DESC:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of an intermediate of clopidogrel bisulphate, wherein the intermediate has a molecular formula as (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride. More particularly, the present invention relates an improved process for synthesis of the intermediate replacing the phosphate buffer with diisopropyl ethyl amine resulting in less number of impurities and higher yield.

BACKGROUND OF THE INVENTION

Methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1) (Clopidogrel bisulphate) is an anti-platelet and antithrombotic drug used in the treatment and prevention of peripheral vascular, cerebrovascular, and coronary artery diseases. Clopidogrel when used alone or in combination with Aspirin is known to reduce risks of cardiovascular mortality, nonfatal myocardial infraction and stroke in patients with a history of atherothrombotic diseases. It belongs to the thienopyridine class inhibitor of P2Y12-ADP platelet receptors. The anti-platelet function of the drug molecule leads to its extensive use as an anticoagulant in treatment of cardiovascular diseases and following the placement of a coronary artery stent (dual anti-platelet therapy). Clopidogrel is a prodrug which is activated in vivo in two steps with the aid of a cascade of cytochromes, first by CYP2C19, CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. The active metabolite then specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is an essential factor in activation of platelets and eventual cross-linking by the protein fibrin. The drug molecule irreversibly suppress hematoblastic gathering by optionally combining with platelet surface adenylate cyclase link coupled ADP receptor and can reduce thrombosis in the blood vessels. The intensity of action, tolerance height and reduced side effect of the drug accounts for its positive attributes in treatment of cardiovascular disorders substituting the traditional drugs like acetylsalicylic acid (Aspirin) and ticlopidine (Ticlopidine). Thus, clopidogrel has gained extensive attention over the last decade and the vast market prospect of the drug resulted in extensive attention of medical world towards the use of this drug molecule.

To meet the global demand of Clopidogrel as a bisulphate salt; methods of synthesizing the drug has been the key field of research for the pharmaceutical industry. Several methods of preparation of the drug and its intermediates have been proposed in order to obtain increased yield of the pure drug. Accordingly, there have been various efforts for the modification in the processes of Clopidogrel synthesis which involves a possible modification in the process of synthesis of it’s intermediate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride. Different methods related to the process of synthesis of the clopidogrel bisulphate and the intermediate have also been reported by different groups of researchers based on alteration of the reactants used in the process. Additionally, most of the processes despite being useful in pilot scale, but pose the problem of industrialization in terms of yield and purity of the product.

US5204469 relates to a process for the preparation of racemic methyl alpha-(4,5,6,7-tetra-hydro-5-thieno[3,2-c]pyridyl)(2-chlorophenyl)acetate and of its two enantiomers, whose dextrorotatory isomer is clopidogrel. The process according to the US patent consists of reacting a formylating agent with methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate wherein the later reactant is prepared from thienylethylamine.

US20070225320A1 relates to a process for the preparation of clopidogrel and intermediates thereof. In particular, it relates a process for the preparation of methyl a-amino-(2-chlorophenyl) acetate, an intermediate useful in the preparation of clopidogrel. The process disclosed in the US patent involves preparing clopidogrel or a salt thereof, comprising reacting racemic methyl alpha-amino-(2-chlorophenyl)acetate with L-(+)-tartaric acid, separating a formed tartaric acid salt of S-(+)-methyl alpha-amino-(2-chlorophenyl)acetate from a reaction mixture, and heating a reaction mixture to form racemic methyl alpha-amino-(2-chlorophenyl)acetate.

CN101333223B provides a method of preparation of clopidogrel and the salts of the same. The preparation method for clopidogrel comprises the following steps: a. synchronous resolution and racemization; b. preparation of (+) alpha-(2-thiophene trimethylamine-yl)-2-(2-chlorophenyl) methyl acetate; c. preparation of target product clopidogrel through cyclization reaction. The clopidogrel thus obtained can generate medicinal salt with acids in a solvent.

IN 1635/MUM/2010 discloses an improved process for the preparation of (S) clopidogrel or its pharmaceutical salt. Accordingly, the patent application discloses an improved process for the preparation of S-Clopidogrel which comprises coupling S-(+)methyl-amino(2-chlorophenyl) ethanoate (an intermediate (A)) with 2-(2-chloroethyl) thiophene (an intermediate (B)) in presence of solvent to obtain methyl(2-chlorophenyl){ [(2-thiophene-2-yl) ethyl]amino] ester and optionally converting to its hydrochloride salt; followed by cyclization with aqueous. formaldehyde to obtain Clopidogrel base and further converting the base to its bisulphate salt.

WO2014/118802Al provides an improved process for the preparation of pure Clopidogrel bisulfate Form-I , which comprises: reacting S(+)-methyl-2- [2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt , which on further treatment with C1 carboxylic acid followed by sulphuric acid yields Clopidogrel Form-I.

