FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
IMPROVED PROCESS FOR THE PREPARATION OF MONTELUKAST
SODIUM
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality : Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India

IMPROVED PROCESS FOR THE PREPARATION OF MONTELUKAST SODIUM
FIELD OF THE INVENTION
The present invention relates to novel l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) and process for the preparation thereof. Furthermore, the invention relates to the use of novel l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) for the preparation of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1 hydroxy-1-methlethyl) phenyl] propyl] thi] methyl] cyclopropane acetic acid or its alkali salts and pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION
[R-(E)]-1 -[[[1 -[3-[2-(7-chloro-2-quinolinyl) thenyl] phenyl]-3-[2-( 1 -hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium salt, also known by the name montelukast sodium, is represented by the structural formula (I) below:

Montelukast is a leukotriene D4 antagonist. Montelukast is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients. It is also indicated for the relief of symptoms of seasonal allergic rhinitis and for perennial allergic rhinitis in adults and pediatric patients.

Montelukast sodium is a hygroscopic, optically active and white to off-white powder. which is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.
Montelukast sodium salt is available in a number of oral formulations including tablets, chewable tablets and oral granules. Montelukast sodium is marketed in USA and other countries by Merck & Co. Inc.under the trade name Singulair®.
Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480717. EP 480717 discloses certain substituted quinoline compounds including [R-(E)-1-[[[1[3-[2-[7-chloro-2-quinolinyl] ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cycloproaneacetic acid sodium salt (Montelukast sodium), method for their preparation, pharmaceutical formulation using these compound and method of treatment of mammals especially humans.
EP 480717 discloses a process for preparing montelukast sodium by condensing 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) 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 tetrahydro 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), which is depicted in Scheme-1. In the mentioned process chromatographic techniques are used for purification of the methyl ester intermediate, which limit industrial usability of the method. Moreover, montelukast sodium obtained by this method is the oily substance.
US 5,614,632 discloses a method of preparing crystalline montelukast sodium which involves the preparation of the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid followed by condensation thereof with 2-(2-(3 -(S)-(3 -(7-chloro-2-quinolinyI)ethenyl)phenyl)-3 -methanesulfonyloxypropyl)-

phenyl)-2-propanol to yield montelukast acid as a viscous oil. It is further converted to its corresponding sodium salt via dicyclohexyl amine salt.
Scheme-1

The above prior art i.e. EP 480717 and US 5,614,632 involve more number of steps, which include a series of protection and deprotection of 2-propanol i.e. diol intermediate, usage of unsafe raw materials and end-up with tedious workup to isolate the required product and thus results in excess time cycle which in turn renders the process more costly and less eco friendly thus the process is not feasible for commercial scale up.

In US patent application no. US 2005/0234241, Montelukast is prepared by mesylation of 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propanol using methane sulfonyl chloride and condensation of resulting mesylated with cyclopropyl derivative. This compound is then hydrolyzed to afford montelukast, and it's isolation into amine salt of montelukast. The amine salt of montelukast is then converted into sodium salt of Montelukast.
The use of tert-butyl ammonium salt of montelukast acid in the preparation of montelukast sodium is disclosed in WO 2006/043846.
An international application WO 2006/008751 discloses the use of 3- halopropyl derivative for the preparation of Montelukast and its salts.
An international application WO 2007/004237 discloses α-methylbenzyl, dicyclohexyl, and cyclohexylethyl ammonium salts of Montelukast for preparing montelukast sodium. Both the prior arts i.e. WO 2006/008751 & WO 2007/004237 require twice amine salt preparations at two different stages for the preparation of Montelukast sodium, which renders process lengthy and cumbersome.
An international application WO 2007/005965 recites using the dipropyl ammonium salt of montelukast acid for preparing purified montelukast sodium.
An application WO 2007/096875 discloses the cycloalkyl amine salts of Montelukast acid such as cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclodocecyl amine, cyclooctyl amine and phenylethyl amine salt.
An application WO 2007/107297 discloses amantadine salt of Montelukast for preparing montelukast sodium. This prior art discloses that the known organic amines i.e. DCHA or TBA, that have been used for this same purpose are flammable, toxic and irritant liquids which are unstable in open air and of unpleasant smell. For

