chilled reaction mixture, a solution of sulfuric acid in methyl isobutyl ketone is added at a temperature of -7 to -2°C. The resulting reaction mixture is stirred at -7 to -2°C for about two to four hours followed by
raising the temperature slowly at 15-20°C. The reaction mixture is stirred for sufficient time to precipitate completely pure amorphous clopidogrel hydrogen sulfate. It usually takes eight to twelve hours at 15-20°C to precipitate amorphous product completely. The product is isolated by well known methods in prior art i.e. by filtration. The filtered product is dried under vacuum to remove solvent and isolate pure amorphous clopidogrel hydrogen sulfate in high yield ad purity.
The present invention meets the need in the art for improved, low cost and environment friendly process for preparing amorphous clopidogrel hydrogen sulfate. The present invention is advantageous over the prior art processes being robust resulting in amorphous form only. The process can be scaled-up easily, conveniently and inexpensively for industrial large-scale production.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
Example-1:
Synthesis of amorphous clopidogrel hydrogen sulphate
Clopidogrel free base (53.2 g) was dissolved in methyl isobutyl ketone (709.6 ml) and methylene chloride (9.5 ml). The reaction mixture was cooled to -7 to -2°C and a solution of sulfuric acid (15.2 g) in methyl isobutyl ketone (357.2 ml) was added at -7 to -2°C. The reaction mass was stirred for 3 hours at same temperature. Thereafter, the temperature was raised to 15-20°C and the reaction mass was further stirred for 10 hours. The product precipitated out was filtered under inert atmosphere, washed with methyl isobutyl ketone (3x95 ml) and dried under vacuum at 50-55°C to yield 66.5 g

of title compound. Powdered X-ray diffraction pattern shows no peaks as shown in Fig 1, thus demonstrating that material is amorphous.
Example-2:
Synthesis of amorphous clopidogrel hydrogen sulphate
Clopidogrel camphor sulfomc acid salt (95 g) was dissolved in methylene dichloride (570 ml) and to this solution; an aqueous solution of sodium bicarbonate was added at 15-20°C till pH 7-8. The organic layer was separated and methylene dichloride was distilled out to yield clopidogrel free base as residue. Clopidogrel free base obtained (53.2 g) was dissolved in methyl isobutyl ketone (709.6 ml) and methylene dichloride (9.5 ml). The reaction mass was cooled to -7 to -2°C and a solution of sulfuric acid (15.5 g) in methyl isobutyl ketone (357.2 ml) was added at -7 to -2°C. The reaction mass was further stirred for 3 hours at same temperature. Thereafter, the temperature was raised to 17 to -2°C and the reaction mass was further stirred for 10 hours. The product precipitated out was filtered under inert atmosphere, washed with methyl isobutyl ketone (3x95 ml) and dried to yield 66.5 g of title compound.

WE CLAIM
1. A process for the preparation of amorphous clopidogrel hydrogen sulfate of formula I,
(Formula I Removed)
which comprises:
dissolving clopidogrel base in a mixture of ketonic solvent and halogenated
solvent;
cooling the reaction mass to below 0 °C,
adding solution of sulfuric acid in ketonic solvent.
raising the reaction temperature to 15-20°C.
stirring the reaction mass for sufficient time to precipitate amorphous product and
isolating amorphous clopidogrel hydrogen sulfate.
2. A process according to claim 1, wherein ketonic solvent is preferably selected of
a group of ketonic solvents which have the ability to dissolve clopidogrel base
completely.
3. A process according to claim 1, wherein ketonic solvent is methyl isobutyl
ketone.
4. A process according to claim 1. wherein halogenated solvent is selected from
methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride.
5. A process according to claim 1, wherein sulfuric acid is added at -7 to -2 °C.
6. A process for the preparation of amorphous clopidogrel hydrogen sulfate of
formula I,

(Formula I Removed)
which comprises:
dissolving clopidogrel camphor sulfonic acid salt in halogenated solvent;
adding a suitable base to the reaction mixture;
distilling off solvent to yield clopidogrel base as residue;
dissolving clopidogrel base in a mixture of ketonic solvent and halogenated
solvent;
cooling the reaction mass to below 0 °C;
adding solution of sulfuric acid in ketonic solvent.
raising the reaction temperature to 15-20 °C;
isolating amorphous clopidogrel hydrogen sulfate.
7. A process according to claim 6, wherein suitable base used is preferably sodium
bicarbonate.
8. A process according to claim 6, wherein ketonic solvent is methyl isobutyl
ketone.
9. A process according to claim 6, wherein halogenated solvent is methylene
di chloride.
10. A process according to claim 6, wherein the reaction is carried out at -7 to -2 °C.