WO2006042481A1

WO2006042481A1 - Method of obtaining clopidogrel

Info

Publication number: WO2006042481A1
Application number: PCT/CZ2005/000077
Authority: WO
Inventors: Josef Hajicek; Pavel Pihera; Hana Stepankova
Original assignee: Zentiva A.S.
Priority date: 2004-10-18
Filing date: 2005-10-17
Publication date: 2006-04-27
Also published as: CZ20041048A3; CZ295920B6

Abstract

Separation of the camphorsulfonic salts of the compounds of formula (I) and (II) by one or more crystallizations from a mixture of two solvents, both R(-)-10-camphorsulfonic acid and its salts with the compounds of formula (I) and (II) being well soluble in at least one of the components, the formula of which can be indicated as RaOH, wherein Ra is a straight or branched C1 to C5 alkyl. In the other components, camphorsulfonic acid and its salts are less soluble; however, they dissolve compounds of formula (I) and (II) very well.

Description

METHOD OF OBTAINING CLOPIDOGREL

Technical Field

The invention relates to a new method of preparation of known antithrombic agent, the S(+) isomer of (2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridme-5(4H)-acetic acid, known under the INN name clopidogrel.

Background Art

The S(+) isomer of (2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid of formula I

I,

known under the INN name clopidogrel, is an effective antithrombic agent, indicated especially for prevention of atherosclerotic events in patients after experienced infarction, apoplectic stroke or with the ischemic disease of lower limbs. It is, therefore, fundamental in preventing relapse of these diseases and it prevents fatal consequences of said diseases.

Procedures of preparation of clopidogrel (the compound of formula I) are described in a number of patents. We cite those that constitute the most pertinent prior art with respect to this invention.

In patent EP 99 802, a group of agents with antiaggregation effect was described, which includes also the compound of formula I. In the patent, optically active isomers of the compounds are also reported. Preparation of compounds of the type of clopidogrel (I) was, according to the patent, performed via reaction of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine with an alpha-chloro-derivative of an ester of alpha-(chlorophenyl)-acetic acid in the presence of a base. Further development reported in patent EP 281 459 showed that of the compounds described in the above-mentioned patent, hydrogen sulfate (the HSO₄ ^" anion) of the compound of formula I is the most advantageous. The salt was tested with respect to its antiaggregation effects and compared with some other salts.

EP 281 459 describes also a method of preparation of this salt. It consists in resolving the racemic mixture of the compound of formula I with the R isomer of formula II

The mixture of compounds I and II was converted to salts of R(-) camphorsulfonic acid in acetone and subsequently crystallized. Then, several recrystallizations were performed also from acetone until sufficiently pure camphorsulfonate of compound I was obtained.

US patent 6,737,411 describes an improved method of this resolution. It consists in preparation of camphorsulfonic acid in a mixture Of C₁ to C₁₂ hydrocarbons with a suitable co- solvent, which is selected from the group of dimethylformamide, butanol or acetone. In a preferable embodiment, camphorsulfonic acid is dissolved in dimethylformamide and added to a solution of a mixture of compounds I and II in toluene. No procedure of further recrystallization, leading to a pure salt of form I, is, however, discussed in the patent.

A number of methods that do not lead to a mixture of I and II can be applied only with problems because of instability of optical purity of the product. From this point of view, the method described in patent EP 1 021 449, wherein a reaction of 4,5,6,7-tetrahydro-thieno[3,2- c]pyridine with optically active methyl (R) alpha-alkylsulfonyloxy-alpha-(2-chlorphenyl)- acetate is applied, is interesting.

The present invention introduces a new solution to resolution of compound I from compound II via a selection of set of solvents, which will ensure the optimal ratio of solubilities of compounds I and II as such, of the diastereoisomeric salt of compound II and of the diastereoisomeric salt of compound I, which is recovered from the solution.

Disclosure of Invention

A method of resolving according to the invention consists in separation of camphorsulfonic salts of the compounds of formulae I and II via one or more crystallizations from a mixture of two solvents, both R(-)-10-camphorsulfonic acid and its salts with the compounds of formulae

I and II being well soluble in at least one of the components, the formula of which can be indicated as R_aOH, wherein R₃ is a straight or branched Ci to C₅ alkyl. hi the other components, camphorsulfonic acid and its salts are less soluble; however, they dissolve compounds of formulae I and II very well.

The solvent in which the compounds of formulae I and II are better soluble, is used in excess in ratios from 1 : 2 to 1 : 100, usually though more than 1 :4.

