FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF
MONTELUKAST SODIUM"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of [R-(E)-l-[[
[l-[3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]
propyl]thio]methyl]cyclopropaneacetic acid sodium salt represented by Formula-(I)
commonly known as Montelukast Sodium.
The process provides Montelukast Sodium in higher yield and purity and avoids formation of sulfoxide impurity compared to the previously known processes.
BACKGROUND OF THE INVENTION
Montelukast Sodium is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies and is marketed under brand name "Singulair" Tablet, Chewable, Oral in US market.
US Patent No. 5,565,473 discloses a process for the synthesis of montelukast and its pharmaceutically acceptable salts especially sodium salt. The process for the preparation comprises of reacting [(E)]-2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(methanesulfonyloxy)propyl)phenyl)-2-propoxy)tetrahydropyran with methyl 1-(acetylthiomethyl)cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as a solvent to get methyl ester of montelukast in pyran protected form. The protected compound is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium.
In US Patent No. 5,614,632 montelukast is prepared by condensing l-(Mercapto-methyl)cyclopropane acetic acid then condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol compound

using n-butyl lithium at -5 °C to afford Montelukast. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
The drawback of this process is that, it involves the usage of pyrophoric and costly raw material such as n-butyl lithium in typical sub-zero reaction conditions. The processes also involves tedious workup to isolate the required product and thus results in the excess time cycle, which in turn renders the process more costly and less eco-friendly thus the process is not suitable for commercial scale-up.
US Patent No. 7,547,787 ('787 patent) discloses a process for the preparation of montelukast sodium by reaction of montelukast diol (MKT) compound with methane sulfonyl chloride in presence of diisopropylethyl amine in tetrahydrofuran to obtain mesylate compound (Mesylate), which is in solution further directly reacted with 1-(mercaptomethyl) cyclopropane acetic acid methyl ester (CYTAM) in a co-solvent such as dimethyl formamide, acetonitrile, N-methyl pyrrolidone or dimethyl acetamide in presence of a base such as 47% sodium hydroxide solution, followed by hydrolysis of the resulting product to obtain montelukast sodium (MLK-Na) as depicted below.

The 787 patent involves use of alkyl esters of l-(mercaptomethyl)cyclopropane acetic acid, which adds an extra synthetic steps to the total synthesis ofmontelukast sodium such as esterification of the corresponding acid compound and hydrolysis of the esters, resulting in a process that is expensive in large scale production of montelukast sodium.
US Patent No. 8,178,680 discloses a process to prepare montelukast sodium by reaction of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxy-propyl)phenyl)-2-propanol with l-(mercaptomethyl)cyclopropane acetic acid in dimethyl sulfoxide in presence of a base such as sodium methoxide solution in methanol, followed by hydrolysis of the resulting product with water, basification with sodium hydroxide and then repeated solvent washings and extractions using toluene and ethyl acetate finally isolating the montelukast as an amine salt which is further converted to montelukast sodium.
Above patent involves tedious workup procedures such as solvent washings and extractions to isolate the required product and thus results in excess time cycle, which in turn renders the process quite expensive.
Additionally, there are disclosures which use primary amines of low molecular weight for the purification of montelukast sodium. However, the process to obtain these amines takes a large number of hours and/or the yields are low. For instance, WO 2006/043846 describes the preparation of pure sodium Montelukast by using the tert-butyl amine salt of montelukast. As described therein, the tert-butyl amine salt of montelukast was obtained after several hours of stirring (32 h) at room temperature.
The styrene impurity and sulfoxide impurity (Impurity-E) of montelukast sodium were first disclosed in J. Org. Chem. 61, 8518-8525, 1996. This journal also disclosed the pathways for the formation of styrene and sulfoxide impurity.



