Claims:
1. A novel process for the synthesis of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1), which process comprises;
a) reacting 7-Chloroquinaldine (Formula 5) with Isophthalaldehyde (Formula 6) in presence of suitable acid catalyst and in suitable solvent(s) to obtain 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (Formula 4);

c) subjecting the 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (formula 4) to Grignard reaction with Vinyl magnesium bromide in presence of suitable inert solvents to obtain 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol ( Formula 3); and

c) reacting the 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) intermediate with 2-(2-Chlorophenyl)propan-2-ol in presence of suitable solvent(s) to obtain [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).

2. The process as claimed in claim 1, wherein the suitable acid catalysts are selected from sulphuric acid, formic acid, hydrochloric acid and acetic acid.
3. The process as claimed in claim 1, wherein the suitable inert solvents used for the Grignard reaction are selected from tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dimethyl formamide, dichloromethane or mixtures thereof.
4. The process as claimed in claim 1, wherein, the solvents used for the preparation of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] are selected from dimethyl formamide, tetra hydrofuran, toluene or mixture thereof.
5. The process as claimed in claim 1, wherein, the 2-(2-Chlorophenyl) propan-2-ol is prepared by a process which comprises;
a) reacting O-chloro bromo benzene with magnesium metal in presence of suitable inert solvent to obtain 2-chloro phenyl magnesium bromide [Formula 2]; and

b) reacting the 2-chloro phenyl magnesium bromide with acetone solvent in presence of an inorganic base to obtain 2-(2-Chlorophenyl) propan-2-ol.

6. The process as claimed in claim 5, wherein, the inert solvents are selected from dimethyl formamide, tetra hydrofuran, toluene or mixture thereof.
7. The process as claimed in claim 5, wherein, the inorganic base is selected from ammonium chloride, ammonium acetate and ammonium sulphate.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula-1), hereinafter referred as a diol intermediate with increased efficiency in terms of yields, which is a key intermediate of Montelukast or pharmaceutically acceptable salts thereof. The present invention further discloses a commercial process for synthesis of 2-(2-Chlorophenyl) propan-2-ol.

BACKGROUND OF THE INVENTION
[2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] is known as a diol intermediate of Montelukast. Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useful as an antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agent and hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatic, and toxemia, uveitis and allograft rejection. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis. Structure of the Montelukast intermediate, viz., [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] is as below.

Montelukast and related compounds are first disclosed in US patent 5,565,473. US’473 Patent discloses preparation of montelukast sodium through 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(hydroxyl-propyl)phenyl-2-propanol. The preparation of diol intermediate is shown in the following scheme.

The preparation of diol intermediate as per the above scheme 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. This 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. US’473 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 the 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 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 cannot be applied for the commercial synthesis.
US patent application publication 2005/0107612 describes a process for the preparation of montelukast sodium by following scheme:

The process involves conversion of mesylate intermediate into 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. The 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 unconsumed 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 isomers. 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 which is under present invention, therefore purity of this intermediate is quite important to obtain drug product, montelukast sodium with high purity with 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 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 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 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 ?,?'-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.

Diol intermediate which is under present invention is an important key intermediate in the preparartion of montelukast. There are several methods known for the preparation and purification of diol intermediate in the literature. Most of the known processes, which provide purification of diol intermediate, are associated with problems of yielding impure diol intermediate or fails to provide appropriate information about the purity and impurity level has not been covered. Some processes are given below for reference.

US patent application 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 hexane 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 mentioned under this patent application is very lengthy i.e. takes around 22 hours for purification and thus is 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.
Thus there is still a need in the art for a process purification of most common starting material i.e. diol intermediate under present invention will be beneficial to employ on commercial scale and yield montelukast sodium of high purity. There is need for 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.

Further present invention provides a technology to manufacture a diol compound in a simple and cost effective way. The process under the present invention is advantageous to obtain diol intermediate with acceptable level of impurities, preferably free from impurities. Further specific solvents used during the process are hitherto not reported in prior art 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. The present invention also covers synthesis of the key compound, 2-(2-Chlorophenyl) propan-2-ol which is required for the manufacturing of the diol intermediate. The present invention mainly focuses towards 3 important factors: cost effective environmental friendly industrial process, higher output with the best quality material of diol intermediate with less number of impurities that make it suitable to use for synthesis of montelukast or pharmaceutically acceptable salts.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel process for the synthesis of Montelukast sodium intermediate which has an industrial advantage of being more efficient for preparation of Montelukast sodium in its purest form with a pharmaceutical acceptable salts.

