PREPARATION OF MONTELUKAST AND ITS SALTS

TECHNICAL FIELD
The application relates to a process for the preparation of Montelukast and its salts.

INTRODUCTION
Montelukast is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-propyl]thio]methyl] cyclopropane acetic acid and can be represented structurally by Formula (I):

Formula (I)
Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor and is useful in the treatment of asthma as well as other conditions mediated by leukotrienes, such as inflammation and allergies.
Montelukast is commercially available in the market in products sold under the trademark SINGULAIR as chewable tablets. Each 10 mg, 4 mg, or 5 mg chewable SINGULAIR tablet respectively contains 10.4 mg, 4.2 mg, and 5.2 mg of montelukast sodium, which is equivalent to 10, 4, and 5 mg of montelukast respectively.
U.S. Patent No. 5,565,473 discloses montelukast and its related compounds along with their pharmaceutically acceptable salts. It also provides processes for their preparation.
Processes for preparation of montelukast and its intermediates have also been described in U.S. Patent No’s. 5,614,632 and 5,523,477, U.S. Patent Application Publication Nos. 2005/0234241 A1, 2005/0256156 A1, and 2005/0107612, and International Application Publication Nos. WO 2005/105749, WO 2005/000807, WO 2004/108679, WO2006/021974, and WO 2006/008751.
Although many processes have been described in the prior art for the preparation of montelukast and its intermediates, there still remains a need for a process for the preparation of montelukast which is industrially viable.

SUMMARY
In one embodiment, there is provided a process for preparing 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol of the Formula (II):

Formula (II)
which process includes:
a) reacting 7-chloroquinalidine of the Formula (III):

Formula (III)
with isophthalaldehyde of the Formula (IV):

Formula (IV)
in the presence of acetic anhydride, in a hydrocarbon solvent,
to afford (3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde of the Formula (V):

Formula (V)
b) reacting the compound of the Formula (V) with methyl magnesium chloride in a hydrocarbon solvent to afford 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol of the Formula (VI):

Formula (VI)
c) treating the compound of Formula (VI) with manganese dioxide to afford (1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanone of the Formula (VII):

Formula (VII)
d) treating the compound of the Formula (VII) with dimethylcarbonate in the presence of sodium methoxide to afford 3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propionic acid methyl ester of the Formula (VIII):

Formula (VIII)
e) reacting the compound of the Formula VIII with methyl-2-bromoethyl benzoate of the Formula (IX) :

Formula (IX)
in the presence of a base to afford (2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl)-benzoic acid methyl ester of the Formula (X);

Formula (X)
f) converting the compound of Formula (X) to 2-(3-{3-[2-(7-chloro-quinolin-2-yl)vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl)-benzoic acid of the Formula (XI):

Formula (XI)
g) treating the compound of the Formula (XI) with methyl iodide in the presence of a base to afford 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester of the Formula (XII):

Formula (XII)
h) treating the compound of the Formula (XII) with (-) diisopionocamphenyl chloroborane to afford methyl 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-benzoic acid methyl ester of the Formula (XIII); and

Formula (XIII)
i) reacting the compound of the Formula (XIII) with methyl magnesium chloride in the presence of a hydrocarbon solvent to afford said compound of the Formula (II).
In another embodiment, there is provided a process for preparing 1-(mercaptomethyl) cyclopropane acetonitrile of the Formula (XIV):

Formula (XIV)
which process includes:
a) reacting diethyl malonate of the Formula (XV):

Formula (XV)
with a base in the presence of more than 5 moles of dichloroethane to afford 1,1 cyclopropane diester of the Formula (XVI):

Formula (XVI)
b) reacting the compound of the Formula (XVI) with sodium borohydride to afford 1,1 cyclopropanedimethanol of the Formula (XVII):

Formula (XVII)
c) reacting the compound of the Formula (XVII) with thionyl chloride in a hydrocarbon solvent to afford 1,1-cyclopropanedimethanol cyclic sulfite of the Formula (XVIII):

Formula (XVIII)
d) reacting the compound of the Formula (XVIII) with sodium cyanide in the presence of sodium iodide to afford 1-hydroxymethyl-cyclopropaneacetonitrile of the Formula (XIX):

Formula (XIX)
e) reacting the compound of the Formula (XIX) with methanesulfonyl chloride in the presence of thioacetic acid to afford 1-(acetylthiomethyl)-cyclopropaneacetonitrile of the Formula (XX):

Formula (XX)
and
f) reacting the compound of the Formula (XX) with sodium methoxide to afford the compound of the Formula (XIV).
In yet another embodiment, there is provided a process for preparing 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol of the Formula (XXI):

Formula (XXI)
the process including reacting a diol of the Formula (II):

Formula (II)
with methane sulfonyl chloride in the presence of a base in a reaction medium that is essentially free of moisture.
In yet another embodiment, there is provided a process for the preparation of montelukast of the Formula (I):

Formula (I)
the process including:
a) reacting a diol intermediate of the Formula (II):

Formula (II)
with methane sulfonyl chloride in the presence of diisopropyl ethyl amine to afford the compound of the Formula (XXI):

Formula (XXI)
b) reacting the compound of the Formula (XXI) with 1-(mercaptomethyl)cyclopropane acetonitrile to afford the compound of the formula (XXII):

Formula (XXII);
and
c) converting said amine salt of into a free acid of montelukast of the Formula (I).
In yet another embodiment, there is provided a process for the purification of dicyclohexylamine salt of montelukast, the process including:
a) providing a solution of dicyclohexylamine salt of montelukast in a combination of an alcoholic solvent and a nitrile solvent;
b) cooling the solution thereby causing a solid dicyclohexylamine salt of montelukast to separate therefrom;
c) isolating the separated solid.

DETAILED DESCRIPTION
As set forth above, in one embodiment, there is provided a process for the preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol (hereinafter referred to as the diol intermediate) of Formula (II):

Formula (II)
which is a key intermediate for the synthesis of montelukast. The process is illustrated in Scheme I:

Scheme I
Suitable hydrocarbon solvents which may be used for steps (a), (b), (c), and (i) include, but are not limited to toluene, xylene, n-heptane, cyclohexane and the like or mixtures thereof.
The molar equivalents of isophthalaldehyde which may be used for the reaction may range form less than about 1.5 to less than about 2.0 to that of the equivalents of 7-chloroquinalidine of Formula (III).
Suitable chlorinated solvents which may be used for the reaction in step (c) include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, and the like or mixtures thereof.
The mole ratio of dimethyl carbonate used in step (d) may range from less than about 3.0 molar equivalents to less than about 2.5 molar equivalents to that of the starting compound of Formula (VI).
The reactions of steps (a) to (i) may be conducted at temperatures of the range of about -20?C to about 200?C.
Suitable solvents which may be used for conducting the reactions of steps (d), (e), (f), (h), and (g) include, but are not limited to aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide, acetonitrile and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; alcohols such as methanol, ethanol and the like; ketonic solvents such as acetone, methylisobutylketone and the like; hydrocarbons such as toluene and the like; or mixtures thereof or their combination with water in various proportions without limitation.
Suitably, the intermediates at each of the stages are isolated and purified by recrystallization or slurry in a suitable solvent. Suitable solvents which may be used for recrystallization or slurry of the compound at each stage include, but are not limited to, alcoholic solvents such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride and the like; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate and the like or mixtures thereof, or their mixtures with water in various proportions.
The diol intermediate obtained using the process described above has a purity of more than about 99%, or more than about 99.5% as determined by High Performance Liquid Chromatography (HPLC). It contains less than about 1.0%, or less than about 0.5% of individual process related impurities. More particularly, it contains less than about 0.5%, or less than about 0.1% of the following potential process related impurities: 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3(hydroxypropyl) acetophenone of the Formula (XIIIa)

Formula (XIIIa)
methyl-2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl) acetophenone of Formula (XIII):

Formula (XIII)
and the isomer 2-(2-(3(R)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropl)phenyl)-2-propanol of Formula (IIa).

