Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
I TITLE OF THE INVENTION
"Commercial Production of Clopidogrel Bisulfate Form I"
2. APPLICANT
a) NAME: USV LIMITED
b) NATIONALITY: Indian Company incorporated under the
Companies Act 1956
c) ADDRESS: B.S.D. Marg, Station Road, Govandi, Mumbai 400 088,
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 application:
This application is a patent of addition of the Indian application number 1396/MUMNP/2006 filed on 20th November, 2006, which is claiming priority from the PCT application number PCT/IN05/00048 filed on 15 February, 2005.
Field of the invention :
The present invention relates to process for commercial production of crystalline methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate (Clopidogrel bisulfate ) Form I represented by Formula I. More particularly, the present invention relates to specially designed reactor for preparing highly pure Clopidogrel bisulfate Form I.

Background and prior art:
Clopidogrel is chemically known as methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5(4H)-acetate and marketed as its hydrogen sulphate salt. Clopidogrel is known potent oral antiplatelet agent and finds medicinal applications in this field. It was first disclosed in US 4529596 in its racemic form represented by Formula-IA.

Formula-IA
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Its antiplatelet activity makes it an effective drug for reducing ischemic strokes, heart attacks and in atherosclerosis (a vascular disease causing claudication). Atherosclerosis is a buildup of plaque in the walls of arteries, which leads to thickening and the reduction in the elasticity of the arteries. High cholesterol, high blood pressure, smoking and infection also causes an injury to the inner walls of the arteries, which leads to atherosclerosis. The plaque formation leads to blood clotting which is due to the platelet aggregation at the site of the injury. This clotting becomes an obstacle for the flow of the blood to the vital organs causing heart attacks or other severe problems. Antiplatelet activity which fights against atherosclerosis is exhibited by Clopidogrel, which binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting against atherosclerosis. (S) enantiomer of Clopidogrel is pharmaceutically active and found to be more effective in inhibiting platelet aggregation than aspirin.
US 4847265 (hereinafter referred as '265 patent) discloses process for preparation of dextrorotatory enantiomer of Clopidogrel which has excellent platelet anti-aggregant activity than the corresponding levorotatory enantiomer. The '265 patent also relates to the pharmaceutically acceptable salts of Clopidogrel with platelet aggregation inhibiting activity.
WO 99/65915 (equivalent to US 6429210, herein after referred as '210 patent)) titled "Polymorphic Clopidogrel hydrogen sulfate form", discloses the existence of a specific polymorphic form, Form II of the hydrogen sulfate of (S)-(+)-Clopidogrel (m.p.=176 ± 3 degree C). This patent application also discloses that the process described in the '265 patent gives Form I (m.p. 184 ± 3 degree C).
It has also been observed that upon formation of Clopidogrel bisulfate salt from (S)-Clopidogrel free base and sulfuric acid in acetone solution according to the conditions described in patent '210, a substantial loss of purity of (S) -Clopidogrel hydrogen sulfate occurs which leads to the spontaneous formation of Form II, but it can be associated with deterioration of the optical purity of the end product, which is a serious limitation of the method. These two crystalline polymorphic forms, Form I and II of Clopidogrel bisulfate differ in their stability, physical properties, spectral characteristics and method of
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preparation. According to the teachings of '210 patent Clopidogrel bisulfate Form II is suggested to be thermodynamically more stable form than Form I.
US 2003114479 describes the crystalline forms, Form III, IV and V of Clopidogrel bisulfate along with the process for preparation of Clopidogrel bisulfate Form I wherein the amorphous form of Clopidogrel bisulfate is converted to crystalline Form I of Clopidogrel bisulfate in ether. This process requires isolation of amorphous form which is chemically unstable and require special isolation techniques such as spray drying or lyophilization.
WO2004020443 (herein after referred as '443 patent) discloses process to produce hydrogen sulphate salt of Clopidogrel Form I using suitable solvent selected from the series of Ci-C5 alcohols or their esters with C1-C4 acids, optionally mixture of alcohols and esters. As the Form I is thermodynamically unstable, the process may result in Clopidogrel bisulfate Form II or Form IV or their mixture with Clopidogrel bisulfate Form I.
