WO2006130852A1

WO2006130852A1 - Recovery of clopidogrel bisulfate

Info

Publication number: WO2006130852A1
Application number: PCT/US2006/021548
Authority: WO
Inventors: Eswaraiah Sajja; Raghupathi Reddy Anumula; Goverdhan Gilla; Muralidhar Reddy Nomula
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2005-06-02
Filing date: 2006-06-02
Publication date: 2006-12-07

Abstract

A process for preparing a racemic clopidogrel acid salt comprises reacting clopidogrel camphor sulfonic acid with an acid. The clopidogrel camphor sulfonic acid can be present in a residue from separating a clopidogrel camphor sulfonic acid optical isomer.

Description

RECOVERY OF CLOPIDOGREL BISULFATE

INTRODUCTION TO THE INVENTION

The present invention relates to a process for the recovery of (±)- clopidogrel bisulfate from the solution comprising (-)-clopidogrel camphor sulfonate or mixtures of (-)-and (+)-clopidogrel camphor sulfonate in various proportions.

Clopidogrel bisulfate is chemically known as methyl (+)-(S)-σ- (2- chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetate sulfate, and is represented by the structural Formula I.

Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of the binding of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP mediated activation of the glycoprotein GPIIb/llla complex.

The drug is currently being marketed in products sold as PLAVIX™ tablets containing about 98 mg clopidogrel bisulfate, which is the equivalent of 75 mg clopidogrel base. PLAVIX works by preventing platelets from sticking together to form clots that would restrict blood flow.

The enantiomer (+)-clopidogrel is particularly preferred since it is the pharmaceutically active compound.

Clopidogrel is disclosed in U.S. Patent Nos. 4,529,596, 6,258,961 , 5,036,156, 6,080,875, and 6,180,793 and in FR 2769313.

Processes for the preparation of clopidogrel and its intermediates have been disclosed in U.S. Patent Nos. 4,529,596, 5,036,156, International Application Publication Nos. WO 98/51681 , WO 98/51689, and WO 98/51681. U. S. Patent Application Publication No. 2005/0059696 A1 describes a multi-step process for the recovery of (±)-clopidogrel bisulfate. The process comprises conversion of (-)- or a mixture of (-)- and (±)-isomers of clopidogrel camphor sulfonate to (-)- or a mixture of (-)- and (±)-isomers of clopidogrel free base; converting the free base to (-) or mixture of (-)- and (±)-clopidogrel bisulfate; and hydrolysis with aqueous sodium hydroxide to give (±)-(2-chlorophenyl)-6,7- dihydro-4H-thieno [3,2-c] pyrid-5-yl) acetic acid. This (±)-acid intermediate was then converted to (±)-clopidogrel by methylation and then treated with sulfuric acid to form the (±)-clopidogrel bisulfate.

International Application Publication No. WO 02/059128 A2 provides a process for the recemization of an unwanted stereoisomer of clopidogrel amide intermediate, which can be used in the process for the preparation of (±)- clopidogrel.

The present invention provides an inexpensive and commercially viable process to recover (±)-clopidogrel bisulfate from the mother liquors generated during the resolution stage in the preparation of (+)-clopidogrel, thus increasing the effective yields of this clinically important active.

SUMMARY OF THE INVENTION

A process for converting clopidogrel camphor sulfonic acid to a clopidogrel acid salt comprises reacting clopidogrel camphor sulfonic acid with an acid.

A process for converting clopidogrel camphor sulfonic acid, comprising (-)- clopidogrel camphor sulfonic acid, (±)-clopidogrel camphor sulfonic acid, or a mixture of (-)-clopidogrel camphor sulfonic acid and (+)-clopidogrel camphor sulfonic acid, to a clopidogrel acid salt, comprises reacting with an acid.

Suitable acids for both of the above processes include inorganic acids.

A process for preparing (+)-clopidogrel comprises: reacting (±)-clopidogrel hydrogen sulfate with an optically active camphor sulfonic acid to form a racemic salt mixture; separating (+)-clopidogrel camphor sulfonic acid from a racemic salt mixture; converting (+)-clopidogrel camphor sulfonic acid to (+)-clopidogrel; and reacting a residue from separating (+)-clopidogrel camphor sulfonic acid from a racemic salt mixture with sulfuric acid, to form (±)-clopidogrel hydrogen sulfate.

