FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process for preparation of clopidogrel hydrogen sulphate "
2. APPLICANT
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Related reference
This patent application is related to our earlier pending Indian patent applications 281/MUM/2004 filed on 05-04-2004; 626/MUM/2004, filed on 12/9/2004; and 861/MUM/2004, filed on 14-11-2004 and corresponding PCT international patent application No. PCT/IN2005/000071 (WO/2005/104663) with international filing date 04/03/2005. The contents of which may be treated as incorporated herein by reference.
Technical Field of Invention:
The present invention relates to an improved process for manufacturing (+)-(S)-alpha-2-(chlorphenyl)-6, 7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester of Formula I, commonly known as Clopidogrel in crystalline FORM -I. The invention is characterized by process improvements in isolation/preparation of Clopidogrel free base and recycling of resolving agent.
Background of the invention:
(+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester known as clopidogrel under the International Non-Proprietary Name is marketed as hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and antithrombotic properties and finds medicinal applications in this field. It can be represented by Formula-I, and was disclosed in Patent US 4529596 (hereinafter referred as '596' patent) in its racemic form for the first time.

The pure enantiomeric forms of clopidogrel (dextro and levo-isomers) was disclosed in EP 281459 which teaches the isolation of the dextro rotatory isomer of Clopidogrel by diastereomeric salt formation of racemic Clopidogrel base using an optically active acid such as 10-L-camphor sulfonic acid in solvents like acetone, followed by successive

recrystallization of the salt until a product with constant rotatory power was obtained. The pure dextrorotatory isomer of clopidogrel (herein after referred as clopidogrel free base) was released from the respective diastereomeric salt by reaction with sodium bicarbonate in an aqueous solvent followed by extractive work-up. The starting racemic clopidogrel free base was obtained from hydrogen sulphate salt of racemic clopidogrel by following an aqueous treatment in presence of bicarbonate. The pure Clopidogrel free base was then converted into its hydrogen sulfate salt which is the marketed salt form of clopidogrel.
Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorph forms of Clopidogrel hydrogen sulfate referred to as Form-I and Form-II. The process to obtain clopidogrel free base from camphor sulphonate salt was carried out in aqueous reaction conditions in presence of potassium carbonate followed by extractive work-up.
WO2004074215 disclosed a racemization process for R-clopidogrel acid salt using liquor ammonia and finally aqueous extractive work-up to isolate the clopidogrel free base. A parallel publication, WO/2004/108665, on process for clopidogrel has used an aqueous extractive work-up to isolate clopidogrel free base from it's acid salt. Another patent application No.WO/2007/032023 also discloses ammonia for basification of clopidogrel salt using an aqueous extractive work-up to produce clopidogrel free base.
In parallel to the above reports on the preparation of clopidogrel, the applicants own publication WO/2005/104663 disclosed the use of ammonia in the preparation of clopidogrel free base from clopidogrel salt, especially camphorsulphonate salt using an aqueous extractive work-up.
According to our search, in all the preparative methods disclosed for clopidogrel, the use of either alkali metal carbonates or bicarobonates for the freeing of clopidogrel acid addition salt with an aqueous extractive work-up is common. Clopidogrel being an oily substance, it is advantageous to convert to an acid addition salt for better handling and storage and therefore, its conversion to a salt form is almost unavoidable for stable storage. Clopidogrel has a methyl ester group as evidenced from the structure of Formula I. The clopidogrel when hydrolyzed it forms an impurity named Clopidogrel free acid of

Formula X, which needs to be monitored in the active substance as per pharmacopoeial specification. The main cause of this impurity is the hydrolysis of methyl ester under aqueous conditions.
COOH

Formula X
In order to control the hydrolysis of ester, very mild bases like bicarbonates and controlled reactions conditions were employed in the art. Due to the poor solubility of either clopidogrel acid addition salt or clopidogrel free base in water, the process of breaking the salt in aqueous conditions were not effective leading to larger reaction time which is detrimental to product purity. Thus, carrying out reactions at higher temperatures or for longer period lead to formation of acid impurity which necessitates extra purification resulting into yield losses and increase in number of operations that are desirable for a practical process.
Owing to the economy of the process, the expensive resolving agent 'camphor sulphonic acid' should be recovered and recycled after resolution, which is almost impractical in reported processes because of its high solubility in aqueous solutions. Being highly soluble in water, the recovery from aqueous reaction solution is very difficult and in most cases requires column purification, which is not economically viable. Thus, the search for a manufacturing process for the preparation of Clopidogrel resulting in a satisfactory yield / purity of final product remains undoubtedly of interest.
It is also an objective of the present to discover an efficient process to recover and recycle camphor sulphonic acid, apart from simplifying the process for clopidogrel.
Summary of the invention:
The present invention thus provides an improved process for preparing clopidogrel free base from its acid addition salt. The present process comprises the step of treating