instance, TBA boils already at about 45° C and DCHA is also a high boiling flammable liquid. Thus, in using them during chemical synthesis, special precautions may be necessary to protect the worker and the environment.
An application WO 2007/072114 discloses quaternary ammonium salt of 1-(mercaptomethyl)-cyclopropane acetic acid and use thereof for the preparation of montelukast sodium.
An application WO 2010/064257 discloses homoveratrylamine salt of 1-(mercaptomethyl)-cyclopropane acetic acid and process for the preparation of montelukast sodium employing the novel homoveratrylamine salt of Mercapto intermediate.
An application WO 2009/113087 discloses benzhydryl piperazine salts of montelukast and a process for the preparation of montelukast and its alkali salt employing the same. According to the process, montelukast benzhydryl piperazine salts is prepared from the montelukast base and then converted into montelukast sodium.
An application WO 2008/083635 discloses process for preparation of montelukast by reaction of 1 -(mercaptomethyl)-cyclopropane acetic acid with 2-(2-(3-(S)-(3- (2- (7-Chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxy propyl phenyl)-2-propanol in presence of base, an inert solvent and polyether compound.
The purity of montelukast acid is affected by various factors like purity of the starting material, as well as on conditions of mesylation, wherein increased reaction temperature results in decreased selectivity of mesylation of the secondary hydroxyl group, the type of the reaction solvent has an impact on reactivity of the diol-intermediate, an intramolecular substitution resulting in formation of a cyclic ether is observed in acidic medium. Like any synthetic compound, Montelukast can also contain process impurities, including unreacted starting materials, chemical

derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Impurities in API are undesirable and some time their presence in excessive amount might be harmful to health of the patient. Hence the purity of the APT produced in the commercial manufacturing process is a necessary condition for commercialization.
There are many patent applications which have tried to isolate montelukast free acid in solid form in an effort to purify and stabilize montelukast sodium salt.
Particularly, when API is desired to obtain in amorphous form, in particular case it may happen that even after the number of purification at amorphous stage might not provide the optimum purity of API. Furthermore, crystallization or purification at the final stage might change the nature of solid state which will not be required, when specific form of the compound is desirable to obtain specific dissolution. The same was observed during experimentation when Montelukast sodium was obtained into amorphous state directly from the Montelukast acid without any intermediate stage of salt preparation and crystallization of Montelukast acid it was difficult to remove the unrequired impurities even after number of purification without changing the nature of the compound.
US 20070184101 & US 20070184108 reveal that composition prepared from the montelukast and its alkali salts undergoes degradation and thus it provides method of stabilizing montelukast in pharmaceutical composition. Thus, it can be said that there still exist a need to provide a stable montelukast and its composition.
It was the aim of present invention to develop novel salts of l-(mercaptomethyl)-cyclopropane acetic acid which is more viable for industrial use and its use for the preparation of montelukast and its alkali salts possessing advantageous physico-chemical properties, thermodynamically stable and with good reproducibility and therefore having appropriate processing parameters facilitating its formulating into the pharmaceutical dosage forms.

The aim of the invention has been achieved by obtaining novel l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II). The process for the preparation of montelukast and its alkali salt according to the present invention has lesser number of steps, is simple, easy and convenient to carry out, gives better yield and purity, economical and commercially viable.
All patents, patent applications, and literature references cited in PCT publication WO 20090113087 are hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
The first embodiment of the present invention is to provide novel 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II),

wherein,
R, Rl, R2 is independently selected from hydrogen, halogen like F, CI, Br & I, (C1-
C6) alkyl, (C1-6) alkoxy, CH2F, CHF2 and CF3.
Another embodiment of the present invention is to provide novel 1-(mercaptomethyl-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II), which includes but are not limited to benzhydryl piperazine, 4-chIoro-benzhydryl piperazine, 4-methoxy- benzhydryl piperazine, 3,5-dichloro-benzhydryl piperazine.

