FIELD 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-1-methylethyl)phenyl]propyl]thio]-methyl]cyclopropaneacetic acid, monosodium salt of Formula I.

BACKGROUND OF THE INVENTION
[R-(E)]-l-[[[143-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(l-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 CysLT1 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)propyl)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) cyclopropyl acetate (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:

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 unprotected 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 (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 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl) phenyl)-2-propanol (VI) can be protected before condensing with 1-(mercaptomethyl)cyclopropaneacetic acid (VII) and the resulting protected intermediate used as such to produce Montelukast of high purity and yield.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, novel and effective process for the preparation of Montelukast sodium of high purity 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-propoxy) tetrahydropyran (II) [mesyl derivative];

ii) treating the tetrahydropyranyl Montelukast (X) with a catalyst followed by treatment with dicyclohexylamine in a solvent to produce dicyclohexylamine salt of l-(((l-(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) Montelukast DCHA salt (IX) is treated 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-1-methylethyl) phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium (I) (Montelukast sodium).
DETAILED DESCRIPTION OF THE INVENTION
The reaction of 1 -(mercaptomethyl)cyclopropane acetic acid (VII) with alkyl lithium is carried out in a solvent selected from tetrahydrofuran, hexanes, toluene, preferably in tetrahydrofuran at a temperature of about -10°C to about -50°C, preferably -15 to -20°C under nitrogen atmosphere. The alkyl lithium is selected from n-butyl lithium, methyl lithium and isopropyl lithium. The mesyl derivative, 2-(2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyloxy)methylethyl)-phenyl)-2-propoxy)tetrahydropyran (II) which is prepared as per the procedure described in US 5,565,473, in a solution of tetrahydrofuran, hexanes or toluene, preferably in tetrahydrofuran is added to the

above reaction mass at a temperature of about 0°C to -20°C, preferably -5°C to about -10°C. The reaction mass is stirred for about 5 to 10 hrs, preferably 7-8 hrs. After completion of the reaction the reaction mass is poured in 1:1 v/v mixture of aqueous sodium chloride and solvent selected from ethylacetate, methylenechloride, toluene, 1,2-dichloroethane. 1 -(((1 -(R)(3 -(2-(7- chloroquinolin-2«yl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranl)oxy) methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate (X)
(tetrahydropyranyl Montelukast) is finally isolated from the organic layer by evaporating the solvent.
Tetrahydropyranyl Montelukast (X) is further treated with a catalyst selected from pyridinium-para-toluenesulfonate, pyridinium-ortho-toluenesulfonate, pyridinium-benzenesulfonate, pyridinium-methanesulfonate, preferably pyridinium-para-toluenesulfonate in a solvent selected from methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, dioxane or mixtures thereof, preferably 3:1 mixture of methanol and tetrahydrofuran. The reaction is carried out at a temperature of about 40°C to 80°C, preferably at about 55 to 60°C for about 8 to 15 hrs, preferably 10 to 12 hrs. The residue containing crude Montelukast is suspended in a solvent selected from toluene, xylene, preferably toluene, and is treated with dicyclohexylamine. The resulting mass is treated with carbon and the filtrate is stirred for 2 to 5 hrs, 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 slowly for about 1 to 2 hrs. The resulting mass is stirred for 10 to 15 hrs 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).
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 and inorganic acid is selected from HC1 or HBr 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 Motelukast 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.
EXAMPLE
Step I:
Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(methanesulfonyl-oxy)methylethyl)phenyl)-2-propoxy)tetrahydropyran (mesyl derivative).
l-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-((tetrahydropyran-2-yl)oxy)-2-propyl) phenyl-1-propanol (18 g, 33 mmol) was dissolved in methylene chloride (300 ml) at 25 - 30°C, triethylamine (5 g, 50 mmol) was added and cooled the solution to -50°C. Methanesulfonyl chloride (4.94 g, 43 mmol) was added at -50°C to -40°C. The resulting solution was stirred at -50°C to -40°C for 1 h. After completion of reaction, the mixture was diluted with saturated sodium bicarbonate and extracted with CH2Cl2, dried over sodium sulfate, and methylene chloride was evaporated under reduced pressure to obtain mesyl derivative as oily mass (19 g).

Step II:
Preparation of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(2-(2-(2-tetrahydropyranl)oxy)methyIethyl)phenyl)propyl)thio)methyl) cyclopropaneacetate (Tetrahydropyranyl Montelukast).
1-(Mercaptomethyl)cyclopropane acetic acid (5.10g, 35 mmol) was dissolved in tetrahydrofuran (150 ml) at 25-30°C and cooled the solution to -15°C. n-Butyl lithium (26.46 g. 413 mmol) was added under nitrogen atmosphere and stirred the slurry at -5°C for 30 min. Prepared a solution of mesyl derivative produced in step I (18g, 29 mmol) in tetrahydrofuran (80 ml) at 0°C under nitrogen and was added to the slurry at -5°C to -10°C slowly. The reaction mass was stirred at -5°C to 0°C for 8h and progress of the reaction was monitored by TLC.
After completion of reaction, the reaction mass was poured into 1:1 v/v mixture of ethyl acetate and 10% w/v aqueous sodium chloride solution. Washed the organic phase with 0.5 M tartaric acid and washed with DM water. The solvent was removed under reduced pressure to obtain tetrahydropyranyl Montelukast as an oily compound (19.80 g).
Step III:
Preparation of l-(((l-(R)-(3-(2-(7-chIoroquino!in-2-yl)ethenyl)phenyl)-3-(2-(l-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid (Crude Montelukast).
A solution of Step II containing tetrahydropyranyl Montelukast (19 g, 28 mmol) was treated with pyridinium p-toluene sulfonate (21.36g, 85 mmol) in a 3:1 mixture of methanol: tetrahydrofuran (160 ml). The reaction mixture was warmed to 60°C and stirred for 12 h, the progress of the reaction was monitored by TLC. After completion of the reaction most of the methanol was evaporated and an

aqueous solution of ammonium chloride was added. The product was extracted with ethyl acetate, washed with sodium chloride and dried over Na2SO4. Ethyl acetate was evaporated to obtain the title compound (16 g).
Step IV:
Preparation of Dicyclohexylamine salt of l-(((l-(R)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyI)-3-(2-(l-hydroxy-l-methyIethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid.
The crude Montelukast (10 g, 17 mmol) was suspended in toluene (75 ml) and the suspension was stirred for 30 min under nitrogen atmosphere to get a clear solution. Dicyclohexylamine (3.38 g, 19 mmol) was added to the clear solution and the reaction mass was stirred for 15 min at 20-25°C. Carbon (1 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 (20 ml). The toluene (50 ml) was added and seeded with DCHA salt of Montelukast (50 mg). The solution was stirred for 3 h at 20-25°C and n-heptane (70 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 (6 g).
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 (5 g, 6.5 mmol) was suspended into a mixture of toluene (100 ml) and DM water (75 ml) and the resulting solution 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 (35 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 hexane (25 ml) and dried. Yield: 3.40 g.