FIELD OF INVENTION
The present invention relates to a process for purification of Montelukast sodium.
BACK GROUND OF THE INVENTION
Montelukast sodium, the active ingredient in SINGULAIR marketed by Merck, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTl receptor. Montelukast sodium is described chemically as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl] cyclo propaneacetic acid, monosodium salt of formula I, is available in a number of oral formulations including tablets, chewable tablets, and oral granules.


COONa
Formula I

EP 480717 (EP c717) discloses Montelukast and its physiologically acceptable salts. EP '717 discloses the preparation of Montelukast sodium as follows.



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Cesium carbonate Hydrazine

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Pyrdinium p-toluenesulfonate

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Sodium hydroxide
Ethnnol
Formula I
IN 237739 discloses the preparation of Montelukast sodium by the conversion of Montelukast amine salt to Montelukast wherein the purification of Montelukast amine salt is carried out
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from toluene, methanol, ethanol, isopropanol, n-propanol, ethylacetate, methylacetate, acetone, acetonitrile or mixtures thereof.
WO 2008/017669 Al discloses the preparation of Montelukast sodium by the conversion of Montelukast chiral amine salt to Montelukast.
WO 2007/069261 Al discloses the preparation of Montelukast sodium by the conversion of Montelukast amine salt to Montelukast, wherein the purification of Montelukast amine salt is carried out with hydrocarbon solvents like toluene, hexanes, heptane or keto solvents like acetone or mixture thereof.
WO 2007/116240 Al discloses the preparation of Montelukast sodium by the conversion of Montelukast amine salt to Montelukast, wherein the purification of Montelukast amine salt is carried out with halogenated organic solvents, ethers, alkyl acetates, aromatic hydrocarbons, etc.
WO 2004/108679 discloses the. preparation of Montelukast sodium by isolation of dicyclohexylamine (DCHA) salt of montelukast acid, followed by purification using lengthy crystallization process in toluene and vacuum drying to get desired purity of 99% of montelukast acid.
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Further, the purity of montelukast sodium obtained as per the prior art process is less due to
£ the interference of couple of impurities in high extent such as montelukast methylstyrene,
montelukast sulfoxide, montelukast cis isomer, montelukast methyl ketone and montelukast

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not viable on industrial scale.
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In view of the above, there is a need to develop a purification process, which is commercially and industrially feasible and the present inventors have now found a purification process by which the obtained product has high yield and purity.
OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide a purification process for preparing
Montelukast sodium.
Another objective of the present invention is to provide a process for preparing pure Montelukast sodium by using highly pure Montelukast amine salt.
Another objective of the present invention is to provide a process for preparing pure Montelukast sodium, which is substantially free of montelukast methylstyrene impurity, montelukast sulfoxide impurity, montelukast cis isomer impurity, montelukast methyl ketone impurity and montelukast michael adduct impurities.
Another objective of the present invention is to provide a process for*the preparation of Montelukast sodium having purity greater than 99.9% and with acceptable level of residual solvents which is suitable for pharmaceutical formulation.
SUMMARY OF THE INVENTION

The present invention provides a process for preparing Montelukast sodium having purity greater than 99.9% (by HPLC) which comprises:
g a. treating Montelukast amine salt with chlorobenzene;
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£ d. optionally removing the solvent;
e. treating the montelukast amine salt with an organic solvent;
f. optionally isolating Montelukast amine; and
g. converting Montelukast amine salt to Montelukast sodium.

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Formula V

5. Montelukast michael adduct impurities of formulae Via (R,R-isomer) and VIb (R,S-isomer)


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COOH
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DETAILED DESCRIPTION OF THE INVENTION

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F F I C E C H E H U A-I

optionally isolating Montelukast amine salt; treating the isolated Montelukast amine salt with organic solvent selected from esters; optionally isolating Montelukast amine salt; converting Montelukast amine salt to Montelukast sodium.
According to another aspect of the present invention, amine salt of Montelukast wherein,the amine is selected from the group comprising of primary amines, secondary amines, tertiary amines or cyclic amines such as methylamine, ethanolamine, isopropyl amine, disiopropyl amine, tertiary butyl amine, n-octyl glucamine, aniline, phenyl ethyl amine, phenyl propyl amine, Phenylisobutylamine; dimethylamine, methylethanolamine, diphenylamine, N-methyl benzyl amine, dicyclohexyl amine; trimethylamine, tri ethyl amine, triphenylamine, (diphenyl methyl) amine; cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, pyrrolidine, morpholine, piperidine. N-methylpiperidine and N-phenylpiperidine.
According to another aspect of the present invention, conversion of Montelukast amine salt to Montelukast sodium is carried out in the presence of sodium source wherein selected from sodium alkoxide such as sodium methoxide, sodium ethoxide, sodium tertiary butoxide or sodium salts of organic acids such as sodium pentanoate, sodium hexanoate, sodium heptanoate in non-aqueous solvent selected from esters, ethers, hydrocarbons, halogenated hydrocarbons or mixtures thereof to obtain stable and pure montelukast sodium salt.
According to another aspect of the present invention, montelukast amine salt used is prepared by following the process known from the prior art.
According to another aspect of the present invention, room temperature referred throughout the invention is temperature from 20 C - 25 C.
According to another aspect of the present invention, removing the solvent is by conventional methods such as filtration, centrifugation and distillation.
In another aspect of the present invention esters used throughout the invention are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate
7

