FIELD OF INVENTION:

Particularly, the present invention provides new intermediates of Montelukast sodium, preparation thereof and improved process of manufacturing of Montelukast sodium and its known intermediates.

BACKGROUND OF THE INVENTION:

Chemically Montelukast sodium is known as 1[[[( R ) -l-[3-[(lE)-2-(7-Chloro-2-quinolinyl) etheny]phenyl] 3-[2-(l-hydroxy- 1-methylethyl) phenylpropyl]thio]methyl] cyclopropane acetic acid sodium salt of formula (A).

Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useful as anti-asthmatic, anti-allergic, anti-inflammatory, cytoprotective agent and hence useful in the treatment of asthma, angina, cerebral spasm, glomerular nephritis, hepatic, end toxemia, uveitis and allograft rejection.

European patent 480717 discloses Montelukast sodium alongwith other related compounds and the methods for their preparation. The reported method of synthesis proceeds through corresponding Methyl 2-[(3S)-[3-{(2E)-(7-Chloro-2-quinolinyl) etheny]phenyl] 3-hydroxypropyl] benzoate ans involves coupling methyl -l-(mercaptomethyl) cyclopropane acetate with in-situ generated mesylate. The methyl ester of Montelukast is hydrolysed to free acids and finally converted to sodium salt. The process is not particularly suitable for large scale production because it requires chromatographic separations and low product yields.

US patent 5,565,473 discloses a synthetic process wherein the compound is obtained as oil that is then dissolved in water and freeze dried. The preparation method of this patent can be altered to allow for the preparation of Montelukast related compounds as J. Org.
Chem., 58: 3731-3735 (1993). The process requires tedious chromatographic purification of methyl ester intermediate and/ or the final product. Further the yield of the product is quite low. Therefore this process is not suitable for large scale production.

US patent 5,614,632 discloses amorphous hygroscopic sodium salts unsuitable for pharmaceutical formulation and provides process for crystalline salts of sodium and DCHA.

US patent 0107612 discloses the preparation of other amine salts of Montelukast for purification purpose but leading to increased number of steps and low yields.

WO 2006/ 008751 and US 2005/ 0107612 describes the process using 3-halopropyl derivative in place of 3-hydroxy propyl, but chlorination step involved exposes aliphatic double bond leading to chloro impurity in API which is an unspecified impurity as per European and Indian Pharmacopoeia. US 2005/0234241 used cyclopropyl nitrile and amides derivatives in coupling step in place of carboxylic acid derivatives followed by hydrolysis to get Montelukast free acid.

Despite of many known processes disclosed, each suffers from one or the other problems, leading to the requirement of further improved and efficient process.

Scheme 1:

Stage I

7-Chloroquinaldine Isophthaladehyde [E]-3-[2-(7- chloro-2-quinolinyl)
ethenyl] Benzaldehyde [CMC-1]

Stage II

[E]-3-[2-(7- chloro-2-quinolinyl) [E]-l-[3-[2-(7- chloro-2-quinolinyl)
ethenyl] Benzaldehyde [CMC-1] ethenyl] phenyl] Ethanol [CMC-2]

Stage III

[E]-l-[3-[2-(7 chloro-2- Methyl-2-Iodo Methyl-E-3-[3-[2-(7- chloro-2-
quinolinyl) ethenyl] phenyl] benzoate quinolinyl) ethenyl] phenyl] -3-oxo-
Ethanol [GMC-2] propyl]phenyl] Propanoate [CMC-3]

SCHEME 3:

OBJECT OF THE INVENTION

The main object of the present invention is to provide improved process of Montelukast sodium, new intermediates and also new polymorphs leading to improved yields and quality, meeting international standards oflCH and of Pharmacopoeia grade.

Other object of the present invention is to provide a process for preparing new intermediates and new polymorphs and also processes of the existing key intermediates in high purity and high yield.

Another object of the present invention is to provide a process that is advantageous to operate, eco- friendly, commercially viable and cost-effective.

Still another object of the present invention is to provide a process for preparing novel crystalline and anhydrous form of one of the key intermediate avoiding dehydration step in subsequent operation.

