FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of [R(E)]4-[[[l-[3-[2K7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(l-hydroxy-1- methylethyl)phenyl]propyl]thio]-methyl]cyclopropaneacetic acid, monosodium salt of Formula I.

BACKGROUND OF THE INVENTION
[R-(E)]-H[[l-[3-[2-(7-cholroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt (I) is generically known as Montelukast sodium. Montelukast and its pharmaceutically acceptable salts are selective Leukotriene receptor antagonists, which inhibit the cysteinyl leukotriene CysLTi receptor. Montelukast sodium is used in the treatment of asthma and allergic rhinitis.
Merck & Co., has disclosed Montelukast and its derivatives for the first time in US Patent No. US 5,565,473. US 5,565,473 also discloses the process of preparing Montelukast sodium by condensing 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)phenyl) -2-propoxy)-tetrahydropyran (II) with methyl-l-(acetylthiomethyl) cyclopropane acetate (III) in presence of cesium carbonate to produce methyl-4-((l(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranyloxy)-2-

methylethyl)phenyl) propyl)thio)cyclopropylacetate (IV), which is de-protected in presence of pyridinium-p-toluenesulfonate and further converted to Montelukast sodium (I) in presence of sodium base in a mixture of solvents selected from methanol and tetrahydrofuran.
The process is as shown in Scheme-I below:

The above process is not particularly suitable for large-scale production, because it requires tedious chromatographic purification of intermediates and final product, which finally results in the low yield of Montelukast sodium.
US 5,614,632 discloses the process for the preparation of Montelukast sodium through Montelukast DCHA salt (IX). The process comprises, condensing 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy) methylethyl)phenyl)-2-propanol (VI) with dilithium anion of 1 -(mercaptomethyl)cyclopropaneacetic acid (VII) [Dilithium anion of 1-

(mercaptomethyl)cyclopropaneacetic acid is produced by the reaction of 1-(mercaptomethyl)cyclopropaneacetic acid with n-Butyl lithium to produce condensed product, Montelukast as solid dicyclohexylamine salt. Montelukast dicyclohexylamine salt is further converted to Montelukast sodium by treating with sodium hydroxide in acetic acid.
The process is as shown in Scheme-II below:

Scheme - II
The above process also suffers with major disadvantage of low yield and low purity of Montelukast. The reason for such low yield is that during the condensation of 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)phenyl)-2-propanol (VI) with 1-(mercaptomethyl)cyclopropaneacetic acid (VII) in presence of strong base n-butyl lithium generate undesired impurities. The removal of these impurities is often

proved to be difficult and requires separate crystallization, which finally results in the low yield of Montelukast sodium (I).
In the process of the present invention we have now found that condensation of 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy) methylethyl)phenyl)-2-propanol (VI) with l-(mercaptomethyl)cyclopropaneacetic acid (III) in presence of mild bases produce Montelukast of high purity and yield.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of Montelukast sodium of high purity and yield on a commercial scale.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of [R-(E)]-l-[[[l-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio] methyl]cyclopropaneacetic acid, monosodium salt of Formula I which comprises;
i) condensing 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl) -3-(methanesulfonyloxy)methylethyl)phenyl)-2-propanol (VI)


with methyl ester of l-(mercaptomethyl)cyclopropaneacetic acid (III)

in presence of base in a solvent to produce methyl-1-(((1 -(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-( 1 -hydroxy-1 -methylethyl) phenyl)propyl)thio)methyl)cyclopropaneacetic acid (V) (Montelukast methyl ester);

ii) treating the methyl ester of Montelukast (X) with a base followed by treatment with dicyclohexylamine in a solvent to produce dicyclohexylamine salt of 1 -(((1 -(R)-(3 -(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3 -(2-( 1 -hydroxy-1 -methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic acid (IX) (Montelukast DCHA salt);