The prior art procedures involve more number of steps, which include a series of protections and deprotections of diol intermediate, usage of hazardous and costly raw materials such as n-butyl lithium, hydrazine, pyridinium p-toluene sulfonate in typical reaction conditions i.e. at very low temperatures (-25 °C). The processes of the prior art references involve tedious workup to isolate the required product and thus results in excess time cycle, which in turn rendering the process more costly and less ecofriendly thus the process is not amenable for commercial scale up.
The present inventors have directed the research work towards preparation of montelukast sodium which not only provides the desired purity but is also devoid of impurities and disadvantages in the prior-art processes. Unexpectedly, when montelukast was converted to tert-butyl amine salt and then it was further converted to montelukast sodium, the final compound was having better yield and free of sulfoxide impurity with overall process efficacy.
The process for the preparation of Montelukast sodium is cost effective and avoids the drawback of the prior art processes.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of Montelukast Sodium of Formula (I) comprising


(a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);

(b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid, a compound of formula (C);

(c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification;

(d) converting Montelukast tert-butyl amine salt (D) to Montelukast acid, compound of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.

An object of the present invention provides a process for the preparation of Montelukast Sodium which is substantially free from impurity and also industrially viable.
It has been surprisingly found that the process according to the present invention provides Montelukast Sodium having sulfoxide impurity less than 0.1%. Dichloromethane as a solvent increases the rate of the reaction of mesylation reaction in stage I and toluene as a solvent for isolation in stage-I increases the purity of montelukast acid, compound of formula (C).
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, n-pentanol and the like; halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1-trichloroethane and the like; hydrocarbons solvents such as toluene, xylene, hexanes, heptanes, petroleum ether and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; dimethyl sulfoxide (DMSO); dimethyl formamide (DMF); dimethyl acetamide; N-Methyl-2-pyrrolidone (NMP); water or mixtures thereof.
As used throughout the specification, the term "organic base" refers tertiary amines such as triethylamine, N,N-diisopropylethylamine (DIPEA), tertiary butyl amine (TBA) and the like. The term alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like. The term "inorganic base" includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, cesium carbonate, potassium carbonate and the like.
In one embodiment, the present invention provides a process for preparation of Montelukast Sodium of Formula (I), comprising


(a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);

(b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C);

(c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification;


(d) converting Montelukast tert-butyl amine salt (D) to Montelukast acid, compound , of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.
In one embodiment, step (a) comprises reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B).
The suitable solvent used in step (a) is as defined supra. Preferably, the solvent used for the process in step (a) is halogenated solvent and base used is an organic base. More preferably, the solvent used in step (a) is dichloromethane and base is N,N-diisopropylethyl amine.
In one embodiment, the conversion of a compound of formula (A) to a compound of formula (B) in step (a) may be performed using methane sulfonyl chloride in dichloromethane as a solvent and N,N-diisopropylethyl amine as base.
In one embodiment, the step (a) comprises, adding and stirring a compound of formula (A) in dichloromethane at a temperature of about -25 °C to about 0 °C, preferably at a temperature of about -20 °C to about -5 °C, more preferably at a temperature of about -15 °C to about -10 °C. Further organic base preferably N,N-diisopropylethyl amine may be added at a temperature of about -25 °C to about 0 °C, preferably at a temperature of about -20 °C to about -5 °C, more preferably at a temperature of about -15 °C to about -10 °C. Further methane sulfonyl chloride in dichloromethane may be added to the reaction mixture in about 3 h to about 6 h, preferably in about 3.5 h to about 5.5 h, more preferably in about 3 h to about 4 h at about -15 °C to about -10 °C. Further, the reaction mixture may be maintained for about 1 h to about 4 h, preferably for about 1.5 h to about 3.5 h, more preferably for about 2 h to about 3 h.
After the completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (a), hexanes, chilled at -25 °C to about 0 °C, preferably at a temperature of about -20 °C to about -5 °C, more preferably at a temperature of about -15 °C to about -10 °C was added to the reaction mixture in about 25 min to about 35 min, preferably in about 20 min to

