FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "Process for the preparation of Montelukast and its salts
thereof1
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered
Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri
(East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in
which it is to be performed.


PROCESS FOR THE PREPARATION OF MONTELUKAST AND ITS SALTS
THEREOF
FIELD OF THE INVENTION:
The present invention relates to a purification process for removing montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III up to below detection limit (Limit of detection = 0.1% w/w and Limit of quantitation =0.25% w/w) from montelukast and its pharmaceutically acceptable salts thereof. The process comprises treating montelukast acid with di-n-butyl amine to get di-n-butyl amine salt of montelukast followed by the treatment of di-n-butyl amine salt of montelukast with base in the presence of molecular sieves.
BACKGROUND OF THE INVENTION:
Montelukast sodium is described chemically as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy-1 -methylethyl)phenyl]propyl]thio] methyl]cyclopropaneacetic acid, monosodium salt having the structural Formula I, and is known from U.S. Patent No. 5,565,473.


The proprietary name of montelukast sodium is Singulair and is indicated for the prophylaxis and chronic treatment of asthma, for prevention of exercise-induced bronchoconstriction and for relief of symptoms of allergic rhinitis in adults.
U.S. Patent No. 5,565,473 discloses a process for preparing montelukast sodium by reacting 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyI) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1-(acetylthiomethyl) cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium of Formula (I). The Process is not suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and / or the final product with low yield.
Montelukast and its pharmaceutically acceptable salts are obtained by complex synthetic procedures which cause the formation of several by-products due to competing side reactions. These processes need tedious workups to isolate the montelukast and its intermediates and thus results in excess time cycle, which in turn rendering the process more costly and less eco friendly.
Montelukast and its precursors are unstable to oxygen and light causing a fast degradation. For the above reasons, montelukast is generally obtained with a low degree of chemical and optical purity.
Some processes for the purification of montelukast have been described in the art which are based on the formation of its salts.

U.S. Patent No. 5,614,632 describes a process for the preparation of montelukast, which comprises reacting the dilithium dianion of l-(mercaptomethyl)-cyclopropane acetic acid with 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol to afford montelukast acid. The crude montelukast acid is purified through the formation of its dicyclohexyl amine salt U.S. Patent Publication No. 2005/0234241 describes a process for the purification of montelukast via the formation of an amine salt using the amine NR1R2R3, wherein R1 = R2 = R3 = H or C1-5 alkyl, CM alkyl, preferably R1= (CH3)3C- and R2= R3= H.
U.S. Patent Publication No. 2005/107612 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as, tert butyl amine salt and phenyl ethylamine.
PCT Application no. 2006/008751 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as diisopropylamine, dipropylamine, tributylamine, dibenzylamine, dicyclohexylamine, alpha-methylbenzylamine.
U.S. Patent Publication No. 2007/0078158 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as di-n-propyl amine.
U.S. Patent Publication No. 2007/0213365 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclododecyl amine, dicyclohexyl amine, phenethyl amine and cyclooctyl amine.
PCT Application no. 2008/017669 describes a process for the purification of montelukast via the formation of an amine salt using the amine selected from the

group consisting of tris-(hydroxymethyl) aminemethane, L-(+)-threo-2-amino-l-phenyl-l,3-propanediol, and L-(+)-a-phenylglycinol, in the presence of an appropriate solvent.
PCT Application no. 2008/062478 describes a process for the purification of montelukast via the formation of an amine salt using the amine selected from cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, pyrrolidine or morpholine or alkyl amines such as methyl amine, isopropyl amine, diisopropyl amine, tert-butyl amine, n-butyl amine, isobutyl amine, sec-butyl amine and n-methyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine.
PCT Application no. 2008/023044 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as trans-4-aminocyclohexanol, cyclohexylamine, dicyclohexylamine, tertiary octylamine.
PCT Application no. 2008/015703 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as isopropyl amine and cyclohexyl amine.
U.S. Patent No. 7,446,116 describes a process for the purification of montelukast via the formation of an amantadine salt of montelukast.
U.S. Patent Publication No. 2009/0005413 describes a process for the purification of montelukast via the formation of tert-butyl amine salt of montelukast.
PCT Application no. 2009/098271 describes a process for the purification of montelukast via the formation of montelukast tert-amylamine salt.

The purification processes hitherto reported for montelukast sodium are not able to remove following impurities up to below detection limit (Limit of detection = 0.1% and Limit of quantitation =0.25%):
1. Montelukast sulphoxide impurity of formula II.