Although a large number of methods are available for the synthesis of (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride, an intermediate in the pathway of synthesis of clopidogrel bisilphate, most of the conventional synthesis methods exhibit poor yield during large scale production of the drug. Further, even if some of the processes exhibit improved yield, the processes suffers from the problem of executing multiple steps for arriving at the product and the usage of the harmful chemicals like potassium dihydrogen phosphate as one of the reagents that might result in the formation of undesired side products and large amount of impurities. This necessitates for an advanced process of synthesis of the intermediate molecule whereby the yield of the desired product is improved even upon using the process on industrial scale such that the process produces pure intermediates for subsequently synthesizing the pure drug. The present invention thus addresses such problems existing in the conventional processes of preparation of the desired molecule in an economic and scientific way.

OBJECTIVES OF THE INVENTION

An object of the present invention is to provide an improved process for the preparation of an intermediate of clopidogrel bisulphate, the intermediate being represented by the molecular formula as (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride.

Another objective of the present invention is to provide an improved process for the synthesis of an intermediate of clopidogrel bisulphate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride without using phosphate buffer, i.e., di-potassium hydrogen phosphate (DPHP) so as to avoid formation of unwanted impurities

Yet another objective of the present invention is to provide an improved process for the synthesis of an intermediate of clopidogrel bisulphate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride by introducing para-toluene sulphonic acid (p-TSA) salt so as to enable to isolate the desired isomer with enantiomeric purity not less than 99.8% irrespective of input chirality.

A preferred object of the present invention is to provide an improved process for the synthesis of an intermediate of clopidogrel bisulphate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride with less impurities and high yield.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of an intermediate of clopidogrel bisulphate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride starting from (S)- methyl 2-amino-2-(2-chlorophenyl)acetate tartrate. The reagents employed in the process do not include a phosphate buffer and consequently formation of large number of unwanted impurities is avoided. Further, the process provides high yield of the product with increased purity.

Thus, the present invention provides a process for preparation of (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride; wherein the process comprises the steps of:
(i) treating a compound of Formula I with a base in presence of a solvent to obtain a clear solution of a compound of Formula II and separating the compound of Formula II in an organic solvent;
Formula I, Formula II

(ii) reacting the compound of Formula II with 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate in presence of an organic base and a catalyst followed by addition of 4-methyl benzene sulfonic acid to obtain a compound of Formula IV;
Formula III, Formula IV

(iii) treating the compound of Formula IV with a base and a solvent to obtain (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride
.

BRIEF DESCRIPTION OF DRAWING

Figure 1 illustrates schematic representation of preparation of (S)-methyl 2-(2-(thiophen-2-yl) ethyl amino)-2-(2-chlorophenyl) acetate hydrochloride

DETAILED DESCRIPTION OF THE INVENTION
The term “clopidogrel” herein refers to clopidogrel or a pharmaceutically acceptable salt of clopidogrel. A preferable pharmaceutically acceptable salt of clopidogrel is bisulphate salt.

The present invention relates to a process for the preparation of an intermediate of clopidogrel bisulphate, the intermediate being represented by the molecular formula as (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride. The present invention advantageously provides an improved process for synthesis of the intermediate replacing the phosphate buffer with diisopropyl ethyl amine resulting in less number of impurities and higher yield..

The present invention provides a process for preparation of (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride; wherein the process comprises the steps of:
(i) treating a compound of Formula I with a base in presence of a solvent to obtain a clear solution of a compound of Formula II and separating the compound of Formula II in an organic solvent;
Formula I, Formula II

(ii) reacting the compound of Formula II with 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate in a solvent in presence of an organic base and a catalyst followed by addition of 4-methyl benzene sulfonic acid to obtain a compound of Formula III;
Formula III

(iii) treating the compound of Formula III with a base and a solvent to obtain (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride
.

After the reaction is completed, the reaction mass is subjected to usual work-up procedures such as washings, extractions etc. The present invention provides a process for the synthesis of an intermediate of clopidogrel bisulphate without using phosphate buffer, i.e., di-potassium hydrogen phosphate (DPHP) and instead uses di-isopropyl ethylamine (DIPEA), which results in very clean reaction with less number of impurities. Further, the reaction with para-toluene sulphonic acid (p-TSA) in step (ii) facilitates isolation of the desired isomer with enantiomeric purity not less than 99.8% irrespective of the chirality of the starting material.

In an embodiment, the base in steps (i) and (iii) in the process of preparation of the intermediate of clopidogrel bisulphate is liquor ammonia.

In an embodiment, the solvent in the process of preparation of the intermediate of clopidogrel bisulphate is selected from the group consisting of methylene dichloride, ethylene dichloride, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, n-hexane, aromatic hydrocarbon, or a combination thereof. Preferably, the organic solvent is methylene dichloride, isopropyl alcohol, and water. The preferable aromatic hydrocarbon is toluene.

In an embodiment, the organic base in step (ii) is selected from the group consisting of methylamine, dimethylamine, triethylamine, di-isopropylamine, N,N-di-isopropylethylamine, butyl amine, or a mixture thereof. Preferably, the organic base is N,N-di-isopropylethylamine (DIPEA).

In an embodiment, the catalyst is a phase transfer catalyst, wherein the phase transfer catalyst is tetrabutylammonium bromide.