clopidogrel acid salt in non-aqueous conditions using ammonia to obtain clopidogrel in free base form.
In one aspect of the invention the process according to the invention comprises treating clopidogrel acid salt, for example, bisulphate, hydrochloride, hydrobrmomide, camphorsulphonate salt or similar salts with ammonia gas in an organic solvent. The clopidogrel free base can be recovered by filtering out the ammonium salt of acid from the organic solvent, followed by elimination of solvent.
In a second aspect of the invention, the process according to the invention comprises treating any clopidogrel acid salt, for example bisulphate, hydrochloride, hydrobromide, camphorsulphonate salt in an organic solvent with a non-aqueous ammonia solution in organic solvent. The clopidogrel free base can be recovered by filtering out the ammonium salt of acid from the organic solvent, followed by elimination of solvent.
In a preferred embodiment of the process, according to the present invention, the process comprises treating clopidogrel camphor sulphonate salt with ammonia gas or ammonia solution in non-aqueous organic solvent. On completion of reaction, ammonium camphor sulphonate salt crystallized out can be isolated in pure form from the solution. The clopidogrel free base can be recovered after filtering out the ammonium salt of acid from the organic solvent, followed by elimination of solvent. The ammonium salt of camphor sulphonate salt can be further processed to obtain camphor sulphonic acid which may be recycled in the resolution step.
Detailed description of Drawings:
Fig 1 illustrates PXRD pattern of clopidogrel hydrogen sulphate Form I. prepared according to Example 3 of the present invention.
Detailed description of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the

preferred methods and materials are described. To describe the invention, certain terms
are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes," "comprising," and
"comprises" mean "including without limitation" and shall not be construed to limit any
general statement that it follows to the specific or similar items or matters immediately
following it. Embodiments of the invention are not mutually exclusive, but may be
implemented in various combinations. The described embodiments of the invention and
the disclosed examples are given for the purpose of illustration rather than limitation of
the invention as set forth the appended claims.
The term "treating" means adding or combining or mixing the stated reagent or materials
to the thing being treated.
The term "non-aqueous medium" means a solvent medium that does not contain water in
significant amounts. The term does not exclude solvents containing insignificant amounts
of water, which may be less than 5%, more preferably less than 2%.
The present improvement in the process for preparation clopidogrel, leading to crystalline forms of clopidogrel are described in detail with the specific embodiments/conditions here after.
It has now been found that new condition / process makes it possible to convert Clopidogrel acid salt to free base in a single step in a non-aqueous condition, thereby, eliminating the occurrence of hydrolysis of ester leading to impurity of formula X. The process is simplifying the isolation of clopidogrel free base as well as resolving agent, making the process industrially more feasible.
Thus, according to the present invention, an improved synthesis of Clopidogrel is provided by reacting clopidogrel acid salt using ammonia in non-aqueous conditions to obtain clopidogrel in free base form. The reaction is performed in presence of an organic solvent.
The clopidogrel acid salts or may be selected from known ones, for example bisulphate, hydrochloride, hydrobromide, naphthalene sulphonate, methane sulphonate, camphor sulphonate, tartarate etc. The ammonia may be employed in gaseous form or as a solution

in suitable non-aqueous organic solvent. The organic solvent may be selected from any inert solvent, where a difference of solubility of ammonium salt and clopidogrel salt can be attained. Examples of solvents include, but not limited to, hydrocarbons, such as toluene, dichloromethane, dichloroethane, alcohols such as isopropanol, ethanol, ketones such as acetone, methyl ethylketone, Methylisobutyl ketone, methylpropylketone, etc., and ethers such as diisopropyl ether, diglyme, ter.butylmethyl ether, cyclopentylmethyl ether etc.
In one embodiment of the present invention the clopidogrel acid salt is reacted with ammonia gas in an organic solvent. The process is accomplished by making a solution or suspension of clopidogrel acid salt in an organic solution and passing ammonia gas to attain a constant pH in the range of about 8 to 9. Alternately an ammonia solution prepared in an organic solution (by passing ammonia into a neat solvent) may be added to a solution/suspension of clopidogrel salt in organic solvent or vise versa. The reaction may be conducted at room temperature, but preferably under cooling to control the exothermicity. While progressing the reaction the ammonium salt separates out from the organic solution and clopidogrel free base remain in solution in the organic solvent in stable form. The ammonium acid salt of camphor sulphonic acid may be conveniently removed/recovered from the reaction by simple filtration. The clopidogrel free base from the mother liquor is recovered after filtering out the ammonium salt of the camphor sulphonic acid from the organic solvent, followed by elimination of solvent. The yield of either clopidogrel free base or ammonium camphor sulphonate is nearly quantitative, whereas in conventional method it is about 75-90%.
The starting clopidogrel acid salt may be obtained by following any conventional methods. In the present invention, preferably the (S)-clopidogrel (L)-camphor sulphonate salt or bisulphate salt is used. (S)-clopidogrel (L)-camphor sulphonate salt is preferably obtained after resolution of racemic clopidogrel into it enantiomers using optically active camphorsulphonic acid. The process of resolution involves contacting Clopidogrel base with (-) camphor sulphonic acid in acetone or a mixture of polar and non-polar/weakly polar organic solvents and crystallizing the camphor sulphonic salt of (S)-clopidogrel according to our parent application publication number WO/2005/104663.