The present invention, in an aspect, provides a process for the recovery of (±)-clopidogrel bisulfate of Formula Il from the solution comprising (-)-clopidogrel camphor sulfonate of Formula III or mixture of (-)-clopidogrel camphor sulfonate and (+)-clopidogrel camphor sulfonate of Formula IV in various proportions.

An embodiment of a process for the recovery of the (±)-clopidogrel bisulfate comprises: a) providing a solution comprising (-)-clopidogrel camphor sulfonate or a mixture of (-)-clopidogrel camphor sulfonate and (+)-clopidogrel camphor sulfonate in a various proportions, in a suitable solvent; b) reacting the solution with sulfuric acid; c) recovering the (±)-clopidogrel bisulfate of Formula II.

The process provides enhanced yields of the product through repetition of the cycle.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is a schematic representation of a process that includes the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the recovery of (±)-clopidogrel bisulfate of Formula Il from the solution comprising (-)-clopidogrel camphor sulfonate of Formula III or mixture of (-)-clopidogrel camphor sulfonate and (+)- clopidogrel camphor sulfonate of Formula IV in various proportions.

An embodiment of a process for the recovery of (±)-clopidogrel bisulfate comprises: a) providing a solution comprising (-)-clopidogrel camphor sulfonate of Formula III or mixture of (-)- and the (+)-clopidogrel camphor sulfonate in various proportions of Formula IV in suitable solvent; CSA . CSA

Formula IU Formula IV

b) reacting the solution with sulfuric acid to form (±)-clopidogrel bisulfate of Formula II; and

Formula Il c) recovering the (±)-clopidogrel bisulfate as solid.

The (±)-clopidogrel bisulfate of Formula Il recovered is converted to (±)- clopidogrel free base by reacting with a suitable base in a suitable solvent, which is then converted to the (+)-clopidogrel bisulfate.

Step a) involves providing a solution comprising (-)-clopidogrel camphor sulfonate of Formula III or a mixture of (-)-and (+)-clopidogrel camphor sulfonate in various proportions of Formula IV in a suitable solvent.

The solution may be prepared by dissolving (-)-clopidogrel camphor sulfonate of Formula III or a mixture of (-)- and the (+)-clopidogrel camphor sulfonates in various proportions, in a suitable solvent; or it may be obtained during the resolution of (±)-clopidogrel using optically active camphor sulfonic acid (CSA). During the resolution process of (±)-clopidogrel hydrogen sulfate using optically active camphor sulfonic acid, (÷)-clopidogrel camphor sulfonate crystallizes out of the solution, leaving (-)-clopidogrel camphor sulfonate in the mother liquor.

The mother liquor obtained from the resolution process is typically concentrated to a suitable volume to get optimum yield and purity. Concentration of the mother liquor can be carried out suitably using evaporation, atmospheric distillation, or distillation under vacuum. Suitable techniques that can be used for the distillation include distillation using a rotational evaporator device such as a Buchi Rotovapor, and the like. Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20 ⁰C to about 70 ⁰C. Any temperature and vacuum conditions can be used as long as the impurity levels of the product remain at acceptable levels.

These techniques are applicable to both aqueous and organic solutions of clopidogrel camphor sulfonate. However, solutions using the more volatile organic solvents are preferred.

Concentration of the solution can be carried out to an extent where the reaction mass volume reaches about 50% or 20% of the initial volume. Usually, concentration will be stopped when the volume of the concentrate is less than about 50% of the initial volume.

Optionally, the concentrated mother liquor may be diluted by adding another suitable solvent. Suitable solvents that can be used include, but are not limited to solvents such as alcohols, ketones, esters hydrocarbons and the like. Examples include alcohol such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; hydrocarbons such as n-hexane.n-heptane, cyclohexane, toluene, xylene and the like or mixtures thereof.

Step b) involves reacting the solution of step a) with sulfuric acid;

The use of a strong acid like sulfuric acid helps in racemization of the (-)- clopidogrel camphor sulfonate of Formula III or mixture of (-)- and (+)-clopidogrel camphor sulfonate in various proportions of Formula IV, to (±)-clopidogrel bisulfate of Formula Il in a single stage.

Inorganic acids such as phosphorous acid, phosphoric acid, nitric acid, hydrochloric acid, hydrobromic acid and the like can be used in the process of present invention instead of sulfuric acid to obtain the corresponding clopidogrel acid addition salt.

The mole ratio of the inorganic acid used to clopidogrel camphor sulfonate can range from about 0.1 to 3. The concentration of acid used can range from about 50 to 100% by weight.