iii) treating the Montelukast DCHA salt (IX) with an acid in a solvent to give Montelukast free acid, which on further treatment with sodium ion source in a solvent to produce [R-(E)]-l-[[[l-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium (I) (Montelukast sodium).
DETAILED DESCRIPTION OF THE INVENTION
The mesyl derivative, 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)phenyl)-2-propanol (VI) is treated with a base selected from cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, rhodium carbonate, in a solvent selected from acetonitrile, acetone and THF at a temperature of about 0°C to about -20°C, preferably 0°C to -5°C under nitrogen atmosphere. Methyl-l-(mercaptomethyl)cyclopropane acetic acid (III), which is prepared as per the procedure described in US 5,534,651 in a solution of acetonitrile, acetone and THF, preferably in acetonitile is added to the above reaction mass at a temperature of -10°C to about 0°C, preferably -7°C to -3°C. The reaction mass is stirred for about 5 to 10 hrs, preferably 5 hrs. After completion of the reaction the reaction mass is poured in aqueous sodium chloride and solvent selected from ethylacetate, methyl acetate and isopropyl acetate. Methyl-1 -(((1 -(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3 -(2-( 1 -hydroxy-

l-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (V) (Montelukast methyl ester) is finally isolated from the organic layer by evaporating the solvent.
Montelukast methyl ester (V) is further treated with a base selected from NaOH, LiOH and KOH in a solvent selected from methanol, tetrahydrofuran, dioxane or mixtures thereof, preferably 3:1 mixture of methanol and tetrahydrofuran. The reaction is carried out at room temperature for about 2 days. After the completion of the reaction solvent is evaporated under reduced pressure at 35°C to 40°C and the pH is adjusted to 5 with acetic acid and ammonium chloride. The residue containing crude Montelukast is suspended in a solvent selected from toluene, xylene, preferably toluene, is treated with dicyclohexylamine. The resulting mass is treated with carbon and the filtrate is stirred for 2 to 5 h, preferably 3 hrs at a temperature of about 10 to 30°C and solvent selected from n-heptane, hexane and n-pentane or mixtures thereof is added to the above filtrate slowly for about 1 to 2 h and the resulting mass is stirred for 10 to 15 h to produce Dicyclohexylamine salt of 1 -(((1 -(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-( 1 -hydroxy-1 -ethylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (IX) (Montelukast DCHA salt).
Montelukast DCHA salt (IX) is acidified with acid selected from organic or inorganic acid, preferably an organic acid such as acetic acid, tartaric acid, oxalic acid in a solvent selected from water, organic solvent such as toluene, xylene or mixtures thereof The organic layer is separated and evaporated completely under reduced pressure and the residue containing Montelukast free acid is dissolved in a solvent selected from methylene chloride or ethylene dichloride and precipitated by adding antisolvent selected from hexane, n-heptane and n-pentane and filtered the Montelukast free acid as a solid. Further Montelukast free acid can be converted to Montelukast sodium by conventional methods such as freezedrying in presence of sodium ion source selected from sodium hydroxide in a solvent selected from water.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
REFERENCE EXAMPLE Step -1
Methyl-4-((l(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyI)phenyl)-3-(2-(2-(2-tetrahydropyranyl-oxy)-2-methylethyl)phenyl)propyl)thio)cyclopropyl acetate (Protected Montelukast methyl ester).
l-(mercaptomethyl) cyclopropane methyl acetate (0.96 g, 6 mmol) was dissolved in acetonitrile (10 ml) at 27-30°C under nitrogen atmosphere. The solution was then added to a suspension of 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)phenyl)-2-propoxy)tetrahydropyran (mesylate derivative) (2.5 g, 4.0 mmol) and potassium carbonate (1.36 g, 9.8 mmol) in acetonitrile (10 ml) at 0°C to -5°C under nitrogen atmosphere over a period of 1 h. the reaction mixture was warmed to 27 - 30°C. The reaction mass was stirred at 27 - 30°C for 36 h. The progress of the reaction was monitored by TLC.
To the above reaction mass water was added (20 ml) and extracted with ethylacetate (50 ml). The ethyl acetate layer was washed with brine and dried over Na2SO4 and then concentrated. Yield 2.0 g (72.5 %).