The actual method of resolving the mixture of the compounds of formulae I and II consists in dissolving camphorsulfonic acid or a mixture of its salts with the compounds of formulae I and

II in a small amount of a solvent of formula R_aOH, and combining the solution with a larger amount of the other components of the solvent, in which the compounds of formulae I and II can be dissolved. This significantly decreases solubility of the camphorsulfonic salts, which start to precipitate out of the solution. Preferably the solution can be further inoculated with several crystals of the respective camphorsulfonic salt or the temperature of the solution can be decreased to 5 to 10 ⁰C.

Other components of the solvent are selected so that they easily dissolve the compounds of formulae I and II. Esters, ethers or ketones have turned out as suitable solvents in case of these compounds (esters of substituted glycine). The total number of carbons in the molecule of these oxygen derivates ranges from 2 to 10, from 4 to 7 carbons turning out to be preferable.

The particularly advantageous mixtures generally include those which require as few recrystallizations as possible. With respect to yields, such method turns out as more preferable which allows to obtain, already in the first operation, a practically pure product, which can merely be refined.

Isopropyl or n-butyl acetates together with methanol or ethanol turn out to be the most preferable solvents from this point of view.

Another aspect of this invention includes the discovery of an appropriate method for obtaining the starting mixture of the compounds of formulae I and II. The method having proved as very advantageous starts from the compound of formula V

which is converted, via reaction with methanesulfonylchloride in a chlorinated solvent at a temperature lower than +25 ⁰C, more preferably at a temperature lower than +15 °C, in the presence of an inorganic or organic base, to the corresponding methanesulfonyl derivative of formula VI

which is then converted to a mixture of the compounds of formulae I and II via reaction with tetrahydrothienopyridine hydrochloride in an organic solvent in the presence of an organic or inorganic base. This reaction is preferably performed in the two-phase arrangement in a system of a chlorinated solvent and an aqueous solution of an inorganic base, preferably of sodium or potassium carbonates. The reaction is performed at temperatures of 40 to 120 °C.

Another aspect of the invention includes another method for obtaining a mixture of the compounds of formulae I and II, which starts from the unwanted compound of formula II, or from a mixture of the compounds of formulae I and II enriched with compound II. The method uses the indicated reaction of potassium salts II -→ I₅ wherein the equilibrium constant of this reaction is equal to 1. The reaction proceeds preferably in an alcohol (C₁ to C₅), in water or in an aqueous alcoholic solution.

It is performed via dissolution or suspension of the compound of formula II or a mixture enriched with this compound in an alcohol, to which a solution of KOH is added and the mixture is heated to temperatures usually between 60 and 120 °C. The resulting mixture of potassium salts is crystallized either via evaporation or cooling, according to the choice of the solvent. The reaction runs to equilibrium degree of conversion usually in 2 to 20 hours.

Esterification is then performed with methyl iodide in solvents of the type of acetone, dimethylformamide, or in a heterogeneous system organics-water under action of a phase- transfer catalyst.

The invention is further illustrated in the following examples.

Examples

Example 1

Preparation of a mixture of the compounds of formulae I and II.

Preparation was performed according to the scheme

10 g (49.84 mmol) of the compound of formula V was dissolved in 50 ml of dichloromethane and 5.55 g (54.83 mmol) of triethylamine was added to the solution and the resulting solution was cooled down to +15 to +10 ⁰C in a water + ice bath. To the cooled solution methanesulfonylchloridej was slowly added drop by drop under stirring at such rate that temperature of reaction mixture does not exceed +15 ⁰C. After the addition the reaction mixture was stirred for another hour at temperatures +10 to + 15 °C. The reaction mixture was then extracted with 5 ml of IN HCl and the dichloromethane solution was added to a previously prepared mixture of 6.9 g K₂CO₃ (49.84 mmol) in 25 ml of water, 25 ml of dichloromethane and the compound of formula III. The resulting reaction mixture was refiuxed for 20.5 hours. After cooling down to room temperature, the aqueous layer was separated from the mixture. The organic fraction was extracted with 15 ml of IN HCl, dried with anhydrous magnesium sulfate, and the solvent was evaporated in a rotary vacuum evaporator. The resulting evaporation residue was dissolved in 50 ml of toluene and extracted with 2x10 ml of 4N HCl. The combined acidic extracts were alkalized with a 10% solution of NaHCO₃ and extracted with 2x30 ml of dichloromethane. The combined dichloromethane fractions were extracted with 10 ml of water and dried with anhydrous magnesium sulfate. After evaporation of the dichloromethane solution, clopidogrel (II) was obtained as a viscous honey-like evaporation residue (11.16 g; 69.6 % of theoretical).

