WO2011012961A1

WO2011012961A1 - An improved process for the preparation of clopidogrel bisulfate

Info

Publication number: WO2011012961A1
Application number: PCT/IB2010/001800
Authority: WO
Inventors: Jagadeeshwar Rao; Harikrishna Nandam; Anjireddy Redamalla; Buchi Reddy Reguri
Original assignee: Orchid Chemicals and Pharmaceuticals Ltd
Current assignee: Orchid Pharma Ltd
Priority date: 2009-07-29
Filing date: 2010-07-23
Publication date: 2011-02-03
Anticipated expiration: 2012-01-29

Abstract

The present invention provides an improved process for the preparation of Clopidogrel of Formula (I) or its pharmaceutically acceptable salts, and its intermediate of Formula (II). Formula (I) Formula (II).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE

Field of the Invention

The present invention provides an improved process for the preparation of

Clopidogrel of formula (I) or its pharmaceutically actable salts and its intermediate of compound of formula (II). More particularly, the invention provides an improved process for the preparation of (+)-2-(2-chlorophenyl)-N- [2-(2-thienyl) ethyl)glycine of formula (II) or its pharmaceutically actable salts; a key intermediate in the preparation of clopidogrel bisulfate.

Background of the Invention

Clopidogrel is used to prevent heart attacks and strokes in persons with heart disease (recent heart attack, unstable angina), recent stroke, or blood circulation disease (peripheral vascular disease). It works by blocking certain blood cells called platelets and prevents them from forming harmful blood clots. This "anti-platelet" effect helps to keep blood flowing smoothly in your body. Clopidogrel is a pro-drug whose action may be related to adenosine diphosphate (ADP) receptor on platelet cell membranes. Clopidogrel is an oral antiplatelet agent (thienopyridine class); chemically known as (+)-(S)-methyl 2-(2-chloroρhenyl)-2-(6, 7-dihydrothieno [3,2- c]pyridin-5(4H)-yl)acetate. This drug is dextrorotatory isomer and is marketed as i

COWFIRMATION COPY its bisulfate salt (Clopidogrel bisulfate of formula (V)) under the brand name Plavix.

US 4,529,596 patent claims the racemic mixture of methyl α-(4,5,6,7- tetrahydro-thieno[3,2-c]-5-pyridyl)-O-chlorophenyl-acetate and discloses a process for the preparation of the same. US 4,847,265 patent specifically claims the bisulfate salt of dextrorotatory isomer of methyl α-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2- chlorophenyl)-acetate substantially separated from the levo-rotatory isomer. This patent discloses a process for the preparation of the same by forming the salt of the racemic compound with an optically active acid in a solvent

US 5,204,469 patent discloses dextrorotatory methyl-α-(2- thienylethylamino) (2-chlorophenyl) acetate hydrochloride. The patent discloses a process for the preparation of methyl-(+)-α-(2-thienylethylamino)(2- chlorophenyl)acetate by the reaction of methyl-(+)-α-amino(2- chlorophenyl)acetate with (2-thienyl)ethyl-para-toluenesulphonate in presence of a base and a solvent. The reaction time for the completion of the reaction is nearly 50 hours and hence is found to be time consuming.

WO 2007/144729 publication discloses the reaction between methyl (2α) amino-(2-chlorophenyl) acetate or its hydrochloride salt with 2-(2-thienyl) ethyl)-4-methylbenzenesulfonate using an organic base in the absence of an organic solvent to obtain an intermediate of formula II In our continued research we have identified a process for the preparation of Clopidogrel or its pharmaceutically acceptable salt; which is simple, efficient. Objective of the Invention

The main objective of the present invention is to provide a process for the preparation of compound of formula (II) or its pharmaceutically acceptable salt in higher yield and greater chemical purity.

Another objective of the present invention is to provide an improved process for the preparation of clopidogrel bisulfate of formula (V), which is easy to implement on commercial scale.

Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of Clopidogrel or its pharmaceutically acceptable salt comprising the steps of:

(i) reacting methyl (+)-α-amino(2-chlorophenyl)acetate of formula (III) or its inorganic acid addition salt

CK^_/OMe

with compound of formula (IV); wherein LG represents a leaving group

(IV)

in presence of a base and a catalyst to obtain a compound of formula (II) or its pharmaceutically acceptable salt;

(ii) cyclizing the compound of formula (II) or its pharmaceutically acceptable salt in presence of formaldehyde to obtain a compound of formula (I) and;

(I)

(iii) optionally isolating the compound of formula (I) and converting into its pharmaceutically acceptable salts; wherein the improvement consists of the use of catalyst in the step(i).

