Title of Invention

"A PROCESS FOR PREPARING (S)- CLOPIDOGREL"

Abstract 1. A process for preparing (S)-clopidogrel by racemization of (R)-clopidogrel mixture comprising the steps of : (a) treating a mixture enriched in (R)-clopidogrel or (R)-clopidogrel isomer with a metal carbonate as herein described and a hydroxide or oxide of a metal as herein described, optionally in the presence of a phase transfer catalyst such as herein described in an organic solvent such as herein described at a temperature ranging between 0° to 60°C for about 4-12 hrs, (b) filtering the reaction mixture of step (a) to obtain a filtrate, (c) washing the filtrate with saturated alkali bicarbonate solution and saturated brine, and (d) eliminating the organic solvent from the filtrate to obtain a racemic mixture of clopidogrel, which is resolved in a known manner to obtain desired (S) -( + ) clopidogrel. (2) A process as claimed in claim 1 wherein the metal carbonate is an alkali or alkaline earth metal carbonate. (3) A process as claimed in claim 2, wherein the metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate. (4) A process as claimed in claim 1, wherein the metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.
Full Text Field of the Invention:
The invention relates to improved and economical process for recycling a mixture containing (R)-(-)-enriched clopidogrel and/or (R)-(-)-clopidogrel to obtain wanted (S)-(+) clopidogrel, by racemization followed by conventional method of resolution.
Background of the Invention
It is known that methyl 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl) acetate and their salts can be used in therapy due to their platelet-aggregation-inhibitory and antithrombotic effects. The compound is represented under general formula (1), wherein it is the dextrorotatory (S)-(+)-methyl 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl) acetate hydrogen sulfate, with the international nonproprietary name (INN) clopidogrel hydrogen sulfate, which is the most preferred one.
The optically active compound of formula (2), is prepared either from optically active intermediates obtained by resolving the intermediates, or by resolving the racemic mixture of the final product (1).
Bakonyi, M. et. al (W09851689,1998) have reported the preparation of intermediates with formula (3), (4), and (5) and by resolving each using a suitable resolving agent, they obtained the respective intermediate in the chiral form. These they used for preparing the optically active end product.
Aubert, D. et al (Sanofi-Synthelabo) (EP 009902,1999), have reported the synthesis of the (+)-clopidogrel by giving a resolution option of all their key intermediates. They prepared (+)-2-amino-2-(2-chlorophenyl)acetic acid (6), (+)-methyl 2-amino-2-(2-chlorophenyl)acetate (7) and (+)-methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate (8).
In another approach, A. Bousquet et al in their patent WO 99/18110 have reported the synthesis of (R)-sulfonyloxyacetic ester derivatives of general formula (9) as possible

chiral intenriediates for the synthesis of (S)-(+)-clopidogrel. The reaction conditions called for here are quite stringent and reagents used are expensive.
Using chiral intermediates necessitates that the reaction conditions are mild so that no racemization occurs during the subsequent reactions. This warrants the use of anhydrous conditions, low temperatures and special reagents.
Another option, which is cheaper, is to resolve the racemic clopidogrel and to recycle the enriched mother liquor containing unwanted (-) isomer by racemization followed by resolution of the racemic mixture. This has not so far been reported as prior art in the synthesis of clopidogrel
Badorc, A. and Frehel, D. (EP 01281459, 1989) have reported a process for preparing (+)-clopidogrel by resolving the racemic hiixture with the (-) camphor - 10- sulphonic acid. They obtained at best 55 % of dextro- isomer based on its content in the starting racemic mixture. Further they treated the levo-enriched mixture with (+) camphor 10-sulphonic acid to remove the unwanted levo-isomer. In this process the unwanted levo-isomer was not recycled in the recovery process to obtain the wanted dextro- isomer.
Large scale preparation of clopidogrel necessitates the development of an efficient, cost effective procedure, which will racemize the (-) enriched clopidogrel mixture and/or (-)-clopidogrel, followed by resolution using an appropriate resolving agent to obtain (S)-(+)-clopidogrel. In other words, a need is felt to have a practical process, whereby adopting racemization-resolution process, high yields of (+)-clopidogrel is obtained starting from a racemic mixture. This method should also ensure that no significant hydrolysis of the methyl ester function present in the clopidogrel takes place during the process of racemization. The present invention provides an optimum process condition achieving all these objectives.
Some a-amino acid esters having primary amino group have been racemized in prior art by heating them in presence of ketones (i.e. through their Schiff base) alone (JP 79109912) or

