FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
''AN IMPROVED PROCESS FOR THE PURIFICATION OF MONTELUKAST ACID AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Enaltcc Labs Pvt Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No. 5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PURIFICATION OF MONTELUKAST ACID AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to an improved process for the purification of montelukast acid and its pharmaceutically acceptable salts thereof comprising treating crude montelukast or its pharmaceutically acceptable salts thereof with amino acids or its ester or amide thereof and isolating substantially pure montelukast or its pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Montelukast sodium is chemically described as the sodium salt of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid and is known from U.S Patent No. 5,565,473 and is represented by formula 1.

Formula 1
Montelukast sodium is a leukotriene antagonist and is indicated for the treatment of asthma allergic rhinitis.

U.S. Patent No. 5,614,632 describes a process for the purification of montelukast via the formation of its dicyciohexyl amine salt
U.S. Patent No. 7.446, 116 describes a process for the purification of montelukast via the formation of its amantadine salt.
U.S Patent Publication No. 2007/0213365 provides a process for preparing montelukast sodium from a crystalline montelukast ammonium salt. The process preferably includes converting the crystalline montelukast ammonium salt to montelukast sodium.
U.S Patent Publication No. 2007/0078158 relates to methods of purifying montelukast comprising converting montelukast free acid to montelukast di-n-propylamine salt and converting the montelukast di-n-propylamine salt to montelukast sodium salt.
U.S. Patent Publication Nos 2008/0097104; 2009/0143590; 2009/0247759; 2009/0005413; 2009/0111849; 2009/0171092 and 2009/0281323, PCT Application nos. 2006/064269; 2007/004237; 2008/062478; 2008/015703; 2008/009970; 2008/023044; 2009/113087; 2009/016191; 2009/027990; 2009/052625; 2009/117381; 2009/144742; 2009/098271 and 2009/006861 describe different processes for the purification of montelukast acid and its pharmaceutically acceptable salts thereof via the formation of an amine salts.
PCT Application No. 2008/049922 describes a process for purifying montelukast acid via the formation of its arginine salt.
Indian Patent Application No. 2406/MUM/2008 describes the process for the purification of montelukast acid via the formation of its dibutyl amine salt.
The process hitherto reported for the purification of montelukast acid or it's pharmaceutically acceptable salts thereof are not able to remove the following potential

b. Montelukast sulfoxide impurity of formula III
impurities below detection limit, wherein detection limit is 0.1% w/w of montelukast acid or it's pharmaceutically acceptable salts thereof. a. Montelukast styrene impurity of formula II


Our own Patent Application No. 9063/MUM/2009 describes the process for the purification of montelukast acid via the formation of its 4-chlorobenzhydryl amine salt.
Accordingly, there is a need in the art to develop an improved process for the purification of montelukast acid and its pharmaceutically acceptable salts thereof

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide an improved process for the purification of montelukast acid and its pharmaceutically acceptable salts thereof, which obviates the disadvantages of prior art processes for the purification of montelukast acid and its pharmaceutically acceptable salts thereof.
A second aspect of the present invention is to provide pharmaceutically acceptable salt of montelukast acid with following amino acids or its esters or its amide thereof:
1. Citrulline 8. Phenylalanine 15. Aspartic acid
2. Tyrosine 9. Tryptophan 16. Cysteine
3. Glutamine 10. Isoleucine 17. Glycine
4. Glutamic acid 11. Threonine 18. Proline
5. Histidine 12. Valine 19. Serine

6. Lysine 13. Leucine 20. Asparagine
7. Methionine 14. Alanine 21. Selenocysteine
A third aspect of the present invention is to provide a purification process of montelukast acid and its pharmaceutically acceptable salts thereof comprising the steps of;
a. treating crude montelukast acid with amino acids or its esters or its amide thereof
selected from the group comprising of citrulline, tyrosine, glutamine, glutamic
acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine to get a salts of montelukast acid,
b. isolating salts of montelukast acid with amino acids or its esters or its amide
thereof selected from the group comprising of citrulline, tyrosine, glutamine,
glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine.