Yet another objective of present invention is to provide an efficient and industrially advantageous process for the synthesis of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol], a key intermediate of montelukast, by reducing time cycle and controlling all unknown and known impurity at acceptable level eventually leading to montelukast sodium of high purity.

Still another objective of the invention is to provide a novel process for 2-(2-Chlorophenyl)propan-2-ol which is a key compound required for the manufacturing of the diol intermediate i.e.[2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol].

SUMMARY OF THE INVENTION
The present invention relates to a novel process for the synthesis of[2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol], a key intermediate of Montelukast sodium using cost effective process which can be commercially viable and industrially scalable.

Accordingly, the present invention provides a novel process for the synthesis of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1) which process comprises;
a) reacting 7-Chloroquinaldine (Formula 5) with Isophthalaldehyde (Formula 6) in presence of suitable acid catalyst and in suitable solvents to obtain 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (Formula 4);
b) Subjecting the 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (formula 4) to Grignard reaction with Vinyl magnesium bromide in presence of suitable inert solvents to obtain 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol ( Formula 3); and
c) reacting the 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) intermediate with 2-(2-Chlorophenyl)propan-2-ol in presence of suitable solvents to obtain [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).

The advantages of Grignard reaction gives best quality and increased yield of product with reduction in total time cycle of product.
The advantage of the present process under invention include an improved yield with high purity.

In another embodiment, the present invention provides a novel process for synthesis of Montelukast sodium by of the reaction of 2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl]phenyl] -3-hydroxypropyl]phenyl-2-propanol (Formula 1) with methyl-1-(mercaptomethyl)cyclopropane acetic acid in presence of organic solvent, alkali oxide and methylsulphonyl chloride to give Montelukast sodium. The prior art publication teaches the use of DIP chloride and other routes for manufacturing of montelukast intermediate on the large scale which not only gives poor yield but also requires longer reaction periods and thus impacts the environment.

In another embodiment, the present invention provides a novel process for synthesis of the compound, 2-(2-Chlorophenyl) propan-2-ol which process comprises reacting magnesium metal with O-chloro bromo benzene in suitable solvent medium and by maintaining suitable reaction conditions to obtain 2-chloro phenyl magnesium bromide, which upon reaction with acetone to yield 2-(2-Chlorophenyl) propan-2-ol. By in-house manufacturing of 2-(2-Chlorophenyl) propan-2-ol, easy availability of key compound along with export substitution has been achieved.

The present invention provides a process using environment-friendly reagents which are cost effective; does not use expensive chemicals, and increases the overall reaction efficiency in terms of yield and the quality of the diol intermediate - [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] and thus makes it suitable to use for synthesis of montelukast or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a novel process for synthesis of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] using low cost and eco-friendly reagents with increased efficiency in terms of yield which can be industrially scalable..

The present invention relates to a novel process for synthesis of 2-(2-Chlorophenyl)propan-2-ol, a key compound used for the synthesis of the diol intermediate by using eco-friendly reagents making product indigenously available, as shown in below scheme.

Accordingly, the present invention provides a novel process for the synthesis of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1), which process comprises;
a) reacting 7-Chloroquinaldine (Formula 5) with Isophthalaldehyde (Formula 6) in presence of suitable acid catalyst and in suitable solvent(s) to obtain 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (Formula 4);

b) subjecting the 3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]benzaldehyde (formula 4) to Grignard reaction with Vinyl magnesium bromide in presence of suitable inert solvents to obtain 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol ( Formula 3); and

c) reacting the 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) intermediate with 2-(2-Chlorophenyl)propan-2-ol in presence of suitable solvents to obtain [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).

The suitable acid catalysts used for condensation reaction are selected from sulphuric acid, formic acid, hydrochloric acid, acetic acid etc.

The suitable inert solvents used for the Grignard reaction are selected from tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dimethyl formamide dichloromethane or mixtures thereof.