about 30 min, more preferably in about 15 min to about 25 min. The reaction mixture obtained may be stirred for about 1 h, more preferably about 45 min and filtered. The product was washed with a suitable solvent as defined supra. Preferably, the solvent used for washing is hexanes.
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B).
In one embodiment, the step (b) comprises reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C).
The suitable solvent used in step (b) is as defined supra. Preferably, the solvent used for the process in step (b) is polar aprotic solvent. More preferably the solvent used in step (b) is dimethyl sulfoxide. Further, base used in step (b) is as defined supra. Preferably alkali earth metal alkoxide is used. More preferably sodium methoxide is used.
In one embodiment, the step (b) comprises, adding and stirring 2-[l-(mercaptomethyl) cyclopropyl]acetic acid in dimethyl sulfoxide at a temperature of about -15 °C to about 10 °C, preferably at a temperature of about -10 °C to about 5 °C, more preferably at a temperature of about -5 °C to about 0 °C. Further sodium methoxide may be added at temperature of about 0 °C to about 25 °C, preferably at a temperature of about 5 °C to about 20 °C, more preferably at a temperature of about 10 °C to about 15 °C. Further, the reaction mixture may be maintained for about 35 min to about 70 min, preferably for about 40 min to about 65 min, more preferably to about 45 min to about 60 min at a temperature of about -15 °C to about 25 °C, preferably at a temperature of about -10 °C to about 20 °C, more preferably at a temperature of about -5 °C to about 15 °C. Further, compound of formula (B) obtained in step (a) added and the reaction mixture may be maintained for about 1 h to about 3.5 h, preferably for about 1.5 h to about 3 h, more preferably to about 2 h to about 2.5 h at a temperature of about -15 °C to about 25 °C, preferably at a temperature of about -10 °C to about 20 °C, more preferably at a temperature of about -5 °C to about 15 °C.

After the completion of the reaction in step (b), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (b), an inorganic base is used as defined supra. Preferably, an inorganic base used is an alkali metal hydroxide solution. More preferably, an inorganic base used in sodium hydroxide solution. Further sodium hydroxide solution may be added at temperature of about -10 °C to about 15 °C, preferably at a temperature of about -5 °C to about 10 °C, more preferably at a temperature of about 0 °C to about 5 °C in about 10 min to about 40 min, preferably in about 15 min to about 30 min, more preferably in about 20 min to about 25 min. Further, the temperature of the reaction mixture is raised to about 10 °C to about 40 °C, preferably to about 15 °C to about 35 °C, more preferably to about 20 °C to about 30 °C and may be maintained for about 50 min, preferably for about 40 min, more preferably to about 30 min. Further, suitable solvent is added and reaction mixture is maintained for about 5 min to about 25 min, preferably to about 10 min to about 20 min, more preferably to about 10 min to about 15 min. Suitable solvent used is as defined supra. Preferably, the solvent used is a hydrocarbon solvent. More preferably the solvent used is toluene. Further, the layers were separated and the toluene layer was stirred for about 12 h, preferably for about 11 h, more preferably for about 10 h at about 15 °C to about 40 °C, preferably at about 20 °C to about 35 °C, more preferably at about 25 °C to about 30 °C. Further, the solid is filtered and washed with suitable solvents to obtain a compound of formula (C). The suitable solvents used is as defined supra. Preferably, the solvent used is hydrocarbon solvent. More preferably, the solvent is toluene and hexanes.
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising
a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);

b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C).
In one embodiment, step (c) comprises converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification.
The suitable solvent or mixture thereof used in step (c) is as defined supra. Preferably the solvent used in step (c) is ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like or alkyl nitrites solvents such as acetonitrile, propane nitrile, cyanonitrile, butyronitrile and the like or mixture of ketone and nitrile solvent. More preferably a solvent mixture of acetonitrile and acetone is used.
In one embodiment, the step (c) comprises, adding and subsequently stirring a compound of formula (C) and tert-butyl amine in solvent mixture of acetone: acetonitrile (1:2 ratio). Further, the reaction mass may be heated up to about 75 °C to about 80 °C, preferably to about 70 °C to about 75 °C, more preferably to about 65 °C to about 70 °C and maintained for about 5 h, preferably for about 4 h, more preferably for about 3 h. Further, the precipitated solid can be filtered and washed with solvent mixture of acetone: acetonitrile. The wet cake obtained may be dried under vacuum at a temperature of about 40 °C to about 65 °C, preferably at a temperature of about 45 °C to about 60 °C, more preferably at a temperature of about 50 °C to about 55 °C to obtain a compound of formula (D).
In one embodiment, the compound of formula (D) is further purified with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is hydrocarbon solvent. More preferably, the solvent is toluene.
In one embodiment, the compound of formula (D) was added to toluene. The reaction mass may be heated up to about 65 °C to about 90 °C, preferably to about 70 °C to about 85 °C, more preferably to about 75 °C to about 80 °C and maintained for about 1 h to about 3.5 h, preferably for about 1.5 h to about 3 h, more preferably for about 2 h to about 2.5 h. Further, the solid obtained may be filtered and washed with suitable solvent as defined supra. Preferably the solvent used in hydrocarbon solvent, more preferably