3,4-dichloro-benzhydryl piperazine, 4-fluoro-benzhydryl piperazine, 4-methyl-benzhydryl piperazine or 4-trifluromethyl-benzhydryl piperazine.
In yet another embodiment, the present invention provides process for the preparation of 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) comprising reacting l-(mercaptomethyl)-cyclopropane acetic acid of formula (V) with Benzhydryl piperazine compound of formula (VI) in suitable solvent to obtain l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II).The above reaction steps are schematically depicted in scheme-3 herein below:
Scheme-3:

wherein R, Rl, R2 are as defined above.
In yet another embodiment, the present invention provides process for the preparation of Benzhydryl piperazine salts of montelukast of formula (IV) comprising condensing l-(mercaptomethyl)-cyclopropane acetic acid benzhydryl piperazine salt of formula (II) with compound of formula (III) in presence of base and suitable solvent to form Benzhydryl piperazine salts of montelukast of formula (IV). The above reaction steps are schematically depicted in scheme-4 herein below:

Scheme-4:
wherein R, R1, R2 are as defined above.
In yet another embodiment, the present invention provides process for the preparation of montelukast or its alkali salts. The process comprises:
(a) reacting l-(mercaptomethyl)-cyclopropane acetic acid of formula (V) with Benzhydryl piperazine compound of formula (VI) in suitable solvent to obtain 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II);
(b) condensing l-(mercaptomethyl)-cyclopropane acetic acid benzhydryl piperazine salts of formula (II) with compound of formula (III) in presence of base and suitable solvent to obtain Benzhydryl piperazine salts of montelukast of formula (IV); and
(c) converting Benzhydryl piperazine salts of montelukast of formula (IV) to montelukast or its alkali salts.

In yet another embodiment, the present invention provides process for the preparation of montelukast sodium. The process comprises:
(a) reacting l-(mercaptomethyl) -cycIopropane acetic acid of formula (V) with Benzhydryl piperazine compound of formula (VI) in suitable solvent to obtain l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II);
(b) condensing 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) with compound of formula (III) in presence of base and suitable solvent to form Benzhydryl piperazine salts of montelukast offormula(IV);and
(c) converting Benzhydryl piperazine salts of montelukast of formula (IV) to montelukast sodium of formula (I).
Yet another embodiment of the present invention is to provide process for the preparation of l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) in solid state.
Yet another embodiment of the present invention is to provide the use of 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) for the preparation of Benzhydryl piperazine salts of Montelukast of formula (IV).
Yet another embodiment of the present invention is to provide the use of 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) for the preparation of Montelukast and its alkali salt.

Yet further embodiment of the present invention provides the pharmaceutical composition of monteiukast or its alkali salts prepared from ]-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II).
Yet further embodiment of the present invention provides improved process for the preparation of monteiukast or its alkali salts comprising:
(a) condensing compound of formula (III) with l-(mercaptomethyl)-cyclopropane acetic acid methyl ester of formula (VII) in presence of base, suitable solvent and phase transfer catalyst;

(b) isolating monteiukast or its alkali salts.
Yet further embodiment of the present invention provides improved process for the preparation of monteiukast or its alkali salts comprising:
(a) condensing compound of formula (III), generated in situ by reaction of 2-(3 (S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxy propyl) phenyl)-2-propanol of formula (VIII) with methanesulfonyl chloride, but not isolated, with l-(mercaptomethyl)-cyclopropane acetic acid methyl ester of formula (VII) in presence of base, suitable solvent and phase transfer catalyst;



(b) isolating montelukast or its alkali salts.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of amorphous montelukast sodium.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
For purposes of the present invention, the following terms are defined below.