c. converting salts of montelukast acid with amino acids or its esters or its amide
thereof selected from the group comprising of citrulline, tyrosine, glutamine,
glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine into substantial pure montelukast acid and
d. optionally converting substantial pure montelukast acid into montelukast sodium
or its pharmaceutically acceptable salts thereof
The amino acids used for the purification of montelukast acid and its pharmaceutically acceptable salts thereof include D and L form.
A fourth aspect of the present invention is to provide crystalline forms of salts of above mentioned amino acids with montelukast acid.
A fifth aspect of the present invention is to provide amorphous form of salts of above mentioned amino acids with montelukast acid.
A sixth aspect of the present invention is to provide substantially pure montelukast acid and its pharmaceutically acceptable salts thereof obtained by neutralizing the salts of above mentioned amino acids with montelukast acid with an inorganic acid.
The substantially pure montelukast acid and its pharmaceutically acceptable salts thereof means the montelukast acid and its pharmaceutically acceptable salts thereof containing less than 0.1% wt/wt of following impurities. a. Montelukast styrene impurity of formula II


b. Montelukast sulfoxide impurity of formula III

DETAIL DESCRIPTION OF THE INVENTION
Crude montelukast acid may be formed by methods known in the art such as those described in U.S Patent nos, 5,565,473; 7,189,853; 7,547,787; 7,501,517; 7,417,149; 7,528,254 and 7,476,748, which are incorporated herein by reference only.
Crude montelukast acid may contain up to the 7,5% weight / weight of montelukast styrene compound of structural formula II and montelukast sulfoxide compound of structural formula III.
The reaction of crude montelukast with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine.

leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine may be carried out for a period of 30 minutes to 12 hours at a temperature in the range of 0°C to 60°C to get a salts of montelukast acid.
The reaction of crude montelukast with amino acids or its esters or its amides thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine may be carried out in an organic solvents.
The examples of organic solvents may include halogenated hydrocarbons, alkyl acetates, alcohols and ethers.
The examples of halogenated hydrocarbon solvents may include but not limited to dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
The examples of alkyl acetate solvents may include but not limited to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
The examples of alcohol solvents may include but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-ethoxy ethanol or mixture(s) thereof.
The examples of ether solvents may include but not limited to tetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether or mixture(s) thereof.
The salts of montelukast acid with amino acids or its esters or its amides thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine may

be isolated by the steps of filtration, centrifugation, washing, drying and the combination(s) thereof.
The salts of montelukast acid with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine may be converted into substantially pure montelukast sodium by treating them with an inorganic acid or organic acid and then with sodium methoxide in an organic solvent.
The examples of inorganic acid may include hydrochloric acid or hydrobromic acid.
The examples of organic acid may include acetic acid or tartaric acid.
The salts of montelukast acid with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine may be treated with above mentioned inorganic acid at a temperature in the range of 0°C to 20°C to get a substantially pure montelukast acid.
The substantially pure montelukast acid refers to the montelukast acid having less than 0.1% weight / weight of montelukast styrene compound of structural formula II and montelukast sulfoxide compound of structural formula III.
The substantially pure montelukast acid may be converted into montelukast sodium by treating substantially pure montelukast acid with a source of sodium ion in an alcohol or ketone solvents.
The source of sodium ion may include sodium hydroxide or sodium methoxide.

The examples of ketone solvents may include acetone, methyl isobutyl ketone, 2-butanone, 3-pentanone or mixture(s) thereof.
The reaction of substantially pure montelukast acid with source of sodium ion may be carried out at a temperature in the range of -10°C to 10°C.
The reaction of substantially pure montelukast acid with source of sodium ion may be carried out for 30 minutes to 8 hours to get montelukast sodium.
The montelukast sodium may be isolated by the steps of filtration, centrifugation, washing, drying or the combination(s) thereof.
The montelukast sodium may be dried at a temperature in the range of 50°C to 60°C for a period of 18 hours to 48 hours.
EXAMPLES
In the following examples, 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 1: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (50gm) in ethyl acetate (500ml) was added to citrulline (15gm) at 0-5°C and then the resulting reaction mixture was agitated for 4 hours at the same temperature. The resulting solids were filtered, dissolved in water (250ml) and then it was treated with acetic acid (7 ml) at 25-30°C. The resulting reaction mixture was extracted with ethyl acetate (300ml) and then sodium methoxide (5.5gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction mixture was stirred for 2 hours at 20-25°C and then the reaction mixture was concentrated under reduced pressure at 30-35°C to get the title compound.

