WO2014118802A1

WO2014118802A1 - An improved process for the preparation of clopidogrel bisulfate form-i

Info

Publication number: WO2014118802A1
Application number: PCT/IN2014/000051
Authority: WO
Inventors: Sridhar Pratha; Wolfgang Burger; Venkata Ramana PALLA; Suneel Kumar KAPUBALU
Original assignee: Pharmazell Gmbh
Priority date: 2013-01-31
Filing date: 2014-01-27
Publication date: 2014-08-07

Abstract

The present invention provides an improved process for the preparation of pure Clopidogrel bisulfate Form-I of formula (I), which comprises: reacting S(+)-methyl-2- [2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt (Formula III), which is on further treatment with C_1-5 carboxylic acid followed by sulphuric acid to get Clopidogrel Form-I.

Description

TITLE: "AN IMPROVED PROCESS FOR THE PREPARATION OF

CLOPIDOGREL BISULFATE FORM-I"

FIELD OF INVENTION:

The present invention provides an improved process for the preparation of Clopidogrel Bisulfate Form-I. The present invention also provides pure crystalline form of Clopidogrel bisulfate Form-I from S(+)-methyl-2-[2-(thiophen-2- yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride.

BACKGROUND OF INVENTION:

Clopidogrel is chemically known as methyl (+)-(S)-a-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. Clopidogrel is marketed as bisulfate salt and has the following structure of formula (I)

(I)

Clopidogrel bisulfate is useful in antiplatelet and atherosclerosis therapy as an anti- /thromobic and marketed under the brand name Plavix^®. Platelet inhibiting activity of Clopidogrel makes an effective drug for reducing the incidence of ischemic strokes, heart attack due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, Clopidogrel reduces the chances of arterial blockage, thus preventing strokes and heart attack.

U.S. Patent No. 4,529,596 discloses a racemic mixture of Clopidogrel and process for preparing such a mixture by the reaction of thienopyridine derivative with a chloro compound in solvents like dimethylformamide, alcohols and ethyl acetate in the presence of metal carbonates.

U.S. Patent No. 4,847,265 discloses the pure enantiomeric forms of Clopidogrel bisulfate (dextro and levo isomers). Further, US '265 discloses a process for the preparation of (S)-Clopidogrel bisulfate from racemic Clopidogrel by resolution with levorotatory camphorsulfonic acid.

U.S. Patent No. 6,429,210 claims the stable crystalline Form II of Clopidogrel bisulfate. Further, US '210 indicates that the process described in US 4,847,265 for the preparation of Clopidogrel bisulfate leads to crystalline form designated as Form- I.

U.S. Patent No. 7,291,735 discloses a process for the preparation of blood-platelet aggregation inhibiting agent, in particular Methyl-(+)-(S)-a-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-S-(4H)acetate bisulfate Form-1. It also reveals the preparation of pure (+)(S)-Clopidogrel from the racemic mixture of Clopidogrel base. The obtained (+)(S)-Clopidogrel is dissolved in ethyl acetate and treated with concentrated sulphuric acid followed by the seeding with Clopidogrel bisulfate Form- 1 to prepare (+) (S)- Clopidogrel bisulfate crystals.

U.S. Patent publication 2009/0247569 discloses a process for the preparation of Clopidogrel bisulphate Form-1 comprising, dissolving Clopidogrel base in an organic solvent like C6 ketone, C6-12 aromatic hydrocarbon to obtain the solution; and addition the sulfuric acid to the solution. It also reveals a novel process for the preparation of Form-1, comprises dissolving Clopidogrel base in MTBE (methyl-t-butyl-ether), cooling, adding formic acid or acetic acid to obtain a cooled solution; and adding the cooled solution to a mixture of sulfuric acid and MTBE (methyl-t-butyl-ether) at a temperature less than about 40°C.

