FORM 2
THE PATENTS ACT, 1970
[39 of 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

Process for purification of 2-(2-(3(S)-(3-(7- chloroquinolinyl)
ethenyl)phenyl)-3-hydroxy-propyl)phenyl-2-propanol

IND-SWIFT LABORATORIES LIMITED,
S.C.O. No. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to 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 of formula I,

Formula I
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 1-[[[(R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl] thio] methyl cyclopropane 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 the treatment of angina, cerebral, spasm, glomerular, 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. The patent discloses synthesis of montelukast sodium through 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(hydroxy-propyl)phenyl-2-propanol (diol intermediate) of formula I as shown by following scheme:

The preparation of diol intermediate of formula I 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 the diol intermediate of formula I. The diol intermediate is isolated after flash column chromatography and then converted to 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 compound.
US patent 5,614,632 discloses preparation of diol intermediate of formula I 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. Crystallization process as described above is lengthy and involves two times seeding of solution. Further, the patent is silent about mode of obtaining seeding compound.
US patent 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 of formula I 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.
Like any synthetic compound, 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.
Most of the prior art processes involves the purification of diol intermediate of formula I with toluene and hydrocarbon solvent such as hexane or heptane. As the boiling point of solvents, toluene is 110ºC and heptane is 98ºC, 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.
In view of above, there is a need to provide an efficient and industrially advantageous process for purification of diol intermediate of formula I which curtail the presence of impurities or make it 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. Present inventors have developed a method for purification of diol intermediate of formula I which is quite effective, simple, industrially applicable and advantageous to yield diol intermediate of formula I 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 of formula I, and makes it suitable to use for synthesis of montelukast or pharmaceutically acceptable salts thereof.
OBJECTIVES OF THE INVENTION
The foremost objective of present invention is to provide an efficient and industrially advantageous process for the purification of diol intermediate of formula I, 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 I 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 I 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 I in order to circumvent chances of getting carry forward of impurities and generation of further by products.
SUMMARY OF THE INVENTION
Accordingly, present invention provides a process for purification of diol intermediate of formula I,

Formula I
a key intermediate for preparing montelukast or pharmaceutically acceptable salts thereof.
According to one embodiment, present invention provides a process for purification of diol intermediate of formula I, comprising the steps of:
a). providing diol intermediate of formula I in a mixture of a halogenated hydrocarbon and a nitrile solvent;
b). stirring the reaction mixture at 10ºC to 35ºC;
c). optionally, cooling the resulting mixture; and
d). isolating pure diol intermediate of formula I.
According to another embodiment, present invention provides diol intermediate of formula I 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 I 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 I; and
e). converting pure diol intermediate of formula I in to montelukast or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “diol intermediate of formula I” or “diol intermediate” refers to 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)- ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl-2-propanol of formula I.
The present invention provides a process for purification of diol intermediate of formula I to minimize amount of impurities and to increase chiral as well as chemical purity of intermediate.
According to one embodiment, present provides a process for purification of diol intermediate of formula I using a halogenated solvent and a nitrile solvent.
Generally, the process involves stirring of suspension of diol intermediate of formula I in the mixture of a halogenated and nitrile solvent at a temperature of 10ºC to 35ºC 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, preferably1:20, more preferably 1:10. Preferably suspension can be stirred at 10ºC to 35ºC temperature for 30 minutes to 24 hours. Reaction mixture can be optionally cooled to a temperature of -25ºC to 10ºC and further stirred for 30 minutes to 24 hours at temperature of -10ºC to 5ºC. The purified product can be isolated from reaction mixture using suitable techniques such as filtration, centrifugation, decantation and the like.
Diol intermediate of formula I, 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 I prepared by the process of present invention is having purity more than 98.5 %, preferably more than 99%, more preferably more than 99.2 %.
Diol intermediate of formula I procured from commercial source or prepared by prior art processes is found to contain following impurities:

Hydroxy ester impurity
Keto impurity

(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 I avoids possibility of generation of more impurities in final product and thus leads to final API i.e. montelukast sodium with high purity.
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 I 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 I, 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 I is reacted with a suitable reagent to form intermediate of formula II.