Formula (IIa)
In another embodiment, there is provided an alternate route for the preparation of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester of Formula (XII) by reacting the compound of the Formula (V) with vinyl magnesium bromide followed by condensation with methyl 2-iodobenzoate to give the compound of the Formula XII.
Suitable solvents which may be used for the reaction include, but are not limited to hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride and the like; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate and the like.
The mole ratio of vinyl magnesium bromide used to the starting compound of Formula (V) may range from about 0.5 to about 2.0, or from about 1 to about 1.5.
The mole ratio of methyl 2-iodobenzoate to the starting compound of Formula (V) may range from about 0.8 to about 1.5, or from about 0.8 to 1.5.
Suitably, the condensation reaction with methyl 2-iodobenzoate takes place in the presence of a base. Suitable bases which may be used include, but are not limited to methylamine, dimethylamine, triethylamine, ethyl diisopropylamine, butylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and the like.
Suitable temperatures for conducting the reaction range from about 10?C to about 100?C.
The obtained 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester of Formula (XII) has a purity of more than about 95%, or more than about 99% by HPLC.
In yet another embodiment, there is provided a process for the preparation of 1-(mercaptomethyl) cyclopropane acetonitrile of the Formula (XIV):

Formula (XIV)
another key intermediate in the synthesis of montelukast. The process is illustrated in Scheme II:

Scheme II
Suitable hydrocarbon solvents which may be used for the reaction in step (c) include, but are not limited to toluene, xylene, n-heptane, cyclohexane and the like or mixtures thereof.
The molar ratio of base used in step (a) may range from less than about 2.0 to less than about 1.5 molar equivalents to that of the diethyl malonate taken. The pure compound can be collected using fractional distillation of the residue obtained after reaction.
Suitable bases which may be used for the reactions in steps (a) and (c) include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions.
Suitable solvents which may be used for the reactions of steps (a), (b), (d), (e), and (f) include, but are not limited to alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol, tertiary-butanol, and the like; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, tetrahydrofuran, 1,4 dioxane, and the like; hydrocarbon solvents such as toluene, xylene, and the like; polar aprotic solvents like dimethylformamide, dimethylsulphoxide, diemthylacetamide, and the like; chlorinated solvents like dichloromethane, chloroform, carbon tetrachloride, chlorobenzene and the like; and mixtures of such solvents and water in various proportions.
The 1-(mercaptomethyl) cyclopropane acetonitrile of Formula (XIV) obtained using the process described above has a purity by GC of more than about 95%, or more than about 98%. It contains less than about 1.0 %, or less than about 0.5% of the corresponding impurities like the dinitrile impurity of Formula (XIVa) and 1-(acetylthiomethyl)-cyclopropaneacetonitrile of Formula XX.

Formula (XIVa)
In yet another embodiment, there is provided a process for the preparation of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol of Formula (XXI):

Formula (XXI)
a key intermediate in the synthesis of montelukast, that includes reacting the diol intermediate of the Formula II with methane sulfonyl chloride in the presence of a base, in a reaction medium which is essentially free of moisture.
The term “reaction medium” is used herein to refer to the entire liquid phase of the reaction mass, including solvent, if any, and reaction components, but excluding the headspace of the reactor or reaction vessel over the reaction mass. The term “essentially free of moisture,” is used herein to denote the total water content of the reaction medium (as determined using standard Karl Fischer methodology) that is less than about 0.6 % w/w. Preferably, the water content of the reaction medium is less than about 0.5% w/w, more preferably, less than about 0.2% w/w.
Suitable solvents which may be used for conducting the reaction include, but are not limited to hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; nitrile solvent such as acetonitrile, propionitrile and the like, or mixtures thereof in suitable ratios.
Suitable bases which may be used for the reaction include but are not limited to: organic bases such as methylamine, dimethylamine, triethylamine, ethyl diisopropylamine, butylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide and the like.
The moisture present in the starting diol intermediate of Formula (II) may be removed by performing azeotropic distillation of its solution in a hydrocarbon solvent such as toluene.
Suitably, a combination of a hydrocarbon solvent with a nitrile solvent is used as the solvent medium, more preferably, a combination of toluene and acetonitrile in a ratio of about 2: 8, or about 1:9 is used for the purpose of this reaction.
The moisture content of the individual reactants such as the methanesulfonyl chloride, diisopropyl ethylamine and the solvents is preferably below about 0.2% w/w to ensure that the moisture content of the total reaction medium is minimized, preferably to below about 0.2% w/w.
The methods which may be used for the removal of water from the reaction medium include but are not limited to azeotropic distillation, using molecular sieves, using drying agents like anhydrous sulphates of alkali or alkaline earth metals, and distillation in the presence or absence of vacuum.
Also provided is a process for the preparation of montelukast from the diol intermediate of the Formula (II). The process is illustrated in Scheme III:

Scheme III
Step (a) involves (i) mesylation of the diol intermediate of Formula (II) with methane sulfonyl chloride in the presence of diisopropyl ethyl amine and a suitable solvent:

The formation of the mesylate is followed by (ii) condensation of the mesylated product with 1-(mercaptomethyl) cyclopropane acetonitrile of Formula (XIV) to afford the compound of the Formula (XXII):

Finally, the compound of the Formula (XXII) is (iii) converted into free acid of montelukast by acidic or basic hydrolysis:

Suitable solvents which can be used include but are not limited to water immiscible solvents including: hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate and the like.
Suitable temperatures for conducting the reaction range from about -20?C to about 50?C, or from about -10?C to about 30?C.
Suitable acids which can be used for hydrolysis include, but are not limited to inorganic acids such as hydrochloric acid hydrobromic acid, and the like; and organic acids such as tartaric acid, succinic acid, acetic acid, citric acid, and the like. Suitable bases which can be used for the purpose include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof.
Suitable temperatures for hydrolysis may range from about 10 to about 200?C, or from about 30 to about 120?C.
The acid obtained in the reaction medium after hydrolysis may be isolated in crude form or can be further purified by recrystallization or slurry in a suitable solvent before proceeding to the next step. Suitable solvents which can be used for isolating and purifying the acid include, but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, and the like; or mixtures thereof or their combinations with water in various proportions.
With reference to the Scheme III, step (b) involves reaction of montelukast acid obtained above with an amine under suitable conditions to afford the corresponding amine salt, which is optionally recrystallized. With reference to Scheme III, the salt forming amine preferably has the formula NR1R2R3, wherein R1, R2, and R3 is each independently, straight-chain or branched, substituted or unsubstituted, hydrogen, C1-C15 alkyl or hydroxyalkyl, C3-C10 single or fused ring, cycloalkyl or aryl. The montelukast acid obtained in step a) can be converted to its amine salt by reaction with the corresponding amine in the presence of a suitable solvent. The organic non-toxic amines which may be used for the preparation of montelukast amine salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, batanine, caffeine, choline, N,N’-dibenzylenediamine, diethylamine, triethylamine, trimethylamine, tripropylamine, and the like. The amine may be added to the reaction mass at temperatures lower than the dissolution temperatures or at the dissolution temperatures. The temperatures for addition of the amine can range from about 0?C to about 60?C or more.
After addition of the amine the reaction mass may be maintained further at temperatures lower than the dissolution temperatures such as for example below about 10?C to about 25?C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete precipitation can be readily determined by a person skilled in the art.
Optionally, small amounts of seeding crystals montelukast amine salt may be added to the reaction mixture. Preferably, small amounts are about 1 to 20 weight %, more preferably about 5 weight %. Seeding crystals may be added before or, where appropriate, after the step initiating the precipitation.
The amine salt may be isolated from the reaction mass using techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor. If desired the crystals can be washed on the filter with a solvent.
In an embodiment, the amine used is tertiary butyl amine giving the corresponding montelukast tertiary butyl amine salt, and the solvent used for its isolation is toluene.
In another embodiment, the amine used is dicyclohexylamine giving the corresponding montelukast dicyclohexylamine salt and the solvent used for its isolation is acetone, or a combination of acetonitrile and isopropanol.
Optionally, the amine salt obtained can be further purified by recrystallization or slurry in a suitable solvent. Suitable solvents which can be used for recrystallization or slurry include, but are not limited to methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof or their combinations with water in various proportions.
With reference to Scheme III, step (c) involves conversion of the amine salt to pure montelukast acid.
The process for obtaining montelukast acid from the amine salt involves breaking of the montelukast amine salt using an acid in a suitable solvent.
Suitable acids which can be used for breaking the salt include, but are not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, and the like; and organic acids such as acetic acid, formic acid, propionic acid, citric acid, and the like. Suitably, aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding acid or base can be used. Any concentration is useful, which will convert the amine salt to montelukast acid.
Suitably, the salt is taken into an organic solvent and treated with an aqueous solution of an acid to break the amine salt and release the free acid which remains in the organic layer. The montelukast acid thus obtained can be further purified by recrystallization or slurry in a suitable solvent. Suitable solvents which can be used for purifying montelukast acid, include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, and the like; or mixtures thereof or their combinations with water in various proportions.
In another embodiment, there is provided a process for the purification of montelukast dicyclohexylamine salt that includes:
a) providing a solution of montelukast dicyclohexylamine sat in a combination of an alcoholic and a nitrile solvent;
b) optionally treating the solution with activated charcoal;
c) crystallizing the solid from the solution;
d) recovering the separated solid.
Step (a) involves providing a solution of montelukast dicyclohexylamine sat in a combination of an alcoholic and a nitrile solvent. Suitable alcoholic solvents which can be used for suspending montelukast dicyclohexylamine salt include, but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; and suitable nitrile solvents which can be used for the purpose include, but are not limited to acetonitrile, propionitrile and the like. The ratio of the alcoholic solvent to the nitrile solvent which can be used for purification ranges from about 1:3 to about 1:5.
The dissolution temperatures may range from about 20?C to about 120°C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as the stability of montelukast is not compromised and a clear solution is obtained.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of montelukast amine in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
Step (b) involves optionally treating the solution with activated charcoal. The solution obtained in step (a) can be optionally treated with activated charcoal to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.
The carbon treatment can be given either at the dissolution temperatures or after cooling the solution to lower temperatures.
Step (c) involves crystallizing the solid from the solution. For crystallization to occur, the reaction mass may be maintained further at temperatures lower than the concentration temperatures such as for example below about 10?C to about 25?C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
Optionally crystallization may be initiated by methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Step (d) involves recovering the separated solid. The method by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor. If desired the crystals can be washed on the filter with a solvent.
In a particular embodiment of the invention the above described process of the invention can be adapted to form the basis of a continuous crystallization process where the steps (a) to (d) are repeated with the wet material obtained in step (d). When the desired purity is attained at step d), the cycle is stopped.
Thus there is established a cycle of operations which can be repeated indefinitely thereby adapting the process of the invention to a continuous process with obvious attendant advantages on the commercial scale.
The wet cake obtained in step d) may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35?C to about 70?C. The drying can be carried out for any desired time periods, times about 1 to 20 hours.
Montelukast acid obtained above may be converted into its sodium salt. Suitable solvents which may be used for suspending montelukast acid include, but are not limited to; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like, ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like.
Sodium hydroxide can be added to the mixture of montelukast acid in a solvent in the form of an aqueous solution or as a solution in an alcoholic solvent.
Isolation of montelukast sodium from the solution can be done by removal of the solvent, which may be carried out suitably using techniques such as evaporation, atmospheric distillation, distillation under vacuum, and the like.
Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20°C to about 70°C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product.
Suitable techniques which can be used for the solvent removal include, distillation using a rotational evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), and the like.
In an embodiment, the present invention also provides a pharmaceutical composition comprising montelukast or its pharmaceutically acceptable salts prepared according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical compositions montelukast or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers of this invention may further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like.
Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
In the compositions of present invention montelukast or its pharmaceutically acceptable salts is a useful active ingredient in the range of 0.5 mg to 50 mg, or 1 mg to 25 mg.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES
Example 1: Preparation of (3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde (Formula V)
7-chloroquinolidine (195 kg), isophthalaldehyde (177 kg), toluene (780 L) and acetic anhydride (213 kg) were taken into a reactor and the resultant reaction mixture was heated to about 105°C, and stirred for about 10 hours. After completion of the reaction, the reaction mass was cooled to about 30°C followed by charging of n-hexane (800 L). The reaction solution was stirred for about 2 hours. The separated solid was filtered and the solid was washed with of n-hexane (200 L) to afford 810 kg of the title compound in a wet form.
290 kg of the above wet title compound was taken into another reactor containing ethyl acetate (1300 L). The resultant reaction suspension was heated to about 70°C followed by stirring for about 60 minutes. The reaction solution was filtered through leaf filter and the filter was washed with ethyl acetate (175 L). The obtained filtrate was distilled to 55% of the original volume and cooled to about 30°C. The resultant reaction mass was stirred for about 2 hours. The separated solid was filtered and washed with ethyl acetate (90 L). The solid obtained was dried at about 70°C till the loss on drying (LOD) comes to below 2% w/w to afford 54 kg of pure title compound.
Purity by HPLC: 94.55%.

Example 2: Preparation of (3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde (Formula V)
7-chloroquinolidine (100 kg), isophthalaldehyde (90.5 kg), toluene (400 L) and acetic anhydride (109.5 kg) were taken into a reactor and the resultant reaction mixture was heated to about 106°C, and stirred for about 12 hours. After completion of the reaction, the reaction mixture was cooled to about 30°C. Petroleum ether (400 L) was charged to the reaction mixture and was stirred for about 2 hours. The separated solid was filtered and the solid was washed with petroleum ether (200 L) to afford 240 kg of the title compound in a wet form.
100 kg of the above wet title compound was taken into another reactor containing ethyl acetate (1700 L). The resultant reaction suspension was heated to about 75°C followed by stirring for about 90 minutes. The reaction solution was filtered through leaf filter. The obtained filtrate was charged into the reactor and cooled to about 2°C. The resultant reaction mass was stirred for about 90 minutes. The separated solid was filtered and washed with ethyl acetate (100 L). The solid obtained was dried at about 70°C till the loss on drying (LOD) comes to below 2% w/w to afford 84.8 kg of pure title compound.