In a preferred embodiment, the solvents that can be used for the preparation of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] are selected from dimethyl formamide, tetra hydrofuran, toluene or mixture thereof.

In an additional embodiment, the invention provides process for preparation of 2-(2-Chlorophenyl) propan-2-ol, which process comprises; reacting
a) O-chloro bromo benzene with magnesium metal in presence of suitable inert solvent to obtain 2-chloro phenyl magnesium bromide [Formula 2]; and

b) reacting the 2-chloro phenyl magnesium bromide with acetone solvent in presence of an inorganic base to obtain 2-(2-Chlorophenyl) propan-2-ol.

The solvents that can be used for the preparation of 2-chloro phenyl magnesium bromide are selected from dimethyl formamide, tetra hydrofuran, toluene or mixture thereof.

The inorganic base is selected from ammonium chloride, ammonium acetate, ammonium sulphate etc.

It will be appreciated that the process described above, with suitable modifications, alterations, optimizations and alternations that are within the scope of a skilled person can be used for obtaining the product under invention i.e. “[2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol].

The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations, alternations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations, alternations, etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification.

Example 1
Synthesis of the intermediate [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (Formula 4).
A solution of 7-chloroquinaldine (100 g) in ethyl acetate (700 ml) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Isophthalaldehyde (90 g) and acetic acid (25 g) was added slowly to the stirred solution to obtain homogenous solution at ambient temperature and maintained for 30 minutes. The reaction mixture was slowly heated to reflux temperature .The reaction mixture was further stirred for 10-15 hours at 75-80°C. The insoluble fraction was filtered off and the content ratio of ethyl acetate was decreased by way of distillation up to 70%. The reaction mass was chilled to 0-5°C. The solid obtained, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (step 1) was filtered, washed with ethyl acetate, and dried at 45-50°C under vacuum for 6hrs.
Yield: 100g, HPLC Purity > 99%.

Example 2
Synthesis of the intermediate [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (Formula 4).
A solution of 7-chloroquinaldine (100 g) in ethyl acetate (800 ml) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Isophthalaldehyde (86 g) and acetic acid (29 g) was added slowly to the stirred solution to obtain homogenous solution at ambient temperature and maintained for 30 minutes. The reaction mixture was slowly heated to reflux temperature .The reaction mixture was further stirred for 10-15 hours at 75-80°C. The insoluble fraction was filtered off and the content ratio of ethyl acetate was decreased by way of distillation up to 70%. The reaction mass was chilled to 0-5°C. The solid obtained, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (step 1) was filtered, washed with ethyl acetate, and dried at 45-50°C under vacuum for 6hrs.
Yield: 98g, HPLC Purity > 99%.

Example 3
Synthesis of the intermediate [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (Formula 4).
A solution of 7-chloroquinaldine (100 g) in ethyl acetate (850 ml) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Isophthalaldehyde (88g) and acetic acid (27 g) was added slowly to the stirred solution to obtain homogenous solution at ambient temperature and maintained for 30 minutes. The reaction mixture was slowly heated to reflux temperature .The reaction mixture was further stirred for 10-15 hours at 75-80°C. The insoluble fraction was filtered off and the content ratio of ethyl acetate was decreased by way of distillation up to 70%. The reaction mass was chilled to 0-5°C. The solid obtained, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (step 1) was filtered, washed with ethyl acetate, and dried at 45-50°C under vacuum for 6hrs.
Yield: 96g, HPLC Purity > 99%.

Example 4
Synthesis of the intermediate [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (Formula 4).
A solution of 7-chloroquinaldine (100 g) in ethyl acetate (850 ml) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Isophthalaldehyde (85g) and acetic acid (28 g) was added slowly to the stirred solution to obtain homogenous solution at ambient temperature and maintained for 30 minutes. The reaction mixture was slowly heated to reflux temperature .The reaction mixture was further stirred for 10-15 hours at 75-80°C. The insoluble fraction was filtered off and the content ratio of ethyl acetate was decreased by way of distillation up to 70%. The reaction mass was chilled to 0-5°C. The solid obtained, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (step 1) was filtered, washed with ethyl acetate, and dried at 45-50°C under vacuum for 6hrs.
Yield: 99g, HPLC Purity > 99%.