It should be understood that the present invention is applicable to racemic clopidogrel as well as enantiomers of clopidogrel in any acid salt form.
In a second embodiment of the present invention the unwanted isomer, (-) (R)-clopidogrel camphor sulphonate salt, left behind in the mother liquor is also treated with ammonia as described above to recover ammonium camphor sulphonate, and thereafter racemized and recycled by treatment with NaOH in alcoholic solvents like methanol at a temperature ranging from 30 to 50°C to obtain a 50:50 ratio of both isomers (referred as racemic mixture) as exemplified in the parent application.
The (+)-(S)-clopidogrel free base obtained above is further converted to polymorph Form I of clopidogrel hydrogen sulphate in according to any one of the processes described in our parent application WO/2005/104663 or pending application numbers; 626/MUM/2004 and 861/MUM/2004.
In another embodiment, the present invention provides processes for recovery and recycling of camphorsulphonic acid, said process comprises treating ammonium camphorsulphonate in an organic solvent with an acid to liberate free camphor sulphonic acid and the by-product ammonium salt is removed by simple filtration. In the process ammonium camphorsulphonate salt was suspended or dissolved in an organic solvent for example, but limited to toluene, ethanol, isopropanol, acetone, methylethylketone, and treated with Hydrochloric acid, preferably in gaseous form or as a solution on organic solvent like Isopropanol until the salt exchange is completed. The free Camphor sulphonic acid can be isolated by filtering out the precipitated ammonium chloride and solvent elimination, followed by optional crystallization. The free Camphor sulphonic acid obtained after filtering out the precipitated ammonium chloride may be directly used as a solution, without further isolation, for resolution of clopidogrel, if the solvent is acetone or its mixtures with other solvents like dichloromethane.
Further details about the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

Examples:
Example 1: (S) (+) clopidogrel base.
93.0 gm (0.28 mole) of racemic base methyl-2- (2-chlorophenyl)-2-(4,5,6,7-
tetrahydrothieno [3,2-c] pyridin-5-yl) acetate was charged in 550 ml of mixture of
acetone and dichloromethane. 73.8 gm (0.31 mole) levo-camphor-10-sulphonic acid was
added in the solution. The clear solution was stirred overnight at 30 ± 2°C and cooled the
reaction mass to -2 to 3°c. The crystals obtained was filtered and washed with acetone
and dried at room temperature under vacuum to give 61 gm of diastereomeric (S)-
clopidogrel camphor sulphonate salt.
(S)-clopidogrel camphor sulphonate salt (60 gm) obtained above was dissolved suspended in dichloromethane at room temperature. The solution suspension is cooled to about 15-20 degrees and passed ammonia gas until a constant pH of 8.5 to 9.0 is reached. The solution was stirred for 3 hours and filtered to obtain ammonium camphor sulphonate which is collected for recycling. The clopidogrel free base is recovered from the mother liquor by concentrating under vacuum to obtain clopidogrel free base in syrup form.
Example 2: (S)(+) clopidogrel base
150.0 gm (0.28 mole) of racemic methyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetate bisulphate was charged in 600 ml dichloromethane at about 20 degrees. To this mixture ammonia gas is passed until a constant pH of 8.5 to 9 is reached. The suspension was stirred for 3 hours, filtered to remove insoluble salt. The dichloromethane solution was concentrated to 200 ml and added 350 ml acetone. 73.8 gm (0.31 mole) levo-camphor-10-sulphonic acid was added to the solution. The clear solution was stirred for 10 hours at 30±2°c. The reaction mass was cooled to -2 to 3°c. The crystals obtained was filtered, washed with acetone and dried under reduced pressure to give (S)(+)-clopidogrel camphor sulphonate. The yield obtained is 80% on the basis of the starting racemate charged. The crystals have [a]o 20 +24.49 (c = 1.89%, methanol); HPLC (AGP(R)column) assay= 99.285%.
The (S)(+)-clopidogrel camphor sulphonate was further taken in dichloromethane (500 ml). To this suspension a solution of 50 ml isopropanol-ammonia solution was added