The term "Montelukast" or "Montelukast acid" refers to [R-(E)]-1-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyI]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid.
The term "Benzhydryl piperazine salts" refers to the compound selected from the group comprising of benzhydryl piperazine, 4-chloro-benzhydryl piperazine, 4-methoxy- benzhydryl piperazine, 3,5-dichloro-benzhydryl piperazine, 3,4-dichloro-benzhydryl piperazine, 4-fiuoro-benzhydryl piperazine, 4-methyl-benzhydryl piperazine, 4-trifluromethyl-benzhydryl piperazine or compound having benzhydryl piperazine moiety.
As used herein," 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II)" means any combination of Benzhydryl piperazine compound of formula (VI) and l-(mercaptomethyl)-cyclopropane acetic acid of formula (V), whether in solid state such as a crystalline substance or dissolved in a solvent. It also includes all polymorphic and pseudo- polymorphic salts, if any, including hydrates, etc. Generally l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) can be represented by the formula (Il-a) to (Il-h) in the following way:

wherein,
R, Rl, R2 is independently selected from hydrogen, halogen like F, CI, Br & I, (C1-
C6) alky], (C1C6) alkoxy, CH2F, CHF2 and CF3.
Different l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of the formula (II):

(a) Benzhydryl Piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (Il-a), wherein R = H, RI= H, R2 =H.
(b) 4-Chloro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-b), wherein R= 4-Ci, Rl = H, R2 = H.
(c) 4-methoxy-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-c), wherein R=4-OMe, Rl= H, R2=H.
(d) 3,5-dichloro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyc1opropane acetic acid (II-d), wherein R=3-CI, R1=5-C1, R2=H.
(e) 3,4-dichloro-benzhydryl piperazine salt of 3-(mercaptomethyl)-cyclopropane acetic acid (II-e), wherein R=3-C1, R1=4-C1, R2=H
(f) 4-fluoro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-f), wherein R=4-F, R1=H, R2=H.
(g) 4-methyl-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-g), wherein. R=4-Me, R]=H, R2=H.
(h) 4-trifluoromethyl-benzhydryl-piperazine salt of l'(mercaptomethyl)-cyclopropane acetic acid (II-h), wherein R=4-CF3, R1=H, R2=H.
The first embodiment of the present invention is to provide novel 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II),

wherein R, Rl, R2 are as defined above.
Another embodiment of the present invention is to provide novel 1-(rnercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula

(II), which includes but are not limited to benzhydryl piperazine, 4-chloro-benzhydryl piperazine, 4-methoxy- benzhydryl piperazine, 3,5-dichloro-benzhydryl piperazine, 3,4-dichloro-benzhydryl piperazine, 4-fluoro-benzhydryl piperazine, 4-methyl-benzhydryl piperazine or 4-trifluromethyl-benzhydryl piperazine.
In general embodiment, the present invention provides process for the preparation of montelukast or its alkali salts. The process comprises,
(a) reacting l-(mercaptomethyl)-cyclopropane acetic acid of formula (V) with Benzhydryl piperazine compound of formula (VI) in suitable solvent to obtain 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II);
(b) condensing 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) with compound of formula (III) in presence of base and suitable solvent to obtain Benzhydryl piperazine salts of montelukast offormula(IV);and
(c) converting Benzhydryl piperazine salts of montelukast of formula (IV) to montelukast or its alkali salts.
in step (a), 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) can be prepared by reacting l-(mercaptomethyl)-cyclopropane acetic acid of formula (V) with Benzhydryl piperazine compound of formula (VI) in suitable solvent.
The suitable solvents in step (a) includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane

and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide or mixture thereof.
The obtained 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) is optionally isolated and crystallized by using one or more solvent as used in above step (a) or it can be directly taken for next stage of condensation without any isolation or crystallization.
In step (b), l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salts of formula (II) is subsequently condensed with compound of formula (III) in presence of base and suitable solvent to obtain Benzhydryl piperazine salts of monteiukast of formula (IV).
The base includes but are not limited to alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide. potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, calcium ethoxide and the like; alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like; organolithium reagents like n-Butyllithium, methyl lithium and the like.
The suitable solvents in step (b) includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide or mixture thereof.