PCT patent publication WO 2011/042804 discloses a process for the preparation of polymorphic Form I of Clopidogrel hydrogen sulphate comprising; dissolving Clopidogrel base in an organic solvent selected from ether, ester or mixture thereof; mixing the resulting solution with sulphuric acid and alcoholic solvent and isolating Clopidogrel hydrogen sulphate Form I.

PCT Patent publication WO 2011/055378 discloses a an one-pot process for the preparation of Clopidogrel bisulfate crystalline Form-I, from S(+)-methyl-2-[2- (thiophen-2-yl)ethylamino]-2-(2-chloropheny() acetate hydrochloride, without isolation of Clopidogrel base as shown below:

Sulphuric acid

S(+)-methyl 2-[2-(thiophen-2-yI) S(+)-Clopidogrel bisulfate Form-1 ethyIamino]-2-(2-chlorophenyI)

acetate hydrochloride

The processes disclosed in the above mentioned prior arts for the preparation of Clopidogrel bisulfate results one or more disadvantages such as the lower yields with impurity levels that exceed the currently prescribed guidelines established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), United States Pharmacopeial Convention (USP) and European Pharmacopeia (EP) and also the above mentioned prior art processes consuming long time for the crystallization of Clopidogrel bisulfate Form-I.

Hence, there is a need in art to develop a process that increases the yield of Clopidogrel bisulfate Form-I while minimizing the formation of impurity level that meets current ICH, USP & EP standards.

In an effort, the inventors of the present application developed a simple, cost effective and industrially feasible method for the preparation of pure Clopidogrel bisulfate Form-I with good yield, high polymorphic purity, which is free from the contamination of other forms preferably Form II and minimizing the formation of impurity levels. OBJECT OF INVENTION:

The main object of the present invention is to provide a simple and cost effective method to prepare pure Clopidogrel bisulfate Form-I with high yield and low level of impurities on a commercial scale.

SUMMARY OF THE INVENTION:

The present invention provides an improved process for the preparation of pure Clopidogrel bisulfate Form-I of formula (I), which comprises: reacting S(+)-methyl-2- [2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt (Formula III), which is on further treatment with Ci_-5 carboxylic acid followed by sulphuric acid to get Clopidogrel Form-I

In an another embodiment the present invention provides a one-pot process for the preparation of S (+)-Clopidogrel camphor sulfonate salt (III) without isolation of S (+)- Clopidogrel base.

In an another embodiment the present invention also provides a process for the preparation of Clopidogrel Form-I by treating S (+)-Clopidogrel camphor sulfonate salt (III) with C^s carboxylic acid followed by sulphuric acid.

DETAILED DESCRIPTION OF THE INVENTION:

More particularly, the present invention provides an improved process for the preparation of pure Clopidogrel Bisulfate Form-I from S(+)-methyl-2-[2-(thiophen-2- yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride.

The improved process for the preparation of pure Clopidogrel Bisulfate Form-I comprises steps of: i) Reacting S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2- chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde solution at the temperature about 50-55°C; ii) Cooling the reaction mass to a temperature about 5-10°C, and adding C1-4 alcohol, Ci_-5 carboxylic acid ester and then pH is adjusted to 7-8 by employing a base;

iii) Separate the organic and aqueous layers and then distilling the organic layer under reduce pressure and adding acetone and R-(-) Camphor sulphonic acid; iv) Cooling the reaction mass to 5-10°C and filter the solid, then making a slurry in acetone and cooling the reaction mass to 5-10°C then filtering to get pure S(+)-Clopidogrel camphor sulfonate salt (Formula III). v) Dissolving S(+)-Clopidogrel camphor sulfonate salt (Formula III) in aqueous base and C₁-5 carboxylic acid ester and adjusting the pH to 7-8 by employing the free base; vi) Separating the organic layer and treating with activated carbon. vii) Filtering the reaction mass and cooling to - 0 to 0°C and adding C_1-5 carboxylic acid followed by premixed solution of sulphuric acid and n-butyl acetate. Then seeding the reaction mass with pure S(+)- Clopidogrel bisulfate Form-I and viii) Filtering the precipitation and drying at 40-45°C to get pure Clopidogrel bisulfate Form-I.