Example 5
Synthesis of the intermediate 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3).
The intermediate compound, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (100 g) was added in toluene (700ml) and tetrahydrofuran (200 ml) at ambient temperature. The reaction mass was chilled to -30°C. Vinyl magnesium bromide (solution in THF) (250 g) was added drop wise into reaction mixture under nitrogen atmosphere. The reaction mixture was further stirred for 6-7 hours at -25 to -30°C. Quenching of reaction mixture was then done slowly into 10% ammonium chloride solution (1000ml) and then the organic layer was separated. The organic layer was washed with water [160 ml x 2 times] and then washed with 10% sodium chloride solution (500ml). The organic layer was separated and dried over sodium sulphate bed. The content ratio of toluene was decreased by way of vacuum distillation up to 85%. The reaction mass was chilled to 0-5°C. The solid obtained, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) was filtered, and proceed to next stage immediately.
Yield: 75g, HPLC Purity > 98%.

Example 6
Synthesis of the intermediate 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3).
The intermediate compound, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (100 g) was added in toluene (850ml) and tetrahydrofuran (150 ml) at ambient temperature. The reaction mass was chilled to -30°C. Vinyl magnesium bromide (solution in THF) (300 g) was added drop wise into reaction mixture under nitrogen atmosphere. The reaction mixture was further stirred for 6-7 hours at -25 to -30°C. Quenching of reaction mixture was then done slowly into 10% ammonium chloride solution (1200ml) and then the organic layer was separated. The organic layer was washed with water [200ml x 2 times] and then washed with 10% sodium chloride solution (600ml). The organic layer was separated and dried over sodium sulphate bed. The content ratio of toluene was decreased by way of vacuum distillation up to 85%. The reaction mass was chilled to 0-5°C. The solid obtained, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) was filtered, and proceed to next stage immediately.
Yield: 70g, HPLC Purity > 98%.

Example 7
Synthesis of the intermediate 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3).
The intermediate compound, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (100 g) was added in toluene (900ml) and tetrahydrofuran (250 ml) at ambient temperature. The reaction mass was chilled to -30°C. Vinyl magnesium bromide (solution in THF) (350 g) was added drop wise into reaction mixture under nitrogen atmosphere. The reaction mixture was further stirred for 7-8 hours at -25 to -30°C. Quenching of reaction mixture was then done slowly into 10% ammonium chloride solution (1300ml) and then the organic layer was separated. The organic layer was washed with water [250ml x 2 times] and then washed with 10% sodium chloride solution (650ml).The organic layer was separated and dried over sodium sulphate bed. The content ratio of toluene was decreased by way of vacuum distillation up to 85%. The reaction mass was chilled to 0-5°C. The solid obtained 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) was filtered, and proceed to next stage immediately.
Yield: 73g, HPLC Purity > 98%.

Example 8
Synthesis of the intermediate 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3).
The intermediate compound, [E]-3-[2-(7- chloro-2-quinolinyl) ethenyl]-benzaldehyde (100 g) was added in toluene (800ml) and tetrahydrofuran (230 ml) at ambient temperature. The reaction mass was then chilled to -30°C. Vinyl magnesium bromide (solution in THF) (280 g) was added drop wise into reaction mixture under nitrogen atmosphere. The reaction mixture was further stirred for 7-8 hours at -25 to -30°C. Quenching of reaction mixture was then done slowly into 10% ammonium chloride solution (1250ml) and then the organic layer was separated. The organic layer was washed with water [230ml x 2 times] and then washed with 10% sodium chloride solution (550ml). The organic layer was separated and then was dried over sodium sulphate bed. The content ratio of toluene was decreased by way of vacuum distillation up to 85%. The reaction mass was chilled to 0-5°C. The solid obtained, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (Formula 3) was filtered, and proceed to next stage immediately.
Yield: 72g, HPLC Purity > 98%.

