This application claims priority to this Indian patent application number 3535/CHE/2012 filed on Aug 27, 2012

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Montelukast or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

1 -[[[(1R)-1 -[3-[( 1 E)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-( 1 -hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid sodium salt, also known by the name Montelukast sodium, is represented by the below structural Formula-I

ONa

U H0JU

H3C CH3 Formula-I

Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.

Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480717. The synthesis of montelukast sodium, as taught in patent EP 480717, involves coupling methyl l-(mercaptomethyl)cyclopropaneacetate with 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl) phenyl-2-propanol followed by hydrolysis of the resulting montelukast methyl ester so as to form a free acid, which is followed by conversion of this montelukast free acid to a corresponding sodium salt, isolated as an amorphous material by freeze-drying.

United States Patent No. 5,614,632 teaches a method of preparing crystalline montelukas sodium, which involves the preparation of the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid, using butyl lithium, followed by condensation thereof with the 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl) phenyl-2-propanol to yield montelukast acid as a viscous oil. The resulting montelukast acid is converted, via the corresponding Dicyclohexyl ammonium salt, to crystalline montelukast sodium.

The extra purification step via the dicyclohexyl ammonium salt, which is disclosed in United States Patent No. 5,614,632, is necessitated from the difficulties encountered in obtaining crystalline materials. Thus, the crude acid is purified via the dicyclohexylamine salt by reacting it with dicyclohexylamine in ethyl acetate, followed by addition of hexanes to effect crystallization of the dicyclohexylamine salt, or by the crystallization from toluene/heptane. It is mentioned by the inventors of patent U.S. Pat. No. 5,614,632, that the crystalline montelukast dicyclohexylamine salt offers an efficient method for the purification of montelukast, which circumvents the need to use chromatographic purification.

Another process for preparing montelukast sodium is provided in patent application WO 2005/105751 (hereinafter the 751 application). The 751 application provides a process for preparing montelukast sodium comprising reacting 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3(hydroxypropyl)phen- yl-2-propanol with methanesulfonyl chloride to obtain 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl)phenyl-2-propanol, which is subsequently reacted with 1-(mercaptomethyl)cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a co-solvent and a base such as Sodium base, followed by hydrolysis of the resulting product of the previous step to obtain montelukast sodium.

IN 236239 discloses an improved process for the preparation of Montelukast and its amine salts comprising dissolving 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanal in halogenated solvents and the obtained compound is condensed with l-(mercaptomethyl) cyclopropane acetic acid in presence of a base and solvents such as tetrahydrofuran or toluene or dimethylformamide.

The present invention provides an improved, simple, cost-effective and environment friendly process for the preparation of Montelukast and its pharmaceutically acceptable salts.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide an improved process for the preparation of Montelukast and its amine salts.

Another object of the present invention is to provide further conversion of Montelukast and its amine salts into Montelukast sodium.

One aspect of the present invention provides an improved process for the preparation of Montelukast comprising reacting 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonylpropyl) phenyl)-2-propanol with l-(mercaptomethyl) cyclopropane acetic acid in presence of sodium alkoxide and a solvent such as N-methyl 2-pyrrolidone.

Another aspect of the present invention provides an improved process for the preparation of Montelukast amine salt of Formula (IV) comprising the steps of;

a) dissolving 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol of Formula (II) in suitable solvent,

b) optionally diluting the reaction mass obtained in step (a) with halogenated solvent comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of toluene or xylene or polar solvent such as dimethylformamide, acetonitrile propionitrile or tetrahydrofuran,

c) adding methane sulfonyl chloride to the reaction mass of step (b) in presence of organic base,

d) dissolving l-(mercaptomethyl) cyclopropane acetic acid in a solvent such as N-methyl 2-pyrrolidone,

e) adding the sodium alkoxide powder or a solution of alkali or alkoxide in C1-C4 straight or branched chain alcohols to the reaction solution of step (c) followed by adding the solution of step (d);

f) converting the obtained compound into Montelukast amine salt compound of Formula-IV by treating with amine.

Another aspect of the present invention provides purification of Montelukast isopropylamine salt comprising the steps of:

a) providing Montelukast in mixture of isopropyl alcohol and toluene,

b) adding isopropylamine, and

c) isolating Montelukast isopropylamine salt free of sulfoxide impurity.

