This application claims priority to Indian patent application No 1176/CHE/2010 filed on April 28, 2010.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Clopidogrel or pharmaceutically acceptable salts. The present invention also relates to Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5%.

BACKGROUND OF THE INVENTION:

Clopidogrel, Methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of formula (I),

Formula I

is an inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation which is effective in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as stroke, thrombosis, embolism, and myocardial infarction. Clopidogrel is administered as its bisulphate salt. Clopidogrel bisulphate is currently being marketed as PLAVIX® tablets. PLAVIX® is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. The enantiomer (S)-Clopidogrel is particularly preferred since it is the pharmaceutically active compound.

US4529596 describes a process for the preparation of racemic Clopidogrel by the reaction of methyl 2-chloro-o-chlorophenylacetate and 4, 5, 6, 7-tetrahydro thieno [3, 2-c] pyridine in dimethylformamide and potassium carbonate at elevated temperature.

US4847265 describes the preparation of (S)-Clopidogrel from racemic Clopidogrel by resolution with levorotatory camphorsulphonic acid. The Clopidogrel camphorsulphonate salt is then neutralized to the free base using sodium bicarbonate followed by the conversion to (S)-Clopidogrel bisulphate, which is isolated from acetone. The polymorphic form obtained is characterized as Clopidogrel bisulphate polymorphic form I.

US5204469 describes the process for the preparation of Clopidogrel free base wherein a-bromo(2-chlorophenyl)acetic acid is converted to methyl a-(2-thienylethylamino)(2-chlorophenyl)acetate, which is then cyclised using formaldehyde solution in the presence of an acid to produce Clopidogrel.

US6429210 discloses the crystalline form I and II of Clopidogrel bisulphate, of which form I is the prior-art form and form II is novel. US6504030 claims a process for the preparation of Clopidogrel bisulphate form II, wherein the polymorph is isolated from acetone.

US7446200 discloses a process for the preparation of Clopidogrel bisulphate polymorphic form I starting from tetrahydrothienopyridine hydrochloride and a-bromo-2-chlorophenyl acetic acid methyl ester to form racemic Clopidogrel base, which is resolved using levorotatory camphor sulphonic acid. Clopidogrel free base is converted to Clopidogrel bisulphate form I using glacial acetic acid, diisopropyl ether and cone, sulphuric acid.

There are several processes in the prior-art for the preparation of Clopidogrel bisulphate using acetone in sulphuric acid. This results in poor quality of the product due to the constant degradation of acetone in sulphuric acid, which leads to formation of the dimer impurity. The present process overcomes this problem by minimizing the dimer impurity.
The present process is also cost-effective and industrially feasible.

OBJECT OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation of Clopidogrel or pharmaceutical acceptable salts.

Another object of the present invention is to provide Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5%.

Yet another object of the present invention is to provide dimer impurity of formula X.

Yet another object of the present invention is to provide Clopidogrel bisulphate having the dimer impurity of formula X in less than 0.1%.

SUMMARY OF THE PRESENT INVENTION:

In one aspect, the present invention provides an improved process for the preparation of Clopidogrel bisulphate, comprising the steps of; a) reacting the compound of formula 2 or its salt with formaldehyde, b) adding sulphuric acid diluted in ether to the product formed in step a) in a solvent, and c) isolating Clopidogrel bisulphate.

In another aspect, the present invention provides Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5%.

In yet another aspect, the present invention provides an improved process for the preparation of Clopidogrel bisulphate form I, having purity greater than 99.5% comprising the steps of; a) reacting the compound of formula 2 or its salt with formaldehyde in a solvent b) adding sulphuric acid diluted in ether to the product formed in step a) in the presence of a solvent, and c) converting Clopidogrel bisulphate to pure Clopidogrel bisulphate form I.

In yet another aspect, the present invention provides an improved process for the preparation of Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5% comprising the steps of; a) dissolving Clopidogrel bisulphate in a mixture of solvent and water, b) adding a suitable base to obtain Clopidogrel, c) dissolving Clopidogrel in a mixture of organic solvents, d) optionally adding an anti-oxidant, e) adding sulphuric acid diluted in ether, and f) isolating pure Clopidogrel bisulphate Form I.

In yet another aspect, the present invention provides a process for the purification of Clopidogrel bisulphate polymorphic form II.

In yet another aspect, the present invention provides a dimer impurity of formula X.

Formula X

Yet another aspect, the present invention also provides pharmaceutical compositions comprising Clopidogrel bisulphate so prepared and an excipient / carrier, known in the art.

The entire process for the preparation of Clopidogrel bisulphate polymorphic form I is depicted in scheme 1 below:

Scheme 1

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Clopidogrel or pharmaceutically acceptable salt thereof, wherein the compound of formula 2 or its salt is reacted with formaldehyde in a solvent to get Clopidogrel free base as a residue. This residue is dissolved in a solvent and sulphuric acid diluted in ether solvent is added to get Clopidogrel bisulphate. Clopidogrel bisulphate is then converted to pure Clopidogrel bisulphate form I.

