WO2010148209A2

WO2010148209A2 - Preparation of montelukast

Info

Publication number: WO2010148209A2
Application number: PCT/US2010/039010
Authority: WO
Inventors: Martin Edward Fox; Satyanarayana Bollikonda; Saravanan Mohanarangam; Rajender Reddy Jinna; Venkata Kiran Kumar Kandirelli
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-06-19
Filing date: 2010-06-17
Publication date: 2010-12-23
Also published as: WO2010148209A3

Abstract

Processes for the preparation of montelukast and its salts.

Description

PREPARATION OF MONTELUKAST

INTRODUCTION

In aspects, the present application relates to the preparation of intermediates of montelukast. Further aspects relate to processes for preparing montelukast and its salts.

The drug compound having the adopted name "montelukast" has a chemical name [R-(E)]-1 -[[[1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1 - hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, and is represented by structural Formula I.

Formula I

Montelukast, including its pharmaceutically acceptable salts, such as the sodium salt, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTi receptor and is useful in the treatment of asthma as well as other conditions mediated by leukotrienes, such as inflammation and allergies.

Processes for the preparation of montelukast and its intermediates of Formula Il and Formula VII have been disclosed in U.S. Patent Nos. 5,614,632, 5,523,477, and 5,565,473, U.S. Patent Application Publication Nos. 2005/0234241 and 2005/0256156, and International Application Publication Nos. WO 2004/108679 and WO 2006/021974.

Formula Il

Formula VII

European Patent No. 480,717 and U.S. Patent Application Publication 2006/0223999 disclose the use of oxazaborolidine complexes in stoichiometric amounts for the reduction of a ketone of the formula,

wherein R¹ is unsubstituted or substituted heteroaryl and R² is phenyl or substituted aryl.

European Patent No. 480,717 also discloses the stereoselective reduction of the keto ester of Formula III with the chiral reducing agent (-)- diisopinocamphylchloroborane, to afford the corresponding S-(-)-alcohol of Formula Ma below.

U.S. Patent No. 5,491 ,077 discloses the stereo selective reduction of the keto ester of Formula III,

Formula III with the chiral reducing agent Microbactehum MB5614, to afford Formula Ma.

Formula Ma

International Application Publication No. WO 2006/008562 discloses catalytic transfer hydrogenation the keto ester of Formula III using a chiral ruthenium or rhodium catalyst in the presence of a hydrogen source. International Application Publication No. WO 2008/131932 discloses asymmetric hydrogenation of a compound having the formula,

wherein R¹ is unsubstituted or substituted heteroaryl and R² is phenyl or substituted aryl, characterized in that the asymmetric hydrogenation is conducted with hydrogen gas in the presence of platinum metal complex catalyst comprising chiral phosphine ligand.

The above processes suffer from major disadvantages, including use of highly expensive reagents, highly expensive and non-recoverable solvents like acetonitrile and tetrahydrofuran, large amounts of catalysts, longer reaction time, low yield and low quality.

SUMMARY

Aspects of the present application provide processes for the preparation of montelukast acid and salts thereof.

In embodiments, there are provided processes for preparing 1 -{3-[2-(7- chloroquinolin^-ylJethenyljphenylJ-S-^^i -hydroxy-i -methylethylJphenyllpropan- 1 -ol (hereinafter referred to as the "diol" intermediate) of Formula II,

Formula Il which processes include:

(a) protecting the ketone group of the Formula

Formula with an alcohol having two or more terminal hydroxyl groups to afford a ketal of Formula IV,

Formula IV wherein R is a C2-C6 straight or branched alkyl group or a C3-C6 cycloalkyl group; (b) reacting the compound of Formula IV with a methylmagnesium halide to afford an alcohol of Formula V;

Formula V

(c) deprotecting the ketal group of Formula V to afford a compound of Formula Vl; and

Formula Vl

(d) asymmetrically reducing a compound of Formula Vl, in the presence of a chiral transition metal complex and a base, to afford 1 -{3-[2-(7-chloroquinolin-2- yl)vinyl]phenyl}-3-[2-(1-hydroxy-1-methylethyl)phenyl]propan-1 -ol of Formula II.

In embodiments, there are provided processes for the preparation of a mesylate compound of Formula VII,

Formula VII which processes include reacting a diol intermediate of Formula II,

Formula Il with methanesulfonyl chloride, in the presence of a base in a commercially viable solvent system, to afford the mesylate compound of Formula VII.

DETAILED DESCRIPTION

In embodiments, there are provided processes for preparing a diol intermediate of montelukast, having Formula II,

Formula Il which processes include:

(a) protecting the ketone group of the compound having Formula

Formula with an alcohol having two or more terminal hydroxyl groups, to afford a ketal of Formula IV,

Formula IV wherein R is a C2-C6 straight or branched alkyl group or a C3-C6 cycloalkyl group; (b) reacting the compound of Formula IV with a methylmagnesium halide, to afford an alcohol of Formula V;

Formula V

Formula Vl

Step (a) involves protecting the ketone group of the Formula III with an alcohol having one or more terminal hydroxyl groups, to afford a ketal of Formula IV.