The obtained Benzhydryl piperazine salts of montelukast of formula (IV) can be optionally re-crystallized by using one or more solvent. The solvent includes but are not limited to esters, acetone, hydrocarbon, alcohol or mixture thereof.
In step (c), Benzhydryl piperazine salts of montelukast of formula (IV) is first converted into montelukast acid, which can be optionally isolated and then further converted into montelukast alkali salt by using appropriate base or Benzhydryl piperazine salts of montelukast of formula (IV) can be converted into montelukast alkali salt directly without in situ generating montelukast acid.
The obtained Benzhydryl piperazine salt of montelukast of formula (IV) is converted into Montelukast and its alkali salt by the method known in WO 20090113087.
Further during the condensation of l-(mercaptomethyl)-cyclopropane acetic acid benzhydryl piperazine salt of formula (II) with compound of formula (III), complete inversion occurs at the carbon carrying the mesyl group, to give the desired enantiomer of Benzhydryl piperazine salt of montelukast of formula (IV) and hence the proportion of the undesired enantiomer does not increase, which makes the process commercially more viable and desirable for bulk manufacturing.
Yet further embodiment of the present invention provides improved process for the preparation of montelukast or its alkali salts comprising:
(a) condensing compound of formula (III) with l-(mercaptomethyl)-cyclopropane acetic acid methyl ester of formula (VII) in presence of base, suitable solvent and phase transfer catalyst;
(b) isolating montelukast or its alkali salts.
In step (a), the base includes but are not limited to alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium

tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, calcium ethoxide and the like; alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like; organolithium reagents like n-Butyllithium, methyl lithium and the like. The preferred base is sodium hydroxide.
The phase transfer catalysts includes but are not limited to tetrabutylammonium bromide (TBAB), tetrabutyl ammonium chloride, tetrabutylammonium hydroxide, tricaprylylrnethylarnmonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, methyl trioctyl ammonium chloride or hexadecyl trimethyl ammonium bromide, more preferably tetrabutylammonium bromide (TBAB).
The suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide or mixture thereof. The preferred solvent is tetrahydrofuran.
In one of the preferred embodiment, 2-(3 (S)-(3-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxy propyl) phenyl)-2-propanol (VIII) is dissolved in an organic solvent and in the presence of organic base followed by activation with methane sulfonyl chloride to provide the compound of formula (III) i.e. mesylate intermediate. The resultant compound of formula (III) formed in situ is not isolated, but is condensed with 1-(mercaptomethyl)-cyclopropane acetic acid methyl ester of formula (VII) in presence of base, suitable solvent and phase transfer catalyst to obtain montelukast ester which on hydrolysis in presence of base gives montelukast

acid. The obtained montelukast acid is reacted with benzhydryl piperazine to get Benzhydryl piperazine salt of montelukast of formula (IV).
Benzhydryl piperazine salt of montelukast of formula (IV) is first converted into montelukast acid, which can be optionally isolated and then further converted into montelukast alkali salt by using appropriate base or Benzhydryl piperazine salt of montelukast of formula (IV) can be converted into montelukast alkali salt directly without in situ generating montelukast acid.
The obtained Benzhydryl piperazine salt of montelukast of formula (IV) is converted into Montelukast and its alkali salt by the method known in WO 20090113087.
The pharmaceutical compositions of the present invention comprise Montelukast or its alkali salts prepared according to present invention, as an active ingredient and may also contain a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, solvent, binder, stabilizer and the like and optionally other ingredients used in pharmaceutical formulations. The compositions may also comprise one or more additional therapeutic agents. The compositions of this invention include compositions suitable for oral, rectal, topical, parenteral, ocular, pulmonary, or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of the pharmacy.
Dosage forms include tablets, troches, dragees, powders, syrups, patches, liposomes, injections, dispersions, suspensions, solutions, capsules, creams, ointments and aerosols. Compositions which provide from 0.1 to 10.0 mg of the active ingredient are preferred.

