The following specification describes the invention and manner in which it is performed

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 CysLT1 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 II 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 II

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 IIa 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 Microbacterium MB5614  to afford Formula IIa.

Formula IIa
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-2-yl)ethenyl]phenyl}-3-[2-(1-hydroxy-1-methylethyl)phenyl]propan-1-ol (hereinafter referred to as the “diol” intermediate) of Formula II 

Formula II
which processes include:
(a) protecting the ketone group of the Formula III 

Formula III
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 VI; and

Formula VI
(d) asymmetrically reducing a compound of Formula VI  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 II
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
Aspects of the present application provide processes for the preparation of montelukast acid and salts thereof.
In embodiments  there are provided processes for preparing a diol intermediate of montelukast  having Formula II 

Formula II
which processes include:
(a) protecting the ketone group of the compound having Formula III 

Formula III
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 VI; and

Formula VI
(d) asymmetrically reducing a compound of Formula VI  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.
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-C6 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  isobutyric 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 dichloride  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 160°C  less than about 140°C  less than about 120°C  less than about 100°C  less than about 80°C  less than about 60°C  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 160°C  less than about 140°C  less than about 120°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  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 60°C  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 100°C  less than about 70°C  less than about 40°C  less than about 20°C  less than about 0°C  less than about -10°C  less than about -20°C  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 60°C  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 VI.
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  isobutyric 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 100°C  less than about 70°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  less than about 0°C  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 150°C  less than about 120°C  less than about 100°C  less than about 60°C  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 VI to afford the compound of Formula II.
Asymmetric reduction of the compound of Formula VI 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 (XI) as shown below. In the structures  Ph indicates a phenyl group  Ts indicates a tosyl group  and Me indicates a methyl group.

Formula VIII (((R)-XYL-BINAP)((R R)-DPEN)RuCl2)

Formula IX

Formula X

Formula XI
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 ((R)-Xyl-BINAP)

Formula XIII ((R R)-DIPEN)

Formula XIV ((R)-DAIPEN)

Formula XV ((R R)-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; triethylamine  tributylamine  N-methylmorpholine  N N-diisopropylethylamine  N-methylpyrrolidine  pyridine  4-(N N-dimethylamino)pyridine  morpholine  imidazole  2-methylimidazole  4-methylimidazole  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-trichloroethane  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 100°C  less than about 80°C  less than about 60°C  less than about 40°C  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 120°C  less than about 100°C  less than about 80°C  less than about 60°C  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.
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 II
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 II may be prepared by a process as disclosed in the present patent application or by any other process. For example  the compound of Formula II 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  tributylamine  N-methylmorpholine  N N-diisopropylethylamine  N-methylpyrrolidone  pyridine  4-(N N-dimethylamino) pyridine  morpholine  imidazole  2-methylimidazole  4-methylimidazole  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 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 0°C  less than about -10°C  less than about -20°C  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 110°C. Water is removed at 110°C 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 60°C 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 5½ 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 VI).
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)-Xyl-BINAP)((R R)-DPEN)RuCl2 (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 40°C and stirred for 30 minutes. The mixture is cooled to 30°C 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 (1-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 3½ 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 15½ hours. The mass is heated to 70°C and stirred for 30 minutes. The mass is then cooled to 30+5°C 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 2½ 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 2½ 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.
(1-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 50°C. 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 50°C. 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 3½ hours. Toluene (15 mL) is added and stirred for 17½ hours. The formed solid is filtered  washed with toluene (5 mL) and suction dried. The wet compound is dried at 65°C for about 7½ 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)  acetonitrile (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 acetonitrile (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 28?C 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 50°C under reduced pressure. The residue is dissolved in methanol (7.6 mL) and the solution is distilled at 50°C under reduced pressure. The residue is dissolved in methanol (15.2 mL) at 28?C 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 50?C 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 50°C. 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 3½ hours. Toluene (15 mL) is added and stirred for 14½ hours. The formed solid is filtered  washed with toluene (10 mL)  and suction dried. The wet solid is dried at 65°C for about 7½ 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±1?C and stirred for 4 hours. n-Hexane (150 mL) is added over 20 minutes at -15±1°C 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 (1-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 2½ 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 50°C 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 2½ 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 0°C  (1-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 20°C 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 51°C 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 2½ 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 80°C for 30 minutes. Isopropanol (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 (2×80 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 51°C. Methanol (25 mL) is added to the obtained residue  followed by stirring at 29?C 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 2½ 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.
(1-Mercaptomethyl)cyclopropaneacetonitrile (8.3 g) and N N-dimethylformamide (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 (2×100 mL). Organic layers are combined and washed with water (4×300 mL). The solvent is evaporated from the organic layer at 61±1°C 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 15½ 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 (4×150 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 (2×100 mL). The combined organic layer is washed with water (5×125 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 60°C 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±1°C 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±1°C 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 10½ 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 8½ 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 50°C under reduced pressure. Methanol (18 mL) is added to the residue and solvent is distilled completely at 50°C 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 70°C for 2½ hours  to afford montelukast sodium (Yield: 7.4 g).

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 II
with methanesulfonyl chloride in the presence of a base.
2. The process of claim 1  wherein a base comprises N N-diisopropylethylamine  triethylamine  N-methylmorpholine  N-methylpyrrolidone  or pyridine.
3. The process of claim 1  wherein a base comprises N N-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 II
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 N N-diisopropylethylamine  triethylamine  N-methylmorpholine  N-methylpyrrolidone  or pyridine.
11. The process of claim 9  wherein a base comprises N N-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.