The compound of Formula III may be prepared by any process, including a process described in International Application Publication No. WO 2008/058118 A2, which is incorporated herein by reference in its entirety. Step (a) may be optionally carried out in a suitable alcohol having two or more terminal hydroxyl groups. Suitable alcohols having a C2-C6 straight or branched alkyl group that may be used in step (a) include, but are not limited to, ethylene glycol, propylene glycol, hexylene glycol, 1 ,3-butylene glycol, 1 ,4- butylene glycol, 1 ,3-trimethylene glycol, 1 ,4-tetramethylene glycol, and 1 ,6- hexamethylene glycol. Suitable alcohols having a C₄-Cβ cycloalkyl group that may be used in step (a) include, but are not limited to, cyclopropane dimethanol, cyclopropane diethanol, cyclopropane dipropanol, cyclopropane dibutanol, cyclopropane dipentanol, cyclobutane dimethanol, cyclobutane diethanol, cyclobutane dipropanol, cyclobutane dibutanol, cyclobutane dipentanol, cyclopentane dimethanol, cyclopentane diethanol, cyclopentane dipropanol, cyclopentane dibutanol, cyclopentane dipentanol, cyclohexane dimethanol, cyclohexane diethanol, cyclohexane dipropanol, cyclohexane dibutanol, and cyclohexane dipentanol. Step (a) may be optionally carried out in the presence of a suitable catalyst.

Suitable catalysts that may be used in step (a) include, but are not limited to: organic acids including formic acid, propionic acid, butyric acid, isobutyhc acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like; inorganic acids, including dry hydrochloric acid, sulphuric acid, phosphoric acid, and the like; organic acids such as methanesulphonic acid, p-toluenesulphonic acid, and the like; metal oxides; metal halides; any mixtures thereof; and any other suitable catalysts or their hydrates.

Optionally, an additional solvent other than the alcohol having one or more terminal hydroxyl groups may be used in step (a). Suitable solvents that may be used in step (a) include, but are not limited to: hydrocarbons such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, ethylene dichlohde, chloroform, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; and any mixtures thereof. Suitable temperatures for carrying out step (a) may be less than about

160⁰C, less than about 140⁰C, less than about 120°C, less than about 100⁰C, less than about 8O⁰C, less than about 6O⁰C, less than about 40°C, less than about 20°C, or any other suitable temperatures. Step (a) may be optionally carried out using azeotropic removal of water from the reaction medium at temperatures less than about 160⁰C, less than about 140⁰C, less than about 120°C, less than about 100⁰C, less than about 80°C, less than about 60°C, less than about 40⁰C, or any other suitable temperatures. Suitable times for completing reaction in step (a) depend on the temperature and other conditions, and may be generally less than about 20 hours, less than about 15 hours, less than about 10 hours, less than about 5 hours, less than 2 hours, less than about 30 minutes, or any other suitable times. Longer times are also acceptable. The reaction product formed in step (a) may optionally be recovered as a solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the isolation of solids. Alternatively, the product may be isolated by an extraction procedure using a suitable solvent. A resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 85°C, less than about 75°C, less than about 60⁰C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.

Optionally, the product of step (a) may be directly used in step (b) without isolation or after conventional work-up, such as, for example, quenching the reaction mixture with a quenching agent, extracting the product in to a solvent and using it in the next stage directly.

Step (b) involves reacting the compound of Formula IV with a methylmagnesium halide to afford an alcohol of Formula V. Step (b) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (b) include, but are not limited to: hydrocarbons such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, anisole, and the like; and mixtures thereof.

Suitable methylmagnesium halides that may be used step (b) include, but are not limited to, methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide.

Addition of the alkylmagnesium halide in portions, at intervals, can significantly improve the yield.

The quantities of methylmagnesium halide that may be used in step (b) may be less than about 10 molar equivalents, less than about 5 molar equivalents, less than about 3 molar equivalents, or about 2 molar equivalents, per mole of compound of Formula IV.

Suitable temperatures for step (b) may be less than about 100⁰C, less than about 70⁰C, less than about 40°C, less than about 20⁰C, less than about 0°C, less than about -10°C, less than about -20⁰C, less than about -40°C, or any other suitable temperatures.

Suitable times for completion of the reaction in step (b) depend on the temperature and other conditions, and may be generally less than about 50 hours, less than about 40 hours, less than about 30 hours, less than about 20 hours, less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 1 hour, or any other suitable times. Longer times also may be used.

The product formed in step (b) may optionally be recovered as a solid, using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the recovery of solids. Alternatively, it may be isolated by an extraction procedure using a suitable solvent. A resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 85°C, less than about 75°C, less than about 60⁰C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer. Optionally, the product of step (b) may be directly used in step (c) without isolation or after conventional work-up, such as, for example, quenching the reaction mixture with a quenching agent, extracting the product in to a solvent and using it in the next stage directly. Step (c) involves deprotecting the ketal group of Formula V to afford a compound of Formula Vl.

Step (c) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (c) include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, and the like; hydrocarbons, such as toluene, xylene, n-hexane, n- heptane, cyclohexane, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; and any mixtures thereof.

Step (c) may be optionally carried out in the presence of a suitable acid. Suitable acids that may be used for deprotection in step (c) include, but are not limited to: organic acids, such as, for example, acetic acid, formic acid, propionic acid, butyric acid, isobutyhc acid, fumaric acid, oxalic acid, tartaric acid, citric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like; inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, and the like; any mixtures thereof; and any other suitable acid, either alone or as an aqueous solution. Step (c) may be optionally carried out in presence of a suitable resin.

Suitable resins that may be used in step (c) include, but are not limited to: chelating resins, such as, for example, neutral resins; and ion exchange resins; including resins bound to metal ions, including sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium, and the like; Suitable temperatures for step (c) may be less than about 100⁰C, less than about 70⁰C, less than about 40°C, less than about 30⁰C, less than about 20°C, less than about 10°C, less than about 0⁰C, less than about -10°C, or any other suitable temperatures. Suitable times for completing the reaction in step (c) depend on the temperature and other conditions, and may be generally less than about 12 hours, less than about 10 hours, less than about 8 hours, less than about 6 hours, less than about 4 hours, less than about 2 hours, less than about 1 hour, or any other suitable times.