Example 3: Preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol (Formula VI)
(3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde (135 kg) was charged into a clean dry reactor containing toluene (2025 L). The reaction mixture was cooled to about -5°C. Methyl magnesium chloride (203 L) was added slowly at about -5°C followed by stirring the reaction mass for about 2 hours. A solution of ammonium chloride (108 kg) dissolved in water (270 L) was added to the reaction mass at about 5°C followed by stirring for about 2 hours. The separated solid was filtered followed by subjecting to vacuum for about 4 hours. The wet solid was taken into another reactor containing water (675 L) and stirred for about 2 hours. The solid was filtered and subjected to vacuum for about 2 hours. The obtained solid was dried at about 70°C until the loss on drying was below 2% w/w to afford 121 kg of the title compound.
Purity by HPLC: 91.35%.

Example 4: Preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol (Formula VI)
(3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde (96 kg) was charged into a clean dry reactor containing toluene (1440 L). The reaction mixture was cooled to about -5°C. Methyl magnesium chloride (144 L) was added slowly at about -5°C followed by stirring the reaction mass for about 2 hours. A solution of ammonium chloride (77 kg) dissolved in water (192 L) was added to the reaction mass at about 5°C followed by stirring for about 90 minutes. The separated solid was centrifuged followed by washing with water (96 L). The wet solid was taken into another reactor containing water (720 L) and stirred for about 90 minutes. The solid was centrifuged and washed with water (96 L). The wet-cake was suck dried for 30 minutes. The obtained solid was dried at about 70°C until the water content was below 5% w/w to afford 77.2 kg of the title compound.

Example 5: Preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanone (Formula VII)
1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol (50 kg) and toluene (750 L) were taken into a clean and dry reactor. Manganese dioxide (52 kg) was added over about 15 minutes. The reaction mixture was heated to about 92°C and collected the water (5 L) from the azeotropic mixture for about 13 hours. On completion of the reaction, reaction mixture was cooled to about 80°C and manganese dioxide solid was isolated by filtration. The manganese dioxide isolated was placed into a reactor containing toluene (350 L) followed by heating to about 85°C. The mixture was stirred for about 1 hour; the solid was filtered off.
The obtained filtrate was combined and about 80% of the total volume was distilled under vacuum. The concentrated solution was cooled to about 5°C and stirring for about 1 hour. The separated solid was filtered and dried at about 70°C until the loss on drying was about 2% w/w to afford 40.7 kg of the title compound.

Example 6: Preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanone (Formula VII)
1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol (75kg) and dichloromethane (3375 L) were taken into a clean and dry reactor. The resultant reaction mixture was heated to about 40°C for clear dissolution followed by cooling to about 30°C. Manganese dioxide (187.5 kg) was added slowly over about 2 hours followed by stirring for about 20 hours. The manganese dioxide solid separated from the reaction mass. Wet manganese dioxide solid was isolated by filtration and was placed into a reactor containing dichloromethane (750 L) followed by stirring for about 2 hours. The solid was filtered and washed with dichloromethane (125 L).
The obtained filtrate was combined and passed through a 5 µm filter to make it particle free. The obtained filtrate was distilled completely at about 40 °C under vacuum to afford a residue. The residue was cooled to about 30°C and n-hexane (375 L) was added followed by stirring for about 2 hours. The separated solid was filtered and washed with n-hexane (75 L). The solid obtained was dried at about 70°C until the loss on drying was about 2% w/w to afford 55 kg of the title compound.
Purity by HPLC: 93.52%.

Example 7: Preparation of 3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propionic acid methyl ester (Formula VIII)
(1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanone (169.5 kg) and sodium methoxide (63 kg) were taken into a reactor containing 1,4-dioxane (508.5 L). The reaction mixture was stirred at 30°C for about 30 minutes. 126 liters of dimethyl carbonate was added to it followed by heating to about 80°C. The resultant reaction mixture was stirred for about 7 ½ hours and then cooled to about 30°C. After completion of the reaction water (1695 L) was added and stirred for about 8 hours. The separated solid was filtered and washed with water (170 L).
The wet solid obtained was taken into another reactor containing methanol (850 L) and stirred for about 2 hours. The solid was filtered and washed with methanol (170 L). The solid obtained was dried at about 70°C till the loss on drying was about 2% w/w to afford 181 kg of the title compound.
Purity by HPLC: 89.73%.

Example 8: Preparation of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl)-benzoic acid methyl ester (Formula X)
3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propionic acid methyl ester (181 kg) and methyl-2-bromomethylbenzoate (136 kg) were taken into a reactor containing N,N-dimethylformamide (725 L). Potassium carbonate (73.1 kg) was added to it followed by heating to about 55°C. The resultant reaction mixture was stirred for about 8 hours. After completion of the reaction, the reaction mass was cooled to about 30°C followed by addition of saturated ammonium acetate solution (ammonium acetate 135.8 kg dissolved in 545 L of water) over about 7 hours. Water (1085 L) was added followed by stirring for about 4 hours. The separated solid was filtered and washed with water (1450 L).
The wet solid obtained was taken into a fresh reactor containing methanol (1085 L) and stirred for about 8 hours. The solid was filtered and washed with methanol (180 L). The wet solid was dried at about 70°C until the loss on drying was about 2% w/w to afford 216 kg of the title compound.
Purity by HPLC: 92.31%.

Example 9: Preparation of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid (Formula XI)
2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl) -benzoic acid methyl ester (222 kg) was taken into a reactor containing glacial acetic acid (1110 L) and conc. hydrochloric acid (225 L). The reaction mixture was heated to about 70°C followed by stirring for about 12 hours. After completion of the reaction, the reaction mass was cooled to about 30°C and ammonium chloride solution (444 kg of ammonium chloride dissolved in 1110 L of water) was added slowly to the reaction mass followed by stirring for 6 hours. The separated solid was filtered and washed with water (445 L).
The wet solid was taken into another reactor containing methanol (1110 L) followed by stirring at 30°C for about 2 hours. The separated solid was filtered and washed with methanol (225 L). The solid obtained was dried at about 70°C until the loss on drying was about 2% w/w to afford 185 kg of the title compound.
Purity by HPLC: 78.5%.

Example 10: Preparation of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester (Formula XII)
2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid (90 kg) was taken into a reactor containing acetone (1125 L) and potassium carbonate (33.75 kg). The resultant reaction mixture was stirred at about 30°C for about 30 minutes. Methyl iodide (20.7 L) was added to it followed by heating slowly to about 55°C. The resultant reaction mixture was stirred for about 13 ½ hours followed by cooling to about 30°C. The separated sold was filtered and washed with acetone (90 L). The filtrate obtained was distilled completely below 60°C under vacuum to obtain a residue.
The residue obtained was dissolved in chloroform (900 L) and the chloroform layer was washed with water 2×340 L). The organic layer was separated and charcoal carbon (4.5 kg) was added to it and stirred at about 30°C for about 15 minutes. The mixture was filtered through candy and leafy filters followed by washing with chloroform (45 L). The filtrate obtained was distilled to 70-75% of the original volume followed by cooling to about 30°C. To the residue, n-hexane (405 L) was added followed by stirring at about 30°C for about 2 hours. The separated solid was filtered and washed with 90 liters of n-hexane. The solid obtained was dried at about 70°C for about 8 hours to afford 61 kg of the title compound.
Purity by HPLC: 95.97%.