In one embodiment, the present invention provides an improved process for the preparation of Clopidogrel bisulphate comprising the steps of; a) reacting the compound of formula 2 or its salt

Formula 2

with formaldehyde in a solvent,

b) adding sulphuric acid diluted in ether to the product formed in step a) in a solvent, and

c) isolating Clopidogrel bisulphate.

According to the present invention, the compound of formula 2 or its salt is dissolved in a solvent, to which formaldehyde is added at room temperature. The reaction is carried out at a temperature range of 25°C to 50°C, preferably at a temperature range of 25°C to 35°C for a time period of 15 to 30 hours. After completion of the reaction the pH of the solution is adjusted to 6.5-7.5 and separated the layers. The organic layer is washed with sodium bicarbonate solution to remove traces of acid, followed by sodium bisulphite solution to remove unreacted formaldehyde. The solvent is distilled off to obtain the Clopidogrel free base as a residue.

The residue is dissolved in organic solvent, optionally treated with charcoal in aqueous alcohol followed by addition of sulphuric acid diluted in ether solvent at -10°C to 10°C and maintained for about 1-3 h. The temperature of the solution is raised to 5-20°C, preferably 5-10°C and the obtained solid is filtered to get wet cake of Clopidogrel bisulphate. The wet cake is suspended and stirred in a mixture of alcohol and water at 50-60°C, cooled to room temperature and isolated Clopidogrel bisulphate.

The solvent used for the dissolution of compound of formula 2 is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, water or mixtures thereof. The pH is adjusted using sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate. The solvent used for extraction of Clopidogrel free base is selected from dichloromethane, dichloroethane, chloroform, ethyl acetate, isopropyl acetate or methyl acetate.

The solvent used in step b) for the dissolution of Clopidogrel free base obtained in step a) is selected from acetone, butanone, methyl isobutyl ketone, methanol, ethanol, propanol, isopropanol, butanol, methyl tert-butyl ether, diisopropyl ether, diethyl ether, acetic acid, water or mixtures thereof. The ether solvent used for dilution of sulphuric acid is selected from diisopropyl ether, diethyl ether or tetrahydrofuran. The alcohol solvent used for the suspension of Clopidogrel bisulphate is selected from methanol, ethanol, propanol, isopropanol or butanol. Clopidogrel bisulphate is isolated as crystalline solid using conventional techniques like filtration or centrifugation.

In another embodiment, the present invention provides Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5%.

In another embodiment, the present invention provides an improved process for the preparation of Clopidogrel bisulphate form I, having purity greater than 99.5% comprising the steps of; a) reacting the compound of formula 2 or its salt

Formula 2

with formaldehyde in a solvent,

b) adding sulphuric acid diluted in ether to the product formed in step a) in a solvent to get Clopidogrel bisulphate, and

c) converting Clopidogrel bisulphate to pure Clopidogrel bisulphate form I.

According to the present invention, the compound of formula 2 or its salt is dissolved in a solvent, to which formaldehyde is added at room temperature. The reaction is carried out at a temperature from 25°C to 50°C, preferably at a temperature range of 25°C to 35°C for a time period of 15 to 30 hours. After completion of the reaction the pH of the solution is adjusted to 6.5-7.5 and separated the layers. The organic layer is washed with sodium bicarbonate solution to remove traces of acid, followed by sodium bisulphite solution to remove unreacted formaldehyde. The solvent is distilled off to obtain the Clopidogrel free base as a residue.

The residue is dissolved in organic solvent, optionally treated with charcoal in aqueous alcohol followed by addition of sulphuric acid diluted in ether solvent at -10°C to 10°C and maintained for about 1-3 h. The temperature of the solution is raised to 5-20°C, preferably 5-10°C and the obtained solid is filtered to get wet cake of Clopidogrel bisulphate. The wet cake is suspended and stirred in a mixture of alcohol and water at 50-60°C, cooled to room temperature and isolated Clopidogrel bisulphate. The Clopidogrel bisulphate is further converted to pure Clopidogrel bisulphate form I.

The solvent used for the dissolution of compound of formula 2 is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, water or mixtures thereof. The pH is adjusted using sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate. The solvent used for extraction of Clopidogrel free base is selected from dichloromethane, dichloroethane, chloroform, ethyl acetate, isopropyl acetate or methyl acetate.