Example 2

27.12 g (84.2 mmol) of the compound of formula II was dissolved in 100 ml of methyl tert- butyl ether (MTBE) at temperature 40 ⁰C. A solution of (R)-(-)-10~carnphorsulfonic acid, prepared via dissolving 10.2 g (43.8 mmol) of the acid in 28.4 ml of ethyl alcohol, was added to the solution. Another 120 ml of MTBE was added to the solution at +40 ⁰C. The solution was inoculated with compound (I) and after heating was removed camphorsulfonate began to crystallize. The mixture was stirred at room temperature and then in a water + ice bath for 3 hours. The crystalline product was sucked off and 23.57 g (50.5 % of theory) of clopidogrel camphorsulfonate was obtained; [a]_D= +0.22 °; MeOH.

Example 3

23.14 g of the product of Example 2 was dissolved in 28 ml of methyl alcohol under stirring at 60 °C and MTBE (230 ml) was added to the solution at the same temperature. The resulting solution was let to cool down gradually to room temperature and then cooled in a water + ice bath for 3 hours. The crystalline product was sucked off and 19.48 g of the product was obtained; [a]_D = +6.2 °; MeOH.

Example 4

19.36 g of the product of Example 3 was dissolved in 25 ml of methyl alcohol under stirring at 60 ⁰C and MTBE (170 ml) was added to the solution at the same temperature. The resulting solution was let to cool down gradually to room temperature and then cooled in a water + ice bath for 2 hours. The crystalline product was sucked off and 15.65 g of the product was obtained; [a]_D = +17.27 °; MeOH.

Example 5

14.43 g of the product of Example 4 was dissolved in 20 ml of methyl alcohol under stirring at 60 °C and MTBE (130 ml) was added to the solution at the same temperature. The resulting solution was let to cool down gradually to room temperature and then stirred at room temperature for 2 hours. The crystalline product was sucked off and 13.55 g of the product was obtained; [a]_D= +24.20 °; MeOH.

Example 6 4.78 g (14.85 mmol) of the compound of formula II was dissolved in 47 ml of i-propyl acetate at room temperature. A solution of (R)-(-)-10-camphorsulfonic acid, prepared via dissolving 1.72 g (7.42 mmol) of the acid in 2.5 ml of methyl alcohol, was added to the solution. The solution was inoculated and stirred at room temperature and it gradually crystallized. Before sucking off, the mixture was in addition cooled down in a water + ice bath. After sucking off on sintered glass and washing with i-propyl acetate, 2.9 g (35.2 % of theory) of the product (I) was obtained; [a]_D = +22.65 °; MeOH.

Example 7

2.5 g of the product of Example 6 was dissolved in 2.5 ml of methyl alcohol at 60 °C and i-propyl acetate (25 ml) was added to the warm solution. The camphorsulfonate of the compound of formula I was let to crystallize at room temperature. 1.96 g of the product (I) (78.4 % of theory) was obtained; [a]_D = +24.70 °; MeOH. Example 8

4.40 g (13.67 mmol) of the compound of formula II was dissolved in 44 ml of n-butyl acetate at room temperature. A solution of (R)-(-)-10-camphorsulfonic acid, prepared via dissolving 1.6 g (6.83 mmol) of the acid in 2.5 ml of methyl alcohol, was added to the solution. The solution was inoculated and stirred at room temperature and it gradually crystallized. Before sucking off, the mixture was in addition cooled down in a water + ice bath. After sucking off on sintered glass and washing with n-butyl acetate, 2.0 g (26.4 % of theory) of the product (I) was obtained; [a]_D= +23.73 °; MeOH.

Example 9

1.8 g of the product of Example 8 was dissolved in 1.8 ml of methyl alcohol at 60 ⁰C and n-butyl acetate (18 ml) was added to the warm solution. The camphorsulfonate of the compound of formula I was let to crystallize at room temperature. 1.48 g of the product (I) (82.2 % of theory) was obtained; [a]_D = +24.50 °; MeOH.

Example 10

6.15 g (19.11 mmol) of the compound of formula II was dissolved in 62 ml of i-propyl acetate at room temperature. A solution of (R)-(-)-10-camphorsulfonic acid, prepared via dissolving 2.22 g (9.56 mmol) of the acid in 1.2 ml of ethyl alcohol, was added to the solution. The solution was inoculated and stirred at room temperature and it gradually crystallized. Before sucking off, the mixture was cooled down in a water + ice bath (4 hours). After sucking off on sintered glass and washing with i-propyl acetate, 4.77 g (45.08 % of theory) of the product (I) was obtained; [a]_D= +3.52 °; MeOH.