The acid is added to the concentrated solution at temperatures ranging from about 0 ⁰C to 50 °C, or 20 ⁰C to 25 °C. The addition step is exothermic and is carried out slowly enough so that the temperature of the mass does not exceed 50 °C.

Suitable temperatures for the maintenance of the mass are below 50 °C. The mass will frequently be maintained at this temperature for not less than about 2 hours, or not less than about 4 hours.

Step c) involves isolation of the (±)-clopidogrel bisulfate of Formula II.

Optionally, seeding crystals of (±)-clopidogrel bisulfate may be added to the reaction mixture. The amount of seed crystals used may range from about 1 to 20 weight %, or about 5-weight %. Seeding crystals may be added before or, where appropriate, after the step initiating the precipitation, e.g., cooling. The present invention encompasses both embodiments where the precipitation is induced, or when the precipitation of the product occurs spontaneously.

The solid isolation can be conducted by conventional techniques such as filtering, decanting, centrifuging and the like, or by filtering under an inert atmosphere using gases such as for example nitrogen and the like.

The isolated solid may be further purified by recrystallization or slurrying, or a combination thereof, in a suitable solvent.

The recrystallization or slurrying can be done using the wet compound obtained after isolation, or the compound may be used after drying at a suitable temperature.

Suitable solvents which can be used for recrystallization or slurrying include, but are not limited to: halogenated solvents such as dichloromethane, ethylene dichloride and the like; alcohols such as methanol, ethanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; hydrocarbons such as toluene and the like; or mixtures thereof or their combination with water in various proportions without limitation.

The (±)-clopidogrel bisulfate thus obtained is converted to (±)-clopidogrel free base by reacting with a suitable base in a suitable solvent, which can then be converted to (+)-clopidogrel bisulfate using known methods such as the process described in U.S. Patent Application Publication No. 2005/0059696 A1.

The (±)-clopidogrel is reacted with an optically active camphor sulfonic acid and (+)-clopidogrel camphor sulfonate is separated. This is then converted to (+)- clopidogrel free base by reacting with a suitable base. The free base is then reacted with sulfuric acid in a suitable solvent to yield (+)-clopidogrel bisulfate.

In practice, mother liquors obtained from different batches of the resolution of (±)-clopidogrel bisulfate using an optically pure camphor sulfonic acid can be combined, or each batch is taken individually and treated to recover the product.

The present invention allows for repeated regeneration of (±)-clopidogrel bisulfate from the mother liquors, wherein (±)-clopidogrel bisulfate is continuously or periodically recovered from recycling of the mother liquor. This repeated regeneration process allows for an efficient process on an industrial scale.

Fig. 1 depicts an embodiment of the present invention, wherein (+)- clopidogrel bisulfate is reacted with an optically pure camphor sulfonic acid, (+)- clopidogrel camphor sulfonate is separated from the resulting mixture of optical isomers, and the residue is reacted with sulfuric acid to form (±)-clopidogrel bisulfate that can subsequently be reacted with an optically pure camphor sulfonic acid. The (+)-clopidogrel camphor sulfonate is reacted with a base to form clopidogrel free base, which is reacted with sulfuric acid to form a desired (+)- clopidogrel bisulfate product. Economic efficiency of the process is enhanced by the recycling of undesired clopidogrel camphor sulfonic acid salts to form a starting racemic clopidogrel bisulfate.

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are not intended to limit the scope of the invention as defined by the appended claims, in any manner.

REFERENCE EXAMPLE

PREPARATION OF (+)-CLOPIDOGREL CAMPHOR SULFONATE (FORMULA V):

200 g of (±)-clopidogrel bisulfate was taken into a round bottom flask and 800 ml of dichloromethane was added to it. The reaction mass was cooled to 4 °C, and the pH of the reaction mass was adjusted to 7.9 with a solution of 62.5 g of sodium carbonate in 514 ml of water. The reaction mass was stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with 400 ml of dichloromethane in two equal lots. The combined organic layer was washed with 350 ml of water in two equal lots. The organic layer was then concentrated under vacuum at a temperature of 45 ⁰C. The residue was then cooled to 30 ⁰C. 800 ml of acetone was added to the residue and stirred for clear dissolution. 7 ml of water and 115 g of camphor sulfonic acid was added to the above reaction mass, and stirred for 45 minutes. 75 mg of (+)-clopidogrel camphor sufonate was added as a seed compound. The reaction mass was stirred for 16 hours at 30 °C. The separated solid was filtered and washed with 75 ml of acetone. The product was dried at 70 ⁰C to yield 81 g of the title compound (61.4%).