The product formed in step (c) may optionally be recovered as a solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the recovery of solids. Alternatively, it may be isolated by an extraction procedure using a suitable solvent. A resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150⁰C, less than about 120⁰C, less than about 100°C, less than about 60⁰C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer. Optionally, the product of step (c) may be directly used in step (d) without isolation or after conventional work-up, such as, for example, quenching the reaction mixture with a quenching agent, extracting the product in to a solvent and using it in the next stage directly.

Step (d) involves an asymmetric reduction of the compound of Formula Vl to afford the compound of Formula II.

Asymmetric reduction of the compound of Formula Vl may be carried out in presence of a suitable catalyst optionally in combination with a suitable ligand. Suitable catalysts that may be used in step (d) include, but are not limited to, catalysts containing metals such as, for example, ruthenium, rhodium, and the like, and mixtures thereof, or any other suitable catalyst, optionally in combination with ligands containing phosphorous, nitrogen, and the like.

Typical examples of suitable catalysts that may be used for the said asymmetric reduction include, but are not limited to: the catalysts of formulae (VIII), (IX), (X) and (Xl) as shown below. In the structures, Ph indicates a phenyl group, Ts indicates a tosyl group, and Me indicates a methyl group.

Ar = 3,5-(CHs)₂-C₆H₃ Formula VIII (((R)-XYL-BINAPX(R₁R)-DPEN)RUCI₂)

Formula IX

Formula X

Formula Xl

Typical examples of suitable ligands that may be present in the said asymmetric induction catalysts include but not limited to: the ligands of formulae (XII), (XIII), (XIV), (XV), (XVI), (XVII) and (XVIII) as shown below. In the structures, Me indicates a methyl group and Ph indicates a phenyl group.

Formula XII ((Rj-XyI-BINAP)

Formula XIII ((R₁R)-DIPEN)

Formula XIV ((R)-DAIPEN)

Formula XV ((R₁R)-DACH)

Formula XVI ((R)-Xyl-SEGPhos)

Formula XVII ((R)-HEXAPHEMP)

Formula XVIII ((R)-PHANEPhos)

Step (d) may be optionally carried out in the presence of a suitable base. Suitable bases that may be used in step (d) include, but are not limited to: organic bases, for example alkali metal alkoxides, such as, for example, sodium methoxide, potassium methoxide, potassium tert-butoxide, and the like; alkaline earth metal alkoxides, such as, for example, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide and the like; thethylamine, thbutylamine, N- methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4- (N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4- methyl imidazole, and the like; inorganic bases, such as, for example, alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as, for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, and the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, and the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, and the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, and the like; and ion exchange resins including resins bound to ions, such as, for example, sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium, and the like; and any other suitable bases.

Step (d) may be optionally carried out in the presence of a suitable solvent. Suitable solvents that may be used in step (d) include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, tert-butanol, pentanol, 2-pentanol , cyclohexanol, ethylene glycol, glycerol, and the like; hydrocarbons such as toluene, xylene, tetraline, n- hexane, n-heptane, cyclohexane, methylcyclohexane, pentane, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, 1 ,1 ,2-thchloroethane, 1 ,2-dichloroethene, chlorobenzene, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; polar aprotic solvents, such as, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; and any mixtures thereof. Step (d) may be carried out at suitable pressures less than about 15 bar, less than about 10 bar, less than about 8 bar, less than about 6 bar, less than about 4 bar, less than about 2 bar, less than about 1 bar, or any other suitable pressures.

Step (d) may be carried out at suitable temperatures less than about 100⁰C, less than about 80⁰C, less than about 60°C, less than about 40⁰C, less than about 20°C, less than about 10°C, or any other suitable temperatures.

Suitable times for completing the reaction of step (d) depend on temperature and other conditions, and may be generally less than about 50 hours, less than about 30 hours, less than about 20 hours, less than about 10 hours, less than about 5 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or any other suitable times.

The product formed in step (d) may optionally be recovered as a solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. Alternatively, it may be isolated by an extraction procedure using a suitable solvent.

A resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 120⁰C, less than about 100°C, less than about 80°C, less than about 60⁰C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 30 hours, or longer.

Formula VII which processes include reacting a diol intermediate of Formula II,

Formula Il with methanesulfonyl chloride in the presence of a base, in a commercially viable solvent system, to afford the mesylate compound of Formula VII.

Formula VII

The diol intermediate of Formula Il may be prepared by a process as disclosed in the present patent application or by any other process. For example, the compound of Formula Il may be prepared by a process described in International Application Publication No. WO 2008/058118 A2, which is incorporated herein by reference in its entirety.

Commercially viable solvent systems that may be used include, but are not limited to: chlorinated hydrocarbons, such as, for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, chlorobenzene, and the like; aromatic hydrocarbons, such as for example, toluene, xylene, tetraline, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, anisole, and the like; aliphatic or alicyclic hydrocarbons, such as, for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, and the like; and any mixtures thereof. Commercial viability is enhanced by the relatively low cost of these solvents. Suitable bases that may be used in the reaction include, but are not limited to: organic bases, such as, for example, triethylamine, thbutylamine, N- methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidone, pyridine, 4- (N,N-dimethylamino) pyridine, morpholine, imidazole, 2-methylimidazole, 4- methyl imidazole, and the like; inorganic bases, such as, for example, alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as, for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, and the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, and the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, and the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, and the like; and ion exchange resins including resins bound to ions, such as, for example, sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium, and the like; and any other suitable bases.