Example 9
Synthesis of the intermediate [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).
A solution of intermediate compound, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (100 g) was added in dimethyl formamide (1000ml) at ambient temperature. The reaction mixture was heated to 105-110°C to remove moisture from the reaction mass azeotropically. Further concentrated the solvent volume up to 50% by vacuum distillation. The reaction mixture was chilled to -15°C. A solution of 2-(2-Chlorophenyl)propan-2-ol (85g) was added slowly under nitrogen atmosphere. The reaction mixture was stirred for 7-8 hours at -10 to -15°C. After reaction completion, the reaction mixture was quenched slowly into 10% ammonium chloride solution (1000ml) at ambient temperature. The reaction mixture was extracted with toluene [250 mL x 4 times] and the organic layer was separated. The organic layer was washed with water (500 ml) and then washed with 10% sodium chloride solution (500 ml) followed by drying over sodium sulphate bed. The solvent recovery was done under vacuum and the solid was crystalized in the mixture of toluene (50 ml) and diisopropylether (300 ml). Further reaction mixture was chilled to 0 to 5 °C and stirred for 2 hrs. The solid obtained, [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Step 3) was filtered, washed with diisopropyl ether, and was dried at 40-45°C for 10 hrs.
Yield: 70g, HPLC Purity > 98 %.
Impurities: NIL

Example 10
Synthesis of the intermediate [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).
A solution of intermediate compound, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (100 g) was added in dimethyl formamide (1200ml) at ambient temperature. The reaction mixture was heated to 105-110°C to remove moisture from the reaction mass azeotropically. Further concentrated the solvent volume up to 50% by vacuum distillation. The reaction mixture was chilled to -15°C. A solution of 2-(2-Chlorophenyl)propan-2-ol (90g) was added slowly under nitrogen atmosphere. The reaction mixture was stirred for 7-8 hours at -10 to -15°C. After reaction completion, quenched the reaction mixture slowly into 10% ammonium chloride solution (1200ml) at ambient temperature. The reaction mixture was extracted with toluene [300 mL x 4 times] and the organic layer was separated. The organic layer was washed with water (600 ml) and then washed with 10% sodium chloride solution (600 ml) followed by drying over sodium sulphate bed. The solvent recovery was done under vacuum and the solid was crystalized in the mixture of toluene (50 ml) and diisopropylether (350 ml). Further the reaction mixture was chilled to 0 to 5 °C and stirred for 2 hrs. The solid obtained, [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Step 3) was filtered, washed with diisopropyl ether, and dried at 40-45°C for 10 hrs.
Yield: 73g, HPLC Purity > 98.5 %.
Impurities: NIL

Example 11
Synthesis of the intermediate [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).
A solution of intermediate compound, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (100 g) was added in dimethyl formamide (1300ml) at ambient temperature. The reaction mixture was heated to 105-110°C to remove moisture from the reaction mass azeotropically. Further concentrated the solvent volume up to 50% by vacuum distillation. The reaction mixture was chilled to -15°C. A solution of 2-(2-Chlorophenyl)propan-2-ol (88g) was added slowly under nitrogen atmosphere. The reaction mixture was stirred for 7-8 hours at -10 to -15°C. After reaction completion, quenched the reaction mixture slowly into 10% ammonium chloride solution (1300ml) at ambient temperature. The reaction mixture was extracted with toluene [350 mL x 4 times] and the organic layer was separated. The organic layer was washed with water (650 ml) and then washed with 10% sodium chloride solution (650 ml) followed by drying over sodium sulphate bed. The solvent recovery was done under vacuum and the solid was crystalized in the mixture of toluene (40 ml) and diisopropylether (320 ml). Further reaction mixture was chilled to 0 to 5°C and stirred for 2 hrs. The solid obtained, [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Step 3) was filtered, washed with diisopropyl ether, and dried at 40-45°C for 10 hrs.
Yield: 71g, HPLC Purity > 98 %.
Impurities: NIL

