WO2012077133A1 - Processes for preparation of montelukast sodium and purification of diol intermediate - Google Patents

Abstract

A process for preparation of montelukast sodium through novel montelukast amine salts is provided, wherein the amine is selected from 1- (l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof. A process for purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxylpropyl)-phenyl-2-propanol is also provided, which uses a halogenated hydrocarbon and a nitrile as solvent.

Description

PROCESSES FOR PREPARATION OF MONTELUKAST SODIUM AND

PURIFICATION OF DIOL INTERMEDIATE

FIELD OF THE INVENTION

The present invention provides a process for the preparation of montelukast sodium through novel montelukast amine salt of formula I,

Formula I wherein (R)₂NH is selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof.

The present invention further provides novel montelukast amine salts and their preparation.

The present invention also provides an effective and industrially advantageous process for purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl-2- propanol (diol intermediate) of formula II,

Formula II

which is a key intermediate for synthesis of montelukast or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Montelukast sodium, chemically known as sodium salt of l-[[[(R)-l-[3-[(lE)-2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-( 1 -hydroxy- 1 -methylethyl)phenyl]propyl]thio]methylcyclo propane acetic acid, having structure

is a leukotriene anatagonist and inhibits synthesis of leukotriene biosynthesis. It is useful as anti- histamatic, anti-allergic, anti-inflammatory, cycloprotective agent and hence useful in treatment of angina, cerebral, nephritis, hepatic, and toxemia, uveitis and allograft rejection. 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 and related compounds are first disclosed in US patent 5,565,473. Patent discloses preparation of montelukast sodium through 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)- 3-(hydro :

Montelukast sodium

The preparation of diol intermediate involves reduction of prochiral ketone ester with chiral reducing agent, (-)-B-diisopinocamphylchloroborane, to give hydroxy ester intermediate followed by Grignard reaction with methyl magnesium bromide to give diol intermediate of formula II. The diol intermediate is isolated after flash column chromatography and then converted to montelukast sodium by protecting tert-hydroxy group of diol intermediate with tetrahydropyran group to form 2- (2-(2-(3 (S)-(3 -(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(methanesulfonyl oxy)propyl)phenyl)- 2-propoxy)tetrahydro pyran followed by its condensation with methyl l-(acetylthiomethyl)cyclo propane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast, wherein tertiary hydroxy group is protected by tetrahydropyran moiety, which is purified by flash chromatography. Above intermediate is then reacted with pyridinium p- toluenesulfonate in a mixture of methanol and tetrahydrofuran as a solvent and then treated with sodium hydroxide to afford montelukast sodium. Patent involves column chromatography for the purification of diol intermediate which is considered as time consuming, tedious and not advisable to use for commercial synthesis. Further patent is silent about purity of diol intermediate. Process involves purification of methyl ester intermediate using flash chromatographic techniques, which is considered to be time consuming and tedious process. Furthermore, the yield of product is quite low. Therefore, this process is not amenable to employ at industrial level. US patent 6,320,052 discloses a process for preparation of montelukast sodium by reaction of hydroxy ester intermediate with methyl magnesium chloride in presence of cerium chloride in tetrahydrofuran and toluene to give diol intermediate which was further crystallized from toluene and hexane/heptane. Crystallization process involves concentration of tetrahydrofuran and toluene solution of diol intermediate followed by seeding, dropwise addition of hexane and again seeding of the mixture. Thereafter, process involves dropwise addition of another aliquot of hexane dropwise followed by aging of crystallization. Similar process is repeated twice and filtration results in isolation of pure diol intermediate which is then converted to corresponding mesylate derivative. Mesylate intermediate is then condensed with l-(acetylthiomethyl)cyclopropane acetic acid dilithium salt to give montelukast which in situ reacted with dicyclohexylamine salt to provide montelukast dicyclohexylamine salt Montelukast dicyclohexylamine is then neutralized using an acid and finally converted to form crystalline montelukast sodium. Crystallization process for diol intermediate as described above is lengthy and involves two times seeding of solution. Further, the patent is silent about mode of obtaining seeding compound. In addition to this, dicyclohexylamine used in the process is a high boiling flammable liquid. Use of this amine during chemical synthesis requires special precautions to protect worker and the environment.

US patent 7,446,116 discloses preparation of pure montelukast by reacting crude montelukast in acetone with amantadine to form montelukast amantadine salt which is then treated with hydrochloric acid to form pure montelukast. Patent does not exemplify the conversion of montelukast thus prepared into montelukast sodium. It has been found in our hands that above process do not yield reproducible result. It is also evident from the exemplified process, which gives montelukast amantadine salt of three different colors: mild grey powder, off white & white colored powder, thus process is not reproducible and can not be applied for the commercial synthesis.

US patent application publication 2005/0107612 describes a process for the preparation of montelukast sodium by following scheme:

Process involves conversion of mesylate intermediate to dicyclohexyl ammonium salt of 2-(3-(l- carboxymethyl-cyclopropylmethylsulfanyl)-3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}- propyl)-benzoic acid methyl ester intermediate, which undergoes Grignard reaction to give montelukast and then conversion into the tert-butyl ammonium salt or phenethyl ammonium salt of montelukast. The resulting salt is then finally converted to montelukast sodium. Process requires preparation of two different amine salts at two different stages and Grignard reaction in the last stage which may affect the stereochemistry of the compound as well as generate several impurities. Removal of such impurities require tedious purification, thus makes the process not suitable for industrial synthesis.

US patent application publication 2009/0005413 discloses use of the tert-butyl ammonium salt of montelukast in the preparation of montelukast sodium. Use of tert-butyl amine salt makes process not amenable as tert-butyl amine is flammable, toxic and irritant liquids. Further it is unstable in open air and of unpleasant smell.

US patent application publication 2010/0168432 discloses a process for preparation of montelukast sodium by the reaction of methyl-2-[3-[3-(2-chloroquinolin-2-yl)ethanyl]phenyl]3- chloropropyl]benzoate with l-(acetylthiomethyl)cyclopropane acetic acid in the presence of alkali carbonate to form montelukast methyl benzoate ester which is then converted to organic salt such as dicyclohexyl amine. Amine salt of above intermediate is then reacted with methyl magnesium chloride in the presence of anhydrous cerium chloride followed by reaction with amine such as a- methylbenzyl, dicyclohexyl, and cyclohexylethyl amine to form corresponding amine salts of montelukast which is finally converted to montelukast sodium. The Process requires synthesis of amine salt preparations at two different stages during preparation of montelukast sodium, which renders process lengthy and cumbersome.

The purity of the active pharmaceutical ingredient is necessary condition in the commercial manufacturing process. Hence it is important to have a purification method in the manufacturing process of any API to remove the impurities which are formed in the chemical reactions as well as by unused reagents and raw materials etc.

Like any synthetic compound, montelukast or intermediate thereof such as diol intermediate can contain extraneous compounds or impurities that can come from many sources which may get carry forward to final API i.e. montelukast sodium or may react with further reagent used for the reaction to form other by products. These extraneous compounds in the intermediate may be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products or different isomer. Impurities generated due to any reason in any active pharmaceutical ingredient (API) like montelukast are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API

In addition impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid- liquid extraction, in the manufacturing process.

The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of an intermediate, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a preparation of final API. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent. The structure of any impurity present at a level of 0.10% or more must be determined. For impurities present at a level of 0.15% or more, a toxicological qualification to assess its risk to humans is required.

The purification can be done in any steps of the manufacturing process for example at an intermediate stage or at the final stage. Prior art references provide two different ways to achieve pure montelukast or salts thereof in one is through amine salts formation and other is purification at intermediate stages. In most of prior art references, montelukast or pharmaceutically acceptable salts has been prepared stating from diol intermediate of formula II, therefore purity of this intermediate is quite important in yield final product of high purity and having less amount of impurities.

Various references are available in the art for the both alternatives but are associated with one or more disadvantages.

Different amine salts are also reported in the literature, some of which are given here:

US patent application publication 2007/0213365 discloses cycloalkyl amine salts of montelukast such as cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclodocecyl amine, cyclooctyl amine and phenylethyl amine salt for the synthesis of montelukast sodium. US patent application publication 2009/0247759 discloses L-(+)-treo-2-amino- 1 -phenyl- 1,3- propanediol, and L-(+)-a-phenylglycinol, tris hydroxymethyl amino methane salt of montelukast for the purification of montelukast.

US patent application publication 2010/0076195 discloses preparation of purified montelukast sodium using dipropyl ammonium salt of montelukast.

PCT publication WO 2008/049922 discloses use of arginine salt of montelukast during the synthesis of montelukast sodium.

PCT publication WO 2009/006861 discloses methylamine, ethylamine, n-propylamine, butylamine, isopropyl amine, t-butyl amine, benzyl amine, a-methylbenzyl amine, 2-methylamino ethanol, dipropyl amine, diisopropyl amine, dicyclohexylamine, diisopropyl ethylamine salts of montelukast. PCT publication WO 2009/052625 discloses crystalline 1,2-ethanedisulfonic acid salt and Ν,Ν'- dibenzylethylenediamine salt of montelukast.