Example 11

4.64 g of the product of Example 10 was dissolved in 4.7 ml of ethyl alcohol at 70 ⁰C and i-propyl acetate (47 ml) was added to the warm solution. The camphorsulfonate of the compound of formula I was let to crystallize at room temperature and then it was cooled down in a water + ice bath. 2.97 g of the product (I) (64 % of theory) was obtained; [a]_D= +23.8 °; - MeOH. Example 12

5.15 g (16.00 mmol) of the compound of formula II was dissolved in 52 ml of n-butyl acetate at room temperature. A solution of (R)-(-)-10-camphorsulfonic acid, prepared via dissolving 1.85 g (8.00 mmol) of the acid in 1 ml of ethyl alcohol, was added to the solution. The solution was inoculated and stirred at room temperature and it gradually crystallized. Before sucking off, the mixture was cooled down in a water + ice bath. After sucking off on sintered glass and washing with n-butyl acetate, 3.45 g (38.9 % of theory) of the product (I) was obtained; [a]D = +17.68 °; MeOH.

Example 13

3.38 g of the product of Example 12 was dissolved in 3.4 ml of ethyl alcohol at 60 °C and n-butyl acetate (34 ml) was added to the warm solution. The camphorsulfonate of the compound of formula I was let to crystallize at room temperature and then it was cooled down in a water + ice bath. 2.95 g of the product (I) (87.27 % of theory) was obtained; [a]_D = +24.3 °; MeOH.

Example 14

5 g (15.6 mmol) of the compound of formula VII was dissolved in 50 ml of methyl alcohol and 0.87 g (15.6 mmol) of KOH was added to the solution. The reaction mixture was refluxed for 20 hours. Subsequently, methyl alcohol was evaporated in a rotary vacuum evaporator and the evaporation residue was divided between dichloromethane (50 ml) and water (50 ml). The organic fraction was separated, extracted with 10 ml of water, dried with anhydrous magnesium sulfate and evaporated on a rotary vacuum evaporator. Clopidogrel (II) was obtained as a viscous honey-like evaporation residue (1.0 g; 20 % of theory); [α]_ϋ= 0° ; MeOH.

Example 15

12.39 g (38.5 mmol) of the compound of formula VII was dissolved in 120 ml of methyl alcohol and 10.6 g (77.00 mmol) OfK₂CO₃ was added to the solution. The reaction mixture was stirred at room temperature for 4 hours and then refluxed for 2 hours. Subsequently, methyl alcohol was evaporated in a rotary vacuum evaporator and the evaporation residue was divided between dichloromethane (100 ml) and water (100 ml). The organic fraction was separated, extracted with 20 ml of water, dried with anhydrous magnesium sulfate and evaporated in a rotary vacuum evaporator. Clopidogrel (II) was obtained as a viscous honey- like evaporation residue (2.73 g; 22 % of theory); [α]_D= 0° ; MeOH.

According to the bellow-indicated scheme, the unwanted enantiomer was reprocessed into a racemic mixture of compounds I and II.

Example 16 34.42 g of the compound of formula VII was dissolved in 30 ml of ethyl alcohol and added to a 50% solution of KOH, which was prepared via dissolving 50 g of KOH in 50 ml of water. The reaction mixture was heated to boil and ethyl alcohol was distilled off. Subsequently, the reaction mixture was heated for another 1 hour at 100 ⁰C. After cooling, the undissolved matter was filtered off on sintered glass and washed with ca 200 ml of acetone. A brownish solid of formula VII was obtained in the amount of 39.8 g.

Example 17

15 g of the compound of formula VII of Example 16 was dissolved in 30 ml of water and tetrabutylammonium hydrogen sulfate (1.0 g), 50 ml dichloromethane and 13.07 g of methyl iodide were added. The resulting mixture was stirred at room temperature for 6 hours.

Subsequently, the dichloromethane layer was separated and washed with water (20 ml), dried with anhydrous magnesium sulfate and concentrated in a rotary vacuum evaporator. Clopidogrel (II) was obtained as a viscous honey-like evaporation residue (7.3 g; 57 % of theory); [α]_D= 0° ; MeOH. Example 18

25 g of clopidogrel hydrogen sulfate (59.5 mmol) was poured into a 50% KOH solution, which was prepared via dissolving 5O g of KOH in 50 ml of water. The reaction mixture was heated to boil for 1 hour. After cooling, the undissolved matter was filtered off on sintered glass and washed with ca 200 ml of acetone. A cream-coloured solid of formula VII was obtained in the amount of 31.82 g.