SUMMARY OF THE INVENTION

The prime aspect of the invention is to deliver most economic, industrially viable process meeting international standards of quality. It helps in reducing number of steps, less number of plant equipments and increased production capacities. It can be summarized below:

Scheme 1: The present invention provides a process for preparing key intermediate, [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-qumolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol [CMC-5] comprising following steps:

a) reacting 7-chloroquinaldine with isophthaldehyde in presence of acetic anhydride or acetic acid in reaction conditions minimizing formation of undesired dimmer/ disubstituted impurity

b) reacting step a) product with vinyl magnesium bromide in organic solvent at cryogenic conditions to avoid impurity formation

c) reacting step b) product without tedious aqueous work up and isolation with methyl 2-iodo benzoate in triethylamine and minimum amount of solvent in presence of palladium acetate

d) reacting step c) product with DIP chloride in organic solvents at elevated temperatures to accelerate the reaction and to yield anhydrous polymorphic form 2

e) reacting step d) product with methyl magnesium chloride in traditional reaction conditions

Scheme 2: The present invention provides a process for preparing Montelukast and its salts comprising following steps:

a) reacting Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl] Benzoate with methane sulfonyl chloride to get its mesylate or with p-toluene sulfonyl chloride to get its tosylate

b) reacting mesylate or tosylate with1-mercaptomethyl cyclopropane acetonitrile/acetamide/ acetic acid/ acetate ester to get corresponding condensation product

c) reacting condensation product with methyl magnesium halide to get tertiary alcohol derivative

d) optionally hydrolyzing tertiary alcohol followed by amine salts preparation to get Montelukast amine salt

e) converting amine salts to Montelukast free acid or in-situ to Montelukast sodium.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be described in detail as given below:

Scheme 1: The present invention provides a process for preparing key intermediate, [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol [CMC-5] comprising following steps:

a) reacting 7-chloroquinaldine with isophthaldehyde in molar excess of isophthaldehyde in presence of acetic anhydride or acetic acid in reaction conditions minimizing formation of undesired dimmer/ disubstituted impurity. Molar excess is 1.1-3, precisely 1.1-2, more precisely 1.1-1.8 and even most precisely 1.1-1.5, anti-solvent is added slowly to reaction mass at high temperature, cooling to RT and filter the slurry. Cake is treated with aqueous solution of sodium meta bisulfite or sodium bi sulfite to extract out excess isophthaldehyde. Optinally cake is extracted with anti-solvent. Excess isophthaldehyde is recovered from bisulfite solution adduct or from anti-solvent solution. Anti-solvent may be water, methanol, ethyl acetate, toluene or a mixture thereof.

b) reacting step a) product with vinyl magnesium bromide in organic solvent at cryogenic conditions to avoid impurity formation. Organic solvent may be toluene, THF, MeTHF or a mixture thereof. Cryogenic temperature may be -55 to -80 deg and more accurately -60 to -75 deg

c) step b) reaction mass is quenched with NH4C1 or other acidic solution and as such is concentrated under vacuum to get residue. Residue is diluted with triethylamine and optionally with 1-3 volumes of organic solvent. Organic solvent may be toluene, THF, MeTHF, acetonitrile, methanol or a mixture therof. Diluted mass is reacted with methyl-2-iodo benzoate or 2-iodo benzoic acid in presence of palladium acetate under reflux condition. After reaction completion, mass is concentrated under vacuum to remove excess solvent and triethylamine. Product is crystallized in methanol-water mixture, acetonitrile or acetonitrile-water mixture.

d) reacting step c) product with DIP chloride in organic sovents at elevated temperatures to accelerate the reaction and to yield anhydrous polymorphic form 2. Which converts to hydrate in aqueous based recrystallization in organic solvents. Organic solvents may be toluene, dichloromethane, THF, methanol or a mixture thereof. Elevated temperature may be 40 deg to reflux temperature and more preferably 5 deg below to reflux temperature of solvents.

e) reacting step d) product with methyl magnesium chloride in traditional reaction conditions but taking optionally polymorphic form 2.

