WO2006064269A2

WO2006064269A2 - Salts of leukotriene antagonist montelukast

Info

Publication number: WO2006064269A2
Application number: PCT/GB2005/004896
Authority: WO
Inventors: Pathi L. Srinivas; Dharmaraj Ramachandra Rao; Rajendra Narayanrao Kankan; Jayamadhava P. Relekar
Original assignee: Cipla Limited; Wain, Christopher, Paul
Priority date: 2004-12-17
Filing date: 2005-12-16
Publication date: 2006-06-22
Also published as: WO2006064269A3

Abstract

An alkaline earth metal salt of montelukast, and processes for preparing alkali or alkaline earth metal salts of montelukast (represented by Formula I).

Description

SALTS OF LEUKOTRIENE ANTAGONIST

Technical Field of the Invention

The present invention relates to salts of a leukotriene antagonist. More particularly the present invention relates to alkaline earth metal salts of montelukast and a process for preparation of montelukast and its alkali and alkaline earth metal salts.

Background and Description of Prior Art

Montelukast is chemically known as 1-(((1(R)-(3(2-(7-chloro-2-quinolinyi)ethenyl)phenyl)-3- (2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and is represented by the Formula I

Montelukast is a selective, reversible leukotriene receptor antagonist. Leukotrienes were first discovered in the 1930's as potent mediators of inflammation and given the name "slow-reacting substance of anaphylaxis". Bronchoconstriction, increased mucous formation, and increased vascular permeability with edema formation are all possible mechanisms of airflow obstruction secondary to leukotrienes.

The cysteinyl leukotrienes (LTC₄, LTD₄, and LTE₄) are products of arachadonic acid metabolism, which are released by mast cells, monocytes, eosinophils, and basophils. Studies have shown LTD₄ to be 140 to 6,000 times more potent than histamine as a bronchoconstrictor. Montelukast binds with high affinity to the LTD₄ receptor, inhibiting bronchoconstriction. In clinical trials, montelukast has been found to inhibit bronchoconstriction at doses ranging from 5 to 250 mg, when administered four hours prior to a nebulized LTD₄ challenge. Montelukast is indicated for the prophylaxis and chronic treatment of asthma in patients greater than six years of age. Unlike the other leukotriene antagonists, zafirlukast and zileuton, montelukast is approved by the Food and Drug Administration (FDA) for use in young children.

In the past, a number of derivatives of Formula I and pharmaceutically acceptable salts thereof, have been disclosed as Leukotriene antagonists and inhibitors of Leukotriene biosynthesis. EP 480717 discloses the compound of Formula I and its sodium salt, and derivatives thereof with the quinoline moiety being optionally substituted. US 5,270,324 discloses derivatives of Formula I having 6-fluoro or 6,7-difluoro-2-quinolinyl substitution. EP 604114 discloses derivatives of Formula I where the quinoline is replaced with a halo- substituted thieno[2,3-b]pyridine group, particularly 2,3-dichlorothieno[2,3-b]pyridin-5-yl.

The prior art syntheses of montelukast involve coupling methyl 1- (mercaptomethyl)cyclopropane acetate with a mesylate of 2-(2-(2(S)-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol to produce the free acid which is then converted directly to the corresponding sodium salt after base hydrolysis. This process is not particularly suitable for large-scale production as it requires tedious chromatographic purification of methyl ester intermediates and/or the final products, and the product yields are low.

US 5,614,632 discloses the compound of Formula I (which has a 7-chloroquinolin-2-yl moiety) and a derivative of Formula I having a 6,7-difluoroquinolin-2-yl moiety. It also discloses isolating Formula I as a dicyclohexylamine (DCHA) salt and further converting it to the sodium salt.

There are major disadvantages associated with the US 5,614,632 disclosure, in that it describes a process for preparation of montelukast sodium via the DCHA salt which needs to be further purified before conversion to the sodium salt. The DCHA salt and the sodium salt are highly hygroscopic in nature which leads to problems in isolation of the product. The hygroscopic nature of these salts results in powder-handling issues at various stages, for example during filtration, isolation, drying and formulation, thereby limiting the scope for achieving high purity and industrial applicability.