Suitable reaction temperatures may be less than about 60⁰C, less than about 40⁰C, less than about 30°C, less than about 20⁰C, less than about 0°C, less than about -10°C, less than about -20⁰C, less than about -40°C, or any other suitable temperatures. Suitable times for completing the reaction depend on the temperature and other conditions, and may be generally less than about 30 hours, less than about 20 hours, less than about 10 hours, less than about 8 hours, less than about 6 hours, less than about 4 hours, less than 2 hours, less than about 1 hour, or any other suitable times. The obtained mesylate compound of Formula VII may be further used for the preparation of montelukast and any of its pharmaceutically acceptable salts, using processes as disclosed in International Application Publication Nos. WO 2008/058118 A2 and WO 2009/117381 A2, which are incorporated herein by reference in their entireties, or using any other processes. Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for purposes of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1 : Preparation of 2-(2-(2-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-(1 ,3- dioxolan-2-yl)ethyl)benzoic acid methyl ester (Formula IV).

2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoic acid methyl ester (75 g), toluene (375 ml_), and p-toluenesulfonic acid monohydrate (7.5 g) are charged into a round bottom flask at 28°C and stirred for 10 minutes. Ethylene glycol (64.3 ml_) is added and the mixture is slowly heated to 110⁰C. Water is removed at 110⁰C and the mass is stirred for 6 hours. The mass is cooled to 30±5°C and stirred for 45 minutes. Water (300 ml_) is charged into the mass at 28°C and stirred for 10 minutes. The organic and aqueous layers are separated. Saturated sodium bicarbonate solution (300 ml_) is added to the organic layer and stirred for 15 minutes. The organic and aqueous layers are separated. Water (300 ml_) is added to the organic layer and stirred for 10 minutes. Solvent is partially distilled from the organic layer at 65°C under reduced pressure, followed by addition of toluene (450 ml_). The resultant organic layer is used for the next stage reaction.

EXAMPLE 2: Preparation of 2-(2-(2-(2-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)- (1 ,3-dioxolan-2-yl)ethyl)phenyl)propan-2-ol (Formula V).

Methylmagnesium chloride (303.5 mL) is added slowly to the organic layer obtained from Example 1 at -5±2°C over 45 minutes, and the mixture is stirred for 8 hours. 30% aqueous ammonium chloride solution (324 mL) is added to the mixture at -3±3°C. The mixture is allowed to reach 25°C over 25 minutes. The organic layer and aqueous layers are separated and the aqueous layer is extracted with toluene (243 mL). The combined organic layer is washed with water (324 mL). The solvent is partially evaporated from the organic layer at 60⁰C under reduced pressure. The organic layer is cooled to 5±5°C and stirred for 20 minutes. Methylmagnesium chloride (182 mL) is added to the organic layer over 25 minutes and stirred for 5/4 hours. 30% aqueous ammonium chloride solution (324 mL) is added at -0±2°C and stirred for 30 minutes. The organic and aqueous layers are separated and the aqueous layer is extracted with toluene (243 mL). The combined organic layer is washed with water (324 ml_) and solvent is distilled at 55°C under reduced pressure, to afford the title compound (Yield: 81 g).

EXAMPLE 3: Preparation of 1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(1- hydroxy-1 -methylethyl)phenyl)propan-1 -one (Formula Vl).

2-(2-(2-(2-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-(1 ,3-dioxolan-2-yl)- ethyl)phenyl)propan-2-ol (81 g) and tetrahydrofuran (405 ml_) are charged into a round bottom flask at 28°C and stirred for 5 minutes. 10% aqueous hydrochloric acid solution (81 ml_) is added at 28°C and stirred for 2 hours, 15 minutes. The formed solid is filtered, washed with tetrahydrofuran (81 ml_) and suction dried. The obtained solid and dichloromethane (648 ml_) are charged into a round bottom flask and stirred for 5 minutes. Saturated sodium bicarbonate solution (405 ml_) is added and the mixture is stirred for 40 minutes. The organic and aqueous layers are separated and the aqueous layer is extracted with dichloromethane (162 ml_). The combined organic layer is washed with water (324 ml_) and solvent is evaporated at 47°C under reduced pressure. A mixture of ethyl acetate and n- hexane (1 :4 by volume, 405 ml_) is added to the residue and stirred for 30 minutes. The solid is filtered, washed with a mixture of ethyl acetate and n-hexane (1 :4 by volume, 81 ml_) and suction dried. The wet solid is dried at 65°C under reduced pressure for 95 minutes to afford the title compound (Yield: 45 g).

EXAMPLE 4: Preparation of 1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(1- hydroxy-1 -methylethyl)phenyl)propan-1 -ol (Formula II).

1 -(3-(2-(7-Chloroquinolin-2-yl)vinyl)phenyl}-3-(2-(1 -hydroxy-1 -methylethyl)- phenyl)propan-1 -one (9 g) and isopropanol (44 mL) are charged into a reaction vessel. The vessel is purged with nitrogen (5*10 bar), then ((R)-XyI- BINAP)((R,R)-DPEN)RuCI₂ (4.4 mg) in deoxygenated isopropanol (1 mL) and potassium t-butoxide (1.0 M in THF, 1.57 mL) are added. The vessel is pressurized to 7.6 bar with hydrogen, then heated to 40⁰C and stirred for 30 minutes. The mixture is cooled to 30⁰C and acetic acid (112 μl) is added. The mass is filtered and the filtrate is concentrated to about 40 mL. Seed product material (~1 mg) is added to the filtrate. Heptane (70 mL) is added and the mixture is stirred for 64 hours. The formed solid is filtered, washed with a mixture of heptane and isopropanol (2:1 by volume, 3*20 ml_), and dried under reduced pressure to afford the title compound (Yield: 7.08 g).