slowly while keeping the reaction mass at about 15-20 degrees C. The mixture was stirred for 2 hours and the precipitated ammonium camphor sulphonate was isolated by filtration. The dichloromethane solution was washed with water, dried over sodium sulphate and concentrated to dryness under vacuum to obtain (S) (+) clopidogrel base.
Example 3:
Clopidogrel base (5.79 kg) was dissolved in methyl isopropyl ketone (37 liter) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter) maintaining temperature -10° to 0° C while addition. The reaction mass was stirred for 1.0 hour and warmed slowly to 10 to 15° C in 30 to 45 minutes. The formed crystals were stirred for 7 hour. The reaction mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with methyl isopropyl ketone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1).
Example 4:
Recovery of camphor sulphonic acid from mother liquor after resolution
The mother liquor comprising mixture of (R)-Clopidogrel (enriched) & (S)-clopidogrel camphor sulphonate salt obtained in Example 1 or 2 after separation of pure (S)-clopidogrel camphor sulphonate salt was evaporated to dryness. To this 500 ml dichloromethane was added and passed gaseous ammonia while maintaining temperature about 15-20 degrees C. to reach a pH of 9. The suspension was stirred for 2 hours, filtered and washed with dichloromethane to obtain ammonium camphorsulphonate.
Example 5:
Recovery of camphorsulphonic acid
175.0 gm of ammonium camphor sulphonate was charged in 1200 ml isopropanol HC1 solution (concentration of HC1 was about 18-20%) at about 20 degrees. The mixture is stirred for 3 hours at room temperature and the precipitated ammonium chloride was filtered out. The filtrate was distilled out under vacuum and 200 ml Isopropanol and 240 ml toluene were added. The mixture was stirred for additional 1 hour and filtered to obtain 148 gm fresh camphor sulphonic acid.

Example 6:
Recovery & recycling of camphorsulphonic acid in situ
175.0 gm of ammonium camphor sulphonate was charged in 875 ml acetone and purged Hydrochloric acid gas till a pH of 1-2 was obtained at about 20 degrees. The mixture was stirred for 3 hours at room temperature and the precipitated ammonium chloride was filtered out. The filtrate was distilled out under vacuum and 900 ml acetone and 182 gm racemic clopidogrel were added. The mixture was stirred for additional 12 hour at room temperature and further cooled to about 0.-5 degree Celsius. The mixture was maintained for further 5 hours at 0-5 degree Celsius, filtered, washed with acetone and dried under vacuum to obtain 110 gm (S)(+)-clopidogrel L-camphor sulphonate salt.

We claim,
1. An improved process for preparation of clopidogrel base or its bisulphate salt
comprising an intermediate step of obtaining clopidogrel free base from clopidogrel acid
salt in non-aqueous conditions in presence of a base.
2. A process according to claim 1, wherein the base is ammonia.
3. A process according to claim 1, wherein the said acid salt is bisulphate,
camphorsulphonate, hydrochloride, or hydrobromide.
4. The process as claimed in claim 3, wherein the camphor sulphonate is L-camphor sulphonate.
5. A process according to any one of the preceding claim wherein the process comprising recovering ammonium camphorsulphonate.
6. A process according to claim 5, wherein the ammonium camphorsulphonate is
liberated to produce camphor sulphonic acid.
7. The process as claimed in claim 6, wherein the camphor sulphonic acid is recycled in resolution of racemic clopidogrel.
8. A process for recovery and recycling of camphorsulphonic acid after its use in the resolution of a racemic substrate comprises:

a) treating the diastereomeric camphor sulphonate salt of substrate with ammonia in a non-aqueous reaction solvent;
b) separating the ammonium camphor sulphonate salt from the substrate;
c) treating said ammonium camphor sulphonate salt with an acid in non-aqueous solvent to exchange the ammonium ion with the acid to free camphor sulphonic acid; and
d) isolating free camphor sulphonic acid from the reaction for recycling.
9. The process as claimed in claim 8, wherein the substrate is clopidogrel.

10. The process as claimed in claim 9, wherein ammonium diastereomeric salt of substrate is clopidogrel L-camphor sulphonic acid salt.
11. The process as claimed in any one of the preceding claim, wherein the non-aqueous solvent is alcohols, ketone or hydrocarbon or their mixtures.
12. The process as claimed in 11, wherein the solvent is acetone, isopropanol, toluene and their mixtures thereof.
13. The process as claimed in claim 8, wherein the acid used in step c) is hydrochloric acid.

ABSTRACT:
Disclosed herein is an improved process for preparation of clopidogrel base or its bisulphate salt which comprises an intermediate step of obtaining clopidogrel free base from clopidogrel acid salt in non-aqueous conditions using a base. Also, disclosed methods of recovery and recycling of camphorsulphonic acid from the mother liquor or corresponding ammonium salts in quantitative yield.