PCT publication WO 2009/113087 discloses 4-chloro benzhydryl piperazine salt, 4-methoxy benzhydryl piperazine salt, 3,5-dichloro benzhydryl piperazine salt, 3,4-dichloro benzhydryl piperazine salt, 4-flouoro benzhydryl piperazine salt, 4-methyl benzhydryl piperazine salt and 4- trifluoromethyl benzhydryl piperazine salt of montelukast.

A number of amine salts of montelukast are known in the art for the purification of montelukast. Even though these amine salts can be useful for the isolation and purification of montelukast before its conversion to montelukast sodium, still it will be appreciable to have a new amine salt to perform the purification and thereby increasing the purity of pharmaceutically useful compounds.

Diol intermediate of formula II, is an important key intermediate in the preparartion of montelukast. There are several methods known for preparation and purification of diol intermediate in literature. Most of the known processes, which provide purification of diol intermediate, are associated with problems of yielding impure diol intermediate or are silent about the purity and impurity level. Some processes are given below for reference.

US patent application publication 2009/0056793 discloses purification of diol intermediate by stirring diol intermediate in toluene for 4 hours, addition of another aliquot of toluene and heating to dissolve the compound. Mixture is cooled, stirred for 8 hours followed by addition of hexane and filtration gives diol intermediate which is further washed with toluene and hexanes to give intermediate having purity 98.10 %. It is again purified with toluene and hexane using similar process to give diol intermediate of purity 99.84 %. The process is very lengthy i.e. takes around 22 hours for purification and thus not suitable for industrial synthesis. PCT publication WO 2008/135966 discloses a process for purification of optically impure diol intermediate of formula I by crystallizing impure compound twice from toluene to give diol intermediate having purity 99.82 % and (R)-enantiomer 0.18 %. The application deals only with chiral purity of compound and is silent about the chemical purity. Chemical purity of any chemical compound is as important as the chiral purity.

PCT publication WO 2010/064109 discloses purification of diol intermediate using toluene, xylene, diisopropyl ether, ethyl acetate, petroleum ether, hexane, heptane or mixture thereof.

PCT publication WO2009010231 discloses purification of diol intermediate by dissolving in toluene followed by addition of n-heptane and seed crystal to induce crystallization, n-heptane is again added slowly and reaction mixture filtered to give diol intermediate having purity 98.4 % with ketone content of 0.6 % . The intermediate of such low purity containing 0.6 % of keto impurity is not suitable for preparation of final API i.e. montelukast sodium.

The prior art teaches number of ways for the purification of montelukast, in which purification through formation of amine salt of an intermediate compound, or final stage compound proves to be beneficial in providing high pure form of montelukast sodium. Also purification of diol intermediate is provided by prior art to yield montelukast or salts thereof with high purity but these processes involves the purification of diol intermediate with toluene and hydrocarbon solvent such as hexane or heptane. As the boiling point of solvents, toluene is 110°C and heptane is 98°C, is very close so solvent recovery is very difficult, which further leads to wastage of solvents and thus increases cost of process. Further hexanes are highly inflammable and difficult to handle at large scale.

Thus there is still a need in the art for a process for preparing other possible amine salts of montelukast as well as purification of most common starting material i.e. diol intermediate of formula II, which will be beneficial to employ on commercial scale and yield montelukast sodium of high purity. There is need for the new amine salt and a purification process for the diol intermediate which curtail the presence of impurities or make final product free from impurities. There is a need for a process which avoids tedious chromatography techniques and use of seeding, involves easy recovery of solvent, and is free from the disadvantages associated with prior art purification processes.

The present invention fulfills the need in art and provides novel amine salt of montelukast which provides a new opportunity to improve the performance characteristics of a pharmaceutical product i.e. montelukast or pharmaceutically acceptable salts thereof and makes the process industrially advantageous and efficient for the synthesis of pure montelukast or pharmaceutically acceptable salts thereof to employ at industrial level. Further present invention provides a method for purification of diol intermediate which is quite effective, simple, industrially applicable and advantageous to yield diol intermediate having acceptable level of impurities, preferably free from impurities. Further specific solvents used for purification are hitherto not reported in prior and found to be solvents of choice as they are quite effective to curtail impurities present in the diol intermediate, and makes it suitable to use for synthesis of montelukast or pharmaceutically acceptable salts thereof. Two alternatives provided by present invention for yielding the final product with high purity i.e. purification via new amine salt formation or purification of starting diol intermediate are proved to be quite effective and advantageous either alone or in combination with each other.

OBJECTIVE OF THE INVENTION

It is the foremost objective of the present invention to provide an industrially advantageous and efficient process for the preparation of pure montelukast or pharmaceutically acceptable salts thereof through novel amine salt.

Another objective of the present invention is to provide novel montelukast amine salt.

Another objective of the present invention is to provide a process for the preparation of montelukast novel amine salts.

Another objective of the invention is to provide a process for purification of montelukast.

Another objective of present invention is to provide an efficient and industrially advantageous process for the purification of diol intermediate of formula II, which would contain unknown and known impurity at a acceptable level eventually leading to montelukast sodium of high purity.

Another objective of present invention is to provide diol intermediate of formula II having identified impurities less than 0.5 % and any unknown impurity NMT 0.1% by HPLC.

Another objective of present invention is to provide diol intermediate of formula II having reduced level of keto-alcohol impurity in diol intermediate of formula I i.e. NMT 0.3% by HPLC.

Another objective of present invention is to provide a process for synthesis of montelukast or pharmaceutically acceptable salts using the highly pure diol intermediate of formula II in order to circumvent chances of getting carry forward of impurities and generation of further by products. SUMMARY OF THE INVENTION

Accordingly, the present invention provides an industrially advantageous and efficient process for the preparation of pure montelukast or pharmaceutically acceptable salts thereof, preferably montelukast sodium through novel amine salt formation.

According to one embodiment, the present invention provides a process for preparation of pure montelukast or pharmaceutically acceptable salts thereof, comprising the steps of: a) , providing montelukast in a suitable solvent;

b) . optionally, adding a suitable anti-oxidant;

c) . reacting with a suitable amine selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof, for a sufficient period of time till formation of montelukast amine salt of formula I,

Formula I wherein (R)2NH is selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof

d). optionally, isolating montelukast amine salt of formula I; and

e). converting the same in to montelukast or pharmaceutically acceptable salts thereof.

According to another embodiment, the present invention provides montelukast amine salt of formula I.

According to another embodiment, present invention provides montelukast 1-(1- naphthyl)ethylamine salt or isomers thereof.

According to another embodiment, present invention provides montelukast (±)- or (R)- or (S)-l-(l- naphthyl)ethylamine salt.

According to one another embodiment, present invention provides montelukast S-methyl-L-cysteine salt or isomers thereof.

According to yet another embodiment, present invention provides montelukast diallylamine salt or isomers thereof.

According to still another embodiment, the present invention provides a process for preparation of montelukast amine salt of formula I, comprising the steps of:

a) , providing montelukast in a suitable solvent;

b) . reacting with a suitable amine selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof for a sufficient period of time till formation of montelukast amine salt of formula I; and

c) . optionally, purifying montelukast amine salt of formula I.

According to yet another embodiment, present invention provides a process for preparation of pure montelukast or pharmaceutically acceptable salts thereof, comprising the steps of: a), reacting a diol intermediate of formula II,

Formula II with a suitable reagent to form an intermediate of formula III,

Formula III wherein LG is selected from alkylsulfonyl, substituted or unsubstituted arylsulfonyl

b) . optionally, isolating intermediate of formula III,

c) . condensing intermediate of formula III with compound of formula IV,

Formula IV

or salts thereof in the presence of a suitable base;

d). optionally, isolating montelukast from the reaction mixture;

e) . reacting the same optionally in the presence of an antioxidant, with a suitable amine selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof for a sufficient period of time for formation of montelukast amine salt of formula I; and

f) . converting montelukast amine salt of formula I in to montelukast or pharmaceutically acceptable salts thereof.

According to one more embodiment, present invention provides a process for preparing pure montelukast having oxidized impurities less than 0.15%, comprising the step of adding a suitable anti-oxidant to a solution of montelukast in a suitable solvent during salt formation or purification. According to one more embodiment, present invention provides a process for purification of diol intermediate of formula II, a key intermediate for preparing montelukast or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , providing diol intermediate of formula II in a mixture of a halogenated hydrocarbon and a nitrile solvent;

b) . stirring the reaction mixture at 10°C to 35°C;

c). optionally, cooling the resulting mixture; and

d).isolating pure diol intermediate of formula II.

According to another embodiment, present invention provides diol intermediate of formula II having identified impurities NMT than 0.5% and/or unidentified impurities NMT than 0.10 % by HPLC. According to another embodiment, present invention provides a process for the preparation of montelukast or pharmaceutically acceptable salts thereof, comprising the steps of:

a), providing diol intermediate of formula II in a mixture of a halogenated hydrocarbon and a nitrile solvent;

b). stirring the reaction mixture;

c) . optionally, cooling the resulting mixture;

d) . isolating pure diol intermediate of formula II; and

e) . converting pure diol intermediate of formula II in to montelukast or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF INVENTION

As used herein "montelukast amine salt" or "amine salt of montelukast" includes their specific isomer like (R), (S) or racemates, dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

As used herein, the term "diol intermediate of formula Π" or "diol intermediate" refers to 2-(2-(3- (S)-(3-(7-chloro-2-quinolinyl)- ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl-2-propanol of formula II.