EXAMPLE 1

REGENERATION OF (±)-CLOPIDOGREL BISULPHATE FROM MOTHER LIQUORS.

1300 liters of the mother liquor (filtrate) obtained in the process similar to that described in the Reference Example after isolation of (+)-clopidogreI camphor sulfonate was taken into a reactor. The solvent was distilled under vacuum at 56 °C until a volume of the mother liquor of 775 liters was achieved. The reaction mass was then cooled to a temperature of 22 ⁰C. 30 liters of 98% sulfuric acid was slowly added to the above reaction mass at a temperature of 22 °C. The reaction mass was maintained at 25 ⁰C for 4 hours and 30 minutes. The reaction mass was then filtered and the solid was washed with 50 liters of acetone to yield the (±)-clopidogrel bisulfate. 140 kg of the wet compound was taken into another reactor and 650 liters of acetone was added to it. The reaction mass was heated to a temperature of 55 ⁰C and maintained for 1 hour 30 minutes. The reaction mass was then cooled to a temperature of 12 °C and maintained at 12 °C for one hour. The reaction mass was then centrifuged and the solid was washed with 50 liters of acetone. The solid was dried under atmospheric air for 60 minutes and then dried at 56 °C for 3 hours to yield 105 kg of the title compound. Purity by HPLC: 99.57%. EXAMPLE 2

PREPARATION OF (+)-CLOPIDOGREL CAMPHOR SULFONATE (FORMULA V):

1400 liters of dichloromethane was taken into a reactor and 350 kg of (±)- clopidogrel bisulfate was added to it. The reaction mass was cooled to 3 °C. A solution of 109 kg of sodium carbonate in 900 liters of water was prepared and added to the above reaction mass at 2 ⁰C. The reaction mass was maintained at 3 °C for 30 minutes. The pH of the reaction mass was checked (pH=7.53). The reaction mass was then allowed to settle for 30 minutes. The organic layer was separated and the aqueous layer was extracted with 700 liters of dichloromethane in two equal lots. The total organic layer was washed with 600 liters of demineralized water in two equal lots. The dichloromethane layer was distilled off under vacuum at 60 °C to distill off the solvent completely under a vacuum of 400 mm/Hg. 1470 liters of acetone was added to the residue, and the reaction mass was stirred for 15 minutes. 14 liters of water was added to the reactor and then 200 kg of L(-)-camphor sulfonic acid monohydrate was added to the reaction mass. The reaction mass was stirred for 45 minutes. 0.15 kg of (-)-clopidogrel camphor sulfonate was added as a seeding to the above reaction mass. The reaction mass was then maintained at 30 °C for 18 hours. The reaction mass was then centrifuged and the wet cake was washed with 130 liters of acetone. The wet compound was dried in an oven at 42 °C for 10 hours to yield 150 kg (64.9%) of the title compound. Chiral Purity by HPLC: 99.55. Specific Optical Rotation: +24.2°. (C=1.68 wt. %, methanol).

EXAMPLE 3

PURIFICATION OF (+)-CLOPIDOGREL CAMPHOR SULFONATE (FORMULA V)

1450 ml of acetone, 28 liters of demineralized water and 145 kg of (+)- clopidogrel camphor sulfonate obtained above were taken into a reactor and the reaction mass was heated to 55 °C for clear dissolution. The reaction mass was maintained at 55 ⁰C for 15 minutes. Then the reaction mass was cooled to 2 ⁰C and maintained for 30 minutes. The reaction mass was centrifuged and the solid was washed with 150 liters of acetone in two equal lots. The wet material was dried at 65 ⁰C for 5 hours 30 minutes to yield 112 g (77.2%) of the title compound. Chiral Purity by HPLC: 99.97%. Specific Optical Rotation: +24.8° (C=1.68 wt. %, methanol).