Yield: 47.2gm
Purity: 99.95% (By HPLC)
Compound of structural formula II: 0.01% (weight/weight by HPLC)
Compound of structural formula III: 0.02% (weight/weight by HPLC)
Example 2: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in n-propyl acetate (1000ml) was added to
tyrosine (32gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(500ml) and then it was treated with acetic acid (26 ml) at 25-30°C. The resulting
reaction mixture was extracted with n-propyl acetate (750ml) and then sodium methoxide
(12gm) was added at 0-5°C into the n-propyl acetate layer and then resulting reaction
mixture was stirred for 3 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 95gm
Purity: 99.99% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable
Example 3: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in toluene (1000ml) was added to
glutamine (26gm) at 0-5°C and then the resulting reaction mixture was agitated for 1
hour at the same temperature. The resulting solids were filtered, dissolved in water
(400ml) and then it was treated with acetic acid (15 ml) at 25-30°C. The resulting
reaction mixture was extracted with toluene (750ml) and then sodium methoxide
(11.5gm) was added at 0-5°C into the toluene layer and then n-heptane (400ml) was
added to get the title compound.
Yield: 96gm
Purity: 99.97% (By HPLC)
Compound of structural formula II: 0.05% weight/weight

Compound of structural formula III: 0.03% weight/weight
Example 4: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in n-propyl acetate (750ml) was added to
glutamic acid (28gm) at 10-15°C and then the resulting reaction mixture was agitated for
2 hours at the same temperature. The resulting solids were filtered, dissolved in water
(500ml) and then it was treated with acetic acid (17 ml) at 25-30°C. The resulting
reaction mixture was extracted with n-propyl acetate (750ml) and then sodium methoxide
(12.5gm) was added at 0-5°C into the n-propyl acetate layer and then resulting reaction
mixture was stirred for 2 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 97.5gm
Purity: 99.98% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable
Example 5: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in butyl acetate (750ml) was added to
histidine (29gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(500ml) and then it was treated with acetic acid (18 ml) at 25-30°C. The resulting
reaction mixture was extracted with butyl acetate (750ml) and then sodium methoxide
(12.5gm) was added at 0-5°C into the butyl acetate layer and then resulting reaction
mixture was stirred for 2.5 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 96gm
Purity: 99.91 % (By HPLC)
Compound of structural formula II: 0.07% weight/weight
Compound of structural formula III: 0.01% weight/weight

Example 6: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (750ml) was added to
lysine (26gm) at 10-15°C and then the resulting reaction mixture was agitated for 3 hours
at the same temperature. The resulting solids were filtered, dissolved in water (350ml)
and then it was treated with acetic acid (17 ml) at 25-30°C. The resulting reaction mixture
was extracted with ethyl acetate (500ml) and then sodium methoxide (12.5gm) was added
at 0-5°C into the ethyl acetate layer and then resulting reaction mixture was stirred for 2
hours at 20-25°C and then the reaction mixture was concentrated under reduced pressure
at 30-35°C to get the title compound.
Yield: 95gm
Purity: 99.98% (By HPLC)
Compound of structural formula II: 0.01% weight/weight
Compound of structural formula III: Not detectable
Example 7: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (750ml) was added to
methionine (26gm) at 10-15°C and then the resulting reaction mixture was agitated for 3
hours at the same temperature. The resulting solids were filtered, dissolved in water
(350ml) and then it was treated with acetic acid (16 ml) at 25-30°C. The resulting
reaction mixture was extracted with ethyl acetate (650m\) and then sodium methoxide
(13gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction
mixture was stirred for 2 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 94gm
Purity: 99.96% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: 0.01% weight/weight