One more aspect of the present invention provides purification of Montelukast comprising the steps of:

a) dissolving Montelukast isopropylamine in a mixture of water and water immiscible organic solvent,

b) adjusting pH to acidic,

c) adding alcoholic sodium hydroxide solution,

d) passing the reaction mass through Silica gel, and

e) isolating Montelukast free of impurities D&E.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of Montelukast. The present invention further relates to improved process for the preparation of Montelukast and its amine salts, preferably primary, secondary and tertiary amine salts. The amine salts of Montelukast are further converted into Montelukast sodium compound of Formula-I as depicted in scheme 1.

One aspect of the present invention provides an improved process for the preparation of Montelukast comprising, reacting 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonylpropyl) phenyl)-2-propanol with l-(mercaptomethyl) cyclopropane acetic acid in presence of sodium alkoxide and a solvent such as N-methyl 2-pyrrolidone.

In one embodiment, sodium alkoxide used in the present invention is selected from sodium methoxide or sodium ethoxide, preferably sodium methoxide.

Another aspect of the present invention provides an improved process for the preparation of Montelukast amine salt of Formula (IV) comprising the steps of;

a) dissolving 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol of Formula (II) in suitable solvent,

b) optionally diluting the reaction mass obtained in step (a) with halogenated solvent
comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of toluene or xylene or polar solvent such as dimethylformamide, acetonitrile propionitrile or tetrahydrofuran,

c) adding methane sulfonyl chloride to the reaction mass of step (b) in presence of
organic base,

d) dissolving l-(mercaptomethyl) cyclopropane acetic acid in a solvent such as N-methyl 2-pyrrolidone,

e) adding the sodium alkoxide powder or a solution of alkali or alkoxide in C1-C4 straight or branched chain alcohols to the reaction solution of step (c) followed by adding the solution of step (d);

f) converting the obtained compound into Montelukast amine salt compound of Formula-IV by treating with amine.

In one embodiment, suitable solvent used in step-a is selected from halogenated solvents like dichloromethane, ethylene dichloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents like of toluene or xylene

In one more embodiment, organic base used in step-c is selected from triethylamine, tributylamine, tertiary butylamine, N, N-Diisopropyl ethylamine, preferably N, N-Diisopropyl ethylamine.

In one more embodiment, alkali or alkoxide used in step-e is selected from sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably sodium methoxide and C1-C4 straight or branched chain alcohols is selected methanol, ethanol, n-propanol, isopropanol or n-butanol.

In one more embodiment, amine compound used in the step-f is selected from primary, secondary or tertiary amines, preferably isopropylamine, di-isopropylamine, dicyclohexylamine, more preferably isopropylamine.

One more aspect of the present invention provides purification of Montelukast isopropylamine salt comprising the steps of:

a) providing Montelukast in mixture of isopropyl alcohol and toluene,

b) adding isopropylamine, and

c) isolating Montelukast isopropylamine salt free of sulfoxide impurity.

In one embodiment, the obtained pure Montelukast isopropylamine is further recrystallized in isopropyl alcohol and toluene to get more pure Montelukast isopropylamine free of sulfoxide impurity. This may further crystallized in acetone to get more pure Montelukast isopropylamine salt.

As per the present invention, Montelukast is dissolved in isopropyl alcohol and toluene at below 45 °C. To this isopropyl amine is added and reaction mixture is cooled to 5 to 25 °C, preferably 5 to 15 °C. The wet material is purified in isopropyl alcohol and toluene at a temperature of 15 to 45 °C, preferably 20 to 40 °C. The obtained reaction mass is filtered and washed with isopropyl alcohol and toluene to get Montelukast free of Sulfoxide impurity.

The obtained Montelukast amine salt is further converted into Montelukast sodium by the process disclosed in prior art for example process disclosed in US 5614632, US 20100168432.

One more aspect of the present invention provides purification of Montelukast comprising the steps of:

a) dissolving Montelukast isopropylamine in a mixture of water and water immiscible organic solvent,

b) adjusting pH to acidic,

c) adding alcoholic sodium hydroxide solution,

d) passing the reaction mass through Silica gel, and

e) isolating Montelukast free of impurities D&E.

In one embodiment, water immiscible organic solvent used in the present invention is selected from dichloromethane, chloroform and ethylacetate, preferably dichloromethane.