The present invention provides an industrially advantageous, efficient and reproducible process for the preparation of highly pure montelukast or pharmaceutically acceptable salts thereof.

According to one embodiment, present invention provides a process for preparation of montelukast or pharmaceutically acceptable salts thereof through novel montelukast amine salt formation.

Generally, process involves reaction of montelukast in a suitable solvent with a suitable amine at a temperature of 0 to 70 °C for 30 minutes to 72 hours, preferably for a time sufficient for the salt formation. Suitable amine can be selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof. Amine employed for salt formation can be a specific isomer of selected amine or mixture of isomers such as (±)-l-(l-naphthyl)ethylamine, (R)-(+)-l-(l- naphthyl)ethylamine, (S)-(-)-l-(l-naphthyl)ethylamine or mixture thereof. Salt formation can be carried out in the presence of a suitable solvent and optionally in the presence of an antioxidant. Solvent includes but not limited to esters such as ethyl acetate, propyl acetate; aliphatic ketone such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone; alkyl nitrile such as acetonitrile, propylnitrile; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; aliphatic or aromatic hydrocarbon such as 1,2- or 1,4 xylene, toluene; halogenated hydrocarbon such as dichloromethane, chloroform, dichloroethane and the like or mixture thereof. Antioxidant can be added to a solution of montelukast prior to mixing with amine. Reaction mixture containing antioxidant can be optionally charcoalised and/or treated with drying agent such as sodium sulfate. Mixture can be stirred for 30 minutes to 48 hours, preferably for 30 minutes to 24 hours. Antioxidant used is selected from natural antioxidant such as ascorbic acid and tocopherols; synthetic antioxidant such as propyl galate, tertiary butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene.

Usually salt formation completes in 30 minutes to 48 hours. In general, salt formation does not require heating and/or cooling of the solution to facilitate precipitation, but such an arrangement is not excluded from the scope of invention. After completion of salt formation, montelukast amine salt can be isolated from reaction mixture or can be in situ converted to montelukast or pharmaceutically acceptable salts thereof.

Preferably, after completion of the salt formation, montelukast amine salt can be isolated from the reaction mixture by filtration or by first lowering the reaction temperature or by adding an antisolvent to precipitate desired compound. Suitable anti solvent can be selected from alkyl nitrile such as acetonitrile, propionitrile; aliphatic ester such as ethyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; aliphatic or aromatic hydrocarbon such as n- pentane, n-hexane, n-heptane, hexanes, pentanes, heptanes and the like or mixture thereof. Resulting product can be isolated by suitable techniques such as filtration, centrifugation and the like.

Present inventors found that montelukast either in isolated form or in solution form may produce some by-products on coming in contact with air. Therefore it is preferable to add an antioxidant during salt formation or any purification to avoids possibility of further oxidation and formation of by -product such as sulfoxide impurity is minimized.

Starting montelukast, employed for salt formation can be taken as solid or oil. Reaction mixture containing montelukast, where it is prepared by the condensation of formula III with IV or prepared by any method known in the art, can be used for further conversion to montelukast amine salt formation without isolating montelukast.

Montelukast, solvent and suitable amine can be added in any order to the reaction vessel as order of adding the reactant does not have any impact on the salt formation.

In one way, montelukast can be combined with a solution of suitable amine in a solvent to form corresponding montelukast amine salt. In an alternate way, solution of montelukast as well as solution of amine can be prepared separately before contacting with each other.

Preferably, a solution of montelukast in a suitable solvent can be prepared by adding a suitable solvent at ambient temperature prior to reaction with a suitable amine. Solvent employed are same as defined above for the salt formation. The solution of montelukast in a solvent can optionally be heated to a temperature of 35 to 100 °C for 10 minutes to 3 hours to dissolve montelukast in solvent and thereafter cooling the reaction mixture, resulting organic solution can be optionally charcoalised and/or dried over suitable drying agent such as sodium sulfate, magnesium chloride and the like. Resulting solution is then reacted with suitable amine to give corresponding montelukast amine salt. Montelukast amine salts described by the present invention includes various forms of salt including dissolved forms, solvent free form or it may be isolated as a hydrate, anhydrate or a solvate, non- solvate form, both in crystalline and amorphous form, which forms the novel feature of the invention. Montelukast amine salt thus prepared can exist in amorphous as well as crystalline form. Montelukast amine salt of formula I thus prepared can be optionally purified to enhance the purity and remove impurities so that final product of high purity can be obtained. Any suitable purification method can be employed such as spray wash, slurry wash, crystallization using a suitable solvent and the like.

Specifically, montelukast amine salt in a suitable solvent can be purified at a temperature of 10 to 75 °C for 10 minutes to 24 hours; preferably mixture can be maintained at a temperature of 15 to 70 °C for 2 to 12 hours. Suitable solvent can be selected from aliphatic ketones such as acetone, diethyl ketone, di-n-propyl ketone, methyl isobutyl ketone, diethyl ketone; alkyl nitriles such as acetonitrile, propionitrile; aliphatic alcohols such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol; aliphatic esters such as ethyl acetate, propyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon solvents such as toluene, xylene; halogenated solvents such as dichloromethane, chloroform, dichloroethane and the like or mixture thereof. Preferably montelukast amine salt can be dissolved in suitable solvent at a temperature of 15 to 65 °C for 10 minutes to 8 hours, more preferably at a temperature of 25 to 30 °C for 2 to 10 hours. The resulting mixture can be optionally stirred for 2 to 3 hours, preferably at a temperature of 0 to 5 °C. Thereafter, purified montelukast amine salt can be isolated from reaction mixture by a suitable techniques such as reducing the temperature of the mixture or precipitating by the addition of anti solvent selected from alkyl nitrile such as acetonitrile, propionitrile; ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; aliphatic or aromatic hydrocarbons such as hexane, pentane, heptane, n-hexane, n-heptane, n-pentane; toluene, xylene and the like or mixture thereof. The reaction mixture can be optionally seeded to obtain the desired the polymorphic of the montelukast amine salt. Montelukast amine salt can be isolated by techniques known in the art such as filtration, centrifugation and the like.

In an alternate way, montelukast amine salt can be purified by slurring in a suitable solvent. Generally, process involves slurry of montelukast amine salt in a suitable solvent at a temperature of 25 to 30 °C for 1 to 12 hours, preferably at a temperature 15 to 25 °C for 2 to 8 hours to provide purified montelukast amine salt. Solvent used for the different purification method can be selected depending upon the nature of montelukast amine salts as well as purification process employed and amount of solvent used. Solvent used for slurry can be selected from water, alkyl nitrile such as acetonitrile, propionitrile; aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol; hydrocarbon solvent such as n-heptane, hexane, cyclohexane, toluene, 1,2- xylene, 1,4- xylene and the like or mixture thereof. Montelukast amine salt can be isolated by suitable techniques known in the art such as filtration, centrifugation and the like.

Any purification process can be repeated or combined with other till product of desired quality is achieved. Montelukast amine salt of the present invention have high purity, preferably montelukast amine salt have purity more than 95 % and preferably more than 99% by HPLC. Montelukast amine salts thus prepared by the present invention are highly advantageous as they are used as an intermediate for purification of montelukast or pharmaceutically acceptable salts thereof and results in the increased purity of final product i.e. montelukast sodium.

Montelukast aipine salts of the present invention are easy to isolate. Montelukast amine salts of the present invention may be precipitated quite easily in various solvents. The readily isolable montelukast amine salts are highly advantageous as they provide a simple and efficient method for the purification of montelukast and circumvent the need of tedious chromatographic purification. Although number of montelukast amine salts are reported in prior art, montelukast amine salts of present invention afford high purity and gives best results in terms of yield and purity due to their solubility characteristics.

Specifically, montelukast amine salt is useful for purification of a crude montelukast, i.e. a product having purity between 50 to 95 % by HPLC or less. Even such an impure starting material may provide montelukast amine salt of present invention in solid form, which, after isolation, has fewer amounts of impurities such as side products. Some of the side products present in the crude montelukast are soluble in the solvents useful for the precipitation of the salt; therefore they remain in the mother liquor and are removed/reduced in the desired product. Further improvement of the purity may be performed by one or more re crystallizations or any purification of montelukast amine salt from a suitable solvent. Purification process involving the montelukast amine salts of present invention provides montelukast or pharmaceutically acceptable salts thereof having purity more than 95 % by HPLC, preferably more than 99 %; or more preferably 99.7 % by HPLC.

Montelukast amine salt as described by the present invention can be in solid or dissolved state and can be characterized by suitable techniques known in the art. Preferably, montelukast amine salt of the present invention can be characterized by various spectroscopic techniques like H and C Nuclear magnetic resonance (NMR), Mass spectrometry (MS), Infrared spectroscopy (IR) and X-ray diffraction chromatogram (XRD). Montelukast amine salt can also be characterized by Thermo gravimetric analysis (TGA), Differential scanning calorimetry (DSC).

According to one embodiment, the present invention provides montelukast (±)-l-(l- naphthyl)ethylamine salt.

