FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A PROCESS FOR THE PREPARATION OF THE ALKALINE EARTH METAL SALTS OF MONTELUKAST"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Centra], Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.


Background and description of prior art
Montelukast is chemically known as !-[[[(lR)-(3(2-(7-Chloro-2-quinolinyl)ethenyl]phenyl}-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid (Montelukast) 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 tEe^tame 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 compounds of Formula (I) and pharmaceutically acceptable salt thereof, have been disclosed as Leukotriene antagonists and inhibitors of Leukotriene biosynthesis.
EP 480717 discloses compounds of Formula (I) with substituted quinoline as its sodium salt.
US 5,270,324 disclose derivatives of Formula (I) having with 6-Fluoro or 6,7-difluoro-2 quinolinyl substitution. The patent no EP 604,114 discloses compounds having halo-substituted theino (2,3-b) pyridine, particularly 2,3 dichloro theino[2,3-b] pyridin-5yl.
US 5,614,632 discloses the compound of Formula I which has a 7-Chloro quinolin-2-yl or 6,7 difluoro quinolin-2-yl and isolating it as a dicyclohexylamine (DCHA) salt and further converting to the sodium salt.
The reported synthesis of montelukast involves coupling methyl l-(mercapto methyl) cyclopropane acetate with a mesylate of 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol to get the free acid and the latter 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.
There are certain major disadvantages associated with the prior art disclosures, 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 and leads to problem in isolation of the product. The hygroscopic nature of these salts results in powder handling issues at various stages, like during filtration, isolation, drying, formulation and 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 takes a step forward in solving the existing problem by providing novel salts of montelukast.
Object of the Invention
The present invention provides for a novel alkali & alkaline earth metal salts of
montelukast.
Another object of the present invention is to provide a process for the preparation of the
said salts of montelukast.
Yet another object is to provide a process for inter-conversion of the said salts of
montelukast.
Statement of the Invention
According to the present invention is provided a novel alkali and alkaline earth metal salts of montelukast and a process for making the same.
Detailed description of the invention
The present invention describes novel alkali and alkaline earth metal salts of montelukast. In one aspect, the present invention provides a novel alkaline earth metal salts of montelukast preferably magnesium and calcium salts.
In another aspect the present invention provides a process (Scheme I) for the preparation of the said novel alkaline earth metal salts of montelukast, which comprises of reacting 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl) -3-hydroxypropyl) phenyl)-2-propanol with methane sulfonyl chloride in an organic solvent or mixtures thereof in presence of an organic base. The organic solvents used comprises of nitriles and aromatic hydrocarbons. The preferred organic solvent is acetonitrile. The preferred organic base is N-N diisopropyl ethyl amine. The reaction is carried out at a temperature range from -40° C to 0° C, preferably -20 to -25° C to obtain 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl)-2-propanol (Formula II) which is

further coupled with methyl-l-(mercapto methyl) cyclopropane acetic acid (Formula-Ill) in the presence of a strong inorganic base at a temperature ranging from -20 to 20° C more preferably at -5° C to obtain montelukast. The inorganic base used from a group consisting of sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, n-Butyl lithium, 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 are carbonates, chloride, acetates, or sulphate of alkali or alkaline earth metal the preferred ionic salts are chlorides. The preferred salts of the present invention are magnesium or calcium. The organic solvent used for isolation is alcohol or alcohol-water mixture. The preferred alcohol used is methanol or ethanol.
In another aspect high purity montelukast is achieved by converting the free montelukast into alkaline earth metal salts, like magnesium, calcium etc. These salts can be used as such for the use in any pharmaceutical composition.
In another aspect the present invention provides a process for the conversion of the first montelukast salt to second salt of montelukast wherein first salt of montelukast is suspended in water and treated with dilute acid and extracted with a suitable organic solvent preferably dichloromethane. The organic layer is dried over sodium sulphate and reacted with ionic salt of second salt. The second salt is isolated from a mixture of organic solvents preferably toluene-heptane mixture.