In one more embodiment, pH of the reaction mixture is adjusted to acidic by adding acid such as hydrochloric acid, hydrobromic acid and acetic acid, preferably hydrochloric acid.
In another embodiment, alcoholic sodium hydroxide solution used in the present invention is selected from methanolic sodium hydroxide solution and ethanolic sodium hydroxide solution, preferably methanolic sodium hydroxide solution.

In another embodiment, the reaction mass is passed through silica gel and washed with 5 to 30% of methanol in dichloromethane solution, preferably 15 to 25% of methanol in dichloromethane solution.

The starting material compounds 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3(hydroxypropyl)phenyl-2-propanol and l-(mercaptomethyl)cyclopropaneacetic acid can be prepared by the prior art processes as disclosed in EP 480717 and US 5614632.

Experimental procedure:

Example-1: Process for the preparation of Montelukast isopropylamine salt

2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol (100 gm) and toluene (360 ml) were charged into a round bottomed flask and stirred. The mixture was heated to reflux and maintained at reflux and water was azeotropically distilled from the reaction mixture followed by distillation of 50 ml of toluene. The reaction mass was cooled to 50°C. To this acetonitrile (900 ml) was added at 25-35°C. To this reaction mass N, N-Diisopropyl ethylamine (DIPEA) was added at -10°C. The reaction mass was further cooled to -23°C and methane sulfonyl chloride diluted with toluene (22 ml in 44 ml) was added at the same temperature. The reaction mass was maintained for 5 hours. The reaction mass was filtered and suck dried. The material was washed with acetonitrile + isopropyl ether and suck dried. The material was again washed with hexane and suck dried. In another flask mixture of N-Methyl 2-pyrrolidone (400 ml) and mercaptomethyl cyclopropyl acetic acid (34 gm) was taken and to this the obtained wet material was added. The reaction mass was stirred for half an hour and sodium methoxide solution (90 ml) was added. To this a mixture of purified water (1210 ml), Sodium chloride (120 gm) and methylene chloride (800 ml) was added. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane. To the combined organic layers L(+)-Tartaric acid solution (45gm in 610 ml of water) was added and organic layer was separated. Carbon BW-280 was added to the organic layer and filtered. Dichloromethane was distilled off under vacuum and ethyl acetate was added. To this isopropylamine (14.5 gm) was added and seeded with Montelukast isopropylamine salt. The reaction mass washed with toluene, filtered and dried to yield Montelukast isopropylamine salt.

Example-2: Purification of Montelukast isopropylamine salt

A mixture of toluene (500 ml) and acetone (300 ml) was added to Montelukast isopropylamine salt (100 gm) at 35°C and the temperature was raised to 55°C. The reaction mass was maintained for 30 min and cooled to 35°C. To this acetonitrile (400 ml) was added and seeded with Montelukast isopropylamine salt. The wet cake was washed with acetonitrile and suck dried. The material was dried under room temperature to yield Montelukast isopropylamine.

ExampIe-3: Process for the preparation of Montelukast sodium

Montelukast isopropylamine (100 gm) and Methylene dichloride (2000 ml) was taken into RBF at 25-35°C and water (1000ml) was added. To this hydrochloric acid solution (18.88 gm in 120 ml of water) was added and layers were separated. The organic layer was purified with water and aqueous layer was discarded. To this ethanolic sodium hydroxide solution, prepared by mixing ethanol (320 ml), water (3 ml) and Sodium hydroxide flakes (6.2 gm) was added and Methylene dichloride was distilled off completely under atmospheric pressure. To this methanol (1000 ml) was added. To this carbon PS-133 (5 gm) and stirred for 20 minutes at 40°C. Carbon was filtered and washed with methanol. Methanol was distilled off completely under vacuum. To this n-heptane was added and solvent was distilled under vacuum. The material was cooled and dried under vacuum to yield Montelukast sodium.