Specifically, the present invention relates to montelukast (±)-l-(l-naphthyl)ethylamine salt in a solid or dissolved state. Solid montelukast (±)-l-(l-naphthyl)ethylamine salt can be in an amorphous or crystalline state.

Montelukast (±)- 1 -( 1 -naphthyl)ethylamine salt is characterized by:

Infra-red spectrum (IR): shows the peak at 3433.94, 2927.07, 1731.03, 1607.77, 1510.14, 1497.54, 1390.64, 1219.64835.34, 775.99 cm^"1.

'H-NMR(CDC1₃): 0.22-0.39 (m, 4H, cyclopropyl H); 1.52 (s, 3H, CH₃); 1.55 (s, 3H, CH₃); 1.63 (t, 3H), 2.05-2.15 (m, 2H); 2.22 (s, 2H); 2.45 ( s, 2H); 2.7-2.9 (m, 2H); 3.05-3.20 (m, 2H); 3.85-4.0 (t, 1H); 5.03-5.18 (t, 1H, olefinic); 5.98 (br s, 4H, exchangeable with D₂₀); 6.90-8.10 ( m, 21H, olefinic and aromatic H).

Melting point: 94 ± 4 °C by capillary method and shows endothermic peak in the range of 99-102°C by DSC.

According to another embodiment, the present invention provides montelukast (R)-(+)-l-(l- naphthyl)ethylamine salt.

Specifically, the present invention relates to montelukast (R)-(+)-l-(l-naphthyl)ethylamine salt in a solid or dissolved state. Solid montelukast (R)-(+)- l-(l-naphthyl)ethylamine salt can be in an amorphous or crystalline state.

Montelukast (R)-(+)-l-(l-naphthyl)ethylamine salt is characterized by:

Infra-red spectrum (IR): 3400.51, 2927.21, 1727.90, 1607.00, 1509.60, 1497.14, 1387.58, 1221.00, 1068.33, 836.13, 761.98 cm^"1

Melting point: 1 15 ± 3 °C

According to one embodiment, the present invention provides montelukast S-methyl-L-cysteine salt. Specifically, the present invention relates to montelukast S-methyl-L-cysteine salt in a solid or dissolved state. Solid montelukast S-methyl-L-cysteine salt can be in an amorphous or crystalline state.

Montelukast S-methyl-L-cysteine salt is characterized by: Infra-red spectrum (IR): 3572.49, 3444.23, 2920.40, 1717.48, 1609.11, 1499.71, 1485.58, 1409.39, 1316.80, 842.41, 765.75 cm^"1

Melting point: 153 ± 4 °C

According to one embodiment, the present invention provides montelukast diallylamine salt.

Specifically, the present invention relates to montelukast diallylamine salt in a solid or dissolved state. Solid montelukast diallylamine salt can be amorphous or crystalline state.

Montelukast diallylamine salt is characterized by:

Infra-red spectrum (IR): 3573.42, 2919.50, 1717.03, 1520.36, 1499.87, 1408.65, 1315.50, 933.27, 842.28, 765.76, 842.28 cm^"1.

Melting point: 143 ± 4 °C

Montelukast amine salts thus prepared can be further converted in to pure montelukast or pharmaceutically acceptable salts thereof.

Generally, process involves neutralization of montelukast amine salt using a suitable acid at a temperature of 0 to 50 °C for 10 minutes to 6 hours, preferably till the completion of the reaction. Suitable acid employed for neutralization include organic acids such as formic acid, acetic acid, propionic acid, butyric acid and the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and the like. Neutralization can be carried out in a suitable solvent for providing the reaction medium. Suitable solvents includes water or water immiscible organic solvents which can be selected from but are not limited to aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert- butyl ether; hydrocarbon solvent such as toluene, 1,2- or 1,4-xylene; halogenated solvents such as dichloromethane, chloroform, 1 ,2-dichloroethane and the like or mixture thereof. Usually, neutralization reaction can be carried out at a temperature of 10 to 30 °C for 10 minutes to 3 hours. After completion of neutralization, pure montelukast can be isolated from the reaction mixture or can be in situ proceeded for the conversion to montelukast pharmaceutically acceptable salts thereof. Specifically, after the completion of neutralization reaction, biphasic reaction mixture can be separated and organic layer can be optionally chacoalised, washed with water or aqueous solution of suitable inorganic base and/or dried over suitable drying agent such as sodium sulfate. Suitable base can be selected from alkali or alkaline metal bicarbonate, carbonate thereof such as sodium bicarbonate, sodium carbonate and the like. Montelukast can be isolated from the resulting organic layer by suitable techniques or organic layer can be used as such for the further conversion to montelukast pharmaceutically acceptable salts. Montelukast or reaction mixture containing montelukast can be converted to pharmaceutically acceptable salts thereof using a suitable base. Preferably montelukast sodium is prepared.

Specifically, process involves the reaction of montelukast with a suitable source of sodium ion in a suitable solvent at a temperature of 0 to 80 °C for 10 minutes to 6 hours preferably till the completion of the salt formation. Salt formation can be carried out using a suitable solvent selected from aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof. Suitable source of sodium ion can be selected amongst sodium hydroxide or sodium alkoxide and the like. Source of sodium ion employed can be used as such or in mixture with a suitable solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof. Source of sodium ion and/or montelukast can be mixed either simultaneously with a suitable solvent during the reaction or separately with a suitable solvent prior to reacting with each other. After completion of salt formation, mixture can be optionally charcoalised and product can be isolated from the resulting solution by the removal of solvent with suitable techniques such as evaporation, distillation and the like.

Product thus obtained can be optionally purified by stirring the reaction mixture in a suitable solvent which include aliphatic ester such as methyl acetate, ethyl acetate, aliphatic or aromatic hydrocarbon such as n-pentane, n-hexane, n-heptane; aliphatic ethers such as diethyl ether, isopropyl ether, methyl tert-butyl ether and the like or mixture thereof.

Alternatively, montelukast amine salt is treated with a suitable acid to form a solution containing montelukast which is directly converted to montelukast sodium without isolation of montelukast. The process involves the treatment of solution containing montelukast with a suitable source of sodium ion to form montelukast sodium by the reaction condition as specified above.

Montelukast sodium obtained by the process of present invention is highly pure in nature; it may have purity more than 99 %, preferably more than 99.5 %. More preferably it may have purity 99.7 % by HPLC. Montelukast sodium is found to have identified and/or unidentified impurity in an amount less than 0.15 %, preferably less than 0.10 %, or more preferably free from the impurities. Montelukast used for the process of present invention can be procured from the commercial source or can be prepared by any method known in the art. Montelukast can be prepared by employing any prior art method specifically starting from diol intermediate of formula II. Diol intermediate of formula II procured from commercial source or prepared by prior art processes is found to contain following impurities:

(R)-isomer impurity

along with other unidentified impurities. All of the above impurities have potential to further react with usual reaction sequence to form corresponding by product in the final API i.e. montelukast or pharmaceutically acceptable salts thereof. Therefore, the present invention provides an efficient process for purification of diol intermediate which will avoid loss of material caused by purification in e final step. Usage of pure diol intermediate of formula II avoids possibility of generation of more impurities in final product and thus leads to final API i.e. montelukast sodium with high purity. Thus, present invention provides a process for purification of diol intermediate of formula II to minimize amount of impurities and to increase chiral as well as chemical purity of intermediate. According to one more embodiment, present provides a process for purification of diol intermediate of formula II using a halogenated solvent and a nitrile solvent.

Generally, the process involves stirring of suspension of diol intermediate of formula II in the mixture of a halogenated and nitrile solvent at a temperature of 10°C to 35°C for 30 minutes to 24 hours. Halogenated solvent includes but not limited to dichloromethane, chloroform, 1, 2- dichloroethane and the like. Nitrile solvent includes but not limited to acetonitrile, propionitrile, butyronitrile and the like. Halogenated solvent and nitrile solvent can be used in a ratio of 1 :5 to 1 :50, preferably 1 : 20, more preferably 1: 10. Preferably suspension can be stirred at 10°C to 35°C temperature for 30 minutes to 24 hours. Reaction mixture can be optionally cooled to a temperature of -25°C to 10°C and further stirred for 30 minutes to 24 hours at temperature of -10°C to 5°C. The purified product can be isolated from reaction mixture using suitable techniques such as filtration, centrifugation, decantation and the like.

Diol intermediate of formula II, thus isolated, can be optionally washed with a suitable solvent, in which diol compound has very less solubility. Suitable solvent can be selected from aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol; aliphatic alkane such as n-pentane, n- hexane, hexanes, n-heptane, heptane; aliphatic ethers such as diethylether, isopropyl ether, methyl tertiary butyl ether; aliphatic ketone such as acetone, ethyl methyl ketone, diethyl ketone; nitrile such as acetonitrile, propionitrile and the like or mixture thereof.

Purification process can be optionally repeated to achieve desired purity level of diol intermediate and having minimum impurities. Diol intermediate of formula II prepared by the process of present invention is having purity more than 98.5 %, preferably more than 99%, more preferably more than 99.2 %.