toluene. Further the wet solid may be dried under vacuum at a temperature of about 45 °C to about 70 °C, preferably at a temperature of about 50 °C to about 65 °C, more preferably at a temperature of about 55 °C to about 60 °C to obtain a compound of formula (D).
In one embodiment, the present invention provides a process for the reparation of Montelukast sodium, comprising converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification.
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising
a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);
b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C);
c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification.
In one embodiment, step (d) comprises converting Montelukast tert-butyl amine salt (D) to Montelukast acid, compound of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.
The suitable solvent used in step (d) is as defined supra. Preferably, the acid used for the process is organic acid and solvent used is halogenated. More preferably, the organic acid used in step (d) is acetic acid and the solvent used is dichloromethane.
In one embodiment, the step (d) comprises, adding and stirring a compound of formula (D) in dichloromethane and water at a temperature of about 15 °C to about 40 °C preferably at a temperature about 20 °C to about 35 °C, more preferably at a temperature at about 25 °C to about 30 °C. Further, acetic acid may be added to the reaction mixture more preferably at about 25 °C to about 30 °C to adjust the pH at about 4.5 to about 7.0,

preferably pH at about 5 to about 6.5, more preferably pH at about 5.5 to about 6.0. Further, the dichloromethane layer was separated and aqueous layer was extracted again with dichloromethane, combined organic layer was distilled under vacuum to give concentrated mass of compound of formula (C).
In one embodiment, the compound of formula (C) was stirred in a suitable solvent as defined supra. Preferably, the solvent used is an alcoholic solvent. More preferably the solvent used is methanol.
In one embodiment, the compound of formula (C) was stirred in methanol. Further, sodium hydroxide solution was added to get a clear solution followed by activated charcoal. Further, the reaction mass may be stirred at a temperature of about 15 °C to about 40 °C, preferably at a temperature about 20 °C to about 35 °C, more preferably at a temperature at about 25 °C to about 30 °C for about 15 min to about 40 min, preferably for about 20 min to 35 min, more preferably for about 25 min to about 30 min. The reaction mass is filtered through Hyflo bed. Hyflo bed is washed with methanol. Further, methanol is distilled off under vacuum at a temperature of about 50 °C, preferably at a temperature of about 45 °C, more preferably at a temperature of about below 45 °C to obtain a free solid of compound of formula (I). Further, the compound of formula (I) was stirred in hydrocarbon solvent. Preferably, the solvent is n-heptane.
In one embodiment, the compound of formula (C) in n-heptane was stirred preferably for about 0.5 h to about 2.5 h, more preferably to about 1 h to about 2 h under inert atmosphere followed by filtration. Further, the compound may be dried under vacuum initially at about 35 °C to about 60 °C, preferably at about 40 °C to about 55 °C, more preferably at about 45 °C to about 50 °C for about 0.5 h to about 2.5 h, more preferably to about 1 h to about 2 h. Further, the drying may be continued at about 55 °C to about 80 °C, preferably at about 60 °C to about 75 °C, more preferably at about 65 °C to about 70 °C for about
11 h to about 16 h, preferably to about 11.5 h to about 15.5 h, more preferably to about
12 h to about 15 h.
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising converting Montelukast tert-butyl amine salt (D) to

Montelukast acid, compound of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.
In one embodiment, the present invention provides a process for the preparation of Montelukast sodium, comprising

a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);

b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl]
acetic acid in presence of suitable solvent and base to obtain montelukast acid a
compound of formula (C);

c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification;


d) converting Montelukast tert-butyl amine salt (D) to Montelukast acid, compound of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.