or mixtures thereof; ethers used throughout the invention are selected from the group comprising of symmetrical or asymmetrical ethers or cyclic ethers selected from diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran or mixtures thereof; hydrocarbons selected from the group comprising aliphatic hydrocarbons comprising alkanes from C1-7 alkanes such as hexane, heptane or mixtures thereof, aromatic hydrocarbons selected from toluene, xylene or mixtures thereof and cycloalkanes selected from cyclohexane, cylcopentane or mixtures thereof; halogenated hydrocarbons are selected from methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof.
According to another aspect of the present invention, Montelukast sodium substantially free of impurities refers to the content of single impurity less than 0.1% area by HPLC preferably less . than 0.05% by HPLC.
According to another aspect of the present invention, pure Montelukast amine salt or pure Montelukast sodium means the degree of purity is higher than 99.9% by HPLC.
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Reference example
"5 Preparation of Montelukast sodium
£ Step-I
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Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinoIin-2-yl) ethyl) phenyl)-3- (methanesulfony-1-oxy) methyl ethyl) phenyl)-2-propanol (mesylated mass)
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jg 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropyl) phenyl)-2-
propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml)
^ mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5
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5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35°
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§ C. to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction
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mixture over a period of 1 lir at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethyl formamide (75ml) was added at same temperature. Further, hexane (100ml) was added at -5°C to - 10°C. The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step. (i.e. Step- II). Mesylated mass conversion by HPLC- 94.47%.
Step-II
Preparation of 2-amino diphenyl methane salt of montelukast from mesylated mass in
organic phase (In-situ process)
9.5grams (0.065 mole) of l-(mercapto methyl) cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 6.8grams (0.12 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C. The reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was further extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane(12.35gm,0.067 mole) were added to degass mass at 35-40°C and the degass mass was stirred at 50-55°C for 10-12 hrs. The precipitated mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained.
Montelukast free acid conversion by HPLC- 93.44%. Yield: 30.00gm (Crude 2-amino diphenyl methane salt)
HPLC Purity: 97.84% Sulfoxide: 0.04% MethylStyrene: 0.50% Cis Isomer: ND Michael adducts: 1.24% Methyl Ketone: O.Q6%
Step-III
Purification of 2-amino diphenyl methane salt of montelukast.
9

Compound obtained in Step-II (25gm, 0.032 mole) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C, a clear solution was obtained which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in Toluene (135ml) at 25-30°C and heated to 75- 80°C and clear solution was obtained, which was further allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitated mass was filtered and the solid was washed by toluene (25ml). The solid mass was further dried under vacuum at 50- 55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.
Yield: 20.00gm (Pure 2-amino diphenyl methane salt of montelukast) HPLC Purity: 99.58% Sulfoxide: 0.01% MethylStyrene: 0.12% Cis Isomer: 0.01% Michael adducts: 0.08% Methyl Ketone: 0,07%
Step-IV
Preparation of montelukast sodium from pure 2-amino diphenyl methane salt of
montelukast using sodium methoxide
Compound obtained in Step-III (15gm, 0.019 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.02gm, 0.019 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was filtered and further added in n-Heptane (450ml) under high agitation, a precipitated mass of montelukast sodium was obtained, which was filtered under nitrogen atmosphere and further washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75 °C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)
Yield: 12.00gm (Montelukast Sodium)
HPLC Purity: 99.53% Sulfoxide: 0.08% MethylStyrene: 0.11%
Cis Isomer: 0.08% Michael adducts: 0.07% Methyl Ketone: 0.02%
10