Scheme 2: The present invention provides a process for preparing Montelukast and its salts comprising following steps:

a) reacting Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl] Benzoate with methane sulfonyl chloride in suitable organic solvent at suitable temperature to get its mesylate or with p-toluene sulfonyl chloride in presence of suitable base to get its tosylate. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyl pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; nitrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo romethane etc. and a mixture thereof. Suitable base may be trithyl amine, diisopropylethylamine. Suitable temperature may be -50 to +50 deg, preferably -40 to 10 deg and more preferably-30 to-10 deg.

b) reacting mesylate or tosylate with 1-mercaptomethyl cyclopropane acetonitrile/ 1-mercaptomethyl cyclopropane acetamide/ 1-mercaptomethyl cyclopropane acetic acid/ 1-mercaptomethyl cyclopropane acetate ester to get corresponding condensation product, in presence of suitable base in a suitable solvent. Suitable base may be butyl lithium, sodium hydride, potassium hydride, potassium-t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyl pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; nitrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo romethane etc. and a mixture thereof.

c) reacting condensation product with methyl magnesium halide to get tertiary alcohol derivative. Halide may be chloride or bromide. optionally hydrolyzing tertiary alcohol derivative in basic conditions in presence of suitable solvents followed by suitable amine salts preparation to get Montelukast amine salt. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyl pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; nitrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo romethane etc. and a mixture thereof. Suitable amines may be ammonia, benzyl amine, dicyclohexyl amine, Propylamine. 2-Propylamine. Methylamine. Dimethylamine. Trimethylamine. Aniline. 4-Methylaniline. 2-Nitroaniline. 3-Nitroaniline. 4-Nitroaniline. 2,6-Dimethylmorpholine, 2,6-Xylidine, 1,3-Diaminopropane (1,3 DAP), 2-Phenylethylamine etc.

d) converting amine salts to Montelukast sodium in-situ extracting Montelukast free acid in suitable organic solvent from acidic water; Organic solvents may be toluene, ethyl acetate, dichloromethane. Contacting the solution with sodium hydroxide solution in water or alcohol (methanol or ethanol), concentrating resultant solution. Re-dissolving the mass in suitable solvent and precipitating the product by pouring this solution in suitable anti-solvent. Suitable solvents may be toluene, ethyl acetate, dichloromethane, methanol etc. and suitable anti-solvent may be heptane, hexane, acetonitrile, disopropyl ether, methyl-t-butyl ether.

The invention can further be described by taking following examples which may not be considered limiting to the invention.

Example 1: Preparation of 3-[2-(7- chloro-2-quinoIinyl) ethenyl] BenzaIdehyde[CMC-l]

A solution of 7-chloroquinaldine (100 g) & isophthaldehyde (150 g) in acetic anhydride (80 g) was heated at 75-125 deg centigrade to get absence of 7-chloroquinaldine in nearly 7 hrs. 400 ml water was slowly added at > 60 deg and res ultant mass was cooled to RT and stirred to get uniform slurry. Slurry was filtered and washed with water to remove excess acid. Cake was heated with 400 ml methanol to 60 deg followed by cooling to 15-20 deg. Slurry was filtered and washed with 300 ml methanol. Cake was dried to get 142 g CMC-1 which was containing < 2% dimerised product.
Methanol filtrate was concentrated to get residue having isophthaldehyde. Residue was used as such for next reaction compensating isophthaldehyde quantity.

Example 2: Preparation of 3-[2-(7- chloro-2-quinoIinyl) ethenyl] BenzaIdehyde[CMC-l]

A solution of 7-chloroquinaldine (100 g) & isophthaldehyde (120 g) in acetic anhydride (90 g) was heated at 75-125 deg centigrade to get absence of 7-chloroquinaldine in nearly 7 hrs. 400 ml water was slowly added at > 60 deg and res ultant mass was cooled to RT and stirred to get uniform slurry. Slurry was filtered and washed with water to remove excess acid. Cake was heated with 400 ml methanol to 60 deg followed by cooling to 15-20 deg. Slurry was filtered and washed with 300 ml methanol. Cake was dried to get 139 g CMC-1 which was containing < 10% dimerised product.

Methanol filtrate was concentrated to get residue having isophthaldehyde. Residue was suspended in water having 60 gram sodium bisulfite. Aqueous solution was washed with 100 ml toluene. Aqueous layer was acidified to precipitate out isophthaldehyde, which was isolated after filtration, water washing, and drying.

Example 3: Preparation of 3-[2-(7- chIoro-2-quinoIinyl) ethenyl] BenzaIdehyde[CMC-l]

A solution of 7-chloroquinaldine (100 g) & isophthaldehyde (200 g) in acetic anhydride (120 g) was heated at 75-125 deg centigrade to get absence of 7-chloroquinaldine in nearly 7 hrs. 400 ml water was slowly added at > 60 deg and res ultant mass was cooled to RT and stirred to get uniform slurry. Slurry was filtered and washed with water to remove excess acid. Cake was heated with 400 ml methanol to 60 deg followed by cooling to 15-20 deg. Slurry was filtered and washed with 300 ml methanol. Cake was dried to get 151 g CMC-1 which was containing < 1% dimerised product.