Example-4: Process for the preparation of Montelukast DCHA salt

2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol (100 gm) and toluene (360 ml) were charged into a round bottomed flask and stirred. The mixture was heated to reflux and maintained at reflux and water was azeotropically distilled from the reaction mixture followed by distillation of 50 ml of toluene. The reaction mass was cooled to 50°C. To this acetonitrile (900 ml) was added at 25-35°C. To this reaction mass N, N-Diisopropyl ethylamine (DIPEA) was added at -10°C. The reaction mass was further cooled to -23°C and methane sulfonyl chloride diluted with toluene (22 ml in 44 ml) was added at the same temperature. The reaction mass was maintained for 5 hours. The reaction mass was filtered and suck dried. The material was washed with acetonitrile + isopropyl ether and suck dried. The material was again washed with hexane and suck dried. In another flask mixture of N-Methyl 2-pyrrolidone (400 ml) and mercaptomethyl cyclopropyl acetic acid (34 gm) was taken and to this the obtained wet material was added. The reaction mass was stirred for half an hour and sodium methoxide solution (90 ml) was added. To this a mixture of purified water (1210 ml), Sodium chloride (120 gm) and methylene chloride (800 ml) was added. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane. To the combined organic layers L(+)-Tartaric acid solution (45gm in 610 ml of water) was added and organic layer was separated. Carbon BW-280 was added to the organic layer and filtered. Dichloromethane was distilled off under vacuum and ethyl acetate was added. To this Dicyclohexyl amine (44 gm) was added and seeded with Montelukast Dicyclohexyl amine salt. The reaction mass washed with hexane, filtered and dried to yield Montelukast DCHA salt.

Example-5: Purification of Montelukast DCHA salt

A mixture of toluene (500 ml) and acetone (300 ml) was added to Montelukast DCHA salt (100 gm) at 35°C and the temperature was raised to 55°C. The reaction mass was maintained for 30 min and cooled to 35°C. To this acetonitrile (400 ml) was added and seeded with Montelukast Dicyclohexyl amine salt. The wet cake was washed with acetonitrile and suck dried. The material was dried under room temperature to yield Montelukast DCHA salt.

Example-6: Process for the preparation of Montelukast sodium

Montelukast Dicyclohexyl amine salt (80 gm) and Methylene dichloride (1200 ml) was taken into RBF at 25-35°C and water (1200ml) was added. To this acetic acid solution (60 gm in 600 ml of water) was added and layers were separated. The organic layer was purified with water and aqueous layer was discarded. To this ethanol solution, prepared by mixing ethanol (190 ml), water (1.7 ml) and Sodium hydroxide flakes (4.2 gm) was added distill off Methylene dichloride completely under atmospheric pressure. To this methanol (580 ml) was added. To this carbon PS-133 (4.8 gm) and stirred for 20 minutes at 45°C. Carbon was filtered and washed with methanol. Methanol was distilled off completely under vacuum. Obtained crude was dissolved in ethanol and solvent was distilled under vacuum. The material was cooled and dried under vacuum to yield Montelukast sodium.

Example-7: Preparation of Montelukast mono isopropyl amine salt

To a stirred solution of 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl) phenyl)-2-propanol (100 gm) in Toluene (310 ml) and Acetonitrile (900 ml), N,N-diisopropylethylamine (39 gm) was added at -8 to -12°C for 30 min. The reaction mass was cooled to -21 to -25°C and Methanesulfonylchloride (32.6 gm) in Toluene (40 ml) was added slowly for 210±30 min at -21 to -25°C and maintained the mass for 270 min at -21 to -25°C. The reaction mass was further cooled to -31 to -35°C and maintained for 270 min at -31 to -35°C. The reaction mass was washed with chilled n-Hexanes. In another flask a stirred solution of l-(Mercaptomethyl)cyclopropane acetic acid (34 gm, 0.23 moles) in N-methyl-2-pyrrolidinone (300 ml) was taken and above obtained wet material was added at -11 to -15°C. The reaction mass was cooled to -31 to -35°C and 28% SMO (sodium methoxide) solution in methanol was added for 210 min at -31 to -35°C and maintained the reaction for 240 min at -2 to 2°C. To this reaction mass a mixture of 10% aqueous sodium chloride solution (120 gm in 1200ml of water) and methylenechloride (800 ml) was added. The organic and aqueous layers were separated, and aqueous layer was extracted with methylenechloride. To the combined organic layers aqueous L-(+)-Tartaric acid solution (45 gm in 600 ml water) was added followed by 5% aqueous sodium chloride solution. Methylenechloride was distilled out and ethyl acetate was added. To this mono isopropyl amine (14.5 gm) was added slowly for 30 min at 11-15°C and maintained for 45 min at 11-15°C and seeded with Montelukast isopropylamine salt. The reaction mass washed with toluene, filtered and dried to yield Montelukast isopropylamine salt.