In one embodiment the present invention provides a process for the preparation of Montelukast sodium, comprising

(a) reacting a compound of formula (A) with methane sulfonyl chloride in dichloromethane in presence N,N-diisopropylethyl amine to obtain a compound of formula (B);


(b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in dimethyl sulfoxide in presence sodium methoxide to obtain montelukast acid a compound of formula (C);

(c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a acetonitrile acetone solvent mixture followed by purification;

(d) converting Montelukast tert-butyl amine salt (D) to Montelukast acid in dichloromethane in presence of acetic acid to a compound of formula (C) which is converted to Montelukast sodium (I) using sodium hydroxide in methanol.

The present invention is explained in detail by referring to examples, which are not to be construed as limitative.

Example-1: Preparation of TBA Salt of 2-(l-((((R)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yI)phenyl)propyl)sulfonyI)methyl)cyclopropyl) acetic acid [MON-TBA Crude]
200 g 2-2-(3S)-3-(2-(7-chloro-2-quinolinyl)ethylphenyl)-3-hydroxypropyl)phenyl-2-propanol (MON-Diol) was added to 800 ml dichloromethane. The reaction mass was cooled up to -10 °C to -15 °C followed by addition of 90.30 g of Diisopropylethylamine. 55.03 g of Methane sulphonyl chloride in 200 ml dichloromethane was added at -10 °C to -15 °C over a period of 4 h to 5 h. The reaction mass was maintained at same temperature for 2 h to 3 h. 1000 ml of chilled hexanes was added at same temperature in 15 min to 25 min. After stirring for 45 min the product was filtered and washed with 200 ml hexanes.
In another round bottom flask 83.00 g 2-[l-(Mercaptomethyl) cyclopropyl] acetic acid (MON-Mercapto acid) was added to 600 ml dimethyl sulphoxide and the reaction mass was cooled up to 0 °C to -5 °C. After achieving temperature of 10 °C to 15 °C charge 25%, 271.19 ml sodium methoxide was added. The reaction mass was stirred for 45 min to 60 min at -5 °C to 15 °C. Above isolated wet mesylate compound was added to the reaction mixture and continued stirring for another 2 h to 2.5 h. After completion the reaction mass was quenched with 240 mL 40% sodium hydroxide solution (96 g NaOH and 240 mL water) in 20 min to 25 min at 0 °C to 5 °C. The temperature of the reaction mass was raised to 20 °C to 30 °C and stirred for 30 min. 1600 ml of toluene was added, stirred for 10 min to 15 min followed by layer separation. Aqueous layer was washed with toluene (1600 ml x 2). Aqueous layer was mixed with 2200 ml toluene and the pH was adjusted to 5.5 and separate layers. The toluene layer was stirred for 10 h at 25-30 °C. Resulting solid was filtered and washed with 200 mL toluene and 200 mL Hexanes.
Above isolated wet intermediate was taken in 720 mL acetone and 1440 mL acetonitrile
stirred for 10 min and 24.66 g of tert-butyl amine was added. The reaction mass was
heated up to 65 °C to 70 °C. After 1 h to 1.5 h the reaction mass was cooled to 50-55 °C
and maintained for 3 h. The product was filtered and washed with 170 ml mixture of
acetonitrile: acetone (115 ml: 55 ml) and dried at 50 °C to 55 °C for 10-12 h under
vacuum.
Yield: 183 g (63%); HPLC Purity: 99.0 to 99.30%

Example-2: Preparation of TBA salt of 2-(1-((((R)-1«(3-((E)-2-(7-chloroquinoIin-2-yl) vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfonyl)methyl)cycIopropyl) acetic acid [MON-TBA pure]
176 g Mon-TBA was taken in 1232 ml of toluene and the reaction mass was heated up to 75 °C to 80 °C. After maintaining for 2 h to 2.5 h the reaction mass was cooled to 50 °C to 55 °C and stirred for 1 h. The solid was filtered and washed with 176 ml toluene. The product was dried at 55 °C to 60 °C for 6 h to 8 h under vacuum. Yield: 171 g (96.6%); HPLC Purity: 99.85 to 99.95%
Example-3: Preparation of Cyclopropane acetic acid, l-[[[l-[3-[2-(7-chloro-2-quinolinyI) ethenyl]-3-[2-(l-hydroxy-l-methyIethyl)phenyl]propyI]thio]methyI]-,sodiumsalt» [R-(E)]
156 g MON-TBA Salt was taken in 780 mL dichloromethane and 312 mL water at 25-30 °C. To this slowly added 340 mL, 5% Acetic acid to pH 5.5 to 6.0. Reaction mass was stirred and layers were separated. Organic layer was washed with 5%, 463 mL acetic acid and then with 463 mL x 3 water. Organic layer was distilled off under vacuum. The concentrated mass was taken in 468 ml methanol and 9.76 g sodium hydroxide solution in 312 ml was added to get a clear solution. 8 g of activated charcoal was added and stirred for 25 min to 30 min at 25 °C to 30 °C. The reaction mass was filtered through Hyflo bed and solvent was removed under vacuum to yield free solid. 1560 ml n-Heptane was added to the solid and stirred under nitrogen. After 1 h to 2 h the solid was filtered and washed with 156 ml n-heptane. The product was dried under vacuum first at 45 °C to 50 °C for 1 h to 2 h and then 65 °C to 70 °C for 12 h to 15 h. Yield: 127 g (88%); HPLC Purity: 99.85 to 99.95%