along with carboxylic acid (hit. J. Pept. Protein Res. 1993, 41, 323-5) or along with tertiary amine (SU 929,629). But this methodology is not applicable to clopidogrel which has tertiary amino group.
Generally, bases are used for the process of racemization; strong bases like sodium hydride, sodium methoxide etc. can cause significant hydrolysis to the ester group (Topics in Sterochemistry by C.J. Shah and S.H. Wu, 1989, 19, 63-125). If strong bases are used, then special care needs to be taken to prevent hydrolysis and transesterification. Thus, Takahashi et al report the use of sodium methoxide in anhydrous methyl acetate to racemize D-phenylalanine methyl ether at 20 °C (JP 79,84,522)
OBJECTS OF THE INVENTION
The main objective of the present invention it to convert clopidogrel mixture having enriched unwanted (-)-isomer and/or (-)-clopidogrel to its racemate, without causing significant hydrolysis of the ester group, so that more of the wanted (S)-(+)-clopidogrel can be obtained by resolution.
Yet another objective of the present invention is to provide a process without using hazardous and expensive chemicals.
Yet another objective of the present invention is to avoid use of anhydrous solvents and to use common solvents like dichloromethane, acetone, toluene, etc.
Yet another objective of the present invention is to use cheap bases like alkali and alkaline earth metal carbonates, hydroxides and oxides.
Yet another objective of the present invention is to keep the work up process very simple.
Yet another objective of the present invention is to reduce time cycle as far as possible by using common phase transfer catalysts in the process.

Yet another objective of the present invention is to provide an easy method to recover the hydrolysed acid, even if formed in small quantities, from the aqueous wash.
Summary of the mvention
The present invention provides a efficient and economical process for recycling a mixture containing enriched unwanted (-)-clopidogrel and/or (-)-clopidogrel by a process of racemization, followed by resolution of the mixture thus obtained by using a conventional process to yield wanted (S)-(+)-clopidogrel.
Detailed Description
Accordingly, the invention provides a process for preparing (S)-(+)-clopidogrel by racemization of (R)- clopidogrel mixture or (R)-clopidogrel isomer comprising the steps of:
(a) treating the mixture of (R)-clopidogrel or (R)-cIopidogrel isomer with a metal carbonate such as hereindescribed and a hydroxide or oxide of a metal such as hereindescribed, optionally in the presence of a phase transfer catalyst such as hereindescribed in an organic solvent such as hereindescribed at a temperature ranging between 0° to 60°C for about 4-12 hrs,
(b) filtering the reaction mixture of step (a) to obtain a filtrate,
(c) washing the filtrate with saturated alkali bicarbonate solution and saturated brine, and
(d) eliminating the organic solvent from the filtrate to obtain a racemic mixture of clopidogrel, which is resolved in a known manner to obtain desired (S)-(+) clopidogrel.
The metal carbonate in the process is an alkali or an alkaline earth metal carbonate. The metal carbonate may be selected from a group consisting of lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate.
The metal hydroxide may be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, zinc hydroxide or magnesium hydroxide. The metal oxide is selected from the group consisting of calcium oxide.

magnesium oxide or zinc oxide. The ratio of metal carbonate to metal hydroxide/oxide is in the range of 1:0 to 1:0.5, preferably 1:0.125. Preferably, the metal carbonate has a moisture content of 15%.
The organic solvent is selected from the group consisting of carbon tetrachloride, dichloromethane, chloroform, hexane, toluene, acetone, ethyl acetate, diethyl ether or diisopropyl ether.
The ratio of the mole equivalent of the substrate and the combined alkali metal carbonate and hydroxide/oxide may be in the range of 1: 0.5 to 1: 1; the optimum being 1:0.85.
Preferably, the reaction is effected at a temperature is in the range of 40°C to 45°C.
The amount of (R)-clopidogrel in the enriched mixture may be 1 to 100%. The ratio of solvent to (R)- clopidogrel enriched mixture is in the range of 3:1 to 10:1, preferably 5:1
In an embodiment, a phase transfer catalyst is used to facilitate solid-liquid biphasic reaction, thereby reducing the reaction time by more than 50%. The phase transfer catalyst is selected from compounds containing quaternary nitrogen or phosphorous linked to alkyl/aryl groups or poly ethers. The groups attached to the quaternary nitrogen, Ri, R2, R3 and R4 may be identical or different and the alkyl groups may vary from Ci to Cio- Typical examples of these catalysts being triethyl benzyl ammonium chloride, triethyl benzyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate, polyethyleneglycol and methyl trialkyl (Cg-Cio) ammonium chloride. The catalyst used may be in the range of 1 to 15 mole % and preferably 2 %.
In an embodiment, the mixture of step (a) is filtered through a celite bed.
In an embodiment, the racemic mixture of clopidogrel obtained contains (+) and (-) isomers in the ratio of 1:1.