In general, an effective amount means that amount of a compound of this invention that will elicit the biological or medical response that is being sought. Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary and nasal administration can be employed.
The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
EXAMPLES:
Example-1: Preparation of 2-(2-3-(S)-(3-(2-(7-Chloro-2-quinolinyl ethenyl)
phenyl)-3-methanesulfonyloxy propyl phenyl)-2-propanol
A 1.0 L round bottom flask fitted with a mechanical stirrer, thermocouple, and addition funnel was purged with nitrogen. The flask was charged with 2-(3(S)-(3-(2-(7-Chloro-2-quinolinyl) - ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol (1.0 kg) in tetrahydrofuran. Diisopropylethylatnine (0.55 kg) was added to the reaction mixture at 30 ± 3 °C to get the clear solution. The reaction mixture was cooled to -27 ± 3 °C. Then methanesulfonyl chloride in tetrahydrofuran (0.31 kg in 0.50 L) was added to the reaction mixture at 27 ± 3 °C and stirred for 4.0 hours. The reaction mixture was filtered and removed the precipitate of hydrochloride salt of diisopropylethylatnine and filtrate was used immediately for thiolation step.
Example-2: Preparation of R-(E)]-l-[[[l-[3-[2-(7-chIoro-2-quinoIinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methyIethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid
A 1.0 L round bottom flask fitted with a mechanical stirrer, thermocouple, and addition funnel was purged with nitrogen. The flask was charged with

tetrahydrofuran (0.50 L), l-(mercaptomethyl)-cyc!opropane acetic acid methyl ester (0.60 kg) and tetra-n-butyl ammonium bromide (0.020 kg) at -7 ± 2 °C. The solution of 2-(2-(3-(S)-(3- (2- (7-Chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesu!fonyloxy propyl phenyl)-2-propanol (obtained in example-1) in tetrahydrofuran was charged to the reaction mixture. Sodium hydroxide (0.50 kg) was added to the reaction mixture and the reaction mixture was stirred for 1.0 hour at -7 ± 2 °C. The temperature was raised to 17 ± 20C and further up to 38 ± 2 °C. Sodium hydroxide (0.50 kg) was added to the reaction mixture at 36 ± 2 °C and was stirred for 4.0 hours.
Then aqueous solution of sodium chloride solution (5%) was added to the reaction mixture. The aqueous layer was discarded and organic layer added with tetrahydrofuran. The obtained organic layer was distilled out under vacuum, followed by adding isopropyl alcohol. The reaction mixture was stirred below 40°C and water was added to it. The pH of the reaction mixture was adjusted to 10 ± 0.3 with acetic acid and the reaction mixture was extracted with toluene and n-heptane twice. The organic layer was discarded and ethyl acetate was added to the obtained aqueous layer. The pH of organic layer was adjusted to 5.8 ± 0.3 with acetic acid and sodium bicarbonate solution was added to the organic layer. The separated aqueous layer was discarded and pH of the reaction mixture was adjusted to 5.8 ± 0.3 with acetic acid. The obtained organic layer was distilled under vacuum to obtain residue. Further the reaction mixture was extracted with ethyl acetate twice and the ethyl acetate was distilled under vacuum to get title compound.
Example-3: Preparation of Montelukast Benzhydryl piperazine Salt
Montelukast acid (obtained from example-2) was added with ethyl acetate and toluene, and the reaction mixture was heated at 45-55°C to get clear solution. Benzhydryl piperazine (0.44 kg) was added to the reaction mixture at 42-48°C and stirred for 30 minutes followed by addition of n-heptane and methylene chloride. The reaction mixture was cooled to 25-30°C and was seeded with the seed of the title compound. The separated precipitate was filtered and washed with mixture of ethyl