In an embodiment, the reactions in the process of preparation of the intermediate of clopidogrel bisulphate are carried over a temperature ranging from 0 to 120°C. Further, the reaction in steps (i) and (iii) are preferably performed at temperature ranging from 0 to 5°C.

In another embodiment, the reaction in step (ii) involving addition of 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate to the compound of Formula II is followed by stirring at a temperature ranging from 95 to 110°C.

In an embodiment, the (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride obtained from the above disclosed is utilized as an intermediate for synthesis of clopidogrel bisulphate.

Some illustrative non-limiting examples of the present invention are described below.

EXAMPLES

Preparation of an intermediate of clopidogrel bisulphate, i.e., (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride (CP-1):

A mixture of water (320 lt), dichloro methane (100 lt) was cooled to 0-5 °C and liquor ammonia (500 lt) was added and stirred for 5 min at 0-5°C. (S)-methyl 2-amino-2-(2-chlorophenyl)acetate tartrate salt (500 kg) of chiral purity 98.85% was charged slowly and stirred for 15 minutes to get clear solution. Organic and aqueous layers were separated and extracted with dichloromethane (200 lt). Dichloromethane layer was washed with sodium chloride solution. The solvent from the dichloromethane layer was distilled off completely under reduced pressure. To the obtained residue was added tetra butyl ammonium bromide (25 kg) and diisopropyl ethyl amine (370 lt) followed by 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate (450 kg) at 25-30 °C and stirred for two hour at 100-105 °C. The reaction mixture was quenched with water (500 lt) and toluene (1500 lt), stirred for 10 minutes. The aqueous and organic layers were separated and extracted with toluene (1000 lt) and the organic layer was washed with water (2000 lt). 4-methyl benzene sulfonic acid (500 kg) and water (500 lt) were added for the formation of Tosylate salt at 50-55°C followed by keeping at room temperature for 1 hour. Wet cake of tosylte salt with chiral purity 99.80% was added to water (1500 lt) and toluene (2000 lt) for the formation of free base by using liquor ammonia(250 lt) and the organic layer was separated and dried with sodium sulphate and cooled to 0-5 °C, IPA.HCl (285 kg) was added slowly at below 10°C. The reaction mixture was initially heated to 60-65°C then cooled to 25-30°C followed by stirring at 0-5 °C for 2 hours. The solid was filtered and washed with toluene (250 lt) and then dried to get the title compound with chiral purity 99.97%.
Yield: 370 kg.

Process of preparation of 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate:
A mixture of water (4500 lt), sodium hydroxide flakes (1200 kg) was cooled to 10-15°C and thiophene 2-ethanol (1475 kg) was added and stirred for 5 min at 10-15°C. Tetra butyl ammonium chloride (75 kg) was charged and para toluene sulfonyl chloride (2430 kg) was added slowly over a period of 5 hours. The reaction mass was stirred for 2 hours and the temperature of the reaction mass was raised to 30-35°C. Toluene (5000 lt) was charged and stirred for 30 minutes. Organic and aqueous layers were separated and the organic layer was washed with water (2500 lt). The solvent from the toluene layer was distilled off completely under reduced pressure. The obtained residue was kept a side for further reaction.
Yield: 3200 kg.
,CLAIMS:1. A process for preparation of (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride; wherein the process comprises:
(i) treating a compound of Formula I with a base in presence of a solvent to obtain a clear solution of a compound of Formula II and separating the compound of Formula II in an organic solvent;
Formula I, Formula II

(ii) reacting the compound of Formula II with 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate in a solvent in presence of an organic base and a catalyst followed by addition of 4-methyl benzene sulfonic acid to obtain a compound of Formula III;
Formula III

(iii) treating the compound of Formula III with a base and a solvent to obtain (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride
.

2. The process as claimed in claim 1, wherein the base in steps (i) and (iii) is liquor ammonia.

3. The process as claimed in claim 1, wherein the organic base in step (ii) is selected from the group consisting of methylamine, dimethylamine, triethylamine, di-isopropylamine, N,N-di-isopropylethylamine, butyl amine, or a mixture thereof.

4. The process as claimed in claim 1, wherein the catalyst is a phase transfer catalyst; and wherein the phase transfer catalyst is tetrabutylammonium bromide.

5. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, dichloromethane, chloroform, methanol, ethanol, isopropyl alcohol, n-hexane, aromatic hydrocarbon, or a combination thereof.

6. The process as claimed in claim 1, wherein steps (i) and (iii) are performed at temperature ranging from 0 to 5°C.

7. The process as claimed in claim 1, wherein in step (ii) addition of 2-(thiophen-2-yl)ethyl 4-methylbenzenesulfonate to the compound of Formula II is followed by stirring at a temperature ranging from 95 to 110°C.

8. The process as claimed in claim 1, wherein (S)-methyl 2-(2-(thiophen-2-yl)ethyl amino)-2-(2-chlorophenyl)acetate hydrochloride is an intermediate for synthesis of clopidogrel bisulphate.