Formula III
wherein LG is selected from alkylsulfonyl, substituted or unsubstituted arylsulfonyl
Generally, the process involves reaction of diol intermediate of formula I with a suitable reagent in the presence of a suitable base in a suitable solvent at a temperature of -80 to +10 ºC for 30 minutes to 12 hours to convert. Preferably reaction can be carried out at a temperature of -50 to 0 ºC for 3 to 8 hours. Suitable base is organic base selected from a tertiary amine such as triethylamine, diisopropylethylamine, tri-n-propyl amine, tri-n-butyl amine, 1,8-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; nitriles such as acetonitrile, propionitrile and the like or a 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 I 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 sulphonyl chloride benzenesulfonyl chloride and the like. Reaction mixture can be optionally seeded with a specific polymorph of intermediate of formula II to get desired polymorph of product. After completion of the reaction, the intermediate of formula II can be isolated from reaction mixture or can be insitu reacted with 1-mercapto methyl cyclopropane acetic acid of formula III or its ester derivative or salts to form montelukast. Intermediate of formula II can be isolated from reaction mixture by suitable techniques such as filtration or centrifugation and the like. It is preferable to proceed further reaction without isolating intermediate of formula II.
Intermediate of formula II is then reacted with a compound of formula III,

Formula III
or salts thereof to form montelukast or pharmaceutically acceptable salts thereof.
Generally, the process involves coupling of an intermediate of formula II with a compound of formula III in presence of a suitable base at a temperature of -10 ºC to 80 ºC for 15 minutes to 72 hours, preferably reaction can be carried out at a temperature of -20 to 50 ºC for 1 to 24 hours, more preferably till completion of 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 reaction can be used as such or its aqueous or alcoholic solution can be used for the reaction. Suitable base is generally used for the generation of dianion of a compound of formula III. Compound of formula III can be optionally reacted with a suitable base prior to condensation with intermediate of formula III to generate corresponding salt of compound of formula III or its anion. The reaction can be carried out in presence of a suitable solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropanol; ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like or mixture thereof. The reaction completion can be monitored by 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 to form montelukast salts. Preferably, reaction mixture can be diluted with water and optionally washed with water immiscible organic solvent. Water immiscible organic solvent include aliphatic esters such as methyl acetate, ethyl acetate, aliphatic or aromatic hydrocarbon such as n-hexane, n-pentane, 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 montelukast can be optionally treated with a suitable acid or acid salt to adjust the pH of aqueous layer to 4.0 to 6.5, preferably to 5.0 to 6.5. The desired product can be extracted from the resulting aqueous layer using a suitable solvent which includes ester 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 removal of solvent using suitable techniques such as evaporation, distillation and the like or can be used as such for further salt formation.
Montelukast free acid can be directly converted to montelukast sodium or it can be first reacted with a suitable amine to form montelukast amine salt and then converted to montelukast amine salt.
In one way, montelukast free acid can be optionally first reacted with a suitable amine to form montelukast amine salt and converted to montelukast sodium.
Generally, the process involves reaction of montelukast free acid in a suitable solvent with a suitable amine at a temperature of 0 to 70 ºC for 30 minutes to 72 hours, preferably for a time sufficient for the salt formation. Suitable amine can be selected from dicylohexylamine, dipropyl amine, arginine, L-(+)-treo-2-amino-1-phenyl-1,3- propanediol, and L-(+)-α-phenylglycinol, tris hydroxymethyl amino methane, cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclodocecyl amine, cyclooctyl amine and phenylethyl amine, α-methylbenzyl amine, cyclohexylethyl amine, tert-butyl amine, amantadine, 1-(1-naphthyl)ethylamine, S-methyl-L-cysteine, diallylamine and the like. Salt formation can be carried out in the presence of a suitable solvent which 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 and the like or mixture thereof. Usually the 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. Montelukast amine salts thus prepared can be further converted in to pure montelukast or pharmaceutically acceptable salts thereof.
Generally, the process involves neutralization of montelukast amine salt using a suitable acid at a temperature of 0 to 50 ºC for 10 minutes to 6 hours, preferably till the completion of the reaction. Suitable acid employed for neutralization includes 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 25 ºC for 10 minutes to 6 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 completion of neutralization reaction, biphasic reaction mixture can be separated and organic layer can be optionally charcoalized, washed with water and/or dried over suitable drying agent such as sodium sulfate. Montelukast free acid 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, the process involves reaction of montelukast acid with a suitable source of sodium ion in a suitable solvent at a temperature of 0 to 80 ºC 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, reaction solution can be optionally charcoalized. The desired product can be isolated from the resulting solution by removal of solvent with suitable techniques such as evaporation, distillation and the like.