Detailed Description of the Invention

In an embodiment of the present invention, the compound of formula (III) is used either as free base or its inorganic acid addition salt selected from hydrochloride, hydrobromide and the like. In another embodiment of the present invention, the leaving group represnted by LG in compound of formula (IV) is selected from to^'syl (-OTs), mesyl (-OMs) and the like. In one embodiment of the present invention, the base used in step (i) is selected from inorganic base comprising Na₂CO₃, NaHCO₃, K₂CO₃, K₂HPO₄ and the like and organic bases selected from triethylamine, diethylamine, N,N- diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, or N,N- diisopropylethylamine, dimethylaminopyridine, diisopropylethylamine, Ν- methylmorpholine, Ν-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine, pyridine and the like.

In one more embodiment of the present invention, the catalyst used in step (i) is selected from quaternary ammonium salts comprising tetrabutylammonium acetate; tetrabutylammonium hydrogensulphate; tetraethylammonium bromide; methyltributylammonium chloride (MTBAC); tetrabutylammonium bromide (TBAB); tetrabutylammonium hydroxide (TBAH); benzyltrimethylammonium hydroxide (BTMAH); tetramethylammonium hydroxide (TMAH); tributylbenzylammonium chloride and the like. Crown ethers are also used as catalyst in the present invention. The use of catalyst like TBAB in the condensation reaction reduces the reaction time to less than 20 hr, more preferably less than 10 hr. The reported prior art process (Example 2 of US 5,204,469) involves about 40 to 50 hr for the completion of reaction, which is not viable for manufacturing. Surprisingly the use of catalyst reduces the reaction time and increases the productivity.

In another embodiment of the present invention, the step (i) is conducted in presence of a solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate, methanol, ethanol, isopropanol, n- propanol, n-butanol, iso-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ketone, toluene, acetonitrile, methylene dichloride, n-hexane and cyclohexane, tetrahydrofurane; dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether and the like or mixtures there of. In yet another embodiment of the present invention, the compound of formula (II) is preferably isolated in the form of pharmacetucally acceptable salt selected from its hydrochloride, hydrobromide and the like. Accordingly the compound of formula (II) is taken in an ester, halocarbon solvent, lower alcohol or mixture there of followed by addition of con HCl or HCl gas or HCl in solvent.

In another embodiment of the present invention the cyclization step (ii) is performed by any of the conventional process known in the prior art. For example the compound of formula (II) is cyclized in presence of aqueous formaldehyde. The pharmaceutically acceptable salts of clopidogrel are prepared by the conventional methods.

In yet another embodiment of the present invention, the starting materials used in the preparation of clopidogrel or its pharmaceutically acceptable salts are prepared as per the process known in the prior art. The methyl ester of 2-amino- 2-(2-chlorophenyl)acetate was resolved using tartaric acid to obtain methyl (+)- α-amino(2-chlorophenyl)acetate having optical purity greater than 99.5%, which was then neutralized with aqueous ammonia and converted to its hydrochloride in presence of methylene dichloride.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention Example 1:

Preparation of methyl-(+)-α-(2-thienylethyIamino)(2-chIorophenyl) acetate hydrochloride. To methyl (+)-(S)-α-amino(2-chlorophenyl)acetate hydrochloride (120 g) in water (200 mL) and toluene (500 mL) was added NaHCO₃ and stirred at 25 to 30⁰C and the layers were separated. To the organic layer was added water, stirred and the layers were separated. To the organic layer containing methyl (+)- α-amino(2-chlorophenyl)acetate was added (2-thienyl)ethyl-p-toluenesulphonate (180 gm); K₂HPO₄ (280 gm) and catalyst (10 g) and heated to 85 to 90⁰C for about 15 - 20 hrs. After completion of the reaction; toluene was distilled out completely and the reaction mass was cooled followed by the addition of ethyl acetate and DM water. The reaction mass was stirred and the layers were separated. To organic layer methanol (50 mL) was added followed by 53 gm of 35% Con. HCl. The solid obtained was filtered and washed with ethyl acetate and dried under vacuum to yield methyl-(+)-α-(2-thienylethylamino)(2- chlorophenyl)acetate hydrochloride. (Yield: 105 g).