ExampIe-8: Purification of Montelukast isopropyl amine salt

Mixture of Montelukast isopropyl amine salt (100 gm) in methylene chloride (1000 ml) and water (1000 ml) was taken and pH was adjusted to 4.0 - 4.5 by using hydrochloric acid (CP) solution (13-18 gm of hydrochloric acid dissolved in 90-120 ml of water) at 10-14°C. The reaction mass was maintained at 21-25°C for 40 min and then layers were separated. Organic layer was washed with water (1000 ml) and methanolic sodium hydroxide solution (dissolved 6.2 gm of sodium hydroxide pellets in 3 ml of water and 320 ml of methanol) was added slowly for 60 min. This reaction mass was passed through silica gel (mesh 100-200) (300 gm) column and column was washed with 20% methanol in methylene chloride solution to get Montelukast free of Impurities D&E. The combine column fractions were cooled to 10-14°C and aqueous L-(+)-Tartaric acid solution (32 gm of L-(+)-Tartaric acid in 600 ml of water) was added. The reaction mass was stirred at 25-35°C for 20 min. The layers were separated and organic layer was washed with 5% aqueous sodium chloride solution. The solvent was distilled off and methylene chloride traces were removed by giving toluene stripping under vacuum to obtain the crude material which was isolated by dissolving in 10% isopropyl alcohol in Toluene (800 ml) at below 45°C. To this mono isopropyl amine was added slowly for 30 min. The resulting solution was maintained for 240 min at 11-15°C and washed with 10% Isopropyl alcohol in Toluene (100 ml) mixture. The wet material obtained was purified in 10% Isopropyl alcohol in Toluene (560 ml) by maintaining for 90 min at 75-85°C and by maintaining for 150 min at 25-35°C. The reaction mass was filtered and washed with 10% Isopropyl alcohol in Toluene (70 ml) to get Montelukast free of Sulfoxide impurity. The wet material was purified twice in acetone and dried at 51-55°C to obtain Montelukast isopropyl amine salt.

Example-9: Preparation of Montelukast sodium

Mixture of Montelukast isopropyl amine salt (100 gm) in methylene chloride (1000 ml) and water (1000 ml) was taken and pH was adjusted to 4.0 - 4.5 by using hydrochloric acid (CP) solution (13-18 gm of hydrochloric acid dissolved in 90-120 ml of water) at 10-14°C. The reaction mass was maintained at 21-25°C for 40 min and then layers were separated. Organic layer was washed with water (1000 ml) and methanolic sodium hydroxide solution (dissolved 6.2 gm of sodium hydroxide pellets in 3 ml of water and 320 ml of methanol) was added slowly for 60 min. The reaction mass was treated with PS-133 carbon (5.0 gm in 20 ml of methylene chloride) and filtered through hyflo bed and washed with methylene chloride (80 ml). The solvent was distilled off and dissolved in methanol and treated with PS-133 carbon (5.0 gm in 20 ml of methanol). The reaction mass was filtered through hyflo bed and washed with methanol. The solvent was distilled off under vacuum and dried to yield Montelukast sodium.

We claim:

1. An improved process for the preparation of Montelukast comprising, reacting 2-(2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-methanesulfonylpropyl) phenyl)-2-propanol with l-(mercaptomethyl) cyclopropane acetic acid in presence of sodium alkoxide and a solvent such as N-methyl 2-pyrrolidone.

2. The process according to claim 1, wherein sodium alkoxide is selected from sodium methoxide or sodium ethoxide.

3. The process according to claim 1, wherein Montelukast is further treated with amine salt to get Montelukast amine compound of Formula-IV.

4. The process according to claim 3, wherein amine salt is selected from primary, secondary or tertiary amines.

5. The process according to claim 4, wherein amine is selected from isopropylamine, di-isopropylamine or dicyclohexylamine.

6. The process according to claim 3, wherein the obtained Montelukast amine salt is further converted into Montelukast sodium.

7. A process for the purification of Montelukast isopropylamine salt comprising the steps of:

a) providing Montelukast in mixture of isopropyl alcohol and toluene,

b) adding isopropylamine, and

c) isolating Montelukast isopropylamine salt free of sulfoxide impurity.

8. A process for purification of Montelukast comprising the steps of:

a) dissolving Montelukast isopropylamine in a mixture of water and water immiscible organic solvent,

b) adjusting pH to acidic,

c) adding alcoholic sodium hydroxide solution,

d) passing the reaction mass through Silica gel and

e) isolating Montelukast free of impurities D&E.