Example 11: Preparation of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester (Formula XII)
Toluene (500 ml), 3-[2-(7-chloro-quinolin-2-yl)-vinyl] benzaldehyde (50 g) were taken into a round bottom flask and stirred for about 10 minutes. The reaction mass was then cooled to 0 to -10°C. Then Vinyl Magnesium bromide (1 M solution in THF) (230 ml) was added slowly at about 0 to -10°C under nitrogen atmosphere. After the addition was complete, the reaction mass was maintained at 0 to -10°C for about 2 hours. After the reaction was completed, the reaction mass was quenched with 10 % aqueous acetic acid solution (300 ml) below 10°C. Toluene (250 ml) was then added to the reaction mass, and the temperature of the reaction mass was raised to 25-35?C and stirred for about 30-45 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (150 ml). The combined organic layer was washed with 5 % aqueous sodium bicarbonate solution (250 ml) followed by washing with water (2X400 ml). The organic layer was distilled azeotropically to remove the traces of water until the reaction volume was 400 ml and then cooled to 25-35°C. Methyl 2-iodo benzoate (22.4 ml), THF (25 ml) and triethylamine (65.1 ml) was added to the residual organic layer. Palladium acetate (0.25 g) was added and the reaction mass was heated to reflux and maintained under reflux for about 24 hrs. After the reaction was completed, the reaction mass was filtered under hot condition and washed the filtered bed with toluene (100 ml). The combined filtrate was washed with water (2 X250 ml) under hot condition (60-70°C). The toluene layer was Distill off completely under vacuum below 60°C. Then toluene (75 ml) was added to the reaction mass and heated to 70-80°C to get the clear dissolution. The solution was then cooled to about 25-35°C and maintained for about 2 hours. Then the reaction mass was further cooled to 0-5°C and stirred for about 4 hours. The separated solid was filtered and washed with chilled toluene (25 ml) and finally washed with hexanes (100 ml). The wet compound was dried at 50-55°C under vacuum to afford 45 g of the title compound.

Example 12: Prepration of 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-benzoic acid methyl ester (Formula XIII)
(-) diisopionocamphenyl chloroborane (81 L) and dichloromethane (225 L) were taken into a clean and dry reactor followed by stirring for about 30 minutes. An additional dichloromethane (225 L) were charged into the reactor followed by cooling to about 0°C. 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester (45 kg) was added slowly over about one hour. The resultant reaction mixture was stirred at about 0°C for about 10 ½ hours. After completion of the reaction, the reaction mixture was decomposed by the addition of ammonia solution (Conc.5-10%) (35 L) at about -5°C followed by stirring at about 30°C for about 2 hours. The reaction solution was washed with saturated sodium chloride solution (9 kg sodium chloride dissolved in 45 L of water) (4×45 L). The aqueous layer with emulsion was filtered through a Nutsche filter and the filtered bed was washed with dichloromethane (45 L). The organic layer was separated and distilled completely at about 55°C under vacuum followed by cooling to about 30 °C to afford a residue.
The residue obtained was dissolved in methanol (540 L) followed by stirring at about 30°C for about 4 hours. The separated gummy solid was filtered and the resultant filtrate was taken into a fresh reactor. Water (135 L) was added slowly over about 4 hours followed by stirring for about 2 hours then methanol (22.5 L) and water (22.5 L) were added. The separated solid was filtered and washed with a mixture of n-hexane (90 L) and water (22.5 L) and spin-dried for 3 hours to afford 37 kg of the title compound.

Example 13: Preparation of 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol (Formula II)
2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-benzoic acid methyl ester (60 kg) and toluene (960 L) were taken into a clean and dry reactor equipped with Dean-Stark type azeotropic apparatus. The resultant reaction suspension was heated to about 112?C followed by stirring for about 2 hours, and simultaneously separated unwanted water was collected in the Dean-Stark apparatus along with solvent from the reaction solution. The resultant reaction mass with a water content = 0.1% w/v by the Karl Fischer (“KF”) method was cooled to about -5°C. Methyl magnesium chloride (280 L) was added slowly into the reaction mass over about 6 hours at about -5°C followed by stirring for about 2 hours. After completion of the reaction, the reaction was decomposed by the addition of sodium bicarbonate solution (80 kg of sodium bicarbonate dissolved in 600 L of water) followed by stirring for about 30 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (60 L). The combined organic layer was washed with sodium bicarbonate solution followed by washing with water (2×480 L).
The separated organic layer was taken into another reactor equipped with a Dean-Stark type azeotropic apparatus followed by heating to about 100°C and the water that separated was collected. Methyl magnesium chloride (140 L) was added slowly at about 0°C over about 6 hours followed by stirring for about 1 hour. The temperature was raised to about 15°C followed by stirring for about 3 hours. The reaction was decomposed by the addition of sodium bicarbonate solution (40 kg of sodium bicarbonate dissolved in 300 L of water) below 20°C followed by stirring for about 30 minutes. The temperature was raised to about 30°C followed by stirring for about 2 hours. The organic layer was separated followed by extraction of the aqueous layer with toluene (60 L). The combined organic layer was washed with sodium bicarbonate solution followed by washing with water (2×300 L). Organic and aqueous layers were separated and the organic layer was distilled completely below 60°C under vacuum to afford a residue.
The resultant residue was dissolved in toluene (100 L) followed by heating to about 60°C for complete dissolution. The resultant solution was cooled to about 30°C followed by stirring for about 3 hours. The mass was cooled to about 0°C and maintained for one hour. The separated solid was filtered and washed with petroleum ether and spin-dried for 30 minutes to afford 43 kg of title compound.

Example 14: Preparation of 1,1 cycloprane diester (Formula XVI)
1,2-dichloroethane (400 L), diethyl malonate (145 kg), N,N-dimethyl formamide (365 L), and potassium carbonate (187 kg) were taken into a reactor equipped with a Dean-Stark type azeoptropic apparatus. The reaction mixture was heated to reflux followed by stirring for about 42 hours, simultaneously removing unwanted water that was collected in the Dean Stark apparatus. The reaction mixture was cooled to about 30°C. The reaction mass was filtered and the filter washed with 510 L of 1,2-dichloroethane. The obtained organic layer was washed with water (4×510 L) and distilled completely under vacuum below 60°C to obtain a residue. The obtained residue was cooled to 35°C and high vacuum applied. The reaction mass was heated slowly below 75°C and collect the first fraction. The second fraction was collected by maintaining the temperature at 90°C and the third fraction was collected by maintaining the temperature below 120°C for about 5 hours to afford 18.5 kg (2nd and 3rd fractions) of the title compound.
Purity by GC: 92.44%.