Example 12
Synthesis of the intermediate [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Formula 1).
A solution of intermediate compound, 1-{3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}prop-2-en-1-ol (100 g) was added in dimethyl formamide (1250ml) at ambient temperature. The reaction mixture was heated to 105-110°C to remove moisture from the reaction mass azeotropically. Further concentrated the solvent volume up to 50% by vacuum distillation. The reaction mixture chilled to -10 to -15°C. A solution of 2-(2-Chlorophenyl)propan-2-ol (87g) was added slowly under nitrogen atmosphere. The reaction mixture was stirred for 7-8 hours at -10 to -15°C. After reaction completion, quenched the reaction mixture slowly into 10% ammonium chloride solution (1250ml) at ambient temperature. The reaction mixture was extracted with toluene [330mL x 4 times] and the organic layer was separated. The organic layer was washed with water (590 ml) and then washed with 10% sodium chloride solution (590 ml) followed by drying over sodium sulphate bed. The solvent recovery was done under vacuum and the solid was crystalized in the mixture of toluene (60 ml) and diisopropylether (290 ml). Further reaction mixture was chilled to 0 to 5 °C and stirred for 2 hrs. The solid obtained , [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol] (Step 3) was filtered, washed with diisopropyl ether, and dried at 40-45°C for 10 hrs.
Yield: 72g, HPLC Purity > 98 %.
Impurities: NIL

Example 13
Synthesis of the compound: 2-(2-Chlorophenyl)propan-2-ol (Formula 2).
Dried magnesium metal (15.6g) was added to ether (250ml) at ambient temperature under inert atmosphere. The reaction mixture was stirred for 30 minutes. O- chloro bromo benzene (100g) was slowly added into reaction mixture under nitrogen atmosphere by maintaining temperature at 25-30°C. The reaction mixture was heated to reflux temperature and maintained for 7 hours. Further reaction mixture was chilled to 0°C and added acetone (65ml) at 0-5°C. The reaction mixture was heated to reflux temperature and maintained for 2 hours till reaction completion. The reaction mixture was quenched in ice and stirred for 1 hr. The reaction mixture was extracted with dichloromethane [100 mL x 3times] and the organic layer was separated and washed with 10% aqueous solution of ammonium chloride. The content ratio of dichloromethane was decreased by distillation. The obtained residue was further purified by high vacuum distillation to obtain liquid mass of 2-(2-Chlorophenyl) propan-2-ol.
Yield: 70g, GC Purity > 98 %.

Example 14
Synthesis of the compound: 2-(2-Chlorophenyl)propan-2-ol (Formula 2).
Dried magnesium metal (15.6g) was added to ether (300ml) at ambient temperature under inert atmosphere. The reaction mixture was stirred for 30 minutes. O- chloro bromo benzene (100g) was slowly added into reaction mixture under nitrogen atmosphere by maintaining temperature at 25-30°C. The reaction mixture was heated to reflux temperature and maintained for 7 hours. Further reaction mixture was chilled to 0°C and added acetone (68ml) at 0-5°C. The reaction mixture was heated to reflux temperature and maintained for 2 hours till reaction completion. The reaction mixture was quenched in ice and stirred for 1 hr. The reaction mixture was extracted with dichloromethane [100 mL x 4times] and the organic layer was separated and washed with 10% aqueous solution of ammonium chloride. The content ratio of dichloromethane was decreased by distillation. The obtained residue was further purified by high vacuum distillation to obtain liquid mass of 2-(2-Chlorophenyl)propan-2-ol.
Yield: 68g, GC Purity > 98 %.

Thus the present invention provided herein a process using low cost raw materials and reagents which makes the process cost effective and sustainable. In the developed process, reaction time has been shortened. Further isolation of intermediate is easy, no side reactions and byproducts were formed during the reaction which helps in increasing overall reaction efficiency in terms of yield of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol].
The process of the present invention uses mild reaction conditions, simple and convenient operation, easy separation for product and low cost reagents having lower environmental impact, reduced amount of by-products and impurities, lower investment cost, does not use expensive catalyst, as well as time of reaction is shortened and increases the overall reaction efficiency in terms of yield of Montelukast sodium. Current innovative process is suitable for industrial production of [2-[2-3(S)-3-[2-(7-Chloro-2-quinolinyl)-ethyl] phenyl]-3-hydroxy propyl] phenyl-2-propanol]..
The present invention also provided herein a commercial synthesis of 2-(2-Chlorophenyl) propan-2-ol by reaction of magnesium metal with O-chloro bromo benzene in specific solvent medium.
As will be readily apparent to those skilled in the art, the present disclosure may easily be produced in other specific forms without departing from its essential characteristics. The present embodiments is, therefore, to be considered as merely illustrative and not restrictive, the scope of the disclosure being indicated by the foregoing description, and all changes which come within therefore intended to be embraced therein.