EXAMPLE 4

PREPARATION OF (+)-CLOPIDOGREL BISULFATE (FORMULA I)

350 liters of dichloromethane was taken into a reactor and 80 kg of (+)- clopidogrel camphor sulfonate obtained above was added to it. The reaction mass was cooled to 2 °C. A solution of 8 kg of sodium carbonate in 80 liters of water was added to the above reaction mass slowly at a temperature of 2 °C. The reaction mass was maintained at 3 °C for 30 minutes. The organic layer was separated and the aqueous layer was extracted with 240 liters of dichloromethane in two equal lots. The combined dichloromethane layer was washed with 240 liters of demineralized water in two equal lots. The dichloromethane layer was distilled under vacuum at 47 °C. The residue was then cooled to 32 °C. To the residue 90 liters of 2-butanol was added. The solvent was distilled off at 53 ⁰C under a vacuum of 620 mm Hg. Then traces of dichloromethane were removed using nitrogen purging for 30 minutes. The reaction mass was then cooled to 40 ⁰C. Then 800 liters of 2-butanol was added to the reaction mass and stirred for 15 minutes. 4.0 kg of activated charcoal was added to the reaction mass and stirred for 10 minutes. The reaction mass was then filtered through a leaf filter, online and cartridge filters into another reactor. The filter bed was washed with 100 liters of 2- butanol. The reaction mass was then cooled to about 24 °C. 7.3 liters of 98% sulfuric acid was added to the reaction mass slowly at 24 °C. The reaction mass was seeded with 450 grams of pure (+)-clopidogrel bisulfate and maintained for about 12 hours. The reaction mass was then cooled to about 23 °C and maintained for about 2 hours. The reaction mass was centrifuged, and the wet cake was washed with 80 liters of 2-butanol. Then the wet cake was washed with 40 liters of cyclohexane. The wet cake was dried in an oven at a temperature of 100 °C and a vacuum of 680 mm/Hg for about 22 hours to yield 34.7 kg (56.9%) of the title compound.

Purity by HPLC: 99.96.

Specific Optical Rotation: +56.2° (C=1.89 wt. %, methanol).

Claims

CLAIMS:

1. A process for converting clopidogrel camphor sulfonic acid to a clopidogrel acid salt, comprising reacting clopidogrel camphor sulfonic acid with an acid.

2. The process of claim 1 , wherein clopidogrel camphor sulfonic acid comprises (-)-clopidogrel camphor sulfonic acid, (±)-clopidogrel camphor sulfonic acid, or a mixture comprising (-)-clopidogrel camphor sulfonic acid and (+)- clopidogrel camphor sulfonic acid.

3. The process of claim 1 , wherein an acid comprises an inorganic acid.

4. The process of claim 1 , wherein an acid comprises sulfuric acid.

5. The process of claim 4, wherein a clopidogrel acid salt is (±)-clopidogrel hydrogen sulfate.

6. The process of claim 4, wherein a molar ratio of clopidogrel camphor sulfonic acid to sulfuric acid is about 0.1 to about 3.

7. The process of claim 4, wherein sulfuric acid has a concentration about 50 to about 100 percent by weight.

8. The process of claim 1 , wherein clopidogrel camphor sulfonic acid is present in a residue after separation from (+)-clopidogrel camphor sulfonic acid.

9. A process for converting clopidogrel camphor sulfonic acid, comprising (-)- clopidogrel camphor sulfonic acid, (±)-clopidogrel camphor sulfonic acid, or a mixture of (-)-clopidogrel camphor sulfonic acid and (+)-clopidogrel camphor sulfonic acid, to a clopidogrel acid salt, comprising reacting with an acid.

10. The process of claim 9, wherein clopidogrel camphor sulfonic acid is present in a residue after separation from (+)-clopidogrel camphor sulfonic acid.

11. The process of claim 9, wherein an acid comprises sulfuric acid.

12. The process of claim 11 , wherein a clopidogrel acid salt is (±)-clopidogrel hydrogen sulfate.

13. The process of claim 11 , wherein a molar ratio of clopidogrel camphor sulfonic acid to sulfuric acid is about 0.1 to about 3.

14. The process of claim 11 , wherein sulfuric acid has a concentration about 50 to about 100 percent by weight.

15. A process for preparing (+)-clopidogrel, comprising: reacting (±)-clopidogrel hydrogen sulfate with an optically active camphor sulfonic acid to form a racemic salt mixture; separating (+)-clopidogrel camphor sulfonic acid from a racemic salt mixture; converting (+)-clopidogrel camphor sulfonic acid to (+)-clopidogrel; and reacting a residue from separating (+)-clopidogrel camphor sulfonic acid from a racemic salt mixture with sulfuric acid, to form (±)-clopidogrel hydrogen sulfate.

16. The process of claim 15, wherein a molar ratio of clopidogrel camphor sulfonic acid to sulfuric acid is about 0.1 to about 3.

17. The process of claim 15, wherein sulfuric acid has a concentration about 50 to about 100 percent by weight.