Process of present invention is very effective for the removal of keto impurity as its presence leads to formation of corresponding montelukast keto impurity in montelukast sodium. Solvent and process used by present inventor is more helpful in reducing the level of keto impurity as compared to prior art as shown by comparative example. Diol intermediate of formula II purified by the present invention having hydroxyl ester and/or (R)-isomer impurity lower than 0.10%, preferably less than 0.08 %, more preferably free from impurities.

Diol intermediate of formula II, thus purified, can be converted to highly pure montelukast or pharmaceutically acceptable salts thereof by using the prior art method or by the method as described herein.

Diol intermediate of formula II is reacted with a suitable reagent to form intermediate of formula III. Generally, the process involves reaction of diol intermediate of formula II with a suitable reagent in the presence of a suitable base in a suitable solvent at a temperature of -80 to +10 °C for 30 minutes to 12 hours to convert. Preferably reaction can be carried out at a temperature of -50 to 0 °C for 3 to 8 hours. Suitable base is organic base is tertiary amine such as triethylamine, diisopropylethylamine, tri-n-propyl amine, tri-n-butyl amine, l,8-diazabicyclo[5.4.0]undec-7-ene and the like. Suitable solvent used for the reaction can be selected from aliphatic ethers such as methyl tert-butyl ether; alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof. Suitable reagent employed for the reaction can be selected from any reagent known in the art that can effectively convert secondary hydroxyl group of diol intermediate of formula II in to a good leaving group. Preferably suitable reagent can be selected from alkylsulfonyl halide such as methanesulfonyl chloride; substituted or unsubstituted arylsulfonyl halide such as toluenesulfonyl chloride, p- nitrobenzene sulfonyl chloride, benzenesulfonyl chloride and the like. Reaction mixture can be optionally seeded with a specific polymorph of intermediate of formula III to get the desired polymorph of the product. After completion of the reaction, the intermediate of formula III can be isolated from the reaction mixture or can be insitu reacted with a compound of formula IV or its ester derivative or salts thereof to form montelukast. Intermediate of formula III can be isolated from the reaction mixture by suitable techniques such as filtration or centrifugation and the like. It is preferable to proceed further without isolating intermediate of formula III. Isolated product can be optionally washed with a suitable solvent selected from alkyl nitrile such as acetonitrile, propionitrile; hydrocarbon solvent such as n-pentane, n-hexane, n-heptane, cyclohexane; alkyl ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like or mixture thereof- Intermediate of formula III is then reacted with a compound of formula IV or its ester derivative or salts thereof to form montelukast.

Generally, the process involves coupling of an intermediate of formula III with compound of formula IV in the presence of suitable base at a temperature of -10 °C to 80 °C for 15 minutes to 72 hours. Preferably reaction can be carried out at a temperature of -20 to 50 °C for 1 to 24 hours, more preferably till the completion of the reaction. Suitable bases used for the reaction include alkali metal hydroxides, carbonates, and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Base employed for the reaction can be used as such or its aqueous or alcoholic solution can be used for the reaction. Base employed for process results in the generation of dianion of a compound of formula IV. Compound of formula IV can be optionally reacted with a suitable base prior to the condensation with intermediate of formula III to generate corresponding salt of compound of formula IV or its anion. The reaction can be carried out in the presence of suitable solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropanol; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, polar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide and the like or mixture thereof. The reaction completion can be monitored using suitable chromatographic techniques such as thin layer chromatography (TLC), ultra pressure liquid chromatography (UPLC), high-pressure liquid chromatography (HPLC) and the like. After completion of the reaction, montelukast can be isolated from the reaction mixture after extractive workup or can be in situ reacted with suitable amine to form montelukast amine salts. Preferably, reaction mixture can be diluted with water and optionally washed with water immiscible organic solvent. Water immiscible organic solvents include aliphatic esters such as methyl acetate, ethyl acetate, aliphatic or aromatic hydrocarbon such as n-pentane, n-hexane, n-heptane, toluene, 1,2- xylene, 1,4-xylene, cyclohexane, cycloheptane; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether and the like or mixture thereof. Thereafter, aqueous layer containing the montelukast can be optionally treated with a suitable acid or acid salt. The desired product can be extracted from the resulting aqueous layer using a suitable solvent which includes aliphatic esters such as methyl acetate, ethyl acetate; propyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane and the like. Montelukast can be isolated from the organic layer by the removal of solvent using suitable techniques such as evaporation, distillation and the like or can be used as such for the preparation of montelukast amine salt.

Montelukast prepared from the diol intermediate of formula II as purified by the process of present invention can be converted to any montelukast amine salt known in the prior art not limited to the novel amine salts of present invention, specifically amine used for the salt formation can be selected from dicylohexylamine, dipropyl amine, arginine, L-(+)-treo-2-amino-l -phenyl- 1,3- propanediol, and L-(+)-a-phenylglycinol, tris hydroxymethyl amino methane, cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclodocecyl amine, cyclooctyl amine and phenylethyl amine, a- methylbenzyl amine, cyclohexylethyl amine, tert-butyl amine, amantadine, 1-(1- naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine and the like.

Main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of highly pure montelukast or pharmaceutically acceptable salts thereof in high yield through novel amine salts of montelukast. The process of present invention is efficient, reproducible as well as industrially advantageous. Another advantage of present invention is to provide diol intermediate of formula II having acceptable level of impurities or preferably free from impurities and easy recovery of solvents after purification. Recovery has been achieved due to difference in boiling point of mixture of two solvents. Boiling point of dichloromethane is 39 °C and of acetonitrile is 82 °C, and therefore it provides a cost effective, easy and efficient process for purification of diol intermediate. Another but not the last advantage of present invention is removal of impurities at the starting diol intermediate which circumvent carry forward of impurities and thus avoids the possibility of generation of other by products, thereby yielding pure montelukast or pharmaceutically acceptable salts thereof.

COMPARATIVE EXAMPLE:

Example 1: Purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyI)-phenyl)-3-(hydroxy- propyl)phenyl-2-propanol

2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl-2-propanol (5g, having purity 98.0 %, keto impurity: 1.01 %) was dissolved in toluene (15 ml) at 60 °C and stirred for 1 hour. n-Heptane (50 ml) was added drop wise at 60 °C over a period of 20 minutes. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled further to 10 to 15 °C and stirred at this temperature for 1 hour. Product this obtained was filtered, washed with n- heptane (5 ml) and dried in oven under vacuum at 40-45 °C for 6 hours to give 4.1 g of title compound having purity 98.83 %; keto impurity: 0.51 %.

EXAMPLES

Example 1: Purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)- ethenyl)-phenyl)-3-(hydroxy- propyI)phenyl-2-propanol

A suspension of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl- 2-propanol (200 g, having purity 98.0 %, keto impurity: 1.01 % by HPLC)) is stirred in a mixture of dichloromethane ( 200 ml) and acetonitrile (2.0 L) for 1 hour at 25-30 °C. The mixture was cooled to 0°C-5 °C, stirred for 1 hour and filtered. The resulting product was slurry washed with chilled acetonitrile 0°C-5°C (200 ml) and dried at 40-45 °C under vacuum to give 180 g of title compound having purity 99.18 %, keto impurity: 0.22 % by HPLC.

Example 2: Purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)- ethenyl)-phenyl)-3-(hydroxy- propyl)phenyl-2-propanol

A suspension of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl- 2-propanol (290 g, having purity 99.01 %, keto impurity: 0.35 %, (R)-isomer impurity: 0.05%) is stirred in a mixture of dichloromethane ( 290 ml) and acetonitrile (270ml) for 1 hour at 25-30 °C.

Mixture was cooled to 0-5 °C, stirred for 1 hour and filtered. Resulting product was slurry washed with acetonitrile and dried at 40-45 °C under vacuum to give 220 g of title compound having purity

99.69 %, keto impurity: 0.04%; R- isomer:0.01% by HPLC.

Example 3: Preparation of [(S)-(E)]-2-[2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyll phenyl]-3- methanesulphonyloxy] propyl] phenyl] -2-propanol

[(S)-(E)]-2-[2-[3-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxypropyl] phenyl]-2- propanol (100 g, 0.22 mol) in methyl-tertiary-butyl ether (400 ml) was stirred under atmosphere of nitrogen gas at 25-30 °C. Reaction mixture was heated to 55-60 °C followed by partial distillation of methyl tert-butyl ether under Dean stark conditions (approximately 200 ml). Acetonitrile (800 ml) was added to the resulting reaction mixture and stirred for 10 minutes. Thereafter, the reaction mixture was cooled to 30-35 °C followed by addition of N,N-diisopropylethyIamine (37.0 g, 0.29 mol). The resulting mixture was further cooled to -10 to -5 °C and methanesulphonyl chloride (37 g, 0.32 mol) was added slowly for 15 minutes to the reaction mixture. Reaction mixture was again cooled to -20 to -15 °C and seeded with crystals of pure title compound. The reaction mixture was stirred for 4 hours at -30 to -25 °C. The resulting product was filtered, under nitrogen gas atmosphere washed with cold acetonitrile (-25 to -30 °C, 200 ml) and n-heptane (200 ml, at -25 to - 30 °C). Product thus obtained was dried at -5 to 0 °C for 15 to 20 minutes to give 230 g of wet title compound which was used as such for the further reaction.