Methanol filtrate was concentrated to get residue having isophthaldehyde. Residue was suspended in water having 110 gram sodium metabisulfite. Aqueous solution was washed with 100 ml ethyl acetate. Aqueous layer was basified to precipitate out isophthaldehyde, which was isolated after filtration, water washing, and drying.

Example 4: Preparation of 3-[2-(7- chloro-2-quinolinyI) ethenyl] Benzaldehyde[CMC-l]

A solution of 7-chloroquinaldine (100 g) & isophthaldehyde (150 g) in acetic acid (100 g) was heated at 75-125 deg centigrade to get absence of 7-chloroquinaldine in nearly 7 hrs. 400 ml water was slowly added at > 60 deg arid res ultant mass was cooled to RT and stirred to get uniform slurry. Slurry was filtered and washed with water to remove excess acid. Cake was heated with 400 ml methanol to 60 deg followed by cooling to 15-20 deg. Slurry was filtered and washed with 300 ml methanol. Cake was dried to get 142 g CMC-1 which was containing < 2% dimerised product.

Methanol filtrate was concentrated to get residue having isophthaldehyde. Residue was used as such for next reaction compensating isophthaldehyde quantity.

Example 5: Preparation of 1-| 3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] Ethanol [CMC-. 2]

CMC-1 (100 gm) was added to 400 ml toluene and mass was cooled to 70 deg. 450 gm vinyl magnesium bromide was added slowly at -60 to -75 deg. Reaction mass was stirred at same temperature to get absence of CMC-1. 5% HC1 (50 ml) was slowly added to quench the reaction mass. Vacuum was applied to the mass to remove water and THF-Toluene mix to get CMC-2 as residue.

Example 6: Preparation of Methyl-E-3-[3-[2-(7- chloro-2-quinoIinyl) ethenyl] phenyl] -3-oxo-propyl]phenyl] Propanoate [CMC-3]

CMC-2 residue from example 5 was refluxed with triethylamine (150 ml) in presence of methyl-2-iodobenzoate (90 g) and 0.2 g palladium acetate to get absence of CMC-2. Vacuum is applied to recover un reacted triethyl amine. 300 ml methanol is added to the mass at 60 deg. 75 ml water is slowly added to get crystallization at 15-20 deg. Slurry is filtered and cake is washed with water. Cake is dried to give 130 g CMC-3.

Example 7: Preparation of Methyl-E-3-[3-[2-(7- chloro-2-quinoIinyl) ethenyl] phenyl] -3-oxo-propyl] phenyl] Propanoate [CMC-3]

CMC-2 residue from example 5 was refluxed with toluene (200 ml) and triethylamine (150 ml) in presence of methyl-2-iodobenzoate (90 g) and 0.3 g palladium acetate to get absence of CMC-2. Vacuum is applied to recover toluene and un reacted tri ethyl amine. 300 ml methanol is added at 60 deg. 75 ml water is slowly added to get crystallization at 15-20 deg. Slurry is filtered and cake is washed with water followed by washing with acetonitrile. Cake is dried to give 122 g CMC-3.

Example 8: Preparation of Methyl-E-3-]3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-oxo-propyl] phenyl] Propanoate [CMC-3]

CMC-2 residue from example 5 was refluxed with acetonitrile (300 ml) and triethylamine (100 ml) in presence of methyl-2-iodobenzoate (100 g) and 0.3 g palladium acetate to get absence of CMC-2. Reaction mass is further diluted with 200 ml acetonitrile and is cooled to 0-5 deg. to get crystallization at 0-5 deg. Slurry is filtered and cake is washed with acetonitrile followed by water. Cake is dried to give 118 g CMC-3.