Example 8: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in isopropyl acetate (750ml) was added to
phenylalanine (23gm) at 10-15°C and then the resulting reaction mixture was agitated for
2 hours at the same temperature. The resulting solids were filtered, dissolved in water
(550ml) and then it was treated with acetic acid (13 ml) at 20-25°C. The resulting
reaction mixture was extracted with isopropyl acetate (650ml) and then sodium
methoxide (13gm) was added at 0-5°C into the isopropyl acetate layer and then resulting
reaction mixture was stirred for 2.5 hours at 15-20°C and then the reaction mixture was
concentrated under reduced pressure at 35-40°C to get the title compound.
Yield: 98gm
Purity: 99.99% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable
Example 9: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (lOOgm) in isopropyl acetate (750ml) was added to
tryptophan (27gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(550ml) and then it was treated with acetic acid (12 ml) at 20-25°C. The resulting
reaction mixture was extracted with isopropyl acetate (750ml) and then sodium
methoxide (12.5gm) was added at 0-5°C into the isopropyl acetate layer and then
resulting reaction mixture was stirred for 2.5 hours at 0-5°C and then the reaction mixture
was concentrated under reduced pressure at 35-40°C to get the title compound.
Yield: 97gm
Purity: 99.99% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable

Example 10: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (550ml) was added to
isoleucine (23gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(550ml) and then it was treated with acetic acid (13 ml) at 20-25°C. The resulting
reaction mixture was extracted with ethyl acetate (750ml) and then sodium methoxide
(12.5gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction
mixture was stirred for 2.5 hours at 0-5°C and then the reaction mixture was concentrated
under reduced pressure at 35-40°C to get the title compound.
Yield: 97gm
Purity: 99.98% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable
Example 11: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (50gm) in ethyl acetate (500ml) was added to
threonine (11 gm) at 0-5°C and then the resulting reaction mixture was agitated for 4
hours at the same temperature. The resulting solids were filtered, dissolved in water
(250ml) and then it was treated with acetic acid (7 ml) at 25-30°C. The resulting reaction
mixture was extracted with ethyl acetate (350ml) and then sodium methoxide (6 gm) was
added at 0-5°C into the ethyl acetate layer and then resulting reaction mixture was stirred
for 2 hours at 20-25°C and then the reaction mixture was concentrated under reduced
pressure at 30-35°C to get the title compound.
Yield: 47.2gm
Purity: 99.95% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: 0.02% (weight/weight by HPLC)

Example 12: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in n-propyl acetate (1000ml) was added to
valine (23gm) at 10-15°C and then the resulting reaction mixture was agitated for 2 hours
at the same temperature. The resulting solids were filtered, dissolved in water (750ml)
and then it was treated with acetic acid (13 ml) at 25-30°C. The resulting reaction mixture
was extracted with n-propyl acetate (900ml) and then sodium methoxide (12gm) was
added at 0-5°C into the n-propyl acetate layer and then resulting reaction mixture was
stirred for 3 hours at 20-25°C and then the reaction mixture was concentrated under
reduced pressure at 30-35°C to get the title compound.
Yield: 98gm
Purity: 99.98% (By HPLC)
Compound of structural formula IT: Not detectable
Compound of structural formula III: Not detectable
Example 13: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in toluene (1000ml) was added to leucine
(26gm) at 0-5°C and then the resulting reaction mixture was agitated for 1 hour at the
same temperature. The resulting solids were filtered, dissolved in water (400ml) and then
it was treated with acetic acid (14 ml) at 25-30°C. The resulting reaction mixture was
extracted with toluene (750ml) and then sodium methoxide (12gm) was added at 0-5°C
into the toluene layer and then n-heptane (750ml) was added to get the title compound.
Yield: 97gm
Purity: 99.97% (By HPLC)
Compound of structural formula II: 0.05% weight/weight
Compound of structural formula III: Not detectable
Example 14: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in n-propyl acetate (750ml) was added to alanine (16gm) at 10-15°C and then the resulting reaction mixture was agitated for 2 hours at the same temperature. The resulting solids were filtered, dissolved in water (600ml) and then it was treated with acetic acid (11 ml) at 25-30°C. The resulting