Example 15: Preparation of 1,1 cyclopropanedimethanol (Formula XVII)
1,1-cyclopropanediester (125 kg), isopropanol (500 L), and sodium borohydride (117 kg) were taken into a clean and dry reactor, followed by stirring for about 3 hours. Methanol (250 L) was added slowly at about 25°C over about 7 hours. The resultant reaction mixture was heated slowly to about 75°C followed by stirring for about 46 hours. The reaction mass was cooled to about 60°C then ethyl acetate (500 L) was charged. Saturated ammonium chloride solution was added to the reaction mass (125 kg of ammonium chloride dissolved in 285 L of water) slowly over about 5 hours at about 30°C and stirred for about 2 hours. The separated salts were filtered and washed with ethyl acetate (625 L). The resultant organic layer was distilled completely at about 75°C under vacuum to afford a residue. The obtained residue was subjected vacuum distillation at a vacuum of about 400-700 mm Hg. The residue was heated slowly and the lower fraction was collected at below 90°C followed by heating the reaction mass to about 110°C and main fraction was collected to afford 27.5 liters of title compound.
Purity by GC 77.2%

Example 16: Preparation of 1,1-cyclopropanedimethanol cyclosulfite (Formula XVIII)
1,1-cyclopropanedimethanol (23 kg) and triethyl amine (63 L) were taken into a glass-lined reactor containing dichloromethane (575 L). The reaction mass was cooled to about -5°C. Thionyl chloride (17.5 L) was added slowly at about -5°C over about 6 hours followed by stirring for about 6 hours at about -5°C. The reaction mass was decomposed slowly at below 15°C by the addition of the reaction mass to a disodium hydrogen orthophosphate solution (19.5 kg of disodium hydrogen orthophosphate dissolved in 575 L of water and the pH adjusted to about 7 by the addition of 1 L of orthophosphoric acid). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×140 L). The combined organic layer was washed with 5% NaHCO3 solution (3 x (7.5 kg dissolved in 155 L of water)).
The obtained organic layer was taken into a clean reactor followed by adding carbon (2.5 kg) and sodium sulfate (5.5 kg). The reaction mixture was stirred at about 30°C for about 20 minutes. The reaction mass was filtered through a celite bed and the bed was washed with dichloromethane (25 L). The resultant filtrate was passed through a micro filter and the solvent distilled completely at about 45°C to afford a residue of the title compound.
To the obtained residue, n-hexane (70 L) was added followed by stirring at about 10°C for about 1 hour. The separated solid was filtered and washed with pre-cooled n-hexane (25 L) to afford 14.5.0 kg of the title compound.
Purity by GC: 92.19%.

Example 17: Preparation of 1-hydroxymethyl-cyclopropane acetonitrile (Formula XIX)
1,1-cyclopropanedimethanol cyclic sulfite (60 kg), N,N-dimethylformamide (216 L), sodium cyanide (24.2 kg), and sodium iodide (12.7 kg) were taken into a clean and dry reactor. The resultant reaction mass was heated slowly to about 100°C followed by stirring for about 17 hours. The reaction mass was cooled to about 70°C followed by quenching the reaction mass by the addition of water (11.2 L) followed by toluene (640 L). The reaction suspension was stirred at about 45°C for about 30 minutes. The reaction mass was cooled to about 30°C and filtered through a celite bed and the bed was washed with toluene (182 L). The filtrate obtained was distilled at about 65°C under vacuum to afford a residue. The residue obtained was charged into a vacuum distillation reactor and heated slowly to below 100°C for collection of the first fraction. Raised the temperature from 100°C and collected the second fraction. Again raised the temperature from 120°C and the main fraction was collected to afford 26 kg of the title compound.
Purity by GC: 82.4%.

Example 18: Preparation of 1-(acetylthiomethyl)-cyclopropanene acetonitrile (Formula XX)
1-hydroxymethyl-cyclopropaneacetonitrile (25 kg), toluene (100 L), and N,N-dimethylformamide (50 L) were taken into a clean and dry reactor. Triethylamine (36 L) was added to it followed by stirring for about 30 minutes. The reaction mass was cooled to about -5°C and slowly methane sulfonyl chloride (18.3 L) was added to the reaction mass at about -5°C over about 3 hours, and then stirred for about 2 hours at about 0°C. The reaction mass was then cooled to -10°C and triethylamine (47 L) was added to the reaction mass at about -10°C followed by the addition of thioacetic acid (18 L) at about 0oC. The reaction mass was maintained at about 0°C for about 2 hours and then the temperature was raised to 30°C and maintained for 16 hours. After the reaction was completed, water (250 L) was added and the organic layer was separated. The aqueous layer was extracted with toluene (3×150 L). The combined organic layer was washed with water (3×125 L). To the obtained organic layer carbon (1.25 kg) was added and maintained for about 30 minutes. The reaction mass was filtered and the filtered cake was washed with toluene (7 L). The resultant filtrate was passed through a micro filter and distilled under vacuum at about 50°C to remove carbon traces and extraneous matter to 80% v/v of the original volume followed by applying high vacuum slowly at about 45°C to afford the title compound.
Purity by GC: 84.81%.

Example 19: Preparation of (1-mercaptomethyl-cyclopropyl)-acetonitrile (Formula XIV)
1-(acetylthiomethyl)-cyclopropaneneacetonitrile (33 kg) and methanol (82 L) were taken into a reactor and cooled to 10°C. Sodium methoxide solution of concentration of about 20% (58.3 kg) was added slowly into the reaction mass at about 10°C followed by addition of methanol (42 L). The reaction mass was maintained at 10°C for about 3 hours and decomposed slowly by addition of water (330 L). N-heptane (165 L) was then added followed by stirring for about 15 minutes at 30°C. Separated the layers and washed the aqueous layer with 4×165 L of n-heptane. The aqueous layer was taken into a fresh reactor containing toluene (198 L). Cooled the reaction solution to 0°C, and then pH of the reaction mass was adjusted to about 4 with acetic acid (42 L) at below 5°C. The organic layer was separated and the aqueous layer was extracted into toluene (2×132 L). The combined organic layer was washed with sodium bicarbonate solution (6.6 kg of sodium bicarbonate dissolved in 264 L of water) in two equal lots followed by washing with water (3×132 L). The separated organic layer was treated with activated carbon (4.95 kg) and maintained for about 30 minutes. Filtered the reaction mass through a leaf filter and washed the cake with toluene (66 L). The reaction solution was distilled off completely under vacuum to 80% of the original volume. The obtained residue was cooled to about 30°C and charged into an agitated thin film evaporator followed by heating to 55°C under a vacuum of 700 mmHg. The obtained crude was cooled to 30°C to obtain 18.4 liters of title compound. The obtained title compound was stored at below 5°C under a nitrogen atmosphere in a dry condition.
Purity by GC: 84.76%.