EXAMPLE 5: Preparation of dicyclohexylamine salt of montelukast. 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)- phenyl)-2-propanol, (diol intermediate, 10 g), and toluene (60 ml_) are charged into a round bottom flask, followed by cooling to -12.5±2.5°C. Diisopropylethylamine (5 ml_) is added to the mixture with stirring for 10 minutes. Methanesulfonyl chloride (1.9 ml_) is added drop-wise over 15 minutes and stirred for 95 minutes, n-hexane (150 ml_) is added over 15 minutes at -12.5±2.5°C and stirred for 15 minutes. The mass is warmed to 2.5±2.5°C and stirred for 85 minutes. The formed solid is filtered, washed with pre cooled n-hexane (50 ml_) and suction dried under an inert atmosphere to afford a mesylated compound of Formula VII. Tetrahydrofuran (150 ml_) is charged into a round bottom flask and cooled to -12.5±2.5°C, followed by addition of (i -mercaptomethylcyclopropyl)acetic acid (4.8 g). The mixture is stirred for 5 minutes. n-Butyllithium (40 ml_, 15% w/w) is added drop-wise to the mixture over 25 minutes and further stirred for 15 minutes. The above obtained mesylated compound of Formula VII is added and the mixture stirred at -2±1 °C for 3/4 hours. 10% sodium chloride solution (60 ml_) is added over 15 minutes. The mass is warmed to 27±1 °C and stirred for 1 hour. The organic and aqueous layers are separated. 40% ammonium chloride solution (120 ml_) is added to the organic layer and stirred for 1 hour. The organic and aqueous layers are separated, followed by washing the organic layer with water (2*40 ml_). Solvent is evaporated from the organic layer at 48°C under reduced pressure. To the residue, acetonitrile (20 ml_) is added and distilled completely under reduced pressure. The residue is dissolved in acetonitrile (75 ml_) followed by addition of isopropanol (30 ml_) at about 29°C. Dicyclohexylamine (4.8 g) is added and stirred for about 5 minutes. The mixture is seeded with a dicyclohexylamine salt of montelukast (0.2 g) and stirred for about 15/4 hours. The mass is heated to 70⁰C and stirred for 30 minutes. The mass is then cooled to 30+5⁰C and stirred for 6 hours, 45 minutes. The solid is filtered, washed with acetonitrile (20 ml_) and suction dried. The wet compound is dried at 55°C for about 2¹/4 hours to afford a dicyclohexylamine salt of montelukast (Yield: 4.2 g). EXAMPLE 6: Preparation of dicyclohexylamine salt of montelukast.

2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)- phenyl)-2-propanol (20 g), and dichloromethane (100 ml_) are charged into a round bottom flask and cooled to -14±3°C. Diisopropylethylamine (10.7 ml_) is added to the mixture over 10 minutes and stirred for 15 minutes. Methanesulfonyl chloride (4.06 ml_) is added drop-wise over 25 minutes and stirred for 2^ΛA hours. Pre-cooled n-hexane (300 ml_) is added over 15 minutes and stirred for 15 minutes. The formed solid is filtered and washed with pre-cooled n-hexane (40 ml_) under an inert atmosphere, to afford a mesylated compound of Formula VII.

(i -Mercaptomethyl-cyclopropyl)-acetic acid (10.2 g) and tetrahydrofuran (300 ml_) are charged into a round bottom flask and cooled to -12.5±2.5°C. n- Butyllithium (80 ml_) is added drop-wise over 25 minutes and stirred for 20 minutes. The above obtained mesylated compound of Formula VII is added under an inert atmosphere and stirred at -2.5±2.5°C for 85 minutes. 10% sodium chloride solution (120 ml_) is added over 10 minutes and mass is allowed to reach 25°C in 15 minutes. The organic and aqueous layers are separated. The organic layer and dichloromethane (300 ml_) are charged into a round bottom flask and stirred for 5 minutes. A solution of acetic acid (4 ml_) and water (160 ml_) is added to the mixture and stirred for 15 minutes. The organic and aqueous layers are separated and the organic layer is washed with water (160 ml_).

The organic layer is divided into three parts: Part A containing a 10 g equivalent of the reaction mass; Part B containing a 5 g equivalent of the reaction mass; and Part C containing a 5 g equivalent of the reaction mass. Part A: The organic layer (10 g equivalent of reaction mass) was charged into a round bottom flask and solvent is evaporated at 50⁰C. The residue is dissolved in a mixture of acetonitrile and isopropanol (7:3 by volume, 100 ml_) and stirred for 10 minutes. Dicyclohexylamine (5.66 ml_) is added and stirred for 35 minutes. The mass is slowly heated to 74°C and stirred for 10 minutes. The resulting solution is slowly cooled to 28°C over 30 minutes and stirred for 12 hours. The formed solid is filtered, washed with a mixture of acetonitrile and isopropanol (7:3 by volume, 20 ml_) and suction dried. The wet solid is dried at 62°C under reduced pressure for 6 hours, to afford the dicyclohexylamine salt of montelukast (Yield about 9.4 g). Part B: The organic layer (5 g equivalent of reaction mass) is charged into a round bottom flask and solvent is evaporated at 50⁰C. The residue is dissolved in toluene (25 ml_) and stirred for 5 minutes. Dicyclohexylamine (2.6 ml_) is added and stirred for 25 minutes. The mixture is seeded with a dicyclohexylamine salt of montelukast (0.1 g) and stirred for 3/4 hours. Toluene (15 ml_) is added and stirred for 17¹/2 hours. The formed solid is filtered, washed with toluene (5 ml_) and suction dried. The wet compound is dried at 65°C for about 1^ΛA hours, to afford a dicyclohexylamine salt of montelukast (Yield: 4.2 g).

Part C: The organic layer is utilized for the preparation of a t-butylamine salt of montelukast (Example 8).

EXAMPLE 7: Preparation of montelukast from a dicyclohexylamine salt of montelukast.