Accordingly, there exists a need for new salts, which are ideally suited for pharmaceutical application, and an efficient synthetic process for the compounds of Formula I. The present invention solves the existing problem by providing novel salts of montelukast, and processes for their preparation.

Statement of the Invention

According to a first aspect of the present invention, there is provided an alkaline earth metal salt of montelukast.

According to a second aspect of the present invention, there is provided a process for the preparation of an alkali or alkaline earth metal salt of montelukast comprising:

(i) coupling 1-(mercaptomethyl)cyclopropane acetic acid with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl)-3-methane sulfonyloxypropyl)phenyl)-2-propanol of formula Il in the presence of a first organic solvent, or mixtures of first organic solvents, and an inorganic base to obtain montelukast free acid; (ii) reacting the montelukast with an ionic salt of an alkali or alkaline earth metal to obtain the alkali or alkaline earth metal salt of montelukast; and

(iii) isolating the salt from a second organic solvent or a mixture of a second organic solvent and water.

According to a third aspect of the present invention, there is provided a process for interconverting a first salt of montelukast to a second salt of montelukast comprising: (i) treating the first salt of montelukast with dilute acid; (ii) extracting montelukast acid in a suitable solvent; (iii) reacting montelukast acid with a second ionic salt; and (iv) isolating the second salt of montelukast from a mixture of organic solvents.

According to a fourth aspect of the present invention, there is provided an alkali metal salt of montelukast, excluding the sodium salt of montelukast, preferably the potassium salt.

Detailed Description of the Invention

In one aspect, the present invention provides an alkaline earth metal salt of montelukast, preferably the magnesium or calcium salt.

It has surprisingly been found that the salts of the present invention are advantageous over the sodium salt of montelukast in terms of hygroscopicity; for example, the magnesium and calcium salts are non-hygroscopic. This property of the salts of the present invention allows for a product with a higher purity and yield than the sodium salt of the prior art. Furthermore, the salts of the present invention are better suited for pharmaceutical application, due to the decreased hygroscopicity. Thus, the salts of montelukast of the present invention are more suitable for large-scale production than the sodium salt of montelukast.

In another aspect, the present invention provides a process (as exemplified in Scheme I) for the preparation of the alkali or alkaline earth metal salts of montelukast. The process may first comprise reacting 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- hydroxypropyl)phenyl)-2-propanol with methanesulfonyl chloride in the presence of an organic solvent, or mixtures of organic solvents, and an organic base. The organic solvent may comprise nitriles and aromatic hydrocarbons. The preferred organic solvent is acetonitrile. The preferred organic base is N,N-diisopropyl ethyl amine. The reaction may be carried out at a temperature ranging from -40° C to 0° C, preferably -20° C to -25° C, to obtain 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxypropyl)phenyl)-2-propanol (Formula II). 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxypropyl)phenyl)-2-propanol (Formula II) is further coupled with 1- (mercaptomethyl)cyclopropane acetic acid (Formula III) in the presence of an inorganic base at a temperature ranging from -20° C to 20° C, preferably -5° C to 5° C, more preferably at -5° C, to obtain montelukast. The inorganic base may be selected from a group consisting of sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, n-butyl lithium and sodium hydride, preferably sodium hydride.

The resulting montelukast is in situ reacted with suitable ionic salts and converted to its corresponding metal salts and isolated from suitable organic solvents. The ionic salts may be carbonates, chlorides, acetates, or sulphates of alkali or alkaline earth metals, preferably chlorides. The preferred salts of the present invention are magnesium and calcium. The organic solvent used for isolation may be an alcohol or an alcohol-water mixture. The preferred alcohols are methanol and ethanol.

The above-described process does not involve the intermediate formation of a salt of montelukast which is different to the alkali or alkaline earth metal salt formed after the reaction with the ionic salt. In other words, the montelukast free acid is reacted directly with the ionic salt in order to produce the desired alkali or alkaline earth metal salt.

Thus, high purity montelukast is obtained by converting the free montelukast into alkali and alkaline earth metal salts, for example magnesium and calcium salts. These salts can be used in any pharmaceutical composition.