Example 9:
A Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinoIinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate anhydrate, polymorphic form 2 [CMC-4]

CMC 3 (100 g) is added to 500 ml of toluene and 10 ml triethylamine. Mass is heated to reflux and 60-65%, 175 g (-) Diisopinocampheyl chloroboarne is added to reaction mass. Reaction mass is stirred at reflux for 1-2 hrs to get reaction completion. Mass is cooled to RT and is quenched with 100 ml ammonia solution. 500 ml hexane is added and stirring is continued for 1 hr to get crystallization at 0-5 deg. Mass is filtered and washed with 100 ml hexane followed by water washing of the cake. Wet Cake is dried to get 105 g target compound as anhydrate. Purification: Wet cake, is dissolved in 1 ltr methanol at reflux and charcolised. Filtrate is diluted with 10 ml tri ethylamine and is chilled to 0-5 deg. to get complete crystallization. Slurry is filtered and washed with 25 ml chilled methanol. Cake is dried to get 88 g target compound as anhydrate.

B: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chIoro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate hydrate [CMC-4]

Wet cake, 105 g from step A above, is dissolved in 1 ltr methanol at reflux and charcolised. Filtrate is diluted with water to get complete crystallization at 0-5 deg. Slurry is filtered and washed with water. Cake is dried to get 94 g target compound as hydrate.

Example 10
A: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate anhydrate, polymorphic form 2 [CMC-4]

CMC 3 (100 g) is added to 500 ml of toluene and 10 ml triethylamine. Mass is heated to 60 deg and 60-65%, 180 g (-) Diisopinocampheyl chloroboarne is added to reaction mass. Reaction mass is stirred at 60-70 deg for 2-3 hrs to get reaction completion. Mass is cooled to RT and is quenched with 100 ml ammonia solution. 500 ml hexane is added and stirring is continued for 1 hr to get crystallization at 0-5 deg. Mass is filtered and washed with 100 ml hexane followed by water washing of the cake. Wet Cake is dried to get 101 g target compound as anhydrate. Purification: Wet cake, is dissolved in 11tr methanol at reflux and charcolised. Filtrate is diluted with 10 ml tri ethylamine and is chilled to 0-5 deg. to get complete crystallization. Slurry is filtered and washed with 25 ml chilled methanol. Cake is dried to get 85 g target compound as anhydrate.

B: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate hydrate [CMC-4]

Wet cake, 101 g from step A above, is dissolved in 1 ltr methanol at reflux and charcolised. Filtrate is diluted with water to get complete crystallization at 0-5 deg. Slurry is filtered and washed with water. Cake is dried to get 92 g target compound as hydrate.

Example 11 A: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate anhydrate, polymorphic form 2 [CMC-4]

CMC 3 (100 g) is added to 500 ml of dichlorb methane and 10 ml triethylamine. Mass is heated to reflux and 60-65%, 178 g (-) Diisopinocampheyl chloroboarne is added to reaction mass. Reaction mass is stirred at reflux 1-3 hrs to get reaction completion. 20 ml ammonia solution is added and solvent is removed through vacuum to get residual mass and is cooled to RT. Mass is diluted with 100 ml ammonia solution. 500 ml hexane is added and stirring is continued for 1 hr to get crystallization at 0-5 deg. Mass is filtered and washed with 100 ml hexane followed by water washing of the cake. Wet Cake is dried to get 103 g target compound as anhydrate.

Purification: Wet cake, is dissolved in 700 ml methanol at reflux and charcolised. Filtrate is diluted with 10 ml tri ethylamine and is chilled to 0-5 deg. to get complete crystallization. Slurry is filtered and washed with 25 ml chilled methanol. Cake is dried to get 84 g target compound as anhydrate.

B: Preparation of Methyl-E-2-[3(S)-l3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl]benzoate hydrate [CMC-4]

Wet cake 103 g from step A above, is dissolved in 700 ml methanol at reflux and charcolised. Filtrate is diluted with water to get complete crystallization at 0-5 deg. Slurry is filtered and washed with water. Cake is dried to get 93 g target compound as hydrate.

Example 12: A: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl] benzoate anhydrate, polymorphic form 2 [CMC-4]

CMC 3 (100 g) is added to 500 ml of THF and 10 ml triethylamine. Mass is heated to reflux and 60-65%, 180 g (-) Diisopinocampheyl chloroboarne is added to reaction mass. Reaction mass is stirred at reflux for 2-3 hrs to get reaction completion. Mass is cooled to RT and is quenched with 100 ml ammonia solution. 500 ml hexane is added and stirring is continued for 1 hr to get crystallization at 0-5 deg. Mass is filtered and washed with 100 ml hexane followed by water washing of the cake. Wet Cake is dried to get 108 g target compound as anhydrate. Purification: Wet cake, is dissolved in 1 ltr methanol at reflux and charcolised. Filtrate is diluted with 10 ml tri ethylamine and is chilled to 0-5 deg. to get complete crystallization. Slurry is filtered and washed with 25 ml chilled methanol. Cake is dried to get 87 g target compound as anhydrate.