The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

2-(2-( 3 (S)-( 3-(2- ( 7-chloro-2-quinolinyl) -ethenyl ) pheny ) -3-methane sulfonyl oxopropyl) phenyl)-2-propanol was synthesized using the disclosure of US5270324, and WO9518107.
Example 1
Preparation of Magnesium l-( ((l(R)-3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl) 3-(2-(1-Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl )cyclopropane acetate
l(Mercapto methyl) 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-methane sulfonyl oxopropyl) 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% NaCl, followed by water. The Ethyl acetate layer was dried and distilled to about 175 ml. To this Mg.Ck 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 reaction mixture was chilled and filtered to obtain the product. 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 0-5°C and filtered.
Example 2
Preparation of Magnesium l-( ((l(R)-3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl) 3-(2-(1-Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl )cyclopropane acetate
l-(mercapto methyl) 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 l-(mercapto methyl)

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-methanesulfonyl oxopropyl) 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 is extracted with 200 ml ethyl acetate. The combined organic layer was dried using sodium sulphate and later distilled about 175 ml. To this Mg.Cl2 6 H20 (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 50-55°C for 30 mins and cooled to 25-30°C, further the mass was chilled to 0-5°C and filtered to obtain pure montelukast magnesium.
Example 3
Preparation of Sodium l-( ( (l(R)-3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl) 3-(2-(l Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl )cyclopropane acetate
Magnesium l-[[[(lR)-(3-(2-(7-Chloro-2-quinolinyl)ethenyl] phenyl}-3-[2-(l-hydroxy-1-ethylethyl)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 is 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 is 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-( ((l(R)-3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl) 3-(2-(l-Hydroxy-1 -methyl ethyl)phenyl)propyl)thio)methyl )cyclopropane acetate
l-(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 quinoIinyl)-ethenyl) phenyl)-3-methane sulfonyl oxopropyl) 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 30°C under nitrogen atmosphere. The product was isolated by filtration.
Example 5
Preparation of Calcium-l-( (l(R)-(3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl) 3-(2-(l Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl cyclopropane acetate.
l-(mercapto methyl)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 l-(mercapto methyl)cyclopropane acetic acid. After the addition of 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-methane sulfonyl oxopropyl) 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 to 175ml. CaCb 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 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 0-5°C and filtered to get montelukast calcium.
Example 6
Preparation of Calcium-l-( ( l(R)-(3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl)-3-(2-(l-Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl cyclopropane acetate.
l-(Mercapto methyl) 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-methane sulfonyl oxopropyl) 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(l:l) at 50-55°C for 30 mins. and cooled to 25-30°C, further the mass was chilled to 0-5 °C and filtered to obtain montelukast calcium.
Example 7
Preparation of Magnesium-1-( ( l(R)-(3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl)-3-(2-(1- Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl cyclopropane acetate.
l-(Mercapto methyl)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-methane sulfonyl oxopropyl) 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)
Example 8
Preparation of Potassium-1-( (l(R)-[3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl)-3-(2-(l-Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl cyclopropane acetate from Magnesium l-(( l(R)-[3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl)-3-(2-(l-Hydroxy-1-methyl ethyl)phenyl)propyl)thio)methyl cyclopropane acetate.

25 g of magnesium-l-((l(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(l-hydroxy-1 -methyl ethyl)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 2.88gin32.5ml 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-l-((l(R)-(3-(2-(7-chloro-2 quinolinyl)ethenyl)phenyl)-3-(2-(l-Hydroxy-1-methyl ethyl)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 l-((l(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(l-hydroxy-1-methyl ethyl)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.

We Claim:
1. A process for the preparation of the novel alkaline earth metal salts comprising;
a) coupling of methyl- l-(mercapto methyl) cyclopropane acetic acid with 2-(2-(2(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula-II in a suitable organic solvent or mixtures thereof in presence of an inorganic base at temperature ranging from -20 to 20°C to obtain montelukast;
b) reacting the montelukast with ionic salts of alkaline earth metals to obtain alkaline earth metal salts of montelukast; and
c) isolating the said salts from a suitable organic solvent or a mixture of organic solvent and water.

2. A process for the preparation of the novel alkaline earth metal salts of montelukast as claimed in claim 1, wherein said organic solvents are selected from tetrahydrofuran, dimethyl sulfoxide or mixtures thereof.
3. A process for the preparation of the novel alkaline earth metal salts of montelukast as claimed in claim 1, wherein said inorganic base used is selected from sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, n-butyl lithium and sodium hydride.
4. A process for the preparation of the novel alkaline earth metal salts of montelukast as claimed in claim 1, wherein said organic solvent used for isolation is alcohol or alcohol water mixture.
5. A process for the preparation of the novel alkaline earth metal salts as claimed in claim 1 further comprising a step of inter-converting first salt of montelukast to second salt of montelukast
6. A process for inter-converting first salt of montelukast to second salt of montelukast as claimed in claim 5, which comprises of
a. treating the said first salt with dilute acid;
b. extracting the montelukast acid in suitable solvent;
c. reacting with second ionic salt and
d. isolating the second salt from toluene heptane mixture.