EXAMPLE -1 Step I:
Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yI)ethenyl) phenyl)-3-(methanesulfonyl-oxy)methylethyl)phenyl)-2-propanol (mesyl derivative).
2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(hydroxypropyl) phenyl)-2-propanol (Diol derivative) (20 g, 0.0437 mol) was dissolved in toluene (60 ml) and acetonitrile (160 ml) mixture under nitrogen atmosphere at room temperature. Diisopropyl ethylamine (8.5 g, 0.0656 mol) was added the temperature was lowered to -35°C to -30°C. Methane sulfonyl chloride (7.0 g, 0.0612 mol) was added slowly over a period of 1 h at - 30°C to -25°C. The reaction mixture was stirred at -27°C to - 25°C for 2 h and lower the temperature to -35°C to -30°C and stirred for another 2h. Filtered the product under nitrogen blanket at -30°C and the product was washed with cold acetonitrile (80 ml, -30°C) followed by hexanes (2 X 80 ml, 0°C). Product was dried at 5°C under positive pressure of nitrogen to get 21 g of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)phenyl)-2-propanol (mesyl derivative). Yield (87.74 %)
Step II:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid methyl ester (Montelukast methyl ester).
Mesyl derivative (5g, 0.00934 mol) was added in a suspension of dried cesium carbonate (6.1g, 0.0187 mol) in acetonitrile (15 ml) at -3°C under nitrogen atmosphere. The resulting suspension was stirred at -7°C to - 3°C for 15 min. 1-(Mercaptomethyl)cyclopropane acetic acid methyl ester (1.5g, 0.009375 mol) in

acetonitrile (15 ml) at -7°C was added to the above solution in one lot. The temperature was slowly raised to room temperature and stirred for 5 h at this temperature the progress of the reaction is monitored by TLC.
After completion of the reaction, DM water (50 ml) was added at below 10°C and extracted with ethyl acetate. Organic layer was washed with brine solution followed by drying with anhydrous sodium sulfate, concentrated under reduced pressure at 40°C to get 5 g residue of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy)methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid methyl ester (Montelukast methyl ester). Yield (89.32 %)
Step III:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yI)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (Montelukast crude).
Montelukast methyl ester (5.0g, 0.00834 mol) was dissolved in a mixture of methanol: tetrahydrofuran (3:1, 40 ml) at room temperature. Cooled the solution to 0°C and added 1M sodium hydroxide solution (20 ml, 0.02 mol) was added to the above solution and stirred the reaction mass at room temperature for 2 days. Most of the methanol and THF was evaporated under reduced pressure at 35 -40°C. The pH of the reaction mass was adjusted to 5 with acetic acid, ammonium chloride solution and extracted with ethylacetate. Organic layer was washed with 20% w/v sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure at 40-45°C to get 3.2g residue of 1-(((1-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl) phenyl)propyl)thio)methyl)cyclopropane acetic acid (Montelukast crude). Yield (65.57 %)

Step IV:
Preparation of Dicyclohexylamine salt of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yI)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyI)propyl)thio)methyl) cyclopropaneacetic acid.
The crude Montelukast (3.2 g, 5.47 mmol) was suspended in toluene (24 ml) and the suspension was stirred for 30 min under nitrogen atmosphere to get a clear solution. Dicyclohexylamine (1.1 g, 6 mmol) was added to the clear solution and the reaction mass was stirred for 15 min at 20-25°C. Carbon (0.32 g) was added and stirred the mass for 1 h at 20-25°C and mass was filtered through hyflo and washed the bed with toluene (6.5 ml). The filtrate was diluted with 16 ml of toluene and seeded with dicyclohexylamine salt of montelukast (25 nfg). The solution was stirred for 3 h at 20-25°C and n-heptane (23 ml) was added very slowly over a period of 2 h at 20-25°C, a thick white slurry was obtained. The slurry containing Montelukast dicyclohexyl amine salt was filtered and dried (2.5 g). Purity 97.0% by HPLC. Yield (59.67 %)
Step V:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Montelukast)
Montelukast DCHA salt (2.5 g, 3.26 mmol) was suspended into a mixture of toluene (50 ml) and DM water (37.5 ml) and the resulting mixture was treated with acetic acid until clear solution obtained. The organic layer was separated and the toluene was evaporated completely under reduced pressure to obtain yellowish residue. Methylene chloride (17.5 ml) was added to the residue and stirred at 35°C to get the clear solution and hexane was added slowly for 1 hr. The product