Alternatively, montelukast amine salt is treated with a suitable acid to form a solution containing montelukast acid which after separation of aqueous layer is directly converted to montelukast sodium without isolation of montelukast free acid. The process involves treatment of solution containing montelukast acid 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 display HPLC purity of more than 99 %, preferably more than 99.5 %. More preferably it may display 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.
Major advantage of present invention is to provide diol intermediate of formula I having acceptable level of impurities or preferably free from impurities. Another advantage is 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 ºC and of acetonitrile is 82 ºC, 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.
Reference is now made to the following examples, which together with the above descriptions; illustrate the invention in a non limiting fashion. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting.
COMPARATIVE EXAMPLE:
Example 1: Purification of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-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 ºC and stirred for 1 hour. n-Heptane (50 ml) was added drop wise at 60 ºC over a period of 20 minutes. The reaction mixture was stirred at 60 ºC for 1 hour. The reaction mixture was cooled further to 10 to 15 ºC 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 ºC 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-propyl)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 ºC. The mixture was cooled to 0ºC-5 ºC, stirred for 1 hour and filtered. The resulting product was slurry washed with chilled acetonitrile 0ºC-5ºC (200 ml) and dried at 40-45 ºC 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 ºC. Mixture was cooled to 0-5 ºC, stirred for 1 hour and filtered. Resulting product was slurry washed with acetonitrile(---- ml) and dried at 40-45 ºC 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)ethenyl] phenyl]-3-methanesulphonyloxy]propyl]phenyl]-2-propanol
A mixture of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3-(hydroxy-propyl)phenyl-2-propanol (100 g,) in methyl tert-butyl ether (400 ml ) was heated to 55-60 ºC and methyl tert-butyl ether (200 ml) was partially distilled off from the mixture. Acetonitrile (800 ml) was added to the reaction mass and stirred for 10 minutes. Reaction mass was cooled to 30-35 ºC and N,N-diisopropylethylamine (28.38 g /38.4 ml) was added to the reaction mass. Reaction mass was cooled to -10 to -5 ºC and methanesulphonyl chloride (25.2 g /17.0 ml ) at -15 to -20 ºC. Reaction mixture was then seeded with crystals of pure title compound. Reaction mixture was then stirred for 4 hours at -30 to -25 ºC. The product thus formed was filtered and washed with chilled acetonitrile (-30 ºC , 200 ml) and n-Heptane (-30 ºC , 200 ml) under nitrogen gas atmosphere and dried at -5 to 0 ºC to give title compound which was used as such for next stage.
Example 4: Preparation of montelukast 1-(1-naphthyl)ethyl amine salt
A solution of 1-(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 ºC. [(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 ºC and temperature of the reaction mixture was slowly raised to 25-30 ºC. The reaction mixture was stirred for 15 hours at 25-30 ºC. 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 ºC 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 ºC and 1-(1-naphthyl)ethyl amine (35 g) followed by acetonitrile (600 ml) were successively added to reaction mixture and stirred for 12 hours. The precipitated solid, thus formed 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.
Example 5: Preparation of montelukast dicyclohexyl amine salt
A solution of 1-(mercaptomethyl)cyclopropaneacetic acid (30 g) in dry methanol (30 ml) was slowly added to a cooled (-15 to -10oC) 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 -10oC. 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 -10oC and the temperature of the reaction mass was raised slowly to 25-30oC. The reaction mixture was stirred for 15 hrs while maintaining temperature at 25-30oC. 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 25-30oC, 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 25-30oC 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 oC. 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 30-45oC for 8 hrs to obtain 112 g of montelukast DCHA salt having purity of 99.0 % by HPLC.
Example 6: Preparation of montelukast sodium
To a stirred suspension of montelukast 1-(1-naphthyl)ethyl amine salt (80 g , 0.105mol) in methyl tert-butyl ether (800 ml) and demineralized (400 ml) at 10-15 ºC, 10% acetic acid (127 ml) was added and mixture was stirred for 15 minutes at 10-15 ºC. The temperature of reaction mixture was raised to 25-30 ºC 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, 0.11 mol) in methanol (300 ml) was added to reaction mixture at 0 to -5 ºC and stirred for 30 minutes at same temperature. Thereafter, temperature of the reaction mixture was raised to 35-40 ºC 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.
Example 7: Preparation of montelukast sodium
To a stirred suspension of montelukast DCHA salt (80 g) in methyl tert-butyl ether (800 ml) and DM water (400 ml) at 10-15oC, acetic acid (10% solution, 160 ml) was charged over a period of 30 minutes and reaction mixture was stirred for 15 minutes at 10-15oC. The temperature was slowly raised to 25-30oC and stirred for 1 hr, methyl tert-butyl ether layer was separated and successively washed with cold (10-15oC, 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 -5oC . To this cold solution, a solution of methanol (300 ml) and sodium hydroxide (4.42 g, 0.11 mol), prepared separately, was added at 0 to -5oC. After stirring at 0 to -5oC for 30 minutes, temperature of reaction mixture was raised to 35-40oC and stirred for 30 minutes. Activated charcoal was added to clear pale yellow solution and after stirring for 1 hr at 35-40oC, 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 25-30oC. The solid was filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at 35-40oC 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.