In one aspect, the benzylic proton a to a carboxylic group in the substrate used thereby giving it acidic character and facilitates racemization process by destroying the chirality at the center to which it is attached.
In an embodiment, the invention provides a process to effectively recover the hydrolysed amino ester lost in the aqueous layer in the form of acid as its soluble alkali salt. The pooled sodium bicarbonate washes is treated with mineral acid like hydrochloric acid or sulphuric acid to take the pH to the iso-electric pH of the said amino acid, when it precipitates. This is then extracted with any water immiscible organic solvent, preferably dichloromethane. The pH range is adjusted between 3.5 to 4.4, preferably 4.2.
The invention described by the following example of clopidogrel should not be construed as limitation on the inventive scope. It can be applicable to all chiral a-amino esters having acidic proton at the alpha position.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
The accompanying drawings depict a preferred embodiment of the invention, wherein: Figure 1 depicts various prior art compounds
EXAMPLE 1
(+)- Methyl 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl) acetate
In a 2L three neck round bottom flask, equipped with mechanical stirrer and reflux condenser, (95 g, 0.295 mole) of levo enriched clopidogrel and/or levo (-) clopidogrel was transferred along with dichloromethane (IL). To this was added K2CO3 (30.53 g, 0.22 mole) and KOH (4.14g, 0.073 mole). The contents were refluxed for 12 hrs with vigorous stirring.
The reaction mixture was filtered through a celite bed in a Buchner funnel to remove the solid bases. The filtrate was washed with saturated sodium bicarbonate twice (2 x 150 ml), finally the filtrate was washed with brine (300 ml) and the solvent was evaporated to get

racemic clopidogrel (90g; 95%) ([a]20 =0, c=l in methanol). HPLC (BDS, C-18 5 |im) RT = 18.4 min. 99.5%.
EXAMPLE -2
Repeating the procedure in example 1 using acetone as the solvent instead of dichloromethane gave an yield of 94 %. Optical rotation and HPLC analysis are identical.
EXAMPLE - 3
Repeating the procedure in example 1 using K2CO3 (22.14g, 0.196 mole) and KOH (5.50g, 0.098 mole) i.e. in the ratio of (3:1) gave a yield of 95 %.
EXAMPLE - 4
Repeating the procedure in example 1 using K2CO3 (45.93 g, 0.33 mole) and KOH (6.21 g, 0.105 mole) gave a yield of 94 %.
EXAMPLE -5
In a three neck round bottom flask, equipped with mechanical stirrer and reflux condenser, dichloromethane (750 ml) was taken along with K2CO3 (32.14 g, 0.23 mole) and KOH (2.02g, 0.036 mole) and 2 g of triethyl benzyl ammonium chloride (2 gm) and stirred. To this was added (lOOg, 0.31 mole) levo (-) enriched clopidogrel and/or levo (-) clopidogrel. The reaction contents were refluxed for 5 hours. The reaction mixture was filtered through celite bed in a Buchner funnel to remove the solid bases. The solid was washed with dichloromethane (50 ml). The total filtrate was washed with saturated bicarbonate solution (2 X 150 ml), followed by 20 % brine (400 ml). The solvent was evaporated to obtain racemic clopidogrel (94g; 94 %) ([a]20 = 0, c=l in methanol).
HPLC (BDS, C-18, 5 µm) RT = 18.4 min. 99.6 %.
Example -6
To the pooled aqueous washes of example 5, was added cone, hydrochloric acid 700 ml drop wise with stirring till the pH was about 4.2. The turbid solution was chilled to 0° C
for 15 min. and extracted twice with dichloromethane (200 ml). The pooled dichloromethane layer was dried and evaporated to obtain clopidogrel acid (yield 0.7g; 0.7 %).
Advantages
1) The process is economical and simple to operate.
2) The process provides complete utilization of unwanted (-)-isomer to obtain (+)-isomer.
3) The process provides high recovery yield for useful (S)-(+)- isomer.
4) The process involves cheap reagents for achieving the desired objective effectively.