WO 2004/048385 discloses process for the preparation of crystalline Form I of S-Clopidogrel bisulfate by reacting the optically active base, (S)-(+) Clopidogrel dissolved in C1-3 aliphatic alcohol with concentrated sulfuric acid, wherein the salt formed in the reaction medium is precipitated with the precipitating solvent such as aliphatic or cyclic ethers and/or their mixture or isobutyl methyl ketone.
WO2007017886 discloses process for preparation of (S)-(+) Clopidogrel bisulfate Form I by dissolving/suspending the (S)-(+) Clopidogrel bisulfate Form II in C1-C3 alcohols and precipitating Form I of Clopidogrel bisulfate using acetate esters of C, to C4 alcohols.
A polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish different polymorphic forms. A particular polymorphic form may also give rise to distinct properties that may be detectable by powder X-ray diffraction, solid state 13C NMR
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spectrometry and infrared spectrometry.
Nucleation is the most critical step in the crystallization of individual polymorph. Nucleation is the process of formation of small nuclei in a supersaturated solution, which can act as a center of crystallization. The nucleation involves formation of cluster - a pre-nucleation molecular assemblies. The total free energy of a cluster is an algebraic sum of volume free energy and surface free energy, which favours aggregation of molecule and dissolution of molecular cluster. In the initial stage the surface free energy dominate over volume free energy and hence cluster has a tendency to dissolve. Super saturation provides driving force to overcome surface free energy and promotes crystal growth. As the cluster grows and attains a critical size at which the two forces balances each other and the cluster attains activation energy, which is the driving force for nucleation. After this stage the cluster becomes viable and grows into a crystal. Supersaturation is required to overcome the free energy barrier to nucleation.
When the two polymorphic forms have different stability then during crystallization different clusters compete for molecules. The free energy barrier will determine the concentration of each type of cluster. The polymorph, which crystallize will correspond to the cluster with lowest free energy barrier and hence exhibits higher growth rate. Although a stable polymorph may have greater thermodynamic drive to crystallize, the less stable polymorph may nucleate first due to its higher nucleation rate. The nature of the polymorph that crystallizes first is determined by the combination of the relative nucleation rate and the relative crystal growth rate of polymorph, which in turn depends on the degree of supersaturation.
In an attempt to prepare Form I of Clopidogrel bisulfate, it is observed that, Clopidogrel bisulfate Form II is formed more readily than Form I. The reason for this may be the cluster of Form II has lower free energy barrier and has higher growth rate, higher nucleation rate, hence crystallize out first.
Even though the process disclosed in WO2006/087729 ( PCT/IN05/00048) is capable of giving crystalline polymorphic Form I of Clopidogrel bisulfate, on carrying out the process for preparation of Clopidogrel bisulfate Form I disclosed in WO2006/087729 on
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commercial scale of greater than 2-50 kg, contamination of concomitant formation of irrepressible impurity of Clopidogrel bisulfate Form II in Form I, is sometimes observed. The process also involves formation of highly viscous gel. Formation of impure gel gives impure product, Clopidogrel bisulfate Form I which rapidly converts into Clopidogrel bisulfate Form II.
Thus this process when carried out in conventional reactor is not suitable for producing Clopidogrel bisulfate Form I consistently on industrial scale. Producing Clopidogrel bisulfate Form I with high chemical as well as polymorphic purity requires proper control of process parameters such as temperature, super saturation, stirring speed , pressure etc. as well as a suitable reactor design and stirrer design.
Since, Form-I of Clopidogrel bisulfate is kinetically controlled form and Form-II is thermodynamically controlled form, they require very specific reaction conditions for getting reproducible results. Also, a minor variation in condition may result in Form-II or a mixture of Form-I and Form-II instead of expected pure Clopidogrel bisulfate Form-I. Since, Form I of Clopidogrel bisulfate is used for pharmaceutical formulation, a rugged method which gives chemically and polymorphically pure Clopidogrel bisulfate Form I consistently on commercial level, is of importance.
Apart from the inconsistency, the process disclosed in WO2006/087729 also suffers from operational problems from commercial scale-up point of view such as during the Clopidogrel salt formation, the product results in sticky and lumpy mass which sticks to the stirrer and is difficult to disperse and due to the non-dispersibility of the sticky mass formed, fast/prolonged stirring was performed for dispersion of the sticky mass. This mass sticks unevenly between the shaft and blades of the reactor's impeller which leads to breaking of the shaft of the reactor and thus shutdown of the process. This process is not suitable for producing pure Clopidogrel bisulfate Form I on large scale. The production of pure Clopidogrel bisufate Form I, consistently on commercial scale and without any contamination of Form II is very difficult.
There exists the above problem which need to be investigated and thus preparation of Clopidogrel bisulfate Form I on commercial scale poses a challenge.
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Accordingly, there remains a need for commercially viable, industrially useful, highly efficient and reliable process and a suitable production facility for the manufacture of highly pure Clopidogrel bisulfate Form I on a scale of greater than 2-50 kg. The inventors of the present invention are successful in arriving at a rugged process in a specially designed reactor wherein the process has been performed at temperature near to ambient temperature for solving the inconsistency/operational problems involved in producing Clopidogrel bisullfate Form I in its pure state on commercial scale. The present invention thus provides an industrially useful and commercially viable process for preparing Clopidogrel bisulfate Form I in high yield and high purity which is carried out in specially designed reactor minimizing or eliminating the formation of impurities formed during the preparation process.
Object of the invention:
The main object of the present invention is to provide process for commercial production of Clopidogrel bisulfate Form I.
Another object of the present invention is to provide a process which is more convenient and industrially reproducible.
A further object is to provide specially designed reactor which has a simple construction and employed in production of Clopidogrel bisulfate Form I in a simple and commercially viable manner.
Summary of the invention:
The present invention discloses specially designed reactor, for commercial production of pure crystalline Clopidogrel bisulfate Form I in high yield, high purity and high productivity, thus making the process commercially viable.
The present invention further discloses process for preparation of Clopidogrel bisulfate Form I with desired chemical and polymorphic purity on a commercial scale which comprises the steps of;
d) converting (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base;
e) dissolving (S) Clopidogrel base in organic solvent to obtain the solution;
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f) mixing the obtained solution with second organic solvent;
g) contacting the obtained solution with acid dissolved in organic solvent; h) mixing the obtained solution with anti-solvent to get viscous gel;
i) decanting the supernatant solvent and washing the obtained gel with anti-solvent;
j) stirring the gel in anti-solvent for several hours in a specially designed reactor and
k) isolating the highly pure (S) Clopidogrel bisulfate Form I. In another aspect the present invention provides process for conversion of (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base in above step (a) which comprises;
a) mixing (S) Clopidogrel camphor sulfonate salt in organic solvent;
b) contacting the obtained solution with base;
c) isolating (S) Clopidogrel base.
Brief description of the figure:
Figure 1 is a sketch of the conventional high pressure reactor.
Figure 2 is a sketch of the specially designed reactor for production of Clopidogrel bisulfate Form I in accordance to this invention.
Figure 3 is sketch of the rotating impeller provided in the reactor according to the present invention.
Figure 4 is a diagrammatic illustration of the process steps for commercial production of Clopidogrel bisulfate Form I.
Figure 5 is an X-ray powder diffraction pattern of Clopidogrel bisulfate Form I in accordance to the present invention.
Detailed description of the invention:
The present invention describes an improved reactor system for carrying out the commercially viable process to prepare compound of formula (I), Clopidogrel bisulfate Form I in good yields, in an effort to reduce the impurities formed during the process, and to overcome the technical difficulties caused by standard/known/conventional reactor when used for preparing Clopidogrel bisulfate Form I.
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A conventional vertical high-pressure reactor (Fig. 1) comprises a stainless steel vessel (1) whose dished ends (3 and 4) are of torispherical dish type. Vessel (1) comprising a center-rotating shaft (6) on which is mounted an axial flow impeller made up of four blades (2), each with width 0.1 D, wherein 'D' is defined as diameter of the reactor . Each of the blades, are inclined downwards to the center line of the impeller at 45° , for agitating the highly viscous gel at 180 revolutions per minute. The width of impeller is 0.5 D The vessel also comprises 2 pair of baffles (8 and 9), equispaced parallel to the shell (5) of the reactor. The height of straight shell (5) is 1.30 times 'D'. The distance between the 2 set of blades of impeller is 0.5 D and the impeller is positioned in the torispherical bottom dish end (4) such that the space between the impeller and the inner wall of the bottom dish end is 0.26D. The torispherical top dish end (3) is provided with a manhole opening (10). The torispherical bottom dish end (4) is provided with a discharge (11) to remove the product from the reactor vessel. When the conventional reactor is employed for stirring highly viscous mass it is observed that the formed semisolid mass sticks unevenly between the shaft and blades due to which the shaft (6) looses balance and bends thereby resulting in ineffective stirring. Since the stirring is not so effective, solidification process is slow and gradual and fails to yield the pure solid.
On carrying out the process for preparation of Clopidogrel bisulfate Form I, as disclosed in WO2006/087729, on commercial scale of greater than 2-50 kg in a conventional reactor, contamination of Clopidogrel bisulfate Form II in Form I, is observed. The process also involves formation of highly viscous gel, which is very difficult to stir. This conventional reactor is improved in several respects in order to render possible, safe and consistent production of pure Clopidogrel bisulfate Form I therein. The present process performed in specially designed reactor in accordance with invention provides a solution to the existing problem in getting the desired product specifications, Clopidogrel bisulfate Form I, in high yield and purity without any detectable impurity of Clopidogrel bisulfate Form II and thus avoids the need for further processing or purification steps. The present invention provides an efficient and reliable process for the manufacture of Clopidogrel bisulfate Form I in high purity, on a commercial scale of greater than 2-50 kg, in a specially designed reactor.
The present invention thus provides chemically and polymorphically pure crystalline
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Clopidogrel bisulfate Form I by employing a specially designed reactor.
Specially designed reactor embodying the invention will now be described in detail with
reference to the accompanying drawings.
Referring to figure 2, cross-sectional view of the vertical high-pressure reactor vessel of the present invention comprises a high-pressure cylindrical stainless vessel (1) with top and bottom dish ends (3, 4) of ellipsoidal type of ratio 2:1. The cylindrical vessel (1) is provided with manhole (15), discharge (16) at the top and bottom dish ends, 3 and 4 respectively, rotating shaft (6) whose axis is coincidental with the longitudinal centerline of the cylindrical shell (5) of vessel (1). As shown in the drawing, the clockwise or anticlockwise rotating shaft (6) is mounted within a bearing mount assembly (7). An impeller (2) (Figure 3) is mounted on the rotating shaft (6).
Referring to Figure 3, the impeller (2) comprises blades (8, 9 and 10) for the purpose of providing intensive mixing or agitation. Each of the blades (8, 9 and 10) have flat plate
(12) stiffed adequately and welded perpendicularly to blades (8, 9 and 10). Blade (8) has a shape similar to the vertical inner wall shell (5) and bottom dish end (4) of the vessel (1) as shown in the figure 2. Blade (9) and (10) are transverse to the shell and perpendicular to the central axis of the reactor. The impeller (2) is positioned in the reactor such that minimum gap is maintained between the blade (8) and the inner wall (11) of the bottom dished end (4) to prevent the settling of the gel at the bottom of the reactor. The blades (8, 9 and 10) rotate and agitate the viscous gel at 20-24 revolutions per minute. The rotating shaft (6) is coupled to speed reduction gear box (13) having a ratio of 70:1. The gear box
(13) is coupled with TEFC (total enclosed fan cooled) Induction motor (14) having power 7.5-30 hp and rotating speed of 1400-1500 revolutions per minute connected to 3 phase electric power supply of 400-440 V 25-60 Hz.
An appreciation of the other aims and objectives of the present invention and understanding of it may be achieved by referring to the accompanying drawings and description of a preferred embodiment.
Preferred embodiment of the invention:
The specially designed reactor system according to the invention is a cylindrical high-
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pressure stainless steel vessel (1) having a capacity of 1000 liter- working volume. The reactor has an internal diameter 'D'. The top and bottom end of the reactor vessel (1) has ellipsoidal dish ends (3, 4) of 2:1 ratio. The height of straight shell (5) of the reactor is 1.45 times 'D'. The stainless steel vessel (1) is provided with manhole (15), discharge (16) at the top and bottom dish ends, 3 and 4 respectively, rotating shaft (6) whose axis is coincidental with the longitudinal centerline of the cylindrical shell (5) of vessel (1). The diameter of the rotating shaft is 0.165 D and length of the shaft is 3D. The impeller (2), having height of 1.0 D and width of 0.8D, is mounted on the rotating shaft (6).
The impeller (2) comprises blades (8, 9 and 10) for the purpose of providing intensive mixing or agitation. The blades (8, 9 and 10) in the impeller (2) have a width 0.1 D. The impeller (2) is positioned in the reactor such that minimum gap of 0.02D is maintained between the blade (8) and the inner wall (11) of the bottom dished end (4) to prevent the settling of the gel at the bottom of the reactor. The impeller (2) coupled to the rotating shaft (6) rotates at 24 revolutions per minute for continuous agitation of the viscous gel. The rotating drive system consists of 70:1 speed reduction gear box (13) coupled with TEFC (total enclosed fan cooled) Induction motor (14) connected to a 3 phase 440 V 50 Hz electric power supply.
According to the present invention, in specially designed reactor (Fig. 2) the rotating shaft (6) and impeller are constructed proportionally wider than the conventional reactor. The impeller of the present specially designed reactor is radial flow impeller having high shear compared to impeller of the conventional reactor alongwith improvement in several respects in order to render possible effective production of pure Clopidogrel bisulfate Form I which prevents sticking of the formed semisolid mass between the shaft and blades which provides continuous and uniform stirring of the semisolid mass and finally yields pure Clopidogrel bisulfate Form I without any detectable contamination of Form II. Thus the process of the conversion of (S) Clopidogrel base to pure (S) Clopidogrel bisulfate form I is advantageously performed in specially designed reactor in accordance with the present invention.
Process scheme for preparation of Form I of Clopidogrel bisulfate is represented by Figure 4.
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The present invention thus provides commercial production of Clopidogrel bisulfate Form I in high yield and high purity which is carried out in specially designed reactor wherein the load offered by the highly viscous gel, formed during the process is easily transformed and sustained.
According to the present invention, process for preparation of Clopidogrel bisulfate Form I with desired chemical and polymorphic purity comprises the steps of;
a) converting (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base;
b) dissolving (S) Clopidogrel base in organic solvent to obtain the solution;
c) mixing the obtained solution with second organic solvent;
d) contacting the obtained solution with acid dissolved in organic solvent;
e) mixing the obtained solution with anti-solvent to get viscous gel;
f) decanting the supernatant solvent and washing the obtained gel with anti-solvent;
g) stirring the gel in anti-solvent for several hours in a specially designed reactor and
h) isolating the highly pure (S) Clopidogrel bisulfate Form I.
The organic solvent used is selected from aprotic ethereal solvents such as diethyl ether, diisopropyl ether, methyl-tert- butyl ether, tetrahydrofuran (THF) and 1,4-dioxane or mixtures thereof, preferably di isopropyl ether.
The second organic solvent is selected from protic solvent. The protic solvent is selected from a group comprising C2-C5 aliphatic carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid preferably acetic acid.
The protic and aprotic solvent is used in the ratio of 1:3 to 3:1 preferably 3:1.
The dilution and mixing is carried out at low temperature range of 0°C to 15°C preferably at 5°C.
The acid is neat sulfuric acid of strength 80-98%, preferably 98%.
The anti-solvent is selected from diethyl ether (DEE), diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), tetrahydrofuran, 1,4-dioxane or mixtures thereof, more preferably DIPE. The total amount of anti-solvent used for complete precipitation of
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Clopidogrel bisulfate gel is 5 to 30 volumes with respect to (S) Clopidogrel base, more preferably 20 volumes.
According to another aspect of the present invention process for conversion of (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base in above step (a) comprises;
a) mixing (S) Clopidogrel camphor sulfonate salt in organic solvent;
b) contacting the obtained solution with base;
c) isolating (S) Clopidogrel base.
The organic solvent is selected from methylene dichloride (MDC), chloroform, ethylene dichloride (EDC), carbon tetrachloride, 1,1,1-trichloro ethane, 1,1,2 ethylenetrichloride or mixtures thereof, preferably MDC. The volume of organic solvent used for dilution of (S) Clopidogrel base is 1 to 5 parts per part of base, preferably 1 part.
The base for carrying out the above process step is selected from alkali metal or alkali earth metal bicarbonates. The preferred alkali metal bicarbonates used is sodium bicarbonates or potassium bicarbonates.
In order to avoid formation of unwanted (R) Clopidogrel base and hydrolysis of (S) Clopidogrel base, basification is preferably carried out under cold condition, preferably at temperature 0-20°C more preferably 0-5°C.
According to the invention, (S) Clopidogrel bisulfate Form I is isolated in pure form in high yield and free of any detectable quantity of undesired Clopidogrel bisulfate Form II.
According to the present invention, (S) Clopidogrel bisulfate Form I thus obtained contains less than 3% of (S) Clopidogrel bisulfate Form II, preferably less than 1% and more preferably 0.25%.
The process of the present invention provides consistent yield of 95-96 % and chemical purity of more than 98%, preferably more than 99% of Clopidogrel bisulfate Form I. The (S) Clopidogrel bisulfate Form I obtained by the process of the present invention has a mean particle size less than 600 microns.
The commercial preparation of Clopidogrel bisulfate Form I, in accordance with the
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present invention is described below in more detail.
(S) Clopidogrel camphor sulfonate salt is dissolved in organic solvent to obtain the solution. The solution is then cooled to 0-5°C and aqueous solution of saturated sodium bicarbonate is added slowly under stirring taking care that temperature of the solution should not exceed above 5°C and further stirred for few minutes. After vigorous stirring, the separated aqueous layer is extracted with organic solvent and the combined organic phase is washed with water. The solvent is evaporated under reduced pressure to yield the viscous gel of (S) Clopidogrel base.
The viscous gel of (S) Clopidogrel base as obtained is dissolved in organic solvent and cooled to 0°C to 15°C. This solution is further mixed with second organic solvent at temperature below 15°C. The obtained solution is cooled to temperature 0-10°C and sulphuric acid in organic solvent is added dropwise at the same temperature. After complete addition of sulphuric acid , the solution is stirred for 30 minutes followed by addition of anti-solvent maintaining the temperature at 0-30°C. A highly viscous gel of Clopidogrel bisulfate is obtained.
This highly viscous gel thus obtained is allowed to settle and the supernatant solution containing unreacted base and other impurities is decanted. The gel is further washed with fresh amount of solvent and again decanted to remove any traces of unreacted (S) Clopidogrel base and other impurities. A fresh anti-solvent is added to the resultant pure (S) Clopidogrel bisulfate gel and the obtained suspension is stirred for 24-36 hours in specially designed reactor to transform a highly viscous gel into chemically and polymorphically pure crystalline Clopidogrel bisulfate Form I. The solid thus obtained is further suspended in fresh organic solvent and stirred at room temperature for 1 hour. The separated solid is centrifuged and filtered to get the pure Clopidogrel bisulfate Form I, free from any detectable quantity of Clopidogrel bisulfate Form II.
The viscous gel must be free from impurities, therefore anti-solvent washings are given to the viscous gel for removing the impurities by decanting the anti-solvent and further stirred in a specially designed reactor alongwith anti-solvent in order to transform it to highly stable and pure Clopidogrel bisulfate Form I. The solidification is not possible if the stirring is not effective as in case of using the above mentioned conventional reactor.
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In case of conventional reactors which are used for commercial production of (S) Clopidogrel bisulfate Form I it is observed that the process results in semisolid mass which sticks unevenly between the shaft and blades of the reactor due to which the shaft bends. As a result there is no formation of solid and thus process is not suitable for commercial production of (S) Clopidogrel bisulfate polymorph. However in the specially designed reactor of the present invention, the shaft and blades are designed in such a way which effectively prevents sticking of semisolid mass between the shaft and the blades of the reactor, thus ensuring continuous stirring of the semisolid and conversion to solid Clopidogrel bisulfate Form I.
The quality of Clopidogrel bisulfate of Form I thus obtained in accordance with this invention is free from any detectable contamination of Form II, documented by the following measurements.
X-ray powder diffraction pattern has been obtained on Panalytical X'pert Pro diffractometer equipped with accelerator detector using Copper Ka (A, = 1.5406 ©) radiation with scanning range between 2-50 6 at scanning speed of 2°/min.
Clopidogrel bisulfate Form I prepared by the process of the present invention is characterized by XRPD peaks ( Fig. 5) as shown in table below.

Pos. d-spacing [A] Rel. Int.