We claim:
1) A process for preparation of Montelukast Sodium of Formula (I) comprising

(a) reacting a compound of formula (A) with methane sulfonyl chloride in presence a suitable solvent and an organic base to obtain a compound of formula (B);

(b) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in presence of suitable solvent and base to obtain montelukast acid a compound of formula (C);

(c) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a suitable solvent followed by purification;


(d) converting Montelukast tert-butyl amine salt (D) to Montelukast acid, compound of formula (C) in a suitable solvent which is converted to Montelukast sodium (I) using sodium hydroxide in a suitable solvent.

2) A process according to claim 1, wherein the suitable solvent of step (a) is a halogenated solvent selected from the group consisting of dichloromethane, chloroform, trichloroethylene, carbon tetrachloride, tetrachloroethylene and 1,1,1-trichloroethane preferably dichloromethane.
3) A process according to claim 1, wherein the organic base of step (a) is selected from the group consisting of N,N-diisopropylethyl amine, triethyl amine and tert-butyl amine preferably N,N-diisopropylethyl amine.
4) A process according to claim 1, wherein the suitable solvent of step (b) is polar aprotic solvent selected from the group consisting of dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidone preferably dimethyl sulfoxide.
5) A process according to claim 1, wherein the base of step (b) is an alkali earth metal alkoxide selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide preferably sodium methoxide.
6) A process according to claim 1, wherein the suitable solvent of step (c) is a polar aprotic solvent selected from the group consisting of acetone, butanone, acetonitrile, propionitrile or mixture thereof, preferably acetone acetonitrile mixture.
7) A process according to claim 1, wherein montelukast tert-butyl amine salt was converted to free acid in a halogenated solvent selected from the group consisting of dichloromethane, chloroform, trichloroethylene, carbon tetrachloride, tetrachloro¬ethylene and 1,1,1-trichloroethane preferably dichloromethane in presence of a

suitable carboxylic acid selected form acetic acid, formic acid, propionic acid preferably acetic acid.
8) A process for preparing a solid sodium salt of montelukast according to claim 1, comprising synthesizing montelukast free acid in dichloromethane in presence of acetic acid, dissolving montelukast free acid in methanol and converting into a sodium salt of montelukast, isolating in n-Heptane.
9) A process for preparation of Montelukast Sodium of Formula (I) comprising

(b) reacting a compound of formula (A) with methane sulfonyl chloride in dichloromethane in presence N,N-diisopropylethyl amine to obtain a compound of formula (B);

(e) reacting the compound of formula (B) with 2-[l-(mercaptomethyl)cyclopropyl] acetic acid in dimethyl sulfoxide in presence sodium methoxide to obtain montelukast acid a compound of formula (C);


(f) converting the compound of formula (C) to Montelukast tert-butyl amine salt, a compound of formula (D) in presence of a acetonitrile acetone solvent mixture followed by purification;

(g) converting Montelukast tert-butyl amine salt (D) to Montelukast acid in dichloromethane in presence of acetic acid to a compound of formula (C) which is converted to Montelukast sodium (I) using sodium hydroxide in methanol.

10) The process as claimed in any of the preceding claims, wherein Montelukast Sodium obtained by the said process contains less than 0.1 % of the undesired sulfoxide impurity.