Example 20: Preparation of Montelukast acid (Formula I)
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol (30 kg) and toluene (150 L) were taken into a clean and dry reactor. The resultant reaction mass was heated to reflux. 120 liters of toluene was distilled off atmospherically from the reaction mass. (The resultant residue had a water content of 0.1% w/v by the Karl Fischer (“KF”) method). The reaction mass was cooled to about 60 ?C and acetonitrile (276 L) with a water content of about 0.03% w/v by KF was added. The reaction mass was heated to 70-80°C and maintained for about 45 minutes (checked for clear dissolution) followed by further cooling to about -15°C. Diisopropylethylamine (9.35 kg) with a water content of about 0.02% w/v by KF was added to the residue at about -13°C followed by maintaining for about 15 to 20 minutes. Methanesulfonyl chloride (7.48 kg) with a water content of about 0.02% w/v by KF was added dropwise to the reaction mass at -13°C followed by maintaining for about 9 hours. The separated solid was filtered and washed with chilled acetonitrile (60 L) followed by washing with chilled cyclohexane (60 L) to afford the intermediate mesylate compound.
N,N-dimethylformamide (150 L) with a water content of about 0.02% w/v by KF and (1-mercaptomethyl-cyclopropyl)-acetonitrile (11.6 kg) were taken into a clean and dry reactor followed by cooling to about -13?C . N-butyllithium in n-hexane (15% w/v) (6.6 kg) was added dropwise to the above reaction mixture at about -17°C under N2 atmosphere. The resultant reaction mass was maintained at about -15?C for about 20 to 30 minutes followed by adding the intermediate mesylated compound under a N2 atmosphere at about -13°C to about -17°C, followed by rinsing the reactor walls with N,N-dimethylformamide (30 L). The reaction mixture was maintained at about -13°C for about 60 minutes. After completion of the reaction, the reaction mass was quenched by adding saturated sodium chloride solution (96 kg sodium chloride in 450 L of water) (450 L) below 0?C, followed by allowing the temperature of the reaction mass to increase to 30°C. The reaction mass was extracted with toluene (300 L) followed by separation of the organic and aqueous layers. The aqueous layer was extracted into toluene (2×180 L). The combined organic layer was washed with water (4×360 L). The organic layer was distilled completely at about 55°C under a vacuum of about 600 mm/Hg to afford a residue.
The above obtained residue and caustic lye (40% NaOH) (120 L) were taken into a clean and dry reactor equipped with a Dean-Stark type azeotropic apparatus. Heated the reaction mass to about 111°C and removed toluene from the reaction mass. The resultant reaction mass was maintained at 125 to 130°C for about 20 hours. After completion of the reaction, the reaction mass was cooled to about 90?C and the caustic lye layer was decanted. Preheated water (to 90?C) (810 L) were added and the mixture maintained for about 1 hour for a homogenous solution. pH of resultant solution was adjusted to about 11 by the addition of glacial acetic acid (30 L) under stirring. The reaction mass was washed with toluene (4×180 L). Toluene (300 L) was then added to the aqueous layer and pH was adjusted to about 6 by the addition of 9 liters of acetic acid. The resultant reaction mass was cooled to about 28°C followed by separation of organic and aqueous phases. The aqueous layer was extracted with toluene (2×180 ml). The combined organic layer was washed with water (5×150 L). The organic layer was distilled completely at about 55°C under a vacuum of about 300 mm/Hg. Toluene (30 L) was charged to the resultant residue and was stirred at about 28°C for about 2 hours. The resultant homogenous solution was cooled to about 2°C for about 6 hours. The separated solid was filtered and the solid obtained was washed with toluene (15 L). The solid was dried at about 70°C for about 5 hours to afford 20.4 kg of the crude title compound.
The obtained crude was taken into a clean and dry reactor containing methanol (70 L) and heated to reflux. The reaction mixture was maintained under reflux for 20-30 minutes and then cooled to 25-35°C. The reaction mass was maintained at 25-35°C for about 6 hours. The reaction mass was further cooled to about 0 to 5°C, and maintained for about 5-6 hours. The isolated solid was filtered and washed with chilled methanol (20 L). The wet solid was taken into another reactor containing methanol (50 L) and heated to reflux. The reaction mixture was maintained under reflux for about 20 to 30 minutes and then cooled to about 25-35°C. The reaction mass was maintained at 25 to 35°C for about 5-6 hours, and then further cooled to 0 to 5°C and maintained for about 5-6 hours. The isolated solid was filtered and washed with chilled methanol (20 L) and the wet solid was dried at about 70°C for about 4 hours to afford 14.6 kg of the title compound.
Purity by HPLC: 99.0%.

Example 21: Preparation of Montelukast acid (Formula I)
30 g of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol of Formula II and 300 ml of toluene were charged into a round bottom flask equipped with a Dean-Stark type azeotropic apparatus. The resultant suspension was heated to about 112?C followed by stirring for about 30 minutes, simultaneously removing unwanted water collected in the Dean-Stark apparatus along with the solvent from the reaction solution. Resultant residue was cooled to about 50?C and 550 ml of acetonitrile was charged to the residue followed by further cooling to –15?C. 27.5 ml of diisopropylethylamine was charged to the residue followed by stirring for about 30 minutes. 10.1 ml of methanesulfonyl chloride was added dropwise over about 30 minutes followed by stirring for about 9 hours. Separated solid was filtered and the solid was washed with 120 ml of acetonitrile followed by allowing the temperature to rise to about 5?C. Solid was washed with 120 ml of cyclohexane afford a crude mesylated compound of Formula II.
19.2 g of (1-Mercaptomethyl-cyclopropyl)-acetic acid and 900 ml of tetrahydrofuran (THF) were charged into a clean and dry 4 neck round bottom flask followed by cooling to about –15?C. 200 ml of n-butyl lithium in n-hexane (15% w/v in n-hexane) was added dropwise over about 30 minutes under a N2 atmosphere. The reaction mass was stirred at -15?C for about 30 minutes, followed by charging of the above obtained mesylated compound of Formula II under a N2 atmosphere. The reaction mixture was stirred for about 60 minutes followed by quenching the reaction mass by the addition of 360 ml of saturated sodium chloride solution (360 g sodium chloride in 1000 ml water) over about 30 minutes. The reaction solution was allowed to reach a temperature of about 30°C followed by extraction with 900 ml of dichloromethane. Organic and aqueous layers were separated followed by washing the organic layer with 4×480 ml of water. The organic and aqueous layers were separated and the organic layer was distilled completely at about 55?C under vacuum of about 300 mm Hg to afford 29.4 g of the title compound.

Example 22: Preparation of Montelukast dicyclohexylamine salt:
Montelukast acid (20 g) and acetone (120 ml) were taken into a round bottom flask followed by stirring for about 15 minutes. Dicyclohexylamine (8.1 ml) was added to the above homogenous reaction solution followed by seeding with montelukast dicyclohexylamine salt (0.2 g). The resultant reaction suspension was stirred for about 45 minutes followed by addition of toluene (60 ml). The resultant reaction suspension was stirred for about 8 hours. The separated solid was filtered and washed with toluene (20 ml).
The obtained wet solid was charged into a round bottom flask containing toluene (60 ml) and the mass was heated to about 90°C. Activated carbon (2 g) was added and maintained for 20-30 minutes. The reaction mass was filtered through a celite bed in the hot condition and the bed was washed with toluene (40 ml). The obtained filtrate was taken into a fresh round bottom flask and maintained for about 16 hours at about 30°C. The separated solid was filtered and washed with toluene (20 ml). The solid obtained was dried at about 55°C under vacuum to afford 20 g of the title compound.
Purity by HPLC: 99.2%.
Example 23: Preparation of Montelukast pure acid (Formula I)
Montelukast dicyclohexylamine salt (30 g) and ethyl acetate (300 ml) were taken into round bottom flask and started stirring. A solution of acetic acid (3.4 ml) in water (150 ml) was prepared and added to the above mixture followed by stirring for about 10 minutes. The organic layer was separated and washed with water (4×150 ml). The organic layer was then distilled at about 65°C completely under vacuum to afford a residue. To the residue, ethyl acetate (90 ml) was added followed by distillation of the solvent completely to afford a foamy solid of the title compound.
Methanol (22.5 ml) was added to the foamy solid followed by cooling to about 5°C. The resultant reaction suspension was stirred at about 0°C for about 4 hours. The separated solid was filtered and washed with methanol (7.5 ml). The solid obtained was dried at about 60°C for about 3 hours to afford 7.4 g of pure title compound.
Purity by HPLC: 99.28%.