A dicyclohexylamine salt of montelukast, obtained from Example 5 or Example 6 (9.0 g), acetonithle (64.3 ml_), and isopropanol (25.7 ml_) are charged into a round bottom flask and heated to 78±2°C. The mixture is allowed to cool to 29±1 °C and is stirred for 13 hours. The formed solid is filtered, washed with acetonithle (12.9 ml_) and isopropanol (5.1 ml_), and suction dried. The wet solid is dried at 65°C for 5 hours under reduced pressure. The solid and dichloromethane (76 ml_) are charged into a round bottom flask and stirred for 5 minutes. A solution of acetic acid (0.9 ml_) and water (38 ml_) is added at 28⁰C and stirred for 10 minutes. The organic and aqueous layers are separated and the organic layer is washed with water (2*30 ml_). Solvent is evaporated from the organic layer at 50⁰C under reduced pressure. The residue is dissolved in methanol (7.6 ml_) and the solution is distilled at 50⁰C under reduced pressure. The residue is dissolved in methanol (15.2 ml_) at 28⁰C and stirred for 70 minutes, then is cooled to 4±1 °C and stirred for 70 minutes. The formed solid is filtered, washed with methanol (7.6 ml_) and suction dried. The wet solid is dried at 5O⁰C for 2 hours, 20 minutes, under reduced pressure, to afford the title compound (yield about 4.7 g). EXAMPLE 8: Preparation of t-butylamine salt of montelukast.

The organic layer obtained as Part C of Example 6 (5 g equivalent of reaction mass) is charged into a round bottom flask and solvent is evaporated at 50⁰C. The residue is dissolved in toluene (40 ml_), then t-butylamine (1.3 ml_) is added and stirred for 10 minutes. The mixture is seeded with a t-butylamine salt of montelukast (0.1 g) and stirred for 3/4 hours. Toluene (15 ml_) is added and stirred for 14¹/2 hours. The formed solid is filtered, washed with toluene (10 ml_), and suction dried. The wet solid is dried at 65°C for about IVi hours, to afford a t- butylamine salt of montelukast (Yield: 4.4 g).

EXAMPLE 9: Preparation of t-butylamine salt of montelukast.

2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)- phenyl)-2-propanol (diol intermediate, 15 g), dichloromethane (52.5 mL), and toluene (37.5 mL) are charged into a round bottom flask and the mixture is cooled to -12.5±2.5°C. Diisopropylethylamine (9.3 mL) is added to the mixture, with stirring, over 15 minutes. Methanesulfonyl chloride (2.8 mL) is added drop-wise over 20 minutes at -15±1⁰C and stirred for 4 hours. n-Hexane (150 mL) is added over 20 minutes at -15±1⁰C and stirred for 45 minutes. The formed solid is filtered, washed with n-hexane (30 mL) and suction dried, to afford a mesylated compound of Formula VII.

Tetrahydrofuran (225 mL) is charged into a round bottom flask and cooled to -12.5±2.5°C, followed by addition of (i -mercaptomethylcyclopropyl)acetic acid (7.2 g). The mixture is stirred for 15 minutes and n-butyllithium (60 mL) is added drop-wise over 45 minutes. The above-obtained mesylated compound of Formula VII is added under an inert atmosphere and the mixture is stirred at -2.5±2.5°C for 2¹/2 hours. 10% sodium chloride solution (90 mL) is added over 10 minutes. The mass is warmed to 28°C and stirred for 30 minutes. The organic and aqueous layers are separated. 40% ammonium chloride solution (300 mL) is added to the organic layer and stirred for 25 minutes. The organic and aqueous layers are separated, followed by washing the organic layer with water (2*60 mL). Solvent is evaporated from the organic layer at 50⁰C under reduced pressure. To the residue, toluene (15 mL) is added and then distilled completely at 58°C. The residue is dissolved in toluene (120 mL) at 28°C. t-Butylamine (4.2 g) is added and stirred for about 10 minutes. The mixture is seeded with a t-butylamine salt of montelukast (0.1 g) and stirred for about 9 hours. n-Hexane (90 ml_) is added over 20 minutes and stirred for 100 minutes. The formed solid is filtered, washed with a mixture of toluene (15 ml_) and n-hexane (15 ml_), and suction dried. The wet solid is dried at 65°C for about 4 hours, 15 minutes to afford a t-butylamine salt of montelukast (Yield: 7.8 g).

EXAMPLE 10: Preparation of t-butylamine salt of montelukast.

2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)- phenyl)-2-propanol (diol intermediate, 75 g), and dichloromethane (450 ml_) are charged into a round bottom flask and stirred for 10 minutes. The mixture is cooled to -12±2°C and stirred for 25 minutes. Diisopropylethylamine (46.5 ml_) is added and stirred for 20 minutes. Methanesulfonyl chloride (14.0 ml_) is added drop-wise over 35 minutes followed by stirring for about 2^ΛA hours. n-Hexane (750 ml_) is added at -12±2°C over 30 minutes and stirred for 80 minutes. The formed solid is filtered, washed with pre-cooled n-hexane (225 ml_) and suction dried to afford the mesylated compound of Formula VII.

Tetrahydrofuran (1050 ml_) is charged into a round bottom flask and cooled to 0⁰C, (i -mercaptomethylcyclopropyl)acetic acid (23.93 g) is added, then n- butyllithium (280 ml_) is added drop-wise over about 40 minutes at -12.5±2.5°C. The mass is stirred at -12.5±2.5°C for about 20 minutes, followed by addition of the above obtained mesylated compound under an inert atmosphere. The mixture is allowed to reach -2±2°C and stirred for 2 hours, 40 minutes. 10% sodium chloride solution (420 ml_) is added at 2.5±2.5°C over 10 minutes and the mass is allowed to reach 20⁰C over 20 minutes. The organic and aqueous layers are separated. 40% ammonium chloride solution (840 ml_) is added to the organic layer and stirred for 15 minutes. The organic and aqueous layers are separated, followed by washing the organic layer with water (2*280 ml_).