B: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chIoro-2-quinolinyl) ethenyl] phenyl] -3-hydroxypropyl] benzoate hydrate [CMC-4]

Wet cake, 108 g from step A above, is dissolved in 1 ltr methanol at reflux and charcolised. Filtrate is diluted with water to get complete crystallization at 0-5 deg. Slurry is filtered and washed with water. Cake is dried to get 92 g target compound as hydrate.

Example 13: Preparation of [(S)-(E)-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-hydroxypropyl]-phenyI]-2-propanol [CMC-5]

CMC 4 anhydrate (100 g) diluted with 300 ml toluene is added drop wise to 400 ml, 3M solution of methyl magnesium chloride in THF and diluted with 200 ml toluene cooled at -5 to -10 deg. Stirring is continued till CMC 4 content less than 5%. Mass is quenched by adding 1 ltr, 10% acetic acid solution below 15 deg. Layers are separated, aqueous layer is re extracted with 200 ml toluene, combined toluene layers are washed with 1 ltr 30% sodium bicarbonate solution. Washed organic layer is partially distilled azeotropically to remove moisture content. Mass is cooled to -5 to -10 deg and 200 ml, 3M solution of methyl magnesium chloride is added slowly. Stirring is continued for 3-4 hrs and work up is repeated as above to get washed organic layer. Toluene layer is charcolised at 60-70 deg and is concentrated to leave behind 200 ml residue. 50 ml hexane is slowly added at 40 deg and mass is cooled slowly to 15-20 deg. Slurry is stirred for 2-3 hrs and filtered followed by washing with toluene-hexane mixture and hexane. Cake was dried to give 75g dried product.

On requirement product can be recrystallized in toluene-hexane.

Example 14 A: Preparation of Methyl-E-2-[3(S)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-methanesulfonyloxypropyl]benzoate [MS-1]

CMC 4, 100 g (0.218 mol) is added to 200 ml of toluene and 400 ml acetonitrile mixture and stirred to get clear solution under N2. Diisopropylethylamine (0.25 mol) is added and solution is cooled to -15 deg. Methane sulfonyl chloride (0.22 mol) diluted with 200 ml acetonitrile is added at -1.0 to -20 deg to the reaction mass. On requirement reaction mass is seeded with CMC 4/ MS 1 or MS 2. Mass is aged for 2-4 hrs and is filtered. Cake is washed with chilled acetonitrile followed by hexane and packed under N2.

Example 15: Preparation of 2-[l-[l(R>[3-[2-(7-chloro-2-quinoIinyl) ethenyl] phenyl] -3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyljcyclopropaneacetic acid [MS-2]

Sodium hydride (0.55 mol) is suspended in 300 ml DMF, cooled to -5 to -10 deg u/N2 atm. A solution of 1-mercaptomethyl cyclopropane acetic acid (0.26 mol) in 150 ml DMF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (500 ml) containing title compound which is used as such for next step.

Example 16: Preparation of 2-[l-[l(R)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetic acid benzylamine salt [MS-3A]

Sodium hydride (0.55 mol) is suspended in 300 ml THF, cooled to -5 to -10 deg u/N2 atm. A solution of 1-mercaptomethyl cyclopropane acetic acid (0.26 mol) in 150 ml THF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (500 ml). Benzylamine (0.22 mol) is added slowly to concentrated mass at RT. Mass is stirred to get crystallization. Slurry is diluted with 500 ml hexane, chilled to 0-5 deg, filtered and washed with hexane.

Example 17: Preparation of 2-[l-[l(R-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetic acid [MS-2]

MS-3A above is suspended in 1:1 (1000 ml) water-toluene mixture. pH is made acidic (5-6) by adding acetic acid. Layers are separated and aqueous layer is re extracted with 100 ml toluene.
Combined organic layer is washed with water and is concentrated under vacuum to a mass (500 ml) containing title compound which is used as such for next step.