reaction mixture was extracted with n-propyl acetate (750ml) and then sodium methoxide
(12gm) was added at 0-5°C into the n-propyl acetate layer and then resulting reaction
mixture was stirred for 3 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 96.5gm
Purity: 99.95% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: Not detectable
Example 15: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in butyl acetate (750ml) was added to
aspartic acid (23gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(500ml) and then it was treated with acetic acid (13 ml) at 25-30°C. The resulting
reaction mixture was extracted with butyl acetate (750ml) and then sodium methoxide
(12.5gm) was added at 0-5°C into the butyl acetate layer and then resulting reaction
mixture was stirred for 3 hours at 25-30°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 94.7gm
Purity: 99.94% (By HPLC)
Compound of structural formula II: 0.02% weight/weight
Compound of structural formula III: 0.01% weight/weight
Example 16: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (lOOgm) in ethyl acetate (750ml) was added to cysteine (22gm) at 0-5°C and then the resulting reaction mixture was agitated for 2 hours at the same temperature. The resulting solids were filtered, dissolved in water (550ml) and then it was treated with acetic acid (13 ml) at 25-30°C. The resulting reaction mixture was extracted with ethyl acetate (500ml) and then sodium methoxide (12gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction mixture was stirred for 3

hours at 20-25°C and then the reaction mixture was concentrated under reduced pressure
at 30-35°C to get the title compound.
Yield: 98gm
Purity: 99.98% (By HPLC)
Compound of structural formula II: 0.01% weight/weight
Compound of structural formula III: Not detectable
Example 17: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (750ml) was added to
glycine (13gm) at 10-15°C and then the resulting reaction mixture was agitated for 2
hours at the same temperature. The resulting solids were filtered, dissolved in water
(650ml) and then it was treated with acetic acid (12 ml) at 25-30°C. The resulting
reaction mixture was extracted with ethyl acetate (750ml) and then sodium methoxide
(12gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction
mixture was stirred for 2 hours at 20-25°C and then the reaction mixture was
concentrated under reduced pressure at 30-35°C to get the title compound.
Yield: 98gm
Purity: 99.96% (By HPLC)
Compound of structural formula II; Not detectable
Compound of structural formula III: Not detectable
Example 18: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in isopropyl acetate (750ml) was added to proline (20gm) at 10-15°C and then the resulting reaction mixture was agitated for 2 hours at the same temperature. The resulting solids were filtered, dissolved in water (550ml) and then it was treated with acetic acid (12 ml) at 20-25°C. The resulting reaction mixture was extracted with isopropyl acetate (750ml) and then sodium methoxide (12.5gm) was added at 0-5°C into the isopropyl acetate layer and then resulting reaction mixture was stirred for 3 hours at 15-20°C and then the reaction mixture was concentrated under reduced pressure at 35-40°C to get the title compound.

Yield: 98gm
Purity: 99.98% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III; .01% weight/weight
Example 19: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in isopropyl acetate (750ml) was added to
serine (19gm) at 10-15°C and then the resulting reaction mixture was agitated for 3 hours
at the same temperature. The resulting solids were filtered, dissolved in water (650ml)
and then it was treated with acetic acid (13 ml) at 20-25°C. The resulting reaction mixture
was extracted with isopropyl acetate (750ml) and then sodium methoxide (13gm) was
added at 0-5°C into the isopropyl acetate layer and then resulting reaction mixture was
stirred for 3 hours at 0-5°C and then the reaction mixture was concentrated under reduced
pressure at 35-40°C to get the title compound.
Yield: 97.5gm
Purity: 99.97% (By HPLC)
Compound of structural formula II: .01% weight/weight
Compound of structural formula III: Not detectable
Example 20: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (650ml) was added to asparagine (23gm) at 10-15°C and then the resulting reaction mixture was agitated for 2 hours at the same temperature. The resulting solids were filtered, dissolved in water (550ml) and then it was treated with acetic acid (13 ml) at 20-25°C. The resulting reaction mixture was extracted with ethyl acetate (750ml) and then sodium methoxide (12gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction mixture was stirred for 3 hours at 0-5°C and then the reaction mixture was concentrated under reduced pressure at 35-40°C to get the title compound. Yield: 96gm Purity: 99.91% (By HPLC)