acetate and heptane, and dried for 6 hour under vacuum at 40-48° C to get Montelukast Benzhydryl piperazine salt (dry weight = 1.0 kg).
Example-4: Preparation of Amorphous Montelukast sodium from Montelukast Benzhydryl piperazine salt
Montelukast Benzhydryl piperazine salt (24 gm), water (240 ml) and ethyl acetate (120 ml) were charged in RBF under nitrogen atmosphere at 27-33° C, followed by addition of acetic acid (6.8 gm). The mixture was stirred for 15 min. at 27-33° C, followed by further addition of ethyl acetate (120 ml) and stirred for 15 min. at 27-33° C. The layers were separated and ethyl acetate layer was washed with water (2x120 ml) and organic layer thus obtained was dried over sodium sulfate. The reaction solution was decanted; solvent from the reaction mass was distilled out under vacuum to afford the residual mass. The obtained residual mass was combined with methanolic sodium hydroxide (1.2 gm NaOH in 72 ml methanol) and stirred for 15 minute at 44-50°C, followed by distillation of solvent from the reaction mass under vacuum at 44-50°C. The obtained residual mass was dissolved in toluene (144 ml) and added with 1.2 gm activated charcoal, filtered through hyflow bed and washed with hot toluene (48 ml), followed by distillation under vacuum at 54-60aC. The residue thus obtained was further dissolved in toluene (72 ml) and was slowly added to heptane (950 ml) under nitrogen atmosphere and stirred for 15 minutes at 27-33° C. The desired compound was filtered under nitrogen atmosphere and washed with heptane (80 ml). The wet compound was dried under vacuum at 40-46° C for 24 hrs to yield amorphous montelukast sodium (dry weight = 14.5 gm & purity = 99.44%).
Example-5: Preparation of l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt
l-(mercaptomethyl)-cyclopropane acetic acid (50 gm) and toluene (500 ml) were charged in RBF and the temperature was raised to 50-55°C to get clear solution. Benzhydryl piperazine (86.2 gm) was charged to the clear solution. The reaction mass was stirred, cooled, filtered and dried under vacuum for 12 hrs to yield 1-

(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt. (Dry weight = 120gm)
Example6: Preparation of Montelukast Benzhydryl piperazine Salt
Dimethylformamide (100 ml), 2-(2-(3-(S)-(3- (2- (7-Chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxy propyl pheny!)-2-propanol (57.0 gm), 1-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt (21.75 gm) and sodium tert-butoxide (10.5 gm) were charged in RBF. The reaction mass was stirred for 8.0 hrs and kept at 0-5°C for overnight. Ethyl acetate (300 ml) and water (300 ml) were charged to the reaction mass and the temperature was raised to 25-30°C. The pH of the reaction mass was adjusted to 5.5-6.0 with acetic acid and the layers were separated. The organic layer was washed with sodium bicarbonate solution (250 ml) followed by adjusting pH to 5.5-6.0 with acetic acid. The organic layer was washed with sodium bicarbonate solution (250 ml). Water (250 ml) was charged to the organic layer and the pH was adjusted to 5.5-6.0 with acetic acid. The layers were separated at 25-30°C. The organic layer was distilled out under vacuum at below 45°C to obtain the residue (32.0 gm).
Ethyl acetate (125 ml) and toluene (125 ml) were charged to the obtained residue at below 45°C to obtain the clear solution and Benzhydryl piperazine (2.75 gm) was charged to it. The reaction mass was stirred for 30 minutes at 40-50°C. n-heptane (250 ml) was further added and the reaction mass was cooled to 25-30°C. The reaction mass was filtered and the wet material was dried under vacuum at 45°C to obtain Montelukast Benzhydryl piperazine Salt. The obtained Montelukast Benzhydryl piperazine Salt was purified with toluene at 40-45°C. Dry weight: 12.0 gm
Example-7: Preparation of Amorphous Montelukast Sodium
Montelukast Benzhydryl piperazine Salt (3.5 gm) and ethyl acetate (35 ml) were charged in RBF. Acetic acid (0.75 gm) was added to the reaction mass to obtain the