The solvent used in step b) for the dissolution of Clopidogrel free base obtained in step a) is selected from acetone, butanone, methyl isobutyl ketone, methanol, ethanol, propanol, isopropanol, butanol, methyl tert-butyl ether, diisopropyl ether, diethyl ether, acetic acid, water or mixtures thereof. The ether solvent used for dilution of sulphuric acid is selected from diisopropyl ether, diethyl ether or tetrahydrofuran. The alcohol solvent used for the suspension of Clopidogrel bisulphate is selected from methanol, ethanol, propanol, isopropanol or butanol.

Clopidogrel bisulphate may be converted to the polymorphic form-l directly or it may involve the isolation of Clopidogrel free base.

In yet another embodiment, the present invention provides an improved process for the preparation of Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5% comprising the steps of:

a) dissolving Clopidogrel bisulphate in a mixture of solvent and water,

b) adding a base to obtain Clopidogrel free base,

c) dissolving Clopidogrel free base in a mixture of organic solvents,

d) optionally adding an anti-oxidant,

e) adding sulphuric acid diluted in ether solvent, and

f) isolating pure Clopidogrel bisulphate Form I.

According to the present invention, Clopidogrel bisulphate in any polymorphic form is dissolved in a mixture of solvent and water at room temperature. pH of the solution is adjusted to 6.5-7.5 using a base. The solution is optionally fed with an anti-oxidant. The solvent is distilled off to obtain Clopidogrel free base as residue. The residue is dissolved in a mixture of organic solvents. To this solution is added sulphuric acid diluted in ether solvent at -20°C to 0°C, preferably -15°C to -10°C and stirred for 5-10 h. The temperature of thesolution is raised to room temperature and stirred for 12-18 h. The obtained solid is isolated as Clopidogrel bisulphate form I.

The solvent used along with water for dissolving Clopidogrel bisulphate is selected from dichloromethane, dichloroethane or chloroform. The base used for pH adjustment is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate. The anti-oxidant is selected from butylated hydroxy toluene (BHT). The mixture of organic solvents used for the dissolution of Clopidogrel free base is selected from ethers such as diisopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, carboxylic acids such as acetic acid or formic acid, aliphatic ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, 2-butanone or diethyl ketone.

According to the present invention, the sulphuric acid is diluted in an ether solvent, which is preferably pre-cooled to a temperature of -20°C to 0°C, more preferably to a temperature of -15°C to -10°C. The ether solvent is selected from diisopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane.

According to the present invention, Clopidogrel bisulphate form I is isolated using conventional techniques like filtration or centrifugation.

The role of anti-oxidant in the present invention is to minimize the formation of oxidized impurities, preferably N-oxide impurity, which is very difficult to remove in purification.

In yet another embodiment, the present invention provides a process for the purification of Clopidogrel bisulphate polymorphic form II comprising the steps of,

a) adding Clopidogrel bisulphate form II in a mixture of solvents and water,

b) heating the suspension,

c) cooling the suspension, and

d) isolating pure Clopidogrel bisulphate form II.

According to the present invention, Clopidogrel bisulphate form II is suspended in a mixture of organic solvent and water, heated to 40-80°C, preferably 50-60°C for about 1-3 h. The mixture is cooled to room temperature and the product is isolated. The purification process may optionally be repeated to obtain pure Clopidogrel bisulphate form II.

The solvent is selected from isopropanol, methanol, ethanol, n-propanol, n-butanol or tert-butanol. Pure Clopidogrel bisulphate form II is isolated using conventional techniques like filtration or centrifugation.

According to the present invention, the word "suspending" means treating or partially dissolving or slurring or mixing.

According to the present invention, pure Clopidogrel bisulphate form I having purity greater than 99.5% and dimer impurity less than 0.5%, preferably less than 0.2 %, more preferably less than 0.1%, most preferably below detectable limit.

Yet another embodiment of the present invention is to provide dimer impurity of formula X, characterized by LC-MS.

Yet another embodiment of the present invention is to provide pharmaceutical compositions comprising Clopidogrel bisulphate so prepared and an excipient / carrier, known in the art.

The advantages of the present invention over the prior-art processes are:

i) the formation of dimer impurity is minimized by using sulphuric acid diluted in ether solvent,

ii) minimize the formation of any individual impurity less than 0.1%,

iii) improves the physical nature of the product,

iv) does not involve the corrosive mineral acids, and

v) minimize the contamination of formaldehyde.