In another aspect of the present invention, there is provided a process for the conversion of a first salt of montelukast to a second salt of montelukast. The first salt of montelukast may be suspended in water, treated with dilute acid and extracted with a suitable organic solvent, preferably dichloromethane. The organic layer may be dried over sodium sulphate and reacted with a second ionic salt. The second salt may be isolated from a mixture of organic solvents, preferably a toluene-heptane mixture. Scheme I

2-(2-(3(s)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)- 3-hydroxypropyl)phenyl-2-propanol

Formula Il

2-(2-(3(s)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)- 3-methanesulfonyloxypropyl)phenyl-2-propanol

1 -(((1 (R)-3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl 3-(2-(1 -hydroxy-1 -methylethyl) phenyl)propyl)thio)methyl)-cyclopropaneacetic acid magnesium salt The following non-limiting examples illustrate the processes of the present invention.

2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxopropyl)phenyl)-2-propanol was synthesised in accordance with the disclosure of US 5,270,324, and WO9518107.

Example 1

Preparation of Magnesium 1-(((1(R)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate

1-(mercaptomethyl)cyclopropane acetic acid (8.4 g) was added to DMSO 70 ml. under nitrogen atmosphere, the reaction mass was cooled to 0 to 5° C. Sodium hydride (4.2 g) was added to the reaction mass and stirred for 30 mins, at 0 to -5° C. A solution of 2-(2- (2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-methanesulfonyloxopropyl)phenyl)-2- propanol (25 gms) in a mixture of tetrahydrofuran and dimethyl sulfoxide (2:1) was added at 0 to -5° C in about 1.5 hours. The reaction mass was stirred at 0 to 5° C for 1 hour. After the completion of reaction, 10 ml of acetic acid was added to the reaction mass at 0 to -5° C and stirred for 30 mins. To this, 200 ml of demineralised water was added at 0 to 5° C. The reaction mass was then extracted with ethyl acetate 100 ml thrice. The combined ethyl acetate layer was washed with 10% NaCI, followed by water. The ethyl acetate layer was dried and distilled to about 175 ml. To this, Mg.Cb 6 H₂O 8.1 gms dissolved in ethyl acetate and methanol mixture (4:1) was added. The contents were stirred at 25 - 30° C for 30 mins., diisopropyl ether 250 ml was added and the reaction mixture was chilled and filtered to obtain the product. The resulting solid was stirred in methanol (100 ml) at 40-45⁰C for 30 min., the suspension was cooled to 25-3O⁰C and further chilled to 0-5⁰C and filtered. Magnesium content = 2.1-2.2 wt%

Example 2 Preparation of Magnesium 1-(((1(R)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate

1-(mercaptomethyl)cyclopropane acetic acid (8 gms) was added to tetrahydrofuran (187 ml) and stirred at - 10° C to -15° C under nitrogen. N-Butyl lithium (62.5 g) was added at - 10 to 15° C in about 2 hours to obtain the lithium addition salt of 1- (mercaptomethyl)cyclopropane acetic acid. The temperature of the reaction mass was raised to -5° C and to this, a solution of 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)- ethenyl)phenyl)-3-methanesulfonyloxopropyl)phenyl)-2-propanol in tetrahydrofuran (25 g in 125 ml tetrahydrofuran) was added at -5 to 0° C in 2 hours and further stirred at 0 to -5° C for about 15 hours. After completion of reaction the reaction mass was quenched with 10% sodium chloride solution (250 ml) slowly at a temperature below 0° C, ethyl acetate 100 ml was then added. The organic layer was separated and the aqueous layer extracted with 200 ml ethyl acetate. The combined organic layer was dried using sodium sulphate and later distilled about 175 ml. To this, Mg. Cl₂6 H₂O (8.1 gms) dissolved in ethyl acetate and methanol mixture (4:1) was added. The contents were stirred at 25 - 30° C for 30 mins. To this reaction mass, diisopropyl ether 250 ml was added, chilled and the resulting solid was filtered. The solid obtained was stirred in 100 ml methanol-water mixture (1 :1) at 50-55⁰C for 30 mins and cooled to 25-30⁰C, further the mass was chilled to 0-5⁰C and filtered to obtain pure montelukast magnesium. Magnesium content = 2.1-2.2 wt%

Example 3

Preparation of Sodium 1-(((1(R)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1 hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate

Magnesium 1-[[[(1 R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl]phenyl}-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl]thio]methyl] cyclopropane acetic acid (50 gms) was added to 650 ml of demineralised water. To this, 96.6 ml of dilute acetic acid solution was added (5.8 ml of acetic acid in 90.8 ml of water). The reaction mass was then stirred at 25 - 30° C for 30 mins. The product was extracted with 100 ml of dichloromethane. Further the aqueous layer was re-extracted with dichloromethane (50 ml) thrice. The organic layer was combined together, washed with water, dried using sodium sulphate and distilled to residue. To this residue, 250 ml of methanol was added and 3 g of activated charcoal added, stirred at 25 - 30° C for 30 mins and filtered. To the resulting clear filtrate, 116 ml of 1% aqueous 0.5 M NaOH solution in ethyl alcohol was added (2.4 g NaOH dissolved in 116 ml ethanol and 1.16 ml water). This mixture was stirred at 25 - 30° C for 30 mins. The solvent was evaporated to residue under vacuum. The residue was dissolved in 150 ml of toluene and stirred at 25 - 30° C for 15 mins and the solvent was again distilled to residue. 350 ml of toluene and 55 ml of n-heptane was added to the residue in about 2 - 3 hours. The reaction mass was then stirred at 25 - 30° C for 2 hours under nitrogen. The product was filtered and dried at 80 - 85° C for 6 hours.

Example 4

Preparation of Potassium-1-(((1(R)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate

1-(mercaptomethyl)cyclopropane acetic acid (8.4 g) was added to 70 ml of DMSO. The reaction mass was flushed with Nitrogen and cooled to 0 to -5° C. To this, 4.2 g of sodium hydride was added and stirred for 30 mins at 0 to -5° C. A solution of 2-(2-(3(S)-[3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxopropyl)-phenyl-2 propanol in a mixture of tetrahydrofuran and dimethylsulfoxide (2:1) (25 g in 69 ml tetrahydrofuran and 35 ml dimethylsulfoxide) was added at 0 to -5° C in 1 to 1.5 hours. The reaction mass was stirred at 0 to -5° C for about 1 hour. After completion of reaction, 10 ml of acetic acid was added to the reaction mass at 0 to -5° C and stirred for 30 mins. 200 ml of water was added to the reaction mass at 0 to 5° C. The reaction mass was then extracted with ethyl acetate 100ml thrice. The organic layers were combined and dried over anhydrous sodium sulphate. The dried ethyl acetate layer was distilled to residue. This residue was dissolved in 125 ml methanol, charcoalised and filtered. To this clear filtrate, potassium hydroxide solution in ethyl alcohol was added (prepared by dissolving 2.88 g of potassium hydroxide in 0.7 ml water and 60 ml ethyl alcohol mixture). The reaction mixture was distilled to residue and stripped with toluene. Further 175 ml toluene was added to the residue and stirred; n-heptane was added slowly in 3-4 hrs at about 30⁰C under nitrogen atmosphere. The product was isolated by filtration.

Example 5

Preparation of Calcium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1 hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate.

1-(mercaptomethyl)cyclopropane acetic acid (8g) was dissolved in 187.5 ml of tetrahydrofuran in a dry reaction flask and chilled to -10 to -15° C under nitrogen. To this, 62.5 g of n-butyl lithium was added at -10 to -15° C in about 2 hours to obtain the lithium addition salt of 1-(mercaptomethyl)cyclopropane acetic acid. After the addition of N-butyl lithium, the temperature of the reaction mass was raised to -5° C and to this reaction mass, a solution of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxopropyl)phenyl-2-propanol in tetrahydrofuran (25 g in 125 ml tetrahydrofuran) was added at -5 to 0° C in 2 hours. After addition, the reaction mass was stirred at 0 to -5° C for about 15 hours. After reaction completion, 250 ml of 10% sodium chloride solution was slowly added at a temperature below 0° C and then 100 ml of ethyl acetate was added. The organic layer was separated and the aqueous layer was re-extracted into ethyl acetate 100 ml twice. The combined ethyl acetate layer was then dried over anhydrous sodium sulphate. The ethyl acetate layer was distilled to175ml. CaCl₂ (7.6 g) dissolved in ethyl acetate(32.4ml):methanol (8.1 ml) was added. The contents were then stirred at 25 - 30° C for 30 mins and 250 ml of diisopropyl ether was added and the solid filtered. The resulting solid was stirred in methanol (100 ml) at 40- 45°C for 30 min., the suspension was cooled to 25-30°C and further chilled to 0-5⁰C and filtered to get montelukast calcium. Calcium content = 3.4-3.5 wt%

Example 6 Preparation of Calcium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate.