2. Montelukast styrene impurity of formula III.


Accordingly there is a need in the art to develop a purification process of montelukast sodium, which removes the montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III up to below detection limit (Limit of detection = 0.1% and Limit of quantitation =0.25%).
SUMMARY OF THE INVENTION:
The first aspect of the present invention is to provide a commercially viable process for the purification of montelukast and its salts thereof.
The second aspect of the present invention is to provide a purification process for removing montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III up to below detection limit (Limit of detection = 0.1% and Limit of quantitation =0.25%) from montelukast and its pharmaceutically acceptable salts thereof.
The third aspect of the present invention is to provide a purification process of montelukast and its pharmaceutically acceptable salts thereof comprising the steps of:
(a) treating montelukast acid with di-n-butyl amine base to get di-n-butyl amine salt of montelukast
(b) treating di-n-butyl amine salt of montelukast with base in the presence of molecular sieves,
(c) isolating montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III and optionally converting into its pharmaceutically acceptable salts.
The fourth aspect of the present invention is to provide crystalline di-n-butyl amine salt of montelukast.

The fifty aspect of the present invention is to provide montelukast and its pharmaceutically acceptable salts thereof substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III.
The present invention relates to a purification process of montelukast sodium, which removes the montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III up to below detection limit (Limit of detection = 0.1% and Limit of quantitation =0.25%). The process comprises treating montelukast acid with di-n-butyl amine to get di-n-butyl amine salt of montelukast followed by the treatment of di-n-butyl amine salt of montelukast with base in the presence of molecular sieves.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depict X-Ray diffraction pattern of the Montelukast di-n-butyl amine salt
Figure .2 depict FTIR spectrum of the Montelukast di-n-butyl amine salt
The powder X-ray diffraction data were obtained by the known method by using PANALYTICAL powder X-ray diffractometer model XPERT-PRO equipped with solid -state detector. Copper radiation of 1.54 A0 was used for the analysis.
IR spectra were obtained by using FTIR-8400 model of Shimadzu in DRS mode.l.Omg of compound is mixed with 300.0mg dried KBr Pellet of this mixture is analysed in the range of 400 to 4000 m-1 .

DETAILS DESCRIPTION OF THE INVENTION
Montelukast acid may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,565,473; 5,523,477; 5,614,632; 7,501,517 and 7,528,254, which are incorporated herein by reference only.
Di-n-butyl amine salt of montelukast may be prepared by reacting montelukast acid with di-n-butyl amine base in an appropriate solvent.
An appropriate solvent may include toluene, ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The reaction of montelukast acid with di-n-butyl atfiine base may be carried out at a temperature in the range of-10°C to 70°C.
The reaction of montelukast with di-n-butyl amine base may be carried out for 30 minutes to 20 hours.
The Di-n-butyl amine salt of montelukast may be isolated by steps consisting of cooling, filtration, washing, drying or combination thereof.
The Di-n-butyl amine salt of montelukast may be dried under reduced pressure at a temperature in the range of 40°C to 50°C.
The Di-n-butyl amine salt of montelukast may be present in crystalline nature.
The crystalline nature of Di-n-butyl amine salt of montelukast may be characterized by X-ray pattern as depicted in Figure 1.

The crystalline nature of Di-n-butyl amine salt of montelukast may be characterized by FTIR spectrum as depicted in Figure 2,
The di-n-butyl amine salt of montelukast may be treated with base in the presence of molecular sieves at a temperature in the range of 0° to 30°C.
The examples of base may include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium amide, potassium-t-butoxide, calcium hydroxide or mixture(s) thereof.
The mesh size of molecular sieve may include between 2 A to 4A.
The di-n-butyl amine salt of montelukast may be treated with base in the presence of molecular sieves for 15 minutes to 12 hours.
The active carbon may optionally be included in the reaction mixture containing di-n-butyl amine salt of montelukast, base and molecular sieves.
The montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III may be isolated by filtration of reaction mixture containg montelukast, molecular sieves and optionally active carbon.
The filtration of reaction mixture may be carried out at an ambient temperature.
The ambient temperature is a temperature in the range of 25°C to30°C.

The montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III may be precipitated by treating montelukast filtrate with non polar solvent.
Example of non polar solvent may include hexane, heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture(s) thereof.
The montelukast filtrate may be treated with non polar solvent at a temperature in the range of25°C to 30°C.
The montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III may be isolated by the steps consisting of cooling, filtration, washing and drying.
The montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III may be dried under reduced pressure at a temperature in the range of 40°C to 60°C.
The pharmaceutically acceptable salts of montelukast may include sodium salt.