clear solution. Water (35 ml) was added to the reaction mass and was stirred for 10 minutes. The layers were separated. Acetic acid (0.25 gm) was added to the organic layer and water (35 ml) was added to it. The layers were separated. The organic layer was washed with water (35 ml), sodium bicarbonate' solution (5%, 17.5 ml) and sodium chloride solution (2%, 35 ml). The solvent was distilled out under vacuum at 40-50°C to obtain residue. Methanol (7.0 ml) was charged to the residue to get the clear solution. The solvent was distilled out under vacuum at 40-50°C to obtain residue. Methanolic sodium hydroxide (10.5 ml) was charged to the residue and the reaction mass was stirred to get the clear solution. The solvent was distilled out under vacuum at 50-55°C. Toluene (14.0 ml) was charged to the residue to get the clear solution. The solvent was distilled out under vacuum. Toluene (24.5 ml) was charged to the residue to get the clear solution, followed by adding activated charcoal (0.35 gm) to the reaction mass. The reaction mass was filtered followed by distillation under vacuum at 50-55°C. Toluene (14.0 ml) was added to the residue to get the clear solution. The solution was added slowly to n-heptane (105 ml). The reaction mass was stirred, filtered and distilled under vacuum to obtain amorphous montelukast sodium. Dry weight: 2.2 gm

We Claim:
1. l-(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt of formula (II)

2. 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt according
to claim 1, which is selected from the group consisting of:
(a) Benzhydryl Piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-a), wherein R = H, R1 = H, R2 = H.
(b) 4-Chloro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-b), wherein R= 4-CI, R1 = H, R2 = H.
(c) 4-methoxy-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-c), wherein R=4-OMe, Rl= H, R2=H.
(d) 3,5-dichloro-benzhydryI piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-d), wherein R=3-CI, R1=5-C1, R2=H.
(e) 3,4-dichloro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-e), wherein R=3-C1, R1=4-C1, R2=H
(f) 4-fluoro-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-f), wherein R=4-F, R1=H, R2=H.
(g) 4-methyI-benzhydryl piperazine salt of l-(mercaptomethyl)-cyclopropane acetic acid (II-g), wherein. R=4-Me, Rl-H, R2=H.
(h) 4-trifluoromethyl-benzhydryl-piperazine salt of l-(mercaptomethyl)-cycloproparie acetic acid (Il-h), wherein R=4-CF3, R1=H, R2=H.
3. A process for the preparation of l-(mercaptomethyl)-cyclopropane acetic acid
Benzhydryl piperazine salt of formula (II) comprising reacting 1-

(mercaptomethyl)- cyclopropane acetic acid of formula (V) with Benzhydryl
piperazine compound of formula (VI) in suitable solvent to obtain 1-
(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt of
formula (II).

4. A process for the preparation of Benzhydryl piperazine salt of montelukast of formula (IV) comprising condensing 1-(mercaptomethyl)-cyclopropane acetic acid benzhydryl piperazine salt of formula (II) with compound of formula (III) in presence of base and suitable solvent to obtain Benzhydryl piperazine salt of montelkast of formula (IV).


5. A process for the preparation of montelukast or its alkali salts which comprises:
(a) condensing compound of formula (III)with 1-(mercaptomethyl)-cyclopropane acetic acid methyl ester of formula (VII) in presence of base, suitable solvent and phase transfer catalyst; and
(b) isolating montelukast or its alkali salts.

6. The process according to any of the preceding claim, wherein the solvent is selected from the group comprising of alcohols, ketones, aliphatic ethers, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated solvent, nitriles, polar aprotic solvent or mixture thereof.
7. The process according to any of the preceding claim, wherein the base is selected
from the group comprising of alkali metal alkoxides, alkali metal hydroxides. alkali metal carbonates or organolithium reagents.
8. The process according to claim 5, wherein the phase transfer catalyst is selected from the group comprising of tetrabutylammonium bromide (TBAB), tetrabutyl ammonium chloride, tetrabutylammonium hydroxide, tricaprylyl methyl ammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, methyl trioctyl ammonium chloride or hexadecyl trimethyl ammonium bromide.
9. Use of 1 -(mercaptomethyl)-cyclopropane acetic acid Benzhydryl piperazine salt
of formula (II) for the preparation of Montelukast or its alkali salts.

10. A process for the preparation of montelukast sodium as herein described, particularly with reference to the foregoing examples.