The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1: Preparation of Clopidogrel bisulphate form II

To a mixture of 34-40% formaldehyde solution (862 ml) and methanol (338 ml) was added methyl a-(2-thienylethylamino) (2-chlorophenyl) acetate hydrochloride (150 g). The mixture was heated to 31-35°C and maintained for 20-25 h. After the completion of the reaction, the solution was cooled and activated carbon (15 g) was added. The mixture was stirred for 1 h, filtered, washed with methanol, dilute hydrochloric acid. Water and dichloromethane was added to the filtrate and the pH was adjusted to 6.5-7.5 with sodium bicarbonate solution, separated the layers. The compound was extracted in dichloromethane (500 ml+200 ml) and dichloromethane layer was washed with sodium bicarbonate solution followed by sodium bisulphite solution. The solvent was distilled off under atmospheric pressure to obtain the Clopidogrel free base as a residue. The residue was dissolved in acetone (640 ml), activated carbon (10 g) suspended in acetone (35 ml) was added, stirred and filtered. Water (5ml), methanol (20 ml) mixture was added to the filtrate and cooled to -5°C to -10°C, followed by the dropwise addition of pre-cooled concentrated sulphuric acid (39 g) diluted in diisopropyl ether (140 ml). The solution was seeded with Clopidogrel bisulphate form II and maintained for 2 h and the obtained solid was filtered as wet cake. The wet cake was washed with acetone and dried under vacuum. The product was suspended in isopropanol and water, heated at 55-60°C for 1 h, cooled to room temperature and filtered and was suck dried under vacuum. The obtained crystals were characterized to be Clopidogrel bisulphate form II.

Dry weight: 97.5-125 g

Yield: 65-83%

HPLC Purity: 99.0%

Example 2: Preparation of Clopidogrel bisulphate Form I from Form II

100 g of Clopidogrel bisulphate form II was suspended in 200 ml of DCM and 200 ml of water, the contents were cooled to 0-5°C and pH was adjusted with sodium bicarbonate solution to 6.8-7.3. The layers were separated and the aqueous layer was extracted with dichloromethane (2X100 ml). Butylated hydroxyl toluene (BHT) (0.52g) was added to the organic layers and solvent was distilled out under reduced pressure to get Clopidogrel free base. Clopidogrel free base was dissolved in diisopropylether (1532ml) and cooled to -15 to -10 °C then acetone (72.7 ml) and acetic acid (3.8 ml) was added. To this solution pre-cooled cone, sulphuric acid diluted in diisopropyl ether (21.5 g, 766 ml) was added at -15 to -10 °C for 1h and maintained for 5 hours at the same temperature. The reaction mixture was raised to ambient temperature and maintained for 12-15 h. The resulting crystals were filtered and washed with diisopropyl ether (2X76 ml) under nitrogen atmosphere. The material was dried under vacuum at 60-65 °C to obtain Clopidogrel bisulphate form I. Dry Wt: 80-90 g HPLC: 99.0 %

Claims:

1) Process for preparation of Clopidogrel bisulfate comprising the steps of:

a) reacting the compound of formula 2 or its salt

Formula 2 with formaldehyde in a solvent,

b) adding sulphuric acid diluted in ether to the product formed in step a) in a solvent, and

c) isolating Clopidogrel bisulphate.

2) Improved process for the preparation of pure Clopidogrel bisulfate form I, comprising the steps of:

a) reacting the compound of formula 2 or its salt

Formula 2

with formaldehyde in a solvent,

b) adding sulphuric acid diluted in ether to the product formed in step a) in a solvent to get Clopidogrel bisulphate, and

c) converting Clopidogrel bisulphate to pure Clopidogrel bisulphate form I.

3) Improved process for the preparation of Clopidogrel bisulphate polymorphic form I, having purity greater than 99.5% comprising the steps of:

a) dissolving Clopidogrel bisulphate in a mixture of solvent and water,

b) adding a base to obtain Clopidogrel free base,

c) dissolving Clopidogrel free base in a mixture of organic solvents,

d) optionally adding an anti-oxidant,

e) adding sulphuric acid diluted in ether solvent, and

f) isolating pure Clopidogrel bisulphate Form I.

4) Process for the purification of Clopidogrel bisulphate polymorphic form II comprising the steps of:

a) adding Clopidogrel bisulphate form II in a mixture of solvents and water,

b) heating the suspension,

c) cooling the suspension, and

d) isolating pure Clopidogrel bisulphate form II.

5) The process according to claim 1, 2 & 4 wherein solvent used in step (a) is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol water or mixtures thereof.

6) The process according to claim 1& 2, where in solvent used in step b) for the
dissolution of Clopidogrel free base obtained in step a) is selected from acetone, butanone, methyl isobutyl ketone, methanol, ethanol, propanol, isopropanol, butanol, methyl tert-butyl ether, diisopropyl ether, diethyl ether, acetic acid, water or mixtures thereof.

7) The process according to claim 3, where in solvent used in step a) is selected from
dichloromethane, dichloroethane or chloroform.

8) The process according to claim 3, where in base used in step b) is selected from
sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.

9) The process according to claim 3, the organic solvent used in step c) is selected from diisopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetic acid or formic acid, acetone, ethyl methyl ketone, methyl isobutyl ketone, 2-butanone, diethyl ketone or mixtures thereof.

10) The process according to claim 3, the anti-oxidant used in step d) is butylated hydroxyl toluene.