Example 4: Preparation of montelukast

A solution of l-(mercaptomethyl)cyclopropaneacetic acid (26 g, 0.18 mol) in methanol (26 ml) was added to a cooled solution of methanolic sodium hydroxide [prepared by dissolving sodium hydroxide (17 g, 0.43 mol) in methanol (120 ml)]. The mixture was stirred for 1 hour at ambient temperature followed by addition of tetrahydrofuran (500 ml). The mixture was cooled to -15 to -10 °C and wet [(S)-(E)]-2-[2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-methanesulphonyloxy] propyl]phenyl]-2-propanol was added to the above reaction mixture at -15 to -10 °C. The temperature of reaction mixture was raised to 25-30 °C and stirred for 5 hours. After completion of the reaction (monitored by TLC), demineralised water (800 ml) was added to the reaction mixture. Thereafter, reaction mixture was extracted with a mixture of n-heptane & ethyl acetate (9: 1, 2 x 500 ml). Aqueous tartaric acid (10 %, 150 ml) was added to the aqueous layer till pH of the reaction reaches to 4.0 to 5.0. The aqueous layer was extracted with ethyl acetate (1 x 500 ml). Ethyl acetate layer was separated and washed with water (2 x 500 ml). Organic layer was stirred with activated charcoal & anhydrous sodium sulfate at 25-30 °C and filtered through hyflo-bed. Solvent was distilled off from the organic layer to give 100 g of the title compound as pale yellow viscous oil having purity 84.88 % by HPLC. A portion of the resulting product was stirred in ethyl acetate and acetonitrile (1 :7) at 20-30 °C, filtered, washed with acetonitrile, and dried at 55-60 °C to give title compound having purity 97.55 % by HPLC.

Example 5: Preparation of montelukast

Step I: Preparation of [(S)-(E)]-2-[2-[3-[3-[2-(7-chIoro-2-quinolinyl)ethenyl] phenyl]-3- methanesulphonyloxy]propyl]phenyl]-2-propanol :[(S)-(E)]-2-[2-[3-[3-[2-(7-Chloro-2- quinolinyl)ethenyl]phenyl] -3-hydroxypropyl] phenyl]-2-propanol (100 g, 0.22 mol) in tetrahydrofuran (500 ml) was heated to 55-60 °C and stirred for 10 minutes. After complete dissolution, the reaction mixture was cooled to 30-35 °C and N.N-diisopropylethylamine (37 g, 0.29 mol) was added slowly to the reaction mixture. Reaction mixture was cooled to -20 to - 15 °C and methanesulphonyl chloride (37 g, 0.32 mol) was added to the reaction mixture at -20 to -15 °C for 15 minutes. The reaction mixture was further cooled to -30 to -25 °C and stirred for 6 hours. The reaction mixture was filtered and successively washed with cold tetrahydrofuran (-30 °C, 100 ml). The combined filtrate was stored at -30 to -25 °C and used as such in the next step.

Step II: Preparation of montelukast: A solution of l-(mercapto methyl)cyclopropaneacetic acid (26 g, 0.18 mol) in methanol (26 ml) was added to a cooled solution of methanolic sodium hydroxide [prepared by dissolving sodium hydroxide (17 g, 0.43 mol) in methanol (120 ml)]. The reaction mixture was stirred for 1 hour at ambient temperature followed by addition of tetrahydrofuran (500 ml). The reaction mixture was cooled to -15 to -10 °C. Solution (as obtained in step I) was added to the above reaction mixture at -15 to -10 °C. The temperature of the reaction mixture was raised to 30 °C and stirred for 5 hours. After completion of the reaction (monitored by TLC), demineralised water (800 ml) was added to the reaction mixture. Thereafter, reaction mixture was stirred with a mixture of n-heptane & ethyl acetate (9: 1, 2 x 500 ml). Layers were separated. Aqueous tartaric acid (10 %, 150 ml) was added to the aqueous layer till pH of the reaction reaches to 4.0 to 5.0. The aqueous layer was extracted with ethyl acetate (1 x 500 ml) and organic layer was separated, washed with water (2 x 500 ml). Organic layer was stirred with activated charcoal, dried over anhydrous sodium sulfate and filtered through hyflo-bed. Solvent was distilled off from the resulting organic layer under vacuum to give 98.3 g of the title compound as pale yellow viscous oil having purity: 88.34 % by HPLC.

Example 6: Preparation of montelukast

To a solution of l-(mercaptomethyl)cyclopropaneacetic acid (60 g, 0.41 mol), sodium hydroxide (43 g ,1.08 mol ), methanol (340 ml) at -15 to -10 °C , wet [(S)-(E)]-2-[2-[3-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-methanesulphonyloxy] propyl]phenyl]-2-propanol (375 g dissolved in 750 ml tetrahydrofuran at -25 to -30 °C) was added and stirred at -25 to -30 °C for 5 hours. After completion of reaction, reaction mixture was basified by the addition of 5% sodium hydroxide solution (200 ml) and resulting reaction mixture was washed with n-heptane (3 x 300 ml) and demineralised water (300 ml). 10 % Aqueous solution of tartaric acid (-300 ml) was added to the aqueous layer till pH 3.0-4.0 and thereafter extracted with ethyl acetate (2 x 750 ml). Combined organic layer was washed with water (2 x 750 ml). The organic layer was stirred with activated charcoal, dried over anhydrous sodium sulfate at 25-30 °C and filtered through hyflo-bed. Solvent was removed from the organic layer to give 190g of the title compound having purity 84 % by HPLC.

Example 7: Preparation of montelukast l-(l-naphthyl)ethylamine salt

Method A: To a stirred solution of montelukast (98 g, 0.16 mol) in ethyl acetate (400 ml), 1-(1- naphthyl)ethylamine salt (38 g, 0.22 mol) was added at 25-30 °C and was stirred for 10 hours. The precipitated solid was filtered off. Acetonitrile (1000 ml) was slowly added to resulting filtrate at 25- 30 °C and stirred for 24 hours. The precipitated solid was filtered and washed successively with acetonitrile (200 ml) and n-heptane (200 ml). The resulting solid was dried for 2 hours and dried under vacuum at 30 °C for 4 hours to give 70 g of crystalline title compound having purity 99.3 % by HPLC.

Method B: A solution of l-(mercaptomethyl)cyclopropaneacetic acid (30 g ,0.21 mol) in methanol (30 ml) was added to a cooled solution of methanolic sodium hydroxide (prepared by dissolving sodium hydroxide (18 g ,0.45 mol ) in methanol (120 ml ) and stirred for 5 hours at ambient temperature. Tetrahydrofuran (500 ml) was added to the reaction mixture and cooled to -15 to -10 °C. [(S)-(E)]-2-[2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl] phenyl]-3-methanesulphonyloxy]propyl] phenyl] -2-propanol (obtained as above) was added to above reaction mixture at -15 to -10 °C and temperature of the reaction mixture was slowly raised to 25-30 °C. The reaction mixture was stirred for 15 hours at 25-30 °C. After completion of reaction, demineralized water (500 ml) was added to the reaction mixture followed by addition of 10 % tartaric acid to adjust the pH of reaction mixture to 9-10 and extracted with n-heptane (3 x 800ml). Another portion of 10 % tartaric acid (180 ml) was added to reaction mixture and aqueous layer was extracted with dichloromethane (2 x 500 ml) and the combined organic layer was successively washed with 2% sodium bicarbonate solution (500 ml) and water (2 x 500 ml). Butylated hydroxy anisole (2 g), activated charcoal (20 g) and anhydrous sodium sulfate were added to dichloromethane layer at 25-30 °C and stirred for 30 minutes. Reaction mixture was filtered through hyflo-bed. dichloromethane was partially distilled off from reaction mixture and resulting reaction mixture was cooled to ambient temperature. Acetonitrile (400 ml) was added to reaction mixture and stirred for 1 hour. The reaction mixture was then heated to 35-40 °C and l-(l-naphthyl)ethyl amine (35 g) followed by acetonitrile (600 ml) were successively added to reaction mixture and stirred for 12 hours. The solid thus precipitated was filtered, successively washed with acetonitrile (200 ml ) and n-heptane (200ml) and dried to give 85.3g of title compound. A portion of resulting product was purified using dichloromethane and acetonitrile to give purified title compound which was again purified with water, methanol and acetonitrile to give title compound having purity 99.84 % by HPLC and melting point: 100.20 °C by DSC.