Example 1.
Preparation of Montelukast Sodium
Step a:
Purification of Montelukast tertiary butylamine salt
Montelukast tertiary butylamine salt (100 gm) was taken in chlorobenzene and heated to 75-80° C until clear solution is observed. Further the reaction mass was cooled to 25-30 C, stirred, filtered and washed with chlorobenzene. The solid thus precipitated was taken in ethylacetate, stirred for 2 hours at 25-30° C, filtered and washed with ethylacetate to yield 73 gm of 99.97% pure Montelukast tertiary butylamine. Sulfoxide impurity: 0.01%
Step b:
Preparation of Montelukast sodium
Sodium methoxide (12 gm) was taken in toluene, stirred and added Montelukast tertiary butylamine (100 gm). The reaction mass was heated to 45-50° C, stirred for 15 minutes, filtered and washed with toluene at 45-50° C. The reaction mass thus obtained was taken in n-Heptane, stirred for 15 minutes at 25-30° C, filtered and dried to yield 75 gm of 99.92% pure Montelukast sodium. Sulfoxide impurity: 0.01% Cis isomer: 0.02%
Example 2.
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a.
E Step a:
Purification of Montelukast tertiary butylamine salt
Montelukast tertiary butylamine salt (50 gm) was taken in chlorobenzene and heated to 75-80 C until clear solution is observed. Further the reaction mass was cooled to 25-30 C, stirred, filtered and washed with chlorobenzene. The solid thus precipitated was taken in ethylacetate,
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S stirred for 2 hours at 25-30° C, filtered and washed with ethylacetate to yield 36 gm of 99.97%
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Step b:
Preparation of Montelukast sodium
Sodium methoxide (6 gm) was taken in toluene, stirred and added Montelukast tertiary butylamine (50 gm).The reaction mass was heated to 45-50° C, stirred for 15 minutes, added carbon, filtered through hyilo bed and washed with toluene at 45-50° C. The reaction mass thus obtained was taken in n-Heptane, stirred for 15 minutes at 25-30 C, filtered and dried to yield 37 gm of 99.92% pure Montelukast sodium. Sulfoxide impurity: 0.01% Cis isomer: 0.02%
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We Claim:
1. A process for the preparation of Montelukast sodium having purity greater than 99.9% (by
HPLC) which comprises:
a. treating Montelukast amine salt with chlorobenzene;
b. heating the reaction mass;
c. cooling to room temperature;
d. optionally removing the solvent;
e. treating the montelukast amine salt with an organic solvent;
f. optionally isolating Montelukast amine; and
g. converting Montelukast amine salt to Montelukast sodium.
2. The process according to claim 1, wherein an organic solvent used in step (e) is selected
form ester solvent.
3. A process as claimed in claim 2, wherein the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof.
4. The process according to claim 1, wherein heating in step (b) is carried out at a temperature of from about 60°C to about 100°C.
5. The process according to claim 1, wherein converting Montelukast amine salt to Montelukast sodium using sodium source selected from sodium alkoxide or sodium salts of organic acids
6. The process as claimed in claim 5, wherein sodium alkoxide is selected form the group consisting of sodium methoxide, sodium ethoxide or sodium tertiary butoxide; sodium salts of organic acids is selected form the group consisting of sodium pentanoate, sodium hexanoate, sodium heptanoate.
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7. A process as claimed in claim 1, wherein the Montelukast amine is selected from the group
comprising of primary amines, secondary amines, tertiary amines or cyclic amines such as
methylamine, ethanolamine, isopropyl amine, disiopropyl amine, tertiary butyl amine, n-octyl
glucamine, aniline, phenyl ethyl amine, phenyl propyl amine, Phenylisobutylamine;
dimethyl amine, methylethanol amine, diphenylamine, N-methyl benzyl amine, dicyclohexyl
amine; trimethylamine, triethylamine, triphenylamine, (diphenyl methyl) amine; cyclo propyl
amine, cyclo pentyl amine, cyclo hexyl amine, pyrrolidine, morpholine, piperidine. N-
methylpiperidine and N-phenylpiperidine.
8. A process as claimed in claim 1, wherein the Montelukast sodium which is free of the
following impurities
1. Montelukast methylstyrene impurity of formula II,


COOH
— Formula II

2. Montelukast sulfoxide impurity of formula III,


COOH
Formula III

3. Montelukast cis isomer impurity of formula IV,

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4. Montelukast methyl ketone impurity of formula V


COOH
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— Formula V

5. Montelukast michael adduct impurities of formulae Via (R,R-isomer) and VIb (R,S-isomer)
COOH
COOH
Formula Via


COOH
COOH
Formula VIb

Dated this 21st day of June, 2016

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^Dr. RATHNAKAR REDDY KURA
DIRECTOR HETERO RESEARCH FOUNDATION
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