227 ml_ of the washed organic layer is charged into a round bottom flask and distilled at 53°C under reduced pressure. Toluene (30 ml_) is added to the residue and solvent is distilled at 51⁰C under reduced pressure. The residue is dissolved in toluene (75 ml_) at 29°C and stirred for 5 minutes. t-Butylamine (3.8 ml_) is added and stirred for 5 minutes. The mixture is seeded with a t-butyl amine salt of montelukast (0.2 g) and stirred for 10 minutes. Toluene (45 ml_) is added at 29°C and stirred for 20 hours, 45 minutes. Hexane (105 ml_) is added to the mass at 29°C over 15 minutes and stirred for 85 minutes. The formed solid is filtered and washed with a mixture of toluene and hexane (1 :1 , 46 ml_). The solid is dried at 55°C for 2^ΛA hours, to afford the t-butylamine salt of montelukast (Yield: 13.5 g).

EXAMPLE 11 : Preparation of montelukast acid.

A t-butylamine salt of montelukast obtained from Example 8, Example 9, or Example 10 (13.0 g) and toluene (130 ml_) are charged into a round bottom flask followed by stirring and heating to 80⁰C for 30 minutes, lsopropanol (3.9 ml_) is added to the solution at 65°C and stirred at 28°C for 15 hours. The precipitated solid is filtered, washed with toluene (26 ml_), and suction dried. The wet solid is dried at 55°C for 2 hours, 40 minutes to afford a pure t-butylamine salt of montelukast (yield: 11.1 g).

The t-butylamine salt (10 g) and dichloromethane (150 ml_) are charged into a round bottom flask and stirred for 10 minutes. A solution of acetic acid (1.3 ml_) and water (80 ml_) is added at 29°C and stirred for 25 minutes. The organic and aqueous layers are separated and the organic layer is washed with water (2^χ80 ml_). The solvent is evaporated from the organic layer at 42°C. The residue is dissolved in methanol (30 ml_) and solvent is distilled at 51⁰C. Methanol (25 ml_) is added to the obtained residue, followed by stirring at 29⁰C for 15 hours. The mass is cooled to 3±1 °C and stirred for 90 minutes. The formed solid is filtered, washed with chilled methanol (20 ml_), and suction dried. The wet solid is dried at 55°C for 2¹/₂ hours, to afford the title compound (Yield: 8.0 g).

EXAMPLE 12: Preparation of montelukast sodium salt.

2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)- phenyl)-2-propanol (25 g) and dichloromethane (125 mL) are charged into a round bottom flask and cooled to -15°C. Diisopropylethylamine (15.5 mL) is added to the suspension at -15°C and stirred for 15 minutes. Methanesulfonyl chloride (4.65 mL) is added drop-wise at -15±2°C over 15 minutes and stirred for 2 hours, 45 minutes. Chilled n-hexane (250 mL) is added at -15±2°C over 15 minutes and stirred for 20 minutes. The formed solid is filtered, washed with chilled n-hexane (50 mL) and suction dried to form a mesylated compound. (I-Mercaptomethyl)cyclopropaneacetonitrile (8.3 g) and N₁N- dimethylfornnannide (125 ml_) are charged into a round bottom flask, cooled to - 15±1 °C and stirred for 15 minutes. n-Butyllithium (50 ml_) is added drop-wise over 30 minutes. The mass is maintained at -15±1 °C for 20 minutes. The mesylated compound prepared above is added and the mass is stirred for 70 minutes. Saturated sodium chloride solution (250 ml_) is added at -15°C. The mass is allowed to reach 27.5±2.5°C and stirred for 40 minutes. Toluene (250 ml_) is added and stirred for 15 minutes. The organic and aqueous layers are separated and the aqueous layer is extracted with toluene (2^χ100 ml_). Organic layers are combined and washed with water (4*300 ml_). The solvent is evaporated from the organic layer at 61 ±1⁰C under reduced pressure. The residue is dissolved in toluene (12.5 ml_) followed by addition of caustic lye (100 ml_). The mass is heated to 111 ±1 °C to remove toluene azotropically. The mass is further heated to 127±2°C and stirred for 15/4 hours. The mass is cooled to 93±2°C and the caustic lye layer is decanted. Pre-heated water (625 ml_) is added and stirred for 1 hour. The mass is cooled to 45°C, the pH is adjusted to 11.3 with acetic acid (10 ml_), and the mass is washed with toluene (4^χ150 ml_) and then cooled to 30±2°C. Toluene (250 ml_) is added and the pH is adjusted to 5.2 with acetic acid (5 ml_). The organic and aqueous layers are separated and the aqueous layer is extracted with toluene (2^χ100 ml_). The combined organic layer is washed with water (5x125 ml_). The organic layer is distilled completely at 65°C under reduced pressure. The residue is dissolved in toluene (25 ml_) at 28°C, stirred for 2 hours, cooled to 3±1 °C, and stirred for 2 hours. The formed solid is filtered, washed with toluene (5 ml_), and suction dried. The wet compound is dried at 60⁰C for 4 hours (Yield: 17.5 g).