obtained was filtered and washed with a mixed solution of methylene chloride and hexane (1:3, 12 ml) and dried. Yield: 1.65 g (86.39 %). Purity 98.21 % by HPLC.
EXAMPLE -2: Step I:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid methyl ester (Montelukast methyl ester).
2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (mesyl derivative) (9 g, 16.8 mmol) was reacted with potassium carbonate (5.8 g, 42 mmol) in acetonitrile (30 ml) at -5°C. 1-(mercaptomethyl)cyclopropane acetic acid methyl ester (4g, 25 mmol) in acetonitrile (30 ml) was added in 15 min at -5°C to 0°C. The reaction mass temperature slowly raised to 20°C and stirred the reaction mass at 20-25°C for 16 h. The reaction compiles by TLC.
Water was added at below 10°C extracted with ethyl acetate. The organic layer was washed with brine solution and dried with anhydrous sodium sulfate, concentrated under reduced pressure to get 10 g residue of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy)methylethyl)phenyl)propyl) thio)methyl)cyclopropaneacetic acid methyl ester (Montelukast methyl ester). Yield (99.3 %)

Step II:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Montelukast crude).
Montelukast methyl ester (10 g, 16.8 mmol) was dissolved in a mixture of methanol:THF (3:1, 63 ml) and cooled the solution below 0°C. 1M sodium hydroxide solution (40.3 ml, 40.3mmol) at 0°C in 15 min. the reaction mass was stirred at room temperature for 2 days. Most of the methanol and THF evaporated under reduced pressure at 40°C. The pH was adjusted to 5 with acetic acid. Ammonium chloride solution was added to the reaction mass and extracted with ethylacetate. The organic layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure at 35-40°C to get 9.0 g residue of 1-(((1-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (Montelukast crude).
Step III:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yI)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Montelukast crude).
Montelukast methyl ester (5.0g, 0.00834 mol) was dissolved in a mixture of methanol: tetrahydrofuran (3:1, 40 ml) at room temperature. Cooled the solution to 0°C and added 1M sodium hydroxide solution (20 ml, 0.02 mol) was added to the above solution and stirred the reaction mass at room temperature for 2 days. Most of the methanol and THF was evaporated under reduced pressure at 35 -40°C. The pH of the reaction mass was adjusted to 5 with acetic acid, ammonium chloride solution and extracted with ethylacetate. Organic layer was washed with

20% w/v sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure at 40-45°C to get 3.2g residue of 1-(((1-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (Montelukast crude). Yield (65.57%)
Step IV:
Preparation of Dicyclohexylamine salt of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid.
The crude Montelukast (3.2 g, 5.47 mmol) was suspended in toluene (24 ml) and the suspension was stirred for 30 min under nitrogen atmosphere to get a clear solution. Dicyclohexylamine (1.1 g, 6 mmol) was added to the clear solution and the reaction mass was stirred for 15 min at 20-25°C. Carbon (0.32 g) was added and stirred the mass for 1 h at 20-25°C and mass was filtered through hyflo and washed the bed with toluene (6.5 ml). The filtrate was diluted with 16 ml of toluene and seeded with dicyclohexylamine salt of montelukast (25 mg). The solution was stirred for 3 h at 20-25°C and n-heptane (23 ml) was added very slowly over a period of 2 h at 20-25°C, a thick white slurry was obtained. The slurry containing Montelukast dicyclohexyl amine salt was filtered and dried (2.5 g). Purity 97.0% by HPLC. Yield (59.67 %)
Step V:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Montelukast)

Montelukast DCHA salt (2.5 g, 3.26 mmol) was suspended into a mixture of toluene (50 ml) and DM water (37.5 ml) and the resulting mixture was treated with acetic acid until clear solution obtained. The organic layer was separated and the toluene was evaporated completely under reduced pressure to obtain yellowish residue. Methylene chloride (17.5 ml) was added to the residue and stirred at 35°C to get the clear solution and hexane was added slowly for 1 hr. The product obtained was filtered and washed with a mixed solution of methylene chloride and hexane (1:3, 12 ml) and dried. Yield: 1.65 g (86.39 %). Purity 98.21 % by HPLC.