Example 19 15 g of the compound of formula VII of Example 18 was suspended in 50 ml of dimethylformamide. 4.85 g of MeI was added to the suspension. The reaction mixture was stirred under a calcium-chloride tube at room temperature for 3.5 hours. The reaction mixture was diluted with 40 ml of water and extracted with 200 ml + 2x40 ml of ether. The combined ether fractions were washed with water (20 ml) and dried with anhydrous magnesium sulfate. After concentration in a rotary vacuum evaporator, 6.96 g of clopidogrel (II) was obtained as a viscous honey-like evaporation residue (72.6 % of theory); [α]π= 0° ; MeOH.

Example 20

1 g of the compound of formula VII of Example 18 was suspended in 20 ml of acetone. 0.4 g of MeI was added to the suspension. The reaction mixture was stirred under a calcium- chloride tube at room temperature for 2 hours, then methyl iodide (0.3 ml) was still added and the reaction mixture was stirred for another 3 hours. Subsequently, the undissolved matter was filtered off and the acetone filtrate was evaporated in a rotary vacuum evaporator. The evaporation residue was divided between 30 ml of dichloromethane and 20 ml of water. The dichloromethane layer was dried with anhydrous magnesium sulfate. After concentration in a rotary vacuum evaporator, 0.46 g of clopidogrel (II) was obtained as viscous honey-like evaporation residue (72.6 % of theoretical); [OC]D= 0° ; MeOH.

Claims

C L A I M S

1. A method of preparation of the methyl ester of the S(+) isomer of (2-chlorophenyl)-6,7- dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid of formula I

( D

from a racemic or enantiomer-enriched mixture with its R isomer of formula II

(H)

via crystallization of their salts with R(-)-10-camphorsulfonic acid, followed by conversion to the compound of formula I by action of a base, characterized in that the method comprises one or more crystallizations from a solvent containing at least two components, at least one of which, in which R(-)-10-camphorsulfonic acid and its salts with the compounds of formulae I and II are well soluble, has the composition R_aOH, wherein R_a is a straight or branched C₁ to C₅ alkyl, the ratio of the volume of component R_aOH to the volume of the other components, in which the compounds I and II are better soluble, ranging from 1 : 2 to 1 : 100.

2. The method according to claim 1, characterized in that the method comprises mixing of a solution of R(-)-10-camphorsulfonic acid in R₃OH with a solution of a mixture of the compounds of formulae I and II, followed by crystallizing their camphorsulfonate salts, the crystallized mixture being enriched in the component containing the compound of formula I with respect to the starting mixture.

3. The method according to claim 1 or 2, characterized in that the method comprises mixing of a solution of camphorsulfonates of the compounds of formulae I and II in R_aOH with another one or more components of the solvent mixture, followed by crystallization of a mixture of camphorsulfonates of the compounds of formulae I and II, the crystallized mixture being enriched in the component containing the compound of formula I with respect to the starting mixture.

4. The method according to any of claims 1 through 3 characterized in that the volume ratio of R_aOH to the other components is 1 : 4 to 1 : 50.

5. The method according to any of claims 1 through 4 characterized in that the other components of the solvent mixture are organic oxygen-containing compounds, being less polar than compound R_aOH.

6. The method according to claim 5, characterized in that the other component or more components, in which the mixture of the compounds of formulae I and II can be optionally dissolved, are selected from the group including aliphatic ethers of general formula R_bOR₀, or esters of general formula R_b(O)OR₀, or ketones of formula Rb(O)R_c, wherein R_b and R₀ are independently a Ci to C₅ straight or branched alkyl.

7. The method according to claim 6, characterized in that the solvent component R_aOH is methanol or ethanol and the other solvent component is butyl or propyl acetate.

8. The method according to any of claims 1 through 7, characterized in that the starting mixture of the compounds of formulae I and II comprises a mixture prepared via reaction of the compound of formula V

with methanesulfonic acid of formula VI

followed by reaction of the resulting ester with the hydrochloride of formula III

III

in the presence of an organic or inorganic alkaline-reacting substance.

9. The method according to claim 8, characterized in that the reaction is performed in a solvent selected from the chloro-derivatives of methane or ethane at temperatures of 40 to 120 ⁰C.

10. The method according to claim 9, characterized in that the reaction is performed in a two- phase arrangement in a system of a chlorinated solvent and an aqueous solution of an inorganic base, preferably an alkali metal carbonate.