We Claim:
1. A process for preparing (S)-clopidogrel by racemization of (R)-clopidogrel mixture comprising the steps of :
(a) treating a mixture enriched in (R)-clopidogrel or (R)-clopidogrel isomer with a metal carbonate as herein described and a hydroxide or oxide of a metal as herein described, optionally in the presence of a phase transfer catalyst such as herein described in an organic solvent such as herein described at a temperature ranging between 0° to 60°C for about 4-12 hrs,
(b) filtering the reaction mixture of step (a) to obtain a filtrate,
(c) washing the filtrate with saturated alkali bicarbonate solution and saturated brine, and
(d) eliminating the organic solvent from the filtrate to obtain a racemic mixture of clopidogrel, which is resolved in a known manner to obtain desired (S)-(+) clopidogrel.

(2) A process as claimed in claim 1 wherein the metal carbonate is an alkali or alkaline earth metal carbonate.
(3) A process as claimed in claim 2, wherein the metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate.
(4) A process as claimed in claim 1, wherein the metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.
(5) A process as claimed in claim 1, wherein the metal oxide is selected from calcium oxide, magnesium oxide and zinc oxide.
(6) A process as claimed in claim 1, wherein the organic solvent is selected from carbon tetrachloride, dichloromethane, chloroform, hexane, toluene, acetone, ethyl acetate, diethyl ether and diisopropyl ether.
(7) A process as claimed in claim 1 wherein the temperature is in the range of 40°C to 45°C.
(8) A process as claimed in claim 1, wherein in step (a), the ratio in mole equivalent of (R)-clopidogrel and the metal carbonate and metal hydroxide/oxide combination is in the range of 1:0.5 to 1:1.
(9) A process as claimed in claim 8, wherein the ratio in mole equivalent of (R) -clopidogrel and the metal carbonate and metal hydroxide/oxide combination is 1:0.85.
(10) A process as claimed in claim 1, wherein the metal carbonate has a moisture content ranging from 10% to 35%.
(11) A process as claimed in claim 10 wherein the metal carbonate has a moisture content of 15%.
(12) A process as claimed in claim 1, wherein the ratio of metal carbonate to metal hydroxide/oxide is in the range of 1:0 to 1:0.5.
(13) A process as claimed in claim 1, wherein the ratio of metal carbonate to metal hydroxide/oxide is 1:0.125.
(14) A process as claimed in claim 1, wherein the amount of
(R)-clopidogrel in the mixture is 1 to 100%.
(15) A process as claimed in claim 1, wherein the ratio of solvent to (R)- clopidogrel enriched mixture is in the range of 3:1 to 10:1, preferably 5:1
(16) A process as claimed in claim 1, wherein the phase transfer catalyst is selected from triethyl benzyl ammonium chloride, triethyl benzyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate, polyethyleneglycol and methyl trialkyl (C8-C10) ammonium chloride.
(17) A process as claimed in claim 1, wherein the reaction mixture of step (a) is filtered through a celite bed.
(18) A process as claimed in claim 1, wherein the ratio of
(+) and (-) isomers in the racemic mixture of clopidogrel obtained is 1:1.
(19) A process for preparing (S)-clopidogrel as
hereindescribed with reference to examples.

Documents:

683-del-2002-abstract.pdf

683-del-2002-claims.pdf

683-del-2002-correspondence-others.pdf

683-del-2002-correspondence-po.pdf

683-del-2002-description (complete).pdf

683-del-2002-drawings.pdf

683-del-2002-form-1.pdf

683-del-2002-form-2.pdf

683-del-2002-form-3.pdf

683-del-2002-form-5.pdf

683-del-2002-form-9.pdf

683-del-2002-gpa.pdf


Patent Number 193363
Indian Patent Application Number 683/DEL/2002
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 06-Jan-2006
Date of Filing 26-Jun-2002
Name of Patentee NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)
Applicant Address SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 UMA RAMACHANDRAN NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), OF SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
2 HARMANDER PAL SINGH CHAWLA NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), OF SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
3 SUDHANSHU KUMAR, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), OF SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
4 LALIT KUMAR WADHAWA IND-SWIFT LABORATORIES LTD, SCO 813, SHIVALIK ENCLAVE, NAC MANIMANJARA, CHANDIGARH.
PCT International Classification Number C07D 495/04
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA