Claims:WE CLAIM:
1) A process for the preparation of [3,2-c] pyridine derivatives of formula I

Formula I
where X is H, halogen, Y is O or S, R1 is OCH3, OC2H5, methyl, Cyclopropyl and R2 is H, OCOCH3 or OCOC2H5.
comprising:
a. reacting a methyl 2-(2-halophenyl) acetate of [V]

[V]
with 4,5,6,7-tetrahydrothieno[3,2,c] pyridine of [VI]

VI
in the electrochemical condition comprising alkali metal halide, alkali metal chlorate and a organic solvent to form racemic [3,2-c] pyridine derivatives of formula I, wherein X, Y, R1 and R2 are same as defined earlier.
2. A process for the preparation of pharmaceutically acceptable salts of [3,2-c] pyridine derivatives of formula I represented by formula IV salt

IV salt
comprising:
a. reacting a methyl 2-(2-halophenyl) acetate of [V]

with 4,5,6,7-tetrahydrothieno[3,2,c] pyridine of [VI]

in the electrochemical condition comprising alkali metal halide, alkali metal chlorate and a solvent to form racemic [3,2-c] pyridine derivatives of formula I, wherein X, Y, R1 and R2 are same as defined earlier.
b. dissolving the compound obtained from step a in organic solvent followed by the addition of acid
c. wherein said acid containing mixture is maintained at temperature -10 to10°C
d. allowing said salt mixture to precipitate to yield the salt of racemic [3,2-c] pyridine derivatives [IVsalt].
4. A process for the preparation of clopidogrel of formula IIA

IIA
a. reacting a methyl 2-(2-chlorophenyl) acetate of formula

with 4,5,6,7-tetrahydrothieno[3,2,c] pyridine of formula

in the electrochemical condition comprising alkali metal halide, alkali metal chlorate and organic solvent to form racemic clopidogrel of [IIA]
4. A process for the preparation of racemic clopidogrel hydrogen sulphate [IVA]

IVA
comprising:
a. reacting a methyl 2-(2-chlorophenyl) acetate of formula

with 4,5,6,7-tetrahydrothieno[3,2,c] pyridine of formula

in the electrochemical condition to form racemic clopidogrel (IIA)b. dissolving the compound of [IIA] from step a in organic solvent followed by the addition of concentrated sulphuric acid
c. wherein said sulphuric acid containing mixture is maintained at a temperature -10 to 10°C
d. allowing said salt mixture to precipitate to yield the racemic clopidogrel hydrogen sulphate of [IVA].
5. Alkali metal halide as claimed in claims 1 and 4 is selected from the group comprising lithium iodide, sodium iodide, potassium iodide and the like preferably potassium iodide.
6. Alkali metal chlorate as claimed in claims 1 and 4 is selected from the group comprising lithium chlorate, sodium chlorate, potassium chlorate and the like preferably lithium chlorate.
7. Organic solvent as claimed in claims 1 and 4 is selected from the group comprising solvents suitable for electrochemical reaction preferably acetonitrile.
8. Acid as claimed in claim 2 is selected from group comprising sulphuric acid, hydrochloric acid, hydrobromic acid and the like which result in the formation of pharmaceutically acceptable salts of clopidogrel and other [3,2-c] pyridine derivatives.
Dated this 04th day of June, 2021

CHIRAG TANNA
of SEHGAL IPR SERVICES
APPLICANT’S PATENT AGENT

, Description:FIELD OF THE INVENTION:
A novel electrochemical process for the preparation of thieno [3,2-c]pyridine derivatives of general formula I has been developed followed by its conversion into pharmaceutically acceptable salts.

In particular, thieno[3,2-c]pyridines, generically used as antiplatelet agents of formula I and salts thereof along with its derivatives wherein X is H, halogen, Y is O or S, R1 is OCH3, OC2H5, methyl, Cyclopropyl and R2 may be H, OCOCH3 or OCOC2H5.
Present invention, more particularly relates to the preparation of thieno[3,2-c]pyridine derivatives of general formula I, wherein X is chlorine, Y is S and R1 is OCH3 group, R2 is H and salts thereof, generically known as Clopidogrel (IIA) followed by its conversion into bisulphate salt (IVA).
In particular, the process of the present invention provides a method which is most suitable for application on an industrial scale due to the more direct, high yield reaction and use of chemicals which are more environmentally friendly.

Process disclosed herein comprises an oxidative ?-amination of benzylic ester and its derivatives with secondary amine using simple C(+)/Cu(-) electrochemical conditions. The use of easily available benzylic ester and its derivatives for direct amination with amine to access thieno[3,2-c]pyridine and its derivatives in one-pot operation is the novel and inventive feature of the process disclosed herein. The present novel invention is a direct oxidative coupling reaction between amine and benzylic position of ester.
The present invention relates to a novel, cost effective and environmentally safe electrochemical process particularly for the preparation of thieno[3,2-c]pyridine and its derivatives. The present method is extended to the rapid access to the formation of thieno[3,2-c]pyridine and its salts comprising the novel concept green electrochemistry thereby making the process environment friendly as disclosed herein below.

BACKGROUND OF THE INVENTION:
Thieno[3,2-c] pyridine derivatives disclosed in FR2,215,948, FR 2,530,247 and FR 2,612,929 are pharmacologically active and have significant anti-aggregating and anti-thrombotic properties, one such example is Clopidogrel and its salt. Also some other derivatives of Thieno[3,2-c] pyridine is reflected as Prasugrel.
Various methods of preparing Clopidogrel are described in European Patent Nos. 0,281,459, 0,466,569, 0,971,915, 0,099,802, 1,021,449, 1,404,681 and 1,353,928 and international publication patent No. WO2004/094374. Among these methods, preferred in terms of commercially applicability methods which involve resolving a racemate composed of Clopidogrel of formula (I) or an intermediate thereof and its levorotatory isomer using an optical resolution agent.
Clopidogrel was disclosed in US4529596 as racemic form for the first time with its method of preparation. The pure enantiomeric forms of clopidogrel (dextro and levo isomers) were disclosed in EP 281459 which teaches the isolation of the dextro rotatory isomer of Clopidogrel by diasteriomeric salt formation of racemic Clopidogrel base using an optically active acid such as L-camphor-10-sulfonic acid. The enantiomer (S)-(+) Clopidogrel is particularly preferred since it is the pharmaceutically active compound. Recent studies have shown that Clopidogrel is more effective in blocking platelet aggregation than aspirin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than aspirin even at much lower dosage.
US5036156 discloses a process for preparing an intermediate, 2-chloro-a-bromophenylacetic acid, which is useful in the synthesis of clopidogrel.
Various methods for preparing clopidogrel are disclosed in US4847265, US5204469, US6080875, US6495691, US6573381, US6635763, US5132435, WO2005/104663 and WO2006/137628. US5132435 describes a process for the preparation of the (R) and (S) enantiomers of methyl a-(4,5,6,7-tetrahydro-5-thieno[3,2-c]-pyridyl (2-chlorophenyl-) acetate. For example when methyl l-chloro-(2-chlorophenyl) acetate is coupled with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine results to obtain a racemic methyl a-(4,5,6,7-tetrahydro-5-thieno[3,2-c]-pyridyl (2-chlorophenyl-) acetate in the presence of an acid acceptor, e.g. an alkali metal carbonate or bicarbonate, and optionally under phase transfer conditions to obtain the desired racemic clopidogrel base, which has been isolated as clopidogrel hydrochloride salt. The isolated racemic clopidogrel hydrochloride is further be resolved with camphor sulfonic acid in acetone.
US7629465B2 discloses an improved process for the preparation of clopidogrel. It also discloses the resolution of racemic clopidogrel and conversion to hydrogen sulphate salt of clopidogrel via crystalline Forms II and IV.
The process described in US5132435 requires the isolation of racemic clopidogrel hydrochloride salt (an additional step), resulting in longer reaction cycle time (more than 75 hours) and low yield (33%-39%).
Patents cited herein above disclose chemical routs of synthesis. The processes disclosed to synthesize such compounds involve multiple steps, and have other drawbacks due to the chemicals/reagents used, which usually are difficult to handle, scale-up and unfavourable for human health as well as environmental point of view. Various other synthetic approaches found in literature, involve expensive or hazardous chemicals, which do not significantly improve the yield of the desired product.
Consequently, the present invention aims to provide an inexpensive and commercially viable and eco-friendly process to prepare compounds of general formula (I) in good yields.
However,(Org. Biomol. Chem., 2018, 16, 8462-8466) discloses an electrochemical/ electrolytic method comprising electrochemical reductive amination between ?-keto-ester (which require additional steps to prepare to convert benzylic ester into keto ester) and secondary amine as depicted herein below:

Electrochemical reductive amination between a-keto ester and amine:

The said closest prior art comprises use of keto ester as a starting material with Zn/Ni electrochemical system and electrolyte and the reaction is an addition reaction and comprises reductive amination reaction. Further, ?-keto ester used as a starting material in the said closest prior art requires additional conversion of benzylic ester into the desired keto ester requiring harsh and eco unfriendly oxidative reaction steps. Zn/Ni electrochemical process of the prior art is not suitable for benzylic ester as a starting material and only keto ester is used as a starting material.
OBJECT AND SUMMARY OF THE INVENTION:
An aspect of the present invention is the preparation of thieno [3,2-c] pyridine derivatives of Formula I using electrochemical oxidative coupling of benzylic ester (V) with 4,5,6,7-tetrahydrothieno(3,2-c) pyridine (VI).
Yet another object of the present invention is to reduce time cycle as far as possible for large scale industrial preparation of thieno [3,2-c] pyridine derivatives of Formula I, where X is H, halogen, Y is O or S, R1 is OCH3, OC2H5, methyl, Cyclopropyl and R2 may be H, OCOCH3 or OCOC2H5.
Yet another aspect of the present invention is the preparation of clopidogrel (IIA) using electrochemical oxidative coupling of (2-Chloro-phenyl)-acetic acid methyl ester and 4,5,6,7-tetrahydrothieno(3,2-c) pyridine. It is a principal object of the present invention to improve upon limitations in the prior arts by providing an improved process comprising electrolysis for the preparation of thieno [3,2-c] pyridine derivatives preferably clopidogrel (IIA) and salts thereof wherein benzylic ester can be used as a starting material.
It is another object of the present invention to provide a commercially viable, economical and environment friendly process particularly for the preparation of clopidogrel hydrogen sulphate (IVA) comprising electrochemistry.
Another aspect of the present invention is the optical resolution of racemic clopidogrel prepared by the process of the present invention to get the dextro-rotatory isomer and laevorotatory isomer and salts thereof.
Another aspect of the present invention also relates to the preparation of pharmaceutically acceptable salts like hydrogen sulphate, camphor sulfonate salt, taurocholate, hydrobromide, hydrochloride, besylate and the like more particularly to the hydrogen sulphate (usually referred as bi sulphate).
The present invention provides a direct process for the preparation of thieno [3,2-c] pyridine derivatives and in particular racemic clopidogrel (IIA) and clopidogrel hydrogen sulphate (IVA) with its structural elucidation of the clopidogrel prepared by the process of present invention.
The foregoing present invention has outlined some of the more pertinent objects of the present invention. These objects should be construed as being merely illustrative of some of the more prominent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the invention.
Accordingly, other objects in a full understanding of the invention may be had by referring to the summary of the invention, the detailed description describing the preferred embodiment in addition to the scope of the invention defined by the claims taken in conjunction with the accompanying drawings.
SUMMARY OF THE INVENTION:
The reaction of benzylic esters (V) with 4,5,6,7-tetrahydrothieno(3,2-c) pyridine (VI) was carried out in the electrochemical condition. Here, an undivided cell containing V, VI, alkali metal halide particularly KI, and alkali metal chlorate particularly LiClO4 was electrolyzed using C(+) and Cu(-), as anode and cathode respectively, under constant current conditions (8 mA) under N2 atmosphere at room temperature to form racemic thieno [3,2-c] pyridine derivatives of formula (I) followed by its conversion into pharmaceutically acceptable salt.

where X is H, halogen, Y is O or S, R1 is OCH3, OC2H5, methyl, Cyclopropyl and R2 is H, OCOCH3 or OCOC2H5.
Optionally, the process for the preparation of dextro rotatory/ levo rotatory thieno [3,2-c] pyridine derivatives (I) comprising optical resolution of racemic thieno [3,2-c] pyridine derivatives obtained by the process of the present invention using the methods available in prior art.
The process for the preparation of racemic/ dextro rotatory/ laevo rotatory thieno [3,2-c] pyridine derivatives (I) /and its pharmaceutically acceptable salts:
a) dissolving the compound of [I] in organic solvent followed by the addition of an acid;
b) wherein said acid containing mixture is maintained at a temperature -10 to 10°C.
c) allowing said salt mixture to precipitate to yield the racemic/ dextro rotatory/ laevo rotatory salt of [3,2-c] pyridine derivatives of formula (I).
A specific embodiment of the present invention is described and shown in the detailed description. The present, invention relates to an improved novel process, environmentally friendly electrolytic process for the preparation of thieno [3,2-c] pyridine derivatives of formula (I) particularly racemic clopidogrel of formula (IIA), and it corresponding bisulphate salts (IVA) thereof.
This novel process comprises electrolytically prepared clopidogrel comprising an oxidative ?-amination of benzylic ester with amine using simple C(+)/Cu(-) electrochemical conditions.
The electrochemical reactions were performed under N2 at room temperature using IKA Electrosyn 2.0., using C(+) anode and Cu (-) cathode.
Optionally, the present invention provides a method to resolve racemic clopidogrel prepared by the process of the present invention.
Optionally, the present invention provides a method to convert the racemic clopidogrel to its corresponding bisulphate salt and opportunity to further resolve the material to optical isomers into their pharmaceutically acceptable salts.
DETAILED DESCRIPTION OF THE INVENTION
The following description is provided to enable any person skilled in the art to make and use the invention and sets forth the best modes contemplated by the inventor of carrying out his invention. Various modifications, however, will remain readily apparent to those skilled in the art, since the general principles of the present invention have been defined herein specifically to provide a novel and an improved process for the preparation of thieno [3,2-c] pyridine derivatives and salts thereof.
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention is more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention provides a process for the preparation of compounds of formula (I) and their salts as shown in scheme 1. Accordingly, the present invention provides a process to prepare compounds of formula (I), and their racemic salts.
In a general embodiment substituted benzylic ester(s) (V) reacts with 4,5,6,7-tetrahydrothieno(3,2-c) pyridine VI, as secondary amine under mild C(+)/Cu(-) electrochemical conditions. Here, an undivided cell containing benzylic ester V, 4,5,6,7-tetrahydrothieno(3,2-c) pyridine VI, alkali metal halide, and alkali metal chlorate in organic solvent was electrolyzed using C(+) and Cu(-), as anode and cathode respectively, under constant current conditions (8 mA) under N2 atmosphere at room temperature to form racemic thieno [3,2-c] pyridine derivatives (I) followed by its conversion into pharmaceutically acceptable salts as depicted herein below:
The present invention is illustrated in best possible manner as shown in general scheme 1 as shown herein below:

Scheme 1:

where X is H, halogen, Y is O or S, R1 is OCH3, OC2H5, methyl, Cyclopropyl and R2 may be H, OCOCH3 or OCOC2H5, A is anionic part of an acid.
Alkali metal halide is chosen from the group comprising halogen salts of alkali metals like Lithium, sodium, potassium and the like particularly potassium iodide.Alkali metal chlorate is chosen from the group comprising chlorate salts of alkali metals like Lithium, sodium, potassium and the like particularly lithium chlorate.
Solvent used therein is to be a suitable solvent that can be used during the electrolytic process particularly acetonitrile.
Wherein, all the electrochemical reactions were performed under N2 at room temperature using IKA Electrasyn 2.0. Cyclic Voltammetric (CV) experiments were performed using CH Instruments electrochemical Analyzer (Model CHI1200B).
In a specific embodiment of the invention the process comprises oxidative ?-amination of (2-Chloro-phenyl)-acetic acid methyl ester with 4,5,6,7-tetrahydrothieno(3,2-c) pyridine using simple C(+)/Cu(-) electrochemical conditions as illustrated in the example furnished herein. Here, an undivided cell containing of (2-Chloro-phenyl)-acetic acid methyl ester, 4,5,6,7-tetrahydrothieno(3,2-c) pyridine, potassium iodide, and Lithium chlorate and acetone as was electrolyzed using C(+) and Cu(-), as anode and cathode respectively, under constant current conditions (8 mA) under N2 atmosphere at room temperature to form racemic clopidogrel followed by its conversion into pharmaceutically acceptable salts as depicted herein below:
Specific embodiment of the present invention is illustrated in best possible manner as shown in Scheme below:

The Structure elucidation clopidogrel prepared the process of the present invention is further confirmed by Infrared spectroscopy, Mass spectra, Nuclear magnetic resonance (NMR) and CMR spectroscopy was recorded on 400 MHz-NMR Spectrometer (Bruker).
1H (as presented in figure I) and 13C NMR spectra (figure II) were recorded in CDCl3 and calibrated to the solvent resonance as internal standard (1H NMR, CDCl3 at 7.26 ppm, 13C NMR, CDCl3 at 77.0 ppm). High-resolution mass spectra were recorded on Agilent 6545 Q-TOF LC/MS (figure III), and IR spectra (figure IV).
Experimental Data for the structural elucidation for Clopidogrel (IIA) prepared by the process of the present invention comprising electrochemical oxidative coupling of benzyl ester(s) and secondary amine is furnished herein below. It has been characterized by spectroscopic technique like, NMR (PMR and CMR), IR
Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate (Clopidogrel) Purified from petroleum ether: EtOAc (8/2) as eluent); colorless liquid.
1H NMR (400 MHz, CDCl3) d7.74 – 7.71 (m, 1H), 7.45 – 7.42 (m, 1H), 7.35 – 7.27 (m, 2H), 7.08 (d, J = 5.1 Hz, 1H), 6.70 (d, J = 5.1 Hz, 1H), 4.95 (s, 1H), 3.81 – 3.76 (m, 1H), 3.75 (s, 3H), 3.66 (d, J = 14.3 Hz, 1H), 2.91 (s, 4H).
13C{1H} NMR (101 MHz, CDCl3): d 171.3, 134.7, 133.8, 133.3 (2C), 130.0, 129.8, 129.4, 127.1, 125.2, 122.7, 67.9, 52.1, 50.7, 48.3, 25.5. HRMS (ESI-TOF) m/z: [M + H+] calcd for C16H17ClNO2S 322.0663, found 322.0673.
MASS SPECTRA: Mass 322 (M+1) by mass spectra confirms clopidogrel.
IR: 2989, 1753, 1477, 1220, 1190, 1159, 1033, 839 cm-1.

Example 1: Miligram scale preparation of preparation of racemic clopidogrel (IIA).