1-(mercaptomethyl)cyclopropane acetic acid (8.4 g) was added to 70 ml of DMSO under nitrogen and cooled to 0 to -5° C .Sodium hydride 4.2 g. was added and stirred for 30 mins at 0 to -5° C. A solution of 2-(2-(3(S)-[3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxopropyl)phenyl-2-propanol in a mixture of tetrahydrofuran (69 ml) and dimethyl sulfoxide (35 ml) was added at 0 to -5° C in 1.5 hours. The reaction mass was then stirred at 0 to -5° C for 1 hour. After reaction completion, 10 ml of acetic acid was added to the reaction mass at 0 to -5° C and stirred for 30 mins and later 200 ml of water was added at 0 to 5° C. The reaction mass was then extracted with ethyl acetate 100 ml thrice, the organic layer was combined and dried over anhydrous sodium sulphate. The solvent was distilled to 175 ml. and calcium chloride 7.6 g dissolved in ethyl acetate (32.4 ml):methanol (8.1 ml) mixture was added. The contents were then stirred at 25 - 30° C for 30 mins. To this 250 ml of diisopropyl and product was filtered. The solid obtained was stirred in 100 ml methanol-water mixture(1 :1) at 50-55⁰C for 30 mins. and cooled to 25- 30⁰C, further the mass was chilled to 0-5⁰C and filtered to obtain montelukast calcium. Calcium content = 3.4-3.5 wt%

Example 7

Preparation of Magnesium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate.

1-(mercaptomethyl)cyclopropane acetic acid (8.4 g) was added to 70 ml of DMSO under nitrogen and cooled to 0 to -5° C . Sodium hydride 4.2 g was added and stirred for 30 mins at 0 to -5° C. A solution of 2-(2-(3(S)-[3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- methanesulfonyloxopropyl)phenyl-2 propanol (25 gm) in a mixture of . tetrahydrofuran (69 ml) and dimethyl sulfoxide (35 ml) was added at 0 to -5° C in 1.5 hours. The reaction mass was then stirred at 0 to -5° C for 1 hour. After reaction completion, 10 ml of acetic acid was added to the reaction mass at 0 to -5° C and stirred for 30 mins and 200 ml of water was added. The reaction mass was then extracted with ethyl acetate 100 ml three times. The combined ethyl acetate layer was then dried over anhydrous sodium sulphate. The ethyl acetate layer was distilled to residue. The residue was dissolved in 125 ml methanol, charcoalised and then filtered. To this clear filtrate, solution of magnesium chloride 8.1 g in 60 ml ethyl alcohol was added. The mixture was then distilled to residue and stripped with toluene; 175 ml toluene added to the residue and 500 ml of n-heptane was added slowly in about 3 - 4 hours at about 30° C under Nitrogen to obtain montelukast magnesium. The product was then isolated by filtration. (Yield : 25 g). Magnesium content = 2.1 -2.2 wt%

Example 8

Preparation of Potassium 1-(((1 (R)-[3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate from Magnesium 1- (((1(R)-[3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-< methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate.

25 g of magnesium-1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy- 1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate was suspended in 250 ml of water and pH was adjusted to about 3.0 using dilute acetic acid. The reaction mass was then extracted into methylene dichloride 300 ml thrice. The organic layer was dried over sodium sulphate and distilled to residue and the residue was dissolve in 125 ml methanol, charcoalised and filtered. To this clear filtrate a solution potassium hydroxide 2.88 g in 32.5 ml ethyl acetate, methanol 8 ml and 1.5 ml water was added and the contents were then distilled to residue. This residue was dissolved in toluene (175 ml). Further 500 ml of n-heptane was added slowly in about 3 - 4 hours at about 30° C under nitrogen to obtain montelukast potassium. The product was isolated by filtration.

Example 9 Preparation of Calcium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate from Magnesium 1- (((1(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-Hydroxy-1 -methyl ethyl)phenyl)propyl)thio)methyl) cyclopropane acetate.