Example 8: Preparation of montelukast (R)-(+)- l-(l-naphthyl)ethylamine salt

To a stirred solution of montelukast (5.0 g, 0.01 mol ) in ethyl acetate (20 ml), (R)-(+)- 1-(1- naphthyl)ethylamine salt (1.7 g, 0.01 mol) was slowly added at 25-30°C and stirred for 10 hours. Reaction mixture was filtered to remove undissolved particles. To the filtrate thus obtained, acetonitrile (50 ml) was added at 25-30 °C and mixture was stirred for 24 hours. Solid thus precipitated was filtered and washed successively with acetonitrile (10 ml) & n-heptanes (25 ml). Resulting solid was dried under vacuum at 30 °C for 4 hours to give 4.5 g of the title compound showing melting point 1 15-1 18°C. Example 9: Preparation of montelukast S-methyl-L-cysteine salt

To a stirred solution of montelukast (5.0 g, 0.01 mol) dissolved in toluene (100 ml), S-methyl-L- cysteine (1.2 g, 0.01 mol, pre-dissolved in 15 ml water) was slowly added at 25-30 °C and the reaction mixture was stirred at 50 °C for 30 minutes. Resulting solution was concentrated (to 50 ml) and cooled to room temperature. Hexane (100 ml ) was added to the resulting solution followed by addition of ethyl acetate (40 ml) and stirred at 25-30 °C for 18 hours. Solid thus precipitated was filtered and washed with n-heptane (20 ml), dried under vacuum at 40 °C for 24 hours to give 4.9 g of the title compound having purity 99.21 % by HPLC and melting point : 152-155 °C.

Example 10: Preparation of montelukast diallylamine salt

To a stirred solution of montelukast (185.0 g, 0.32 mol) dissolved in ethyl acetate (185 ml), di-allyl amine (30 g,0.31 mol) was slowly added at 25-30°C and the reaction mixture was stirred for 10 hours. Reaction mixture was filtered to remove insoluble particles and acetonitrile (1850 ml) was added to the resulting filtrate over a period of 1.5 hours at 25-30 °C. Reaction mixture was stirred at 25-30 °C for 24 hours. The solid thus precipitated was filtered and washed successively with acetonitrile (370 ml) & n-heptanes (370 ml). Solid thus obtained was dried under vacuum at 30 °C for 4 hours to give 185g of the title compound having purity 98.99 % by HPLC and melting point: 140-145 °C.

Example 11: Preparation of montelukast dicyclohexyl amine salt

A solution of l-(mercaptomethyl)cyclopropaneacetic acid (30 g) in dry methanol (30 ml) was slowly added to a cooled (-15 to -10°C) solution of methanolic sodium hydroxide solution {prepared by dissolving sodium hydroxide (18 g,) in methanol (120 ml ) in a 3.0 lt/4- neck round bottomed flask fitted with a mechanical stirrer, thermometer inlet under nitrogen atmosphere . The mixture was stirred for 5 hr at ambient temperature. Tetrahydrofuran (500ml) was added to the reaction mixture and was cooled slowly to -15 to -10°C. The wet solid monomesylate compound obtained in first stage was charged in lots into above slurry over a period of 5 minutes at -15 to -10°C and the temperature of the reaction mass was raised slowly to 25-30°C. The reaction mixture was stirred for 15 hrs while maintaining temperature at 25-30°C. After completion of reaction, DM water (500 ml) was added to reaction mixture and pH of reaction mixture is brought down to 9-10 using 10 % tartaric acid aqueous solution and extracted with n-heptane (3x800ml). pH of aqueous layer was further adjusted to 4.0-5.0 with aqueous solution of tartaric acid. The aqueous layer was extracted with dichloromethane (2 x 500 ml) and combined dichloromethane layer was successively washed with 2% aqueous solution of sodium bicarbonate (500 ml) and water (2 x 500 ml). To dichloromethane layer, butylated hydroxy anisole (2 g), activated charcoal (20 g) and anhydrous sodium sulfate were successively added at 25-30°C, stirred for 30 min and filtered through hyflo-bed. Dichloromethane was completely distilled off under vacuum to provide crude dark tan oily residue. The residue was cooled to 25-30°C and to this, ethyl acetate (400 ml) and toluene ( 300 ml) were slowly added and stirred for 15 min. N, N-Dicyclohexylamine (DCHA, 52 g) was slowly added to reaction mass over a period of 15 minutes and reaction mass was stirred for 12 hrs at 25-30 °C. The solid, thus obtained, was filtered and washed successively with a mixture of ethyl acetate and toluene (1 :1/ 100 ml) and n-heptane (400ml) and suck dried for 2 hrs. The product was dried under vacuum at 30-45°C for 8 hrs to obtain 1 12 g of montelukast DCHA salt having purity of 99.0 % by HPLC.

Example 12: Preparation of montelukast sodium

Method A: Step I: Preparation of montelukast: To a stirred suspension of montelukast 1-(1- naphthyl)ethylamine salt (70 g, 0.09 mol), in ethyl acetate (700 ml) and demineralised water (700 ml) at 25-30 °C, acetic acid (3 M, 560 ml) was added and reaction mixture was stirred for 45 minutes at 25-30 °C. Layers were separated and ethyl acetate layer was washed with water (2 x 700 ml). The organic layer was charcoalised and dried over anhydrous sodium sulfate and filtered through hyflo-bed. Organic layer was used as such in the next step.

Step 2: preparation of montelukast sodium: Sodium hydroxide (3.6 g, 0.09 mol) was dissolved in methanol (250 ml) under an atmosphere of nitrogen gas at 25-30 °C. After complete dissolution, the reaction mixture was cooled slowly to 0 to -5 °C. Organic layer (as obtained in step I) was added to the resulting reaction mixture and at 0 to -5 °C for 30 minutes. Reaction mixture was heated to 25-30 °C and stirred for 30 minutes. Activated charcoal was added to the resulting solution and stirred for 1 hour at 25-30 °C. Reaction mixture was filtered through a hyflo-bed and washed with methanol (50 ml). Solvent was evaporated under vacuum and n-heptane (500 ml) was added to the resulting residue. Mixture was stirred for 5 hours at 25-30 °C. Solid thus precipitated was filtered, washed with n-heptane (100 ml) and dried at 35-40 °C to give 50 g of the title compound as a very hygroscopic white powder having purity 99.70 % by HPLC.

Method B: To a stirred suspension of montelukast (R)-(+)- l-(l-naphthyl)ethylamine salt (4.5 g ) in ethyl acetate (45 ml) and demineralised water (45 ml) at 25-30 °C, acetic acid (3M, 36 ml) was slowly added and mixture was stirred for 15 minutes at 25-30 °C. Ethyl acetate layer was separated and washed with water (2 x 45 ml). Resulting organic layer was charcoalised, dried over anhydrous sodium sulfate for 15 minutes and filtered through hyflo-bed. Resulting filtrate was slowly added to a solution of sodium hydroxide (0.32 g, 0.008 mol) and methanol (20 ml) at 0 to - 5 °C and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-30 °C and stirred for 30 minutes. Activated charcoal was added to resulting reaction mixture and stirred for 1 hour at 25-30 °C. The mixture was filtered through hyflo-bed and bed was washed with methanol (5 ml). Methanol was evaporated under vacuum and residue was stirred in a mixture ethyl acetate (5 ml) and n- heptane (50 ml) for 5 hours at 25-30 °C. The resulting solid was filtered, washed with n-heptane (100 ml) and dried at 35-40 °C under vacuum to give 3.5 g of the title compound having purity 99.4 % by HPLC.

Method C; To a stirred suspension of montelukast S-methyl-L-cysteine salt (II) (4.9 g, 0.01 mol), in ethyl acetate (49 ml) and demineralised water (49 ml) at 25-30 °C, acetic acid (2.0 M, 30 ml) was slowly added over a period of 30 minutes and the mixture was stirred for 15 minutes at 25-30 °C. Ethyl acetate layer was separated and washed with water (2 x 49ml). The resulting organic layer was stirred with activated charcoal, dried over anhydrous sodium sulfate for 15 minutes and filtered through hyflo-bed. The filtrate was slowly added to a solution of sodium hydroxide (0.36 g, 0.01 mol) & methanol (25 ml) at 0 to -5 °C and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-30 °C and stirred for 30 minutes. Activated charcoal was added to the resulting solution, stirred for 1 hour at 25-30 °C, filtered through a hyflo-bed and bed was washed with methanol (5 ml). Methanol was evaporated under vacuum and the residue was stirred with a mixture ethyl acetate (5ml) and n-heptane (50ml) for 5 hrs at 25-30 °C. The resulting solid was filtered, washed with n-heptane (100 ml) and dried at 35-40 °C to give 4 g of the title compound having purity 99.20 % by HPLC.