Example 24: Preparation of Montelukast pure acid (Formula I)
Montelukast (50 g), isopropyl alcohol (150 ml) acetonitrile (375ml), and DCHA salt (20.4 ml) were taken into a round bottom flask and stirred for about 5 minutes. The mixture was heated to about 75°C and checked for clear dissolution. Carbon (5 g) was added to the solution and stirred for another 30 minutes. The reaction mass was filtered over a celite bed under hot condition and the celite bed was washed wit a mixture of isopropyl alcohol and acetonitrile in a ratio of 1:3 (100 ml). The combined filtrate was taken into another round bottom flask and allowed to cool to 25 to 35°C under stirring. The filtrate was maintained at 25 to 35°C for another 2 hours and then filtered. The filtered solid was washed with 100 ml of acetonitrile and dried under suction. The above process of recrystallization was repeated twice with the same quantities of solvents and dichloromethane (500 ml) was added to the final wet solid. The mixture obtained was washed with a solution of acetic acid (72.5 ml) in water (7500 ml) in 5 equal lots. The organic layer was separated and washed with water (1000 ml) in two equal lots. The organic layer was then distilled in a rota vapor flask at about 50°C under a vacuum of about 350 mm/Hg to get a crude. To the crude obtained, methanol (150 ml) was added and again distilled out completely. The obtained residue was taken in methanol (75 ml) and stirred at about 25 to 35°C for about 4 hours, and then cooled to about 0 to 5°C and maintained for about 5 hours. The separated solid was filtered and washed with methanol (25 ml). The wet compound was then dried at about 50°C for about 6 hours to yield 31 g of the title compound.
Purity By HPLC: 99.69%.

Example 25: Preparation of Montelukast sodium
Sodium hydroxide pellets (1.69 g) and methanol (125 ml) were taken into a round bottom flask and stirred for about 15 minutes at 25 to 35°C. A mixture of montelukast (25 g) in methanol (125 ml) was prepared and the solution of methanolic sodium hydroxide prepared above was added to it and stirred at 25 to 35°C for about 10 minutes. Activated carbon (2.5 g) was added to the solution and stirred for about 10 minutes at the same temperature. The mixture was then filtered over a celite bed and the bed was washed with methanol (50 ml). The combined filtrate was distilled under a vacuum of about 650 mm/Hg at a temperature of about 50°C and the obtained solid was dried at about 70°C for 7 hours to yield 24.5 g of the title compound.
Purity By HPLC: 99.7%
Chiral Purity: 99.9%
Residual Solvents: Methanol: 545 ppm, All other solvents: Below LOD.

We claim:
1. A process for preparing 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-ol of Formula II:

(II)
said process comprising:
a) reacting 7-chloroquinalidine of the Formula III:

(III)
with isophthalaldehyde of the Formula IV:

(IV)
in the presence of acetic anhydride, in a hydrocarbon solvent, to afford 3-[2-(7-chloro-quinolin-2-yl)-vinyl]-benzaldehyde of the Formula V:

(V)
b) reacting the compound of the Formula V with methyl magnesium chloride in a hydrocarbon solvent to afford 1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanol of the Formula VI:,

(VI)
c) treating the compound of Formula VI with manganese dioxide to afford (1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-ethanone of the Formula VII:

(VII)
d) treating the compound of the Formula VII with dimethylcarbonate in the presence of sodium methoxide to afford 3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propionic acid methyl ester of the Formula VIII:

(VIII)
e) reacting the compound of the Formula VIII with methyl-2-bromoethyl benzoate of the Formula IX :

(IX)
in the presence of a base to afford (2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl)-benzoic acid methyl ester of the Formula X;

(X)
f) converting the compound of the Formula X to 2-(3-{3-[2-(7-chloro-quinolin-2-yl)vinyl]-phenyl}-2-methoxycarbonyl-3-oxo-propyl)-benzoic acid of the Formula XI:

(XI)
g) treating the compound of the Formula XI with methyl iodide in the presence of a base to afford 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-oxo-propyl)-benzoic acid methyl ester of the Formula XII:

(XII)
h) treating the compound of the Formula XII with (-) diisopionocamphenyl chloroborane to afford methyl 2-(3-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-benzoic acid methyl ester of the Formula XIII; and

Formula XIII
i) reacting the compound of the Formula XIII with methyl magnesium chloride in the presence of a hydrocarbon solvent to afford said compound of the formula (II).

2. The process of claim 1, wherein said hydrocarbon solvent of step b) is toluene.

3. The process of claim 1, wherein said step c) is conducted in a chlorinated solvent.

4. The process of claim 3, wherein said chlorinated solvent is dichloromethane.

5. The process of claim 1, further comprising purifying said product of step g) by precipitation from a chloroform/n-hexane mixture.

6. A process for preparing 1-(mercaptomethyl) cyclopropane acetonitrile of the Formula XIV:

(XIV)
said process comprising:
a) reacting diethyl malonate of the Formula XV:

(XV)
with a base in the presence of more than 5 moles of dichloroethane to afford 1,1 cyclopropane diester of the Formula XVI:

(XVI)
b) reacting the compound of the Formula XVI with sodium borohydride to afford 1,1 cyclopropanedimethanol of the Formula XVII:

(XVII)
c) reacting the compound of the Formula XVII with thionyl chloride in a hydrocarbon solvent to afford 1,1-cyclopropanedimethanol cyclic sulfite of the Formula XVIII:

(XVIII)
d) reacting the compound of the Formula XVIII with sodium cyanide in the presence of sodium iodide to afford 1-hydroxymethyl-cyclopropaneacetonitrile of the Formula XIX:

(XIX)
e) reacting the compound of the Formula XIX with methanesulfonyl chloride in the presence of thioacetic acid to afford 1-(acetylthiomethyl)-cyclopropaneacetonitrile of the Formula XX:

(XX)
and
f) reacting the compound of the Formula XX with sodium methoxide to afford said compound of the Formula XIV.

7. The process of claim 6, wherein the hydrocarbon solvent is toluene.

8. A process for preparing 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol, represented by the Formula XXI:

(XXI)
said process comprising reacting a diol of the Formula II:

(II)
with methane sulfonyl chloride in the presence of a base in a reaction medium that is essentially free of moisture.

9. The process of claim 8, wherein the reaction medium has water content of less than about 0.5%.

10. The process of claim 8, wherein the reaction medium has water content of less than about 0.2%.

11. A process for the preparation of montelukast of the Formula I:

(I)
said process comprising:
a) reacting a diol intermediate of the Formula II:

(II)
with methane sulfonyl chloride in the presence of diisopropyl ethyl amine to afford the compound of the formula (XXI):

(XXI)
b) reacting the compound of the formula (XXI) with 1-(mercaptomethyl)cyclopropane acetonitrile to afford the compound of the formula (XXII):

(XXII);
c) converting said the compound of the formula (XXII) into a free acid of montelukast of the formula (I).

12. The process of claim 11, further comprising reacting said free acid of montelukast produced in said step c) with a salt-forming amine to produce an amine salt of montelukast.

13. The process of claim 12, further comprising converting said amine salt of montelukast into a sodium salt of montelukast.

14. The process of claim 12, further comprising purifying said amine salt of montelukast by recrystallization.

15. The process of claim 12, wherein said salt-forming amine is dicyclohexylamine.

16. The process of claim 12, wherein said salt-forming amine is tertiary butyl amine.

17. The process of claim 15, wherein the dicyclohexylamine salt of montelukast is isolated from acetone.

18. The process of claim 16, wherein the tertiary butyl amine salt of montelukast is isolated from acetone.

19. A process for the purification of dicyclohexylamine salt of montelukast, said process comprising:
a) providing a solution of dicyclohexylamine salt of montelukast in a combination of an alcoholic solvent and a nitrile solvent;
b) cooling said solution thereby causing a solid dicyclohexylamine salt of montelukast to separate from said solution;
c) isolating said separated solid.

20. The process of claim 19, wherein the alcoholic solvent is isopropyl alcohol, and the nitrile solvent is acetonitrile.