25 g of magnesium ^(((^^-(S^-CT-chloro^-quinolinyOethenyOphenyO-S^-CI-hydroxy- 1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetate was suspended in 250 ml of water and pH adjusted to about 3.0 using dilute acetic acid. The reaction was then extracted with methylene dichloride 300 ml three times. The organic layer was then dried over sodium sulphate, distilled to residue. The residue was dissolved in 125 ml of methanol, charcoalised and filtered. To this clear filtrate a solution of calcium chloride in 60 ml ethyl alcohol was added and the contents were then distilled to residue. The residue was dissolved in toluene (175 ml) and further 500 ml of n-heptane was added slowly in about 3 - 4 hours at about 30° C under nitrogen to obtain montelukast calcium. The product was isolated upon filtration. Calcium content = 3.4-3.5 wt%

It will be appreciated that the invention may be modified within the scope of the appended claims.

Claims

1. An alkaline earth metal salt of montelukast.

2. A salt according to claim 1 , wherein the alkaline earth metal salt is the magnesium salt.

3. A salt according to claim 1 , wherein the alkaline earth metal salt is the calcium salt.

4. A process for the preparation of an alkali or alkaline earth metal salt of montelukast comprising:

(i) coupling 1-(mercaptomethyl)cyclopropane acetic acid with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol of formula Il in the presence of a first organic solvent, or mixtures of first organic solvents, and an inorganic base to obtain montelukast free acid;

(ii) reacting the montelukast with an ionic salt of an alkali or alkaline earth metal to obtain the alkali or alkaline earth metal salt of montelukast; and

5. A process according to claim 4, wherein said first organic solvent is selected from tetrahydrofuran, dimethyl sulfoxide or mixtures thereof.

6. A process according to claim 4 or 5, wherein said inorganic base is selected from sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, n-butyl lithium and sodium hydride.

7. A process according to claim 4, 5 or 6, wherein said ionic salt is a carbonate, chloride, acetate, or sulphate of an alkali or alkaline earth metal.

8. A process according to claim 7, wherein said ionic salt is MgCl2.6H₂O, KOH or CaCI₂.

9. A process according to any of claims 4 to 8, wherein said second organic solvent is an alcohol or an alcohol-water mixture.

10. A process according to claim 9, wherein said alcohol is methanol or ethanol.

11. A process according to any of claims 4 to 10, wherein step (i) is carried out at a temperature ranging from -20⁰C to 2O⁰C.

12. A process according to claim 11, wherein step (i) is carried out at a temperature ranging from -5⁰C to 5°C.

13. A process according to claim 11 , wherein step (i) is carried out at a temperature of - 5°C.

14. A process according to any of claims 4 to 13, wherein the 2-(2-(2(S)-(3-(2-(7-chloro- 2-quinolinyl)-ethenyl)phenyl)-3-methane sulfonyloxypropyl)phenyl)-2-propanol is prepared by reacting 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- hydroxypropyl)phenyl)-2-propanol with methanesulfonyl chloride in the presence of a third organic solvent, or mixtures of third organic solvents, and an organic base.

15. A process according to claim 14, wherein the third organic solvent is selected from a nitrile and an aromatic hydrocarbon, preferably acetonitrile.

16. A process according to claim 14 or 15, wherein the organic base is N₁-N- diisopropyl ethyl amine.

17. A process according to claim 14, 15 or 16, wherein the reaction of the methanesulfonyl chloride is carried out at a temperature ranging from -40° C to 0° C.

18. A process according to claim 17, wherein the reaction of the methanesulfonyl chloride is carried out at a temperature ranging from -20° C to -25° C,

19. A process for interconverting a first salt of montelukast to a second salt of montelukast comprising:

(i) treating the first salt of montelukast with dilute acid;

(ii) extracting montelukast acid in a suitable solvent; (iii) reacting the montelukast acid with a second ionic salt; and

(iv) isolating the second salt of montelukast from a mixture of organic solvents.

20. A process according to claim 19, wherein the mixture of organic solvents comprises a toluene-heptane mixture.

21. A process according to claim 19 or 20, wherein the first or second salt is the magnesium, calcium or potassium salt.

22. A process according to claim 19, 20 or 21 , wherein said acid is acetic acid.