In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE:
STEP 1:
PREPARATION OF l-[[[(lR)-l-[3-[(lE)-2-(7-CHLORO-2-QUINOLINYL) ETHENYLJ PHENYL]-3-[2-(l-HYDROXY-l-METHYLETHYL) PHENYL] PROPYL] THIO] METHYLCYCLO PROPANE ACETIC ACID DI-N-BUTYL AMINE SALT
To a solution of 2-[2-[(3S)-[3-[(2E)-(7-chIoro quinolin-2-yl) ethenyl] phenyl]-3-hydroxypropyl) phenyl-2-propanol (100 gm) in acetonitrile (400 ml) and dichloromethane (100ml), diisopropylethylamine (38 gm) was added and resulting reaction mixture was cooled to 20 to -15°C. Methane sulfonyl chloride (28 gm) was added in the above reaction mixture at -20 to -15 C and resulting reaction mixture was agitated for 12 hours and then resulting solids were filtered.
The above wet solids were dissolved in tetrahydrofuran (400ml) and added into a reaction mixture containing a solution of 1 -(mercaptomethyl) cyclopropane acetic acid (51 gm) in dimethylformamide (400 ml) and sodium hydroxide (58 gm, 50% aqueous solution) at -10 to -5°C for 1 hour. The reaction mixture was stirred for 4 hours at 25°C and then it was quenched into a solution of heptane (1000 ml) and water (500 ml). Organic layer was separated and discarded and aqueous layer was extracted with ethyl acetate (1000 ml). The ethyl acetate layer was treated with 5% tartaric acid to adjust pH to 5-6 and then aqueous layer was separated and discarded and ethyl acetate layer was concentrated under reduced pressure at 35°C to obtain an oily residue.

The oily residue was dissolved in acetonitrile (1000 ml) and isopropanol (100 ml) solvents and di-n-butyl amine (30 gm) was added and then resulting reaction mixture was agitated for 15 minutes at 60°C. The resulting reaction mixture was gradually cooled to 25-30°C, agitated for 12 hours and resulting solids were filtered, washed with acetonitrile (50 ml) and dried under reduced pressure at 45°C. Yield: 45 gm
STEP 2:
PREPARATION OF MONTELUKAST SODIUM SUBSTANTIALLY FREE FROM MONTELUKAST SULPHOXIDE IMPURITY OF FORMULA II AND MONTELUKAST STYRENE IMPURITY OF FORMULA III
Montelukast di-n-butyl amine salt (45 gm) was taken into toluene (400 ml) and
resulting suspension was agitated for 30 minutes at 25°C. Sodium methoxide (5 gm),
molecular sieve (20 gm) and active carbon (2.5 gm) were added into the suspension
and then resulting reaction mixture was agitated for 30 minutes. The reaction mixture
was filtered through celite bed and filtrate was treated with heptane (1350 ml).The
reaction mixture was agitated for 1 hour at 25°C and resulting solids were filtered,
washed with heptane (50 ml) and dried under reduced pressure at 50°C.
Yield: 30 gm
Purity: 99.95 %( By HPLC)
Montelukast sulphoxide impurity of formula II: Non detectable
Montelukast styrene impurity of formula III: Non detectable
Limit of detection: 0.1% w/w
Limit of quantitation: 0.25% w/w

WE CLAIM:
1. A purification process of montelukast and its pharmaceutically suitable salts thereof
comprising the steps of:
(a) treating montelukast acid with di-n-butyl amine base to get di-n-butyl amine salt of montelukast
(b) treating di-n-butyl amine salt of montelukast with base in the presence of molecular sieves,
(c) isolating montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III and optionally converting into its pharmaceutically acceptable salts.

2. The process according to claim 1, wherein montelukast acid is treated with di-n-butyl amine base in a solvent selected from the group comprising of toluene, ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
3. The process according to claim 1, wherein reaction of montelukast acid with di-n-butyl amine base is carried out at a temperature in the range of -10°C to 70°C for 30 minutes to 20 hours.
4. The process according to claim 1, wherein di-n-butyl amine salt of montelukast is crystalline in nature and characterized by X-ray pattern as depicted in Figure 1 and FTIR spectrum as depicted in Figure 2.
5. The process according to claim 1, wherein di-n-butyl amine salt of montelukast is treated with base in the presence of molecular sieves at a temperature in the range of 0° to 30°C for 15 minutes to 12 hours.

6. The process according to claims 1 and 5, wherein base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium amide, potassium-t-butoxide, calcium hydroxide or mixture(s) thereof.
7. The process according to claim 1, wherein montelukast substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III is isolated by precipitation with non polar solvent at a temperature in the range of 25°C to 30°C.
8. The process according to claim 7, wherein non polar solvent is selected from the group comprising of hexane, heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture(s) thereof.
9. The process according to claim 1, wherein isolated montelukast, substantially free from montelukast sulphoxide impurity of formula II and montelukast styrene impurity of formula III is optionally converted into its pharmaceutically acceptable salts.
10. A purification process of montelukast and its pharmaceutically suitable salts
thereof as herein described in specification and example.

Dated this 06th day of November 2009
Signature:
Name: Dr. Rajendra Agarwal