Compound of structural formula II: Not detectable Compound of structural formula III: .01% weight/weight
Example 21: Preparation of substantially pure montelukast sodium.
A solution of crude montelukast acid (100gm) in ethyl acetate (650ml) was added to
selenocysteine (29gm) at 10-15°C and then the resulting reaction mixture was agitated for
3 hours at the same temperature. The resulting solids were filtered, dissolved in water
(650ml) and then it was treated with acetic acid (14 ml) at 20-25°C. The resulting
reaction mixture was extracted with ethyl acetate (750ml) and then sodium methoxide
(12gm) was added at 0-5°C into the ethyl acetate layer and then resulting reaction
mixture was stirred for 3 hours at 0-5°C and then the reaction mixture was concentrated
under reduced pressure at 35-40°C to get the title compound.
Yield: 97gm
Purity: 99.97% (By HPLC)
Compound of structural formula II: Not detectable
Compound of structural formula III: .01% weight/weight

WE CLAIM:
1. A purification process of montelukast acid and its pharmaceutically acceptable salts thereof comprising the steps of:
a. treating crude montelukast acid with amino acids or its esters or its amide thereof
selected from the group comprising of citrulline, tyrosine, glutamine, glutamic
acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine to get a salts of montelukast acid,
b. isolating salts of montelukast acid with amino acids or its esters or its amide
thereof selected from the group comprising of citrulline, tyrosine, glutamine,
glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine.
c. converting salts of montelukast acid with amino acids or its esters or its amide
thereof selected from the group comprising of citrulline, tyrosine, glutamine,
glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine,
threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline,
serine, asparagine or selenocysteine into substantial pure montelukast acid and
d. optionally converting substantial pure montelukast acid into montelukast sodium
or its pharmaceutically acceptable salts thereof
2. The process according to claim no.l wherein crude montelukast acid is having up to the 7.5% weight / weight of montelukast styrene compound of structural formula II and montelukast sulfoxide compound of structural formula III.


3. The process according to claim no.1 wherein reaction of crude montelukast with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine is carried out for a period of 30 minutes to 12 hours at a temperature in the range of 0°C to 60°C to get a salts of montelukast acid.
4. The process according to claim no. 1, wherein reaction of crude montelukast with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine is carried out in an organic solvents.
5. The process according to claim no. 4, wherein organic solvent is selected from the group comprising of halogenated hydrocarbons, alkyl acetates, alcohols and ethers.
6. The process according to claim no. 5, wherein halogenated hydrocarbons solvent is dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof; alkyl acetate solvent is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof; alcohol solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-ethoxy ethanol or mixture(s) thereof and ether solvent is tetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether or mixture(s) thereof
7. The process according to claim no. 1, wherein salts of montelukast acid with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine. proline, serine, asparagine or selenocysteine is isolated by the steps of filtration, centrifugation, washing, drying and the combination(s) thereof.

8. The process according to claim no. 1, wherein salts of montelukast acid with amino acids or its esters or its amide thereof selected from the group comprising of citrulline, tyrosine, glutamine, glutamic acid, histidine, lysine, methionine, phenylalanine, tryptophan, isoleucine, threonine, valine, leucine, alanine, aspartic acid, cysteine, glycine, proline, serine, asparagine or selenocysteine is converted into substantially pure montelukast sodium by treating them with an inorganic acid or organic acid and then with sodium methoxide in an organic solvent.
9. The process according to claim no. 8, wherein inorganic acid is hydrochloric acid or hydrobromic acid and organic acid is acetic acid or tartaric acid.
10. The process according to claim no. 8 wherein substantially pure montelukast sodium
is having less than 0.1% weight / weight of montelukast styrene compound of structural
formula II and montelukast sulfoxide compound of structural formula III.