Method D: To a stirred suspension of montelukast diallylamine amine salt (185.0 g, 0.27 mol), in ethyl acetate (1850 ml) and demineralised water (1850 ml) at 25-30 °C, acetic acid (2.0 M, 740 ml) was slowly added and the mixture was stirred for 15 minutes at 25-30°C. Ethyl acetate layer was separated and washed with water (2 x 700 ml). Resulting organic layer was charcoalised, dried over anhydrous sodium sulfate for 15 minutes and filtered through hyflo-bed. The filtrate was slowly added to a solution of sodium hydroxide (13.3 g, 0.33 mol) and methanol (925 ml) at 0 to -5 °C and stirred for 30 minutes. The temperature of the reaction mixture was raised to 25-30 °C and stirred for 30 minutes. Activated charcoal was added to the resulting solution and stirred for 1 hr at 25-30 °C. The mixture was filtered through a hyflo-bed and the bed was washed with methanol (370 ml). Methanol was evaporated under vacuum and the residue was stirred with a mixture ethyl acetate (185 ml) and n-heptane (1850 ml) for 5 hours at 25-30°C. The resulting solid was filtered, washed with n-heptane (370 ml) and dried under vacuum to give 121 g of amorphous title compound having purity 99.10 % by HPLC. Method E; To a stirred suspension of montelukast l-(l-naphthyl)ethyl amine salt (80 g, 0.105mol) in methyl tert-butyl ether (800 ml) and demineralized (400 ml) at 10-15 °C, 10% acetic acid (127 ml) was added and mixture was stirred for 15 minutes at 10-15 °C. The temperature of reaction mixture was raised to 25-30 °C and stirred for 1 hour. Layers were separated and organic layer was washed with 2 % sodium bicarbonate (400 ml) and water (2 x 800 ml). Resulting organic layer was stirred with activated charcoal and anhydrous sodium sulfate for 15 minutes and filtered through hyflow bed. Solvent was distilled off from organic layer and methanol (160 ml) was added to resulting residue followed by distilled off. Methanol (400 ml) was added to resulting residue. A solution of sodium hydroxide (4.42g, 0.1 1 mol) in methanol (300 ml) was added to reaction mixture at 0 to -5 °C and stirred for 30 minutes at same temperature. Thereafter, temperature of the reaction mixture was raised to 35-40 °C and stirred for 30 minutes. Resulting reaction mixture was charcoalised, filtered and washed with methanol (50 ml). Methanol was evaporated under vacuum. n-Heptane (400ml) was added to resulting residue and stirred for 1 hour at ambient temperature. Reaction mixture was filtered, washed with n-heptane (100 ml) and dried to give 59.2 g of title compound having purity 99.90 % by HPLC.

Method F: To a stirred suspension of montelukast l-(l-naphthyl)ethyl amine salt (80 g , 0.105mol) in methyl tert-butyl ether (800 ml) and demineralized (400 ml) at 10-15 °C, 10% acetic acid (127 ml) was added and mixture was stirred for 15 minutes at 10-15 °C. The temperature of reaction mixture was raised to 25-30 °C and stirred for 1 hour. Layers were separated and organic layer was washed with 2 % sodium bicarbonate (400 ml) and water (2 x 800 ml). Resulting organic layer was charcoalised. Solvent was distilled off from organic layer and methanol (160 ml) was added to resulting residue followed by distilled off. Methanol ( 400 ml) was added to resulting residue. A solution of sodium hydroxide (4.42g, 0.1 1 mol) in methanol (300 ml) was added to reaction mixture at 0 to -5 °C and stirred for 30 minutes at same temperature. Thereafter, temperature of the reaction mixture was raised to 35-40 °C and stirred for 30 minutes. Resulting reaction mixture was charcoalised, filtered and washed with methanol (50 ml). Methanol was evaporated under vacuum. n-Heptane (400ml) was added to resulting residue and stirred for 1 hour at ambient temperature. Reaction mixture was filtered, washed with n-heptane (100 ml) and dried to give59.2 g of title compound having purity 99.90 % by HPLC.

Method G: To a stirred suspension of montelukast DCHA salt (80 g) in methyl tert-butyl ether (800 ml) and DM water (400 ml) at 10-15°C, acetic acid (10% solution, 160 ml) was charged over a period of 30 minutes and reaction mixture was stirred for 15 minutes at 10-15°C. The temperature was slowly raised to 25-30°C and stirred for 1 hr, methyl tert-butyl ether layer was separated and successively washed with cold (10-15°C, 2 % aqueous solution of sodium bicarbonate (400 ml) and water (2 x 800 ml). The organic layer was stirred with activated charcoal and anhydrous sodium sulfate for 15 minutes and filtered through hyflo-bed. Methyl tert- butyl ether was completely distilled off under vacuum and anhydrous methanol (160 ml ) was added to it . Methanol was distilled off under vacuum to remove traces of methyl tert-butyl ether. To the resulting reaction mass, methanol ( 400 ml) was added and cooled to 0 to -5°C . To this cold solution, a solution of methanol (300 ml) and sodium hydroxide (4.42 g, 0.1 1 mol), prepared separately, was added at 0 to -5°C. After stirring at 0 to -5°C for 30 minutes, temperature of reaction mixture was raised to 35-40°C and stirred for 30 minutes. Activated charcoal was added to clear pale yellow solution and after stirring for 1 hr at 35-40°C, the mixture was filtered through a hyflo-bed and washed with methanol (50ml). Methanol was evaporated under vacuum <40°C to get a residue .To the residue n-heptane (400ml) was added and the suspension was stirred for 1 hr at 25-30°C. The solid was filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at 35-40°C under vacuum to afford 62.2 g of pure montelukast sodium as white to almost white, a very hygroscopic powder, having purity 99.62% by HPLC.

Claims

WE CLAIM:

1). A process for preparation of pure montelukast or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , providing montelukast in a suitable solvent;

b) . optionally, adding a suitable anti-oxidant;

c) . reacting with a suitable amine selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof, for a sufficient period of time till formation of montelukast amine salt of formula I,

Formula I wherein (R)₂NH is selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof

d) . optionally, isolating montelukast amine salt of formula I; and

e) . converting the same in to montelukast or pharmaceutically acceptable salts thereof.

2) . The process according to claim 1, wherein in step a) suitable solvent is selected from aliphatic esters such as ethyl acetate, propyl acetate; aliphatic ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone; alkyl nitriles such as acetonitrile, propylnitrile; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; aliphatic or aromatic hydrocarbon such as 1,2- or 1,4 xylene, toluene; halogenated hydrocarbon such as dichloromethane, chloroform or dichloroethane and the like or mixture thereof.

3) . The process according to claim 1, wherein in step b) anti-oxidant is selected from natural antioxidant such as ascorbic acid and tocopherols; synthetic antioxidant such as propyl galate, tertiary butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene.

4) . Montelukast a

Formula I wherein (R)₂NHis selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof. 5) . The compound according to claim 4, wherein l-(l-naphthyl)ethylamine is selected from (R)-l-

(l-naphthyl)ethylamine, (S)- l-(l-naphthyl)ethylamine or (±) l-(l-naphthyl)ethylamine.

6) . The compound according to claim 4, is in solid form.

7) . The compound according to claim 6, solid is in amorphous or crystalline form.

8) . A process for preparation of montelukast amine salt of formula I,

Formula I wherein (R)₂NH is selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof

comprising the steps of:

d) . providing montelukast in a suitable solvent;

e) . reacting with a suitable amine selected from l-(l-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine or isomers thereof for a sufficient period of time till formation of montelukast amine salt of formula I; and

f) . optionally, purifying montelukast amine salt of formula I.

9) . The process according to claim 8, wherein in step a) suitable solvent is selected from aliphatic esters such as ethyl acetate, propyl acetate; aliphatic ketones such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone; alkyl nitriles such as acetonitrile, propylnitrile; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; aliphatic or aromatic hydrocarbon such as 1,2- or 1,4 xylene, toluene; halogenated hydrocarbon such as dichloromethane, chloroform or dichloroethane and the like or mixture thereof.

10) . A process for preparing pure montelukast or pharmaceutically acceptable salts thereof having oxidized impurities less than 0.15%, comprising the step of adding an antioxidant to a solution of montelukast in a solvent during salt formation or purification .

11) . The process according to claim 10, wherein antioxidant is selected from natural antioxidant such as ascorbic acid and tocopherols; synthetic antioxidant such as propyl galate, tertiary butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene.

12) . The process according to claim 10, wherein solvent is selected from halogenated solvent such as dichloromethane, 1 ,2-dichloroethane, chloroform; ethers such as tetrahydrofuran, 2- methyl tetrahydrofuran, 1,2-dimethoxyethane; ester such as ethyl acetate and the like or mixture thereof..

13) . A process for the purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)- ethenyl)-phenyl)-3- (hydroxy-propyl)phenyl-2-propanol of formula II, comprising the steps of:

a), providing diol intermediate of formula II in a halogenated hydrocarbon and nitrile solvent; b) .stirring the mixture at temperature of 10-35°C;

c) . optionally, cooling the resulting mixture; and

d) . isolating pure diol intermediate of formula II.

14) . The process according to claim 13, wherein in step a) halogenated hydrocarbon is selected from dichloromethane, chloroform and 1 ,2-dichloroethane.

15) . The process according to claim 13, wherein in step a) nitrile solvent is selected from acetonitrile and propionitrile.

16) . The process according to claim 13, wherein step a) ratio of halogenated solvent to nitrile solvent is 1 :5 to 1 :50..

17). The process according to claim 13, wherein in step c) reaction mixture is cooled to a temperature of -25°C to +10 °C.

18) . The process according to claim 13, wherein diol intermediate of formula II is optionally washed with a suitable solvent selected from aliphatic alcohols such as methanol, ethanol, n- propanol, isopropanol; aliphatic alkane such as n-pentane, n-hexane, hexanes, n-heptane, heptane; aliphatic ethers such as diethylether, isopropyl ether, methyl tertiary butyl ether; nitrile such as acetonitrile, propionitrile and the like or mixture thereof.

19) . The process according to claim 13, wherein diol intermediate of formula II is further converted to montelukast or pharmaceutically acceptable salts thereof.

20) . Diol intermediate of formula II having identified impurities NMT than 0.5% and/or unidentified impurities NMT than 0.10 % by HPLC.