[°2Th.] [%]
9.4262 9.38265 11.88
11.0893 7.97893 12.43
11.7699 7.51907 9.33
14.0638 6.29738 3.82
14.6035 6.06585 8.64
15.0735 5.87776 12.45
15.7472 5.62776 12.18
16.5486 5.35698 3.36
18.7140 4.74173 9.71
19.2062 4.62132 14.40
19.8851 4.46505 9.35
20.8035 4.26996 28.14
21.7919 4.07846 9.06
22.8115 3.89844 5.91
23.4121 3.79977 100.00
24.0646 3.69819 16.44
24.6396 3.61318 4.64
25.2914 3.52152 4.83

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25.7269 3.46289 31.82
26.8290 3.32309 9.21
27.6110 3.23073 6.65
28.1039 3.17517 3.49
28.7080 3.10972 7.86
29.1451 3.06407 14.71
30.9972 2.88508 11.88
31.5417 2.83651 3.37
33.1364 2.70356 5.81
34.1701 2.62410 3.03
35.0693 2.55885 2.13
35.7821 2.50949 3.21
36.3769 2.46982 3.24
37.2306 2.41512 3.27
37.7147 2.38523 2.14
41.3904 2.17970 2.09
Thus, the present invention has been described herein with reference to a particular embodiment for a particular application. Those having ordinary skill in the art and access to the present teachings will recognize additional modifications, applications and embodiments within the scope thereof.
The following examples are presented to illustrate the objects and advantages of the invention. It is not intended, however, that the invention should be limited to the specific embodiments presented therein.
Example 1
Preparation of (S) Clopidogrel camphor sulfonate salt.
125kg tetrahydrothienopyridine hydrochloride was reacted with 207.5 kg a-bromo-2-chlorophenyl acetic acid methyl ester in 1250 liter dimethylformamide (DMF) in presence of 207.5 kg potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 hrs. The reaction mixture was filtered at room temperature and the residue was washed with DMF. The solvent was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the product racemic Clopidogrel was extracted from the aqueous layer using methylene dichloride (MDC). The solvent was concentrated under vacuum at temperature 50-55°C to yield racemic Clopidogrel as viscous oil.. The oil was dissolved in 462.5 liter acetone.
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To this solution 87.5 kg. L-(-)-camphor sulfonic acid was added. 462.51iter methyl tertiary butyl ether was added to the resultant solution under stirring maintaining the temperature at 50-55°C for 2 hrs. The solution was cooled to 0-5°C and the same temperature was maintained for 30-40 min. The solid was centrifuged and washed with chilled acetone.
Example 2
Purification of (S) Clopidogrel camphor sulfonate salt.
Crude Clopidogrel camphor sulfonate salt obtained in example 1 was dissolved in 3927 liter acetone at temperature of 50-55°C. 3073 liter acetone was distilled out at temperature of 50-55°C and at atmospheric pressure. The solution thus obtained was cooled to temperature of 15-20°C, centrifuged and dried at 50-55°C under vacuum to obtain 110 kg pure (S) Clopidogrel camphor sulfonate salt.
Example 3
Preparation of (S) Clopidogrel Base.
60 Kg of the pure (S) Clopidogrel camphor sulfonate salt obtained from example 2 was dissolved in 240 liter of MDC and the obtained solution was cooled to 0-5°C. To this cold solution 240 liter aqueous solution of saturated sodium bicarbonate was added taking care that temperature of the solution does not rise above 5°C followed by stirring for 30 minutes. After vigorous stirring, the separated organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to yield 34 kg (S) Clopidogrel base.
Example 4
Conversion of (S) Clopidogrel base to Clopidogrel bisulfate form I from in specially
designed reactor
(S) Clopidogrel base as obtained from example 3 was dissolved in 35 liter diisopropyl ether (DIPE) and cooled to temperature of 15°C. To this solution 105 liter glacial acetic acid was added at temperature below 15°C. The obtained solution was cooled to temperature range of 0-10°C. To this resultant cooled clear solution 35 liter of di isopropyl ether (DIPE) containing 10.61 Kg concentrated sulphuric acid was added dropwise at the same temperature. After complete addition of acid, the solution was
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stirred for 30 minutes and further 627 liter diisopropyl ether was added by maintaining temperature 0-30°C broad range within 1 hour followed by stirring the reaction mixture at same temperature for 15 min.
A highly viscous gel was obtained which was allowed to settle and the supernatant solution was decanted. The gel was further washed with 200 liter DIPE. 697 liter fresh DIPE was added to the reactor (specially designed) containing viscous gel of Clopidogrel bisulfate and stirred the solution for 24-36 hours broad range. The solid thus obtained was further suspended in fresh 240 liter DIPE and stirred at room temperature for 1 hour. The separated solid was centrifuged, filtered the solid and dried under vacuum at temperature 50-55°C to get pure (S) Clopidogrel bisulfate Form I free from its Form II.
Yield :85-95%. Melting point = 184-186°C, [a]D20 = 55.6,
The invention thus being described, it will be apparent that it can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention. It is therefore intended by the appended claims to cover any and all such applications, modifications and embodiments within the scope of the present invention as would be apparent to one skilled in the art.
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We claim,
1. Specially designed reactor for commercial production of methyl (+)-(S)-a-(2-
chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate
(Clopidogrel bisulfate) Form I wherein the reactor comprises:
a) a high pressure cylindrical stainless steel vessel with top and bottom dish ends of ellipsoidal type and a rotating shaft whose axis is coincidental with the longitudinal centerline of the cylindrical shell of vessel;
b) an impeller comprising 3 sets of blades, mounted on the rotating shaft, and positioned in the reactor such that minimum gap is maintained between the blade and the inner wall of the bottom dish end of the reactor,
c) one set of blade having shape similar to the vertical inner wall of the shell and bottom dish end of the vessel and other two sets are placed transverse to the shell and perpendicular to the central axis of the reactor and each blade of the impeller having a flat plate stiffed adequately and welded perpendicularly to blades.
2. Commercial production of methyl (+)-(S)-a-(2-chlorophenyl)-6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate (Clopidogrel
bisulfate) Form I in specially designed reactor as claimed in claim 1 comprising
the steps of;
a) converting (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base;
b) dissolving (S) Clopidogrel base in organic solvent to obtain the solution;
c) mixing the obtained solution with second organic solvent;
d) contacting the obtained solution with acid dissolved in organic solvent;
e) mixing the obtained solution with anti-solvent to get viscous gel;
f) decanting the supernatant solvent and washing the obtained gel with anti-solvent;
g) stirring the gel in anti-solvent for several hours in a specially designed reactor and
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h) isolating the highly pure (S) Clopidogrel bisulfate Form I having chemical purity of more than 98%, preferably more than 99%.
3. The process as claimed in claim 1 wherein organic solvent is selected from diethyl ether, diisopropyl ether, methyl-tert- butyl ether, tetrahydrofuran and 1,4-dioxane or mixtures thereof.
4. The process as claimed in claim 1 wherein second organic solvent is selected from C2-C5 aliphatic carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid.
5. The process as claimed in claim 1 wherein acid is sulphuric acid of strength 80-98%.
6. The process as claimed in claim 1 wherein anti-solvent is selected from diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane or mixtures thereof.
7. The process as claimed in claim 1 wherein total amount of anti-solvent used is 5 to 30 volumes with respect to (S) Clopidogrel base.
8. The process as claimed in claimed in claim 1 wherein conversion of (S) Clopidogrel camphor sulfonate salt to (S) Clopidogrel base in step (a) comprises the steps of;

a) mixing (S) Clopidogrel camphor sulfonate salt in organic solvent;
b) contacting the obtained solution with base and
c) isolating (S) Clopidogrel base.

9. The process as claimed in claim 8, wherein organic solvent is selected from methylene dichloride, chloroform, ethylene dichloride, carbon tetrachloride, 1,1,1-trichloro ethane and 1,1,2 ethylenetrichloride or mixtures thereof.
10. The process as claimed in claim 8 wherein base used is sodium bicarbonates or potassium bicarbonate.
11. The process as claimed in claim 1 wherein (S) Clopidogrel bisulfate Form I has less than 3% of Form II, preferably less than 1% more preferably less than 0.25%.
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12. The process for commercial production of (S) methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate Form I in specially designed reactor as substantially described herein with respect to the foregoing examples 1 to £%

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Abstract
Disclosed herein commercial production of highly pure crystalline methyl (+)-(S)-oc-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (Clopidogrel bisulfate ) Form I formula (I) in specially designed reactor.