The entire process for the preparation of Clopidogrel bisulfate Form-I, depicted in the below: scheme.

C1.5 carboxylic acid ester Inorganic base

C[.₅ carboxylic acid Sulphuric acid

Activated charcoal Seeding

(I)

S(+)-Clopidogrel bisulfate Form-1

In an embodiment of the present invention, the Ci-4 alcohol employed in step (ii) is selected from methanol, ethanol and more preferably methanol. Ci_-5 carboxylic acid ester is selected from group consisting of ethyl acetate n-butyl acetate more preferably n-butyl acetate. Base is selected from inorganic base, preferably alkali metal carbonates or bicarbonates more preferably sodium bicarbonate.

In one more embodiment of the present invention, Ci_-5 carboxylic acid is selected from acetic acid, Formic acid, propionic acid more preferably acetic acid.

EXAMPLES:

The following examples illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to limit the scope of the invention.

Example-I: Preparation of S(+)-methyl-2-[2-(thiophen-2-yl)ethyl amino]-2-(2- chlorophenyl) acetate hydrochloride To methyl (+)-(S)-a-amino (2-chlorophenyl) acetate tartrate (100.0 gm.) in water (200 mL) and toluene (300mL) was added aqueous ammonia and stirred at 0 to 5°C and the layers were separated. The separated organic layer was washed with water. The separated organic layer containing methyl (+)-a-amino (2-chlorophenyl) acetate was added (2-thienyl) ethyl-p-toluenesulphonic acid (129.2 gm.), K₂HP0₄ (99.5 gm.) and triethylbenzylammonium chloride (TEBAC) (4.0 gm.) then heated to 110 to 115°C for about 15-20 hrs. Then reaction mass was cooled to 25-30°C followed by the addition of water. The reaction mass was stirred and the layers were separated. To the organic layer methanol (25.0 mL) was added followed by 35% cone. HCI (28.0ml_). The solid obtained was filtered and washed with Toluene and dried under vacuum to yield S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride. (Yield: 69.3 gm.).

Example-ll: Preparation of Clopidogrel bisulfate Form-I

Reacting S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (200.0g)(Formula II) with 37% Formaldehyde solution(1600.0mL) at a temperature of 50-55°C for 3 hours and the reaction was cooled to 25-30°C. Methanol (200.0 mL) and n-butyl acetate (1200mL) were added to the reaction mass and then pH was adjusted to range of 7-8 by employing a free base. Separating the n-butyl acetate layer, followed by distillation, add acetone (681. OmL), treating with R- (-) Camphor sulphonic acid (147.8g) and maintained for 10-12 hours at 25-30°C to get S (+)-Clopidogrel camphor sulfonate salt (Formula III).

Making slurry of S(+)-Clopidogrel camphor sulfonate salt (300.0g) with acetone (1365. OmL) to remove impurities and dissolving S(+)-Clopidogrel camphor sulfonate(240.0g) in aqueous sodium bicarbonate(720.0mL) and n-butyl acetate(1440.0mL), Separating the n-butyl acetate layer, treating with activated charcoal. Cooling the n-butyl acetate layer, adding acetic acid (155.0mL) followed by premixed solution of sulphuric acid (47.23g) and n-butyl acetate (3 0. OmL). Further, seeding the reaction mass with (+)-Clopidogrel bisulfate Form-I. Filtering the precipitation and drying to get substantially pure Clopidogrel bisulfate Form-I. Dry Wt.:180.5g Yield: 75.95% HPLC Purity: 99,80%

Example-Ill: Preparation of Clopidogrel bisulfate Form-I

Reacting S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (200.0g)(Formula II) with 37% Formaldehyde solution(1600.0mL) at a temperature of 50-55°C for 3 hours and the and the reaction was cooled to 25-30°C. Methanol (200.0 mL) and n-butyl acetate (1200ml_) are added to the reaction mass and then pH was adjusted to range of 7-8 by employing a base. Separating the n- butyl acetate layer, followed by distillation, add acetone (681.OmL), treating with R-(-) Camphor sulphonic acid (147.8g) and then maintained for 10-12 hours at 25-30°C to get S (+)-Clopidogrel camphor sulfonate salt (Formula III).