The dried solid obtained above and methanol (61.2 ml_) are charged into a round bottom flask and heated to 64°C for 30 minutes. The mixture is allowed to cool to 29±1⁰C and is stirred for 5 hours. The mixture is further cooled to 3±2°C and stirred for 5 hours. The formed solid is filtered, washed with methanol (17.5 ml_), and suction dried. Methanol (43.5 ml_) is added to the wet solid and heated to 64°C for 30 minutes. The mixture is cooled to 29±1 °C and stirred for 5 hours. The mixture is further cooled to 4±1⁰C and stirred for 5 hours. The formed solid is filtered and washed with methanol (17.5 ml_). The wet solid is dried at 65°C for 6 hours (Yield about 12.5 g). The dried solid (12 g) and acetone (120 ml_) aere charged into a round bottom flask, followed by addition of t-butylamine (2.81 ml_) at 28°C. The mixture is seeded with a t-butylamine salt of montelukast (0.1 g) and stirred for 2 hours. Acetone (60 ml_) is added and stirred for 10/4 hours. The formed solid is filtered, washed with acetone (12 ml_), and suction dried. The wet solid is dried at 65°C for 3 hours, to afford the t-butylamine salt of montelukast (Yield: 12.5 g).

The t-butylamine salt of montelukast (12 g) and toluene (66 ml_) are charged into a round bottom flask and heated to 87.5±2.5°C for 15 minutes. Carbon (1.2 g) is added at 85°C. The hot mixture is filtered through a Hyflow (flux- calcined diatomaceous earth) bed under reduced pressure and the bed is washed with preheated toluene (42 ml_). The filtrate is maintained at 28°C for 8 hours. The formed solid is filtered, washed with toluene (6 ml_) and suction dried. The wet solid and toluene (54 ml_) are placed into a round bottom flask, heated, and stirred at 85±2°C for 35 minutes. Carbon (1.2 g) is added at 83°C and stirred for 20 minutes. The hot mixture is filtered through a Hyflow bed and the bed is washed with preheated toluene (42 ml_). The filtrate is maintained at 28°C for 8 hours. The formed solid is filtered, washed with toluene (6 ml_), and suction dried. The wet solid and toluene (54 ml_) are placed into a round bottom flask and heated to 85±3°C. Carbon (1.2 g) is added at 82°C. The hot mixture is filtered through a Hyflow bed under reduced pressure and the bed is washed with preheated toluene (42 ml_). The filtrate is maintained at 28°C for 8/4 hours. The formed solid is filtered, washed with toluene (6 ml_) and suction dried. The wet solid is dried at 65°C for 5 hours, to afford a pure t-butylamine salt of montelukast (Yield: 9.7 g). The dried montelukast t-butylamine salt (9 g) and dichloromethane (90 ml_) are placed into a round bottom flask and stirred for 5 minutes. A solution of water (45 ml_) and acetic acid (1.22 ml_) is added to the suspension at 28°C and stirred for 45 minutes. The organic and aqueous layers are separated and the aqueous layer is extracted with dichloromethane (18 ml_). The combined organic layer is washed with water (5*45 ml_). The organic layer is distilled completely at 50⁰C under reduced pressure. Methanol (18 ml_) is added to the residue and solvent is distilled completely at 50⁰C under reduced pressure. Methanol (45 ml_) is added to the residue and stirred for 10 minutes. A solution of sodium hydroxide (0.54 g) in methanol (45 ml_) is added and stirred for 45 minutes. Carbon (0.9 g) is added and stirred for 15 minutes. The mixture is filtered through a Hyflow bed under reduced pressure and the bed is washed with methanol (18 ml_).The filtrate is distilled completely at 55°C under reduced pressure. The residue is dried at 70⁰C for 2¹/2 hours, to afford montelukast sodium (Yield: 7.4 g).

Claims

CLAIMS:

1. A process for preparing 2-(2-(3(S)-(3-(2-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol, having Formula VII,

Formula VII comprising reacting a diol compound of Formula II,

Formula Il with methanesulfonyl chloride in the presence of a base.

2. The process of claim 1 , wherein a base comprises N₁N- diisopropylethylamine, thethylamine, N-methylmorpholine, N-methylpyrrolidone, or pyridine.

3. The process of claim 1 , wherein a base comprises N₁N- diisopropylethylamine.

4. The process of claim 1 , wherein reacting is conducted in the presence of a solvent comprising dichloromethane, toluene, xylene, ethyl acetate, hexane, heptane, or any mixtures thereof.

5. The process of claim 1 , wherein reacting is conducted in the presence of a solvent comprising dichloromethane, toluene, or a mixture thereof.

6. The process of claim 1 , further comprising isolating the compound having Formula VII, by combining a solution containing the compound with an anti-solvent.

7. The process of claim 6, wherein an anti-solvent comprises hexane, heptane, pentane, cyclohexane, methylcyclohexane, or any mixtures thereof.

8. The process of claim 6, wherein an anti-solvent comprises hexane, heptane, or a mixture thereof.

9. A process for preparing montelukast or a salt thereof, comprising: a) reacting a diol compound of Formula II,

Formula Il with methanesulfonyl chloride in the presence of a base to form 2-(2-(3(S)-(3-(2- (7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2- propanol, having Formula VII; and

Formula VII b) further reacting 2-(2-(3(S)-(3-(2-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol to form montelukast or a salt thereof.

10. The process of claim 9, wherein a base comprises N₁N- diisopropylethylamine, thethylamine, N-methylmorpholine, N-methylpyrrolidone, or pyridine.

11. The process of claim 9, wherein a base comprises N₁N- diisopropylethylamine.

12. The process of claim 9, wherein reacting in a) is conducted in the presence of a solvent comprising dichloromethane, toluene, xylene, ethyl acetate, hexane, heptane, or any mixtures thereof.

13. The process of claim 9, wherein reacting in a) is conducted in the presence of a solvent comprising dichloromethane, toluene, or a mixture thereof.

14. The process of claim 9, wherein the compound having Formula VII is isolated, by combining a solution containing the compound with an anti-solvent.

15. The process of claim 14, wherein an anti-solvent comprises hexane, heptane, pentane, cyclohexane, methylcyclohexane, or any mixtures thereof.

16. The process of claim 14, wherein an anti-solvent comprises hexane, heptane, or a mixture thereof.