To a 10 mL undivided cell was equipped with a graphite plate anode and a Copper plate cathode which was connected to a DC regulated power supply. To the cell were added, (2-Chloro-phenyl)-acetic acid methyl ester (100 mg, 0.54 mmol), 4,5,6,7-tetrahydrothieno(3,2-c) pyridine (188 mg, 1.35 mmol), KI (45 mg, 0.27 mmol), and LiClO4 (106 mg, 0.1 M) dissolved in 10 mL of CH3CN. The mixture was electrolyzed under constant current conditions (8 mA) under N2 atmosphere at room temperature while stirring. The reaction was monitoring by TLC. Electrodes were washed with ethyl acetate (10 mL), when the reaction was finished; the solvent was removed under reduced pressure. The residue was poured into a saturated aqueous Na2S2O3, and the product was then extracted with ethyl acetate (2 x 10 mL). The combined organic layer was separated, washed with brine, and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The pure racemic clopidogrel was obtained by column chromatography on silica gel (petroleum ether: EtOAc (9/1) as eluent). Purification with petroleum ether: EtOAc (8/2) as eluent); colorless liquid. 1H NMR (400 MHz, CDCl3) d7.74 – 7.71 (m, 1H), 7.45 – 7.42 (m, 1H), 7.35 – 7.27 (m, 2H), 7.08 (d, J = 5.1 Hz, 1H), 6.70 (d, J = 5.1 Hz, 1H), 4.95 (s, 1H), 3.81 – 3.76 (m, 1H), 3.75 (s, 3H), 3.66 (d, J = 14.3 Hz, 1H), 2.91 (s, 4H). 13C{1H} NMR (101 MHz, CDCl3) d 171.3, 134.7, 133.8, 133.3 (2C), 130.0, 129.8, 129.4, 127.1, 125.2, 122.7, 67.9, 52.1, 50.7, 48.3, 25.5. HRMS (ESI-TOF) m/z: [M + H+] calcd for C16H17ClNO2S 322.0663, found 322.0673.Example 2: Gram scale preparation of racemic clopidogrel (IIA).
A 100 mL three-neck round bottom flask (as undivided cell) was equipped with a graphite plate anode and a Copper plate cathode which was connected to a DC regulated power supply. To the cell were added methyl 2-(2-chlorophenyl) acetate (1 g, 5.4 mmol), 4,5,6,7-tetrahydrothieno(3,2-C) pyridine (1.8 g, 13.5 mmol), KI (0.45 g, 2.7 mmol), and LiClO4 (0.42 g, 0.1 M) dissolved in 40 mL of CH3CN. The mixture was electrolyzed under constant current conditions (8 mA) under N2 atmosphere at room temperature while stirring. The reaction was monitoring by TLC. Electrodes were washed with ethyl acetate (10 mL), when the reaction was finished; the solvent was removed under reduced pressure. The residue was poured into a saturated aqueous Na2S2O3 (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was separated, washed with brine and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel using petroleum ether: EtOAc (9/1) afforded pure racemic clopidogrel (II) (1.1 g, 64% yield).
Example 3: Preparation of racemic clopidogrel hydrogen sulphate.
Clopidogrel (IIA) base (1.1 g, 3.4 mmol) as obtained in example 2 was dissolved in acetone at room temperature. This mixture was cooled to 0°C and conc. sulphuric acid 0.34 g (98%, density=1.83) was added. The reaction mass was stirred for 10 hours at 0°C. The solid obtained was filtered under suction and washed with acetone and dried to afford the pure salt product (IVA). White solid; (1.3 g, 95% yield), purity: 99.36% (By HPLC). IR: 2989,1753,1477,1220,1190,1159,1033,839 cm-1
Example 4: Preparation (+) Clopidogrel camphor sulfonate salt
Clopidogrel (IIA) base (1.1 g, 3.4 mmol) as obtained in example 3 was dissolved in acetone 4 ml at room temperature. (-) Camphor sulfonic acid (0.79 g) added to above acetone solution and stir the reaction mass for 12 hours at ambient temperature. The solid obtained was filtered under suction and washed with acetone and dried to afford the pure camphor sulfonate salt as a White solid; (1.65 g, 87% yield), purity: 99.6% (By HPLC), SOR (5 % in Methanol at 25 °C):(+) 24°
Example 5: Preparation (+) Clopidogrel free base
Clopidogrel camphor sulfonate salt (1.65 g) as obtained in example 4 was charged in round bottom flask. Charge water (5 ml) and dichloromethane (5 ml). Stir the reaction mass for 30 minutes. Add slowly sodium carbonate (0.33 g) to reaction mass. Stir the reaction mass for 30 minutes and kept for settling of layers. Organic layer separated ad wash twice with water. Organic layer further distilled under reduced pressure gives pure (+) Clopidogrel free base as a light pale yellow semisolid; (0.94 g, 96% yield). SOR (5 % in Methanol at 25 °C): (+) 51°.
Example 6: Preparation (+) Clopidogrel Hydrogen Sulphate
(+) Clopidogrel free base (0.94 g,) as obtained in example 5 was dissolved in acetone at room temperature. This mixture was cooled to 0°C and conc. sulphuric acid 0.29 g (98%, density=1.83) was added. The reaction mass was stirred for 10 hours at 0°C. The solid obtained was filtered under suction and washed with acetone and dried to afford the pure salt product as a white to off white solid; (1.18 g, 96% yield), purity: 99.7% (By HPLC). IR: 2551, 1753, 1497, 1189, and 1029 cm-1. SOR (1 % in Methanol at 25 °C): (+) 56°. Chiral purity: 99.9 %
Example 8: Preparation (-) Clopidogrel camphor sulfonate salt
Clopidogrel (IIA) base (1.1 g, 3.4 mmol) as obtained in example 2 was dissolved in acetone 4 ml at room temperature. (+) Camphor sulfonic acid (0.79 g) added to above acetone solution and stir the reaction mass for 12 hours at ambient temperature. The solid obtained was filtered under suction and washed with acetone and dried to afford the pure camphor sulfonate salt as a White solid; (1.58 g, 83% yield), purity: 99.4% (By HPLC), SOR (5 % in Methanol at 25 °C):(-)23°
Example 9: Preparation (-) Clopidogrel free base
Clopidogrel camphor sulfonate salt (1.58 g) as obtained in example 8 was charged in round bottom flask. Charge water (5 ml) and dichloromethane (5 ml). Stir the reaction mass for 30 minutes. Add slowly sodium carbonate (0.33 g) to reaction mass. Stir the reaction mass for 30 minutes and kept for settling of layers. Organic layer separated ad wash twice with water. Organic layer further distilled under reduced pressure gives pure (-) Clopidogrel free base as a light pale yellow semisolid; (0.85 g, 91% yield). SOR (5 % in Methanol at 25 °C):(-) 50°.
Example 10: Preparation (-) Clopidogrel Hydrogen Sulphate
(+) Clopidogrel free base (0.85 g,) as obtained in example 9 was dissolved in acetone at room temperature. This mixture was cooled to 0°C and conc. sulphuric acid 0.26 g (98%, density=1.83) was added. The reaction mass was stirred for 10 hours at 0°C. The solid obtained was filtered under suction and washed with acetone and dried to afford the pure salt product as a white to off white solid; (1.06 g, 96% yield). purity: 99.7% (By HPLC). IR: 2551, 1753, 1497, 1189, and 1029 cm-1. SOR (1 % in Methanol at 25 °C): (-) 55°. Chiral purity : 99.8 %.