WE CLAIM:
1. 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 I, comprising the steps of:
a). providing diol intermediate of formula I 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 I.
2. The process according to claim 1, wherein in step a) halogenated hydrocarbon is selected from dichloromethane, chloroform and 1,2-dichloroethane.
3. The process according to claim 1, wherein in step a) nitrile solvent is selected from acetonitrile and propionitrile.
4. The process according to claim 1, wherein step a) ratio of halogenated solvent to nitrile solvent is 1:5 to 1:50..
5. The process according to claim 1, wherein in step c) reaction mixture is cooled to a temperature of --25ºC to +10 ºC.
6. The process according to claim 1, wherein diol intermediate of formula 1 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.
7. A process for the preparation of montelukast or pharmaceutically acceptable salts thereof, comprising the steps of:
a). providing diol intermediate of formula I in a halogenated hydrocarbon and nitrile solvent;
b). stirring the reaction mixture;
c). optionally, cooling the resulting mixture;
d). isolating pure diol intermediate of formula I; and
e). converting pure diol intermediate of formula I in to montelukast or pharmaceutically acceptable salts thereof.
8. The process according to claim 7, wherein in step a) halogenated hydrocarbon is selected from dichloromethane, chloroform and 1,2-dichloroethane; and nitrile solvent is selected from acetonitrile and propionitrile.
9. The process according to claim 7, wherein in step b) reaction mixture is stirred at temperature of 10ºC-35ºC; in step c) reaction mixture is cooled to a temperature of -25ºC to +10 ºC.
10. Diol intermediate of formula I having identified impurities NMT than 0.5% and/or unidentified impurities NMT than 0.10 % by HPLC.