COMPARISON TABLE

From this table it is evident that the use of catalyst significantly reduces the reaction time and increases the productivity. Reference Example:

Preparation of (+)-(S)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2- c]pyridin-5-yl)acetic acid methyl ester hydrogensulfate (clopidogrel bisulfate of formula (V)):

To an aqueous solution of formaldehyde (1 L) at 25 to 35°C was added methyl-(+)-(S)-α-(2-thienylethylamino)(2-chlorophenyl)acetate hydrochloride and stirred for the completion of the reaction. After completion of reaction, water and methylene dichloride were added to the reaction mass and the pH was adjusted to 7 to 8 using solid sodium bicarbonate solution, The layers were separated and methylene dichloride layer was distilled out completely under vacuum at to obtain methyl-(2α)-(2-chlorophenyl)(6,7-dihydrothieno[3,2- c]pyridine-5-(4H)-yl)acetate freebase as a residue. The residue obtained was dissolved in a mixture of acetone (500 mL) and methanol, cooled and added concentrated H₂SO₄ at 0 to 5⁰C. The temperature of the reaction mass was raised to 25 to 30⁰C, stirred and the solid was filtered and washed with cold acetone. To the wet solid was added methylene dichloride (500 mL); cooled to 20 to 25°C and added NaHCO₃ solution and stirred. The Organic layer was separated and washed with water and subjected to carbon treatment. The methylene dichloride was distilled out completely from the reaction mass to obtain a thick mass. The thick mass thus obtained was dissolved in methylisobutyl ketone (MIBK) (900 mL), cooled to 5 to 12°C. The reaction mass was optionally seeded with Clopidogrel bisulfate Form -I; followed by the addition of Cone. H₂SO₄ in methylisobutyl ketone (MIBK) at -5 to 0⁰C. The temperature of the reaction mass was raised slowly to 25 to 30⁰C, stirred and the solid was filtered. The solid was washed with methylisobutyl ketone (MIBK) and dried under vacuum to yield Clopidogrel bisulfate Form -I.

Claims

We claim:

1. An improved process for the preparation of compound of formula (II) and its pharmaceutically acceptable salts, which comprises the steps of:

(H)

a) reacting methyl (+)-α-amino (2-chlorophenyl)acetate of formula (III) or its inorganic acid addition salt

CK _/OMe

(III)

with compound of formula (IV)

(IV)

in presence of a base and a catalyst to obtain a compound of formula (II); and b) Optionally converting the compound of formula (II) into its pharmaceutically acceptable salts in the presence of solvent; wherein the improvement consists of use of catalyst in step a).

2. A process according to the claim I₅ wherein the base in step a) is selected from inorganic bases comprising Na₂CO₃, NaHCO₃, K₂CO₃, and K₂HPO₄ and organic bases selected from triethylamine, diethylamine, N,N-diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, or N₁N- diisopropylethylamine, dimethylaminopyridine, diisopropylethylamine, Ν- methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine, and pyridine.

3. A process according to the claim I₅ wherein the catalyst in step a) is selected from quaternary ammonium salts comprising tetrabutylammonium bromide

(TBAB); tetrabutylammonium acetate; tetrabutylammonium hydrogensulphate; tetraethylammonium bromide; methyltributylammonium chloride (MTBAC); tetrabutylammonium hydroxide (TBAH); benzyltrimethylammonium hydroxide (BTMAH); tetramethylammonium hydroxide (TMAH); tributylbenzylammonium chloride and crown ethers.

4. A process according to the claim 1, wherein the step a) is conducted in the presence of solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate, methanol, ethanol, isopropanol, n- propanol, n-butanol, iso-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ketone, toluene, acetonitrile, methylene dichloride, n- hexane and cyclohexane, tetrahydrofurane; dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether or mixtures there of; preferably toluene.

5. A process according to claim 1, wherein the reaction in step a) is carried out at a temperature in the range of 50⁰C to 100⁰C.

6. A process according to claim 1, wherein the time required form completion of step (a) reaction is less than 20 hours.

7. A process according to claim 1, wherein the solvent used in step b) is selected from mixture of alcohol and ester, halocarbon or mixtures there of ; preferably mixture of ethyl acetate and methanol

8. The process according claim I₅ further comprsing converting the compound of formula (II) or its pharmaceutically acceptable salt into compound of formula (I) to its pharmaceutically acceptable salts by in cyclizing the compound of formula (II) with formaldehyde.

9. An improved process for the preparation of compound of formula (II) and its hydrochloric acid salt, which comprises the steps of:

(II)

a) reacting methyl (+)-α-amino(2-chlorophenyl)acetate of formula (III)

CK ^OMe

(III)

with (2-thienyl)ethyl-p-toluenesulphonate compound of formula (IV)

(IV)

in presence of base and catalyst in toluene to obtain a compound of formula (II); and

b) optionally converting the compound of formula (II) into its hydrochloride salt in the presence of mixture of methanol and ethyl acetate.