Making slurry of S(+)-Clopidogrel camphor sulfonate salt (325. Og) with acetone (2048. OmL) to remove impurities and dissolving S(+)-Clopidogrel camphor sulfonate(240.0g) in aqueous sodium bicarbonate(720.0mL) and n-butyl acetate(1440.0mL), Separating the n-butyl acetate layer, treating with activated charcoal. Cooling the n-butyl acetate layer, adding acetic acid (155.0mL) followed by premixed solution of sulphuric acid (47.23g) and n-butyl acetate (310. OmL). Further, seeding the reaction mass with (+)-Clopidogrel bisulfate Form-I. Filtering the precipitation and drying to get substantially pure Clopidogrel bisulfate Form-I.

Dry Wt.:170.5g Yield: 73.80% HPLC Purity: 99.83%

Claims

CLAIMS:

1. An improved process for the preparation of Clopidogrel bisulfate Form-I of formula (J);

which comprises: i) reacting S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt (Formula III); ii) S (+)-Clopidogrel camphor sulfonate salt (Formula III) obtained in the above step is treated with Ci._s carboxylic acid followed by sulphuric acid to get pure Clopidogrel bisulfate Form-I of formula (I) characterised in that S (+)- Clopidogrel free base is not isolated in the process.

2. An improved process for the preparation of Clopidogrel bisulfate Form-I as claimed in claim 1 , comprises further steps:- a) reacting S(+)-methyl-2-[2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde solution at the temperature about 50-55°C;

b) cooling the reaction mass obtained in step (a) to a temperature about 5- 10°C, and adding C₁-4 alcohol, C₁-5 carboxylic acid ester;

c) pH of the reaction mixture is adjusted to 7-8 by employing a base;

d) separating the organic and aqueous layers and then distilling the organic layer under reduce pressure and adding acetone and R-(-) Camphor sulphonic acid;

e) cooling the reaction mass obtained in step (d) to 5-10°C and filter the solid, then making a slurry in acetone to get pure S(+)-Clopidogrel camphor sulfonate salt (Formula III); f) dissolving S(+)-Clopidogrel camphor sulfonate salt (Formula III) in aqueous base and C1.5 carboxylic acid ester and adjusting the pH to 7-8 by employing the free base;

gj separating the organic layer and treating with activated carbon;

h) filtering the reaction mass obtained in step (g)

i) and cooling to -10 to 0°C and adding C1.5 carboxylic acid followed by premixed solution of sulphuric acid and n-butyl acetate, then seeding the reaction mass with pure S(+)-Clopidogrel bisulfate Form-I and

j) filtering the precipitation and drying at 40-45X to get pure Clopidogrel bisulfate Form-I.

3. The process as claimed in claim 2, wherein C1-4 alcohol is selected from methanol, ethanol and more preferably methanol.

4. The process as claimed in claim 2, wherein C1.5 carboxylic acid ester is selected from group consisting of ethyl acetate n-butyl acetate more preferably n-butyl acetate.

5. The process as claimed in claim 2, wherein base is selected from inorganic base, preferably alkali metal carbonates or bicarbonates more preferably sodium bicarbonate.

6. The process as claimed in claim 2, wherein Ci-₅ carboxylic acid is selected from acetic acid, formic acid, propionic acid more preferably acetic acid.

7. The process as claimed in claim 2, the usage of acetone in step (e) is to control the impurities levels.