Example 18: Preparation of 2-[l-ll(R)-[3-[2-(7-chloro-2-quinoIinyl) ethenyl] phenyl]-3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetic acid benzylamine salt [MS-3B]

Sodium hydride (0.55 mol) is suspended in 300 ml THF, cooled to -5 to -10 deg u/N2 arm. A solution of 1-mercaptomethyl cyclopropane acetic acid (0.26 mol) in 150 ml THF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 11tr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (500 ml). Ammonia (0:22 mol) is purged slowly to concentrated mass at RT. Mass is stirred to get crystallization. Slurry is diluted with 500 ml hexane, chilled to 0-5 deg, filtered and washed with hexane.

Example 19: Preparation of 2-[l-[l(R)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-12-(methoxycarbonyl) phenyl] propylsulfanyImethyl]cycIopropaneacetic acid [MS-2]

MS-3B above is suspended in 1:1 (1000 ml) water-toluene mixture. pH is made acidic (5-6) by adding acetic acid. Layers are separated and aqueous layer is re extracted with 100 ml toluene. Combined organic layer is washed with water and is concentrated under vacuum to a mass (500 ml) containing title compound which is used as such for next step.

Example 20: Preparation of 2-[l-[l(R)-]3-[2-(7- chIoro-2-quinolinyl) ethenyl] phenyl] -3-]2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetic acid [MS-2]

Potassium hydroxide (0.55 mol) is suspended in 300 ml DMF, cooled to -5 to -10 deg u/N2 arm. A solution of 1-mercaptomethyl cyclopropane acetic acid (0.26 mol) in 150 ml DMF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (500 ml) containing title compound which is used as such for next step.

Example 21: Preparation of 2-[l-[l(R)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(methoxycarbonyl) phenyl] propylsulfanyImethyl]cyclopropaneacetonitrile [MS-2A]

Potassium hydroxide (0.55 mol) is suspended in 300 ml DMF, cooled to -5 to -10 deg u/N2 arm. A solution of 1-mercaptomethyl cyclopropane acetonitrile (0.26 mol) in 150 ml DMF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (200 ml) containing title compound which is used as such for next step.

Example 22: Preparation of l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3[2-(l-hydroxy-l-methylethyl) phenyl propyl] thio] methyl cyclopropane acetic acid dicyclohexylamine salt, DCHA Salt [MS-3]

MS-2A mass (200 ml) as obtained from Example 17 is added to 400 ml, 30% caustic solution. Refluxing is continued to get absence of MS-2A. Product is extracted in toluene at acidic pH. Toluene layer is washed and dried and concentrated azeotropically to a volume of 500 ml. It is added drop wise to 400 ml, 3M solution of of methyl magnesium chloride in THF and diluted with 200 ml toluene cooled at -5 to -10 deg. Stirring is continued till MS-2 content less than 5%. Mass is quenched by adding lltr, 10% acetic acid solution below 15 deg. Layers are separated, aqueous layer is re extracted with 200 ml toluene, combined toluene layers are washed with lltr 30% sodium bicarbonate solution. Washed organic layer is partially distilled azeotropically to remove moisture content. Mass is cooled to -5 to -10 deg and 200 ml, 3M solution of methyl magnesium chloride is added slowly. Stirring is continued for 3-4 hrs and work up is repeated as above to get washed organic layer. Toluene layer is charcolised at 60-70 deg and is concentrated to leave behind 200 ml residue. Dicyclohexylamine (0.22 mol) diluted with 200 ml toluene is added slowly at RT. Mass is seeded to get effective crystallization. 800 ml hexane is slowly added at 40 deg and mass is cooled slowly to 15-20 deg. Slurry is stirred for 2-3 hrs and filtered followed by washing with toluene-hexane mixture and hexane. Cake was dried to give 80g dried product. On requirement product can be recrystallized in toluene-hexane.

Example 23: Preparation of 2-[1-[l(R)-[3-12-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetonitrile [MS-2B]

Potassium hydroxide (0.55 mol) is suspended in 300 ml DMF, cooled to -5 to -10 deg u/N2 atm. A solution of 1-mercaptomethyl cyclopropane acetamide (0.26 mol) in 150 ml DMF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (200 ml) containing title compound which is used as such for next step.

Example 24: Preparation of l-[[[(lR)-l-[3-[(1E)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3[2-(l-hydroxy-l-methylethyl) phenyl propyl] thio] methyl cyclopropane acetic acid dicyclohexylamine salt, DCHA Salt [MS-3]

MS-2B mass (200 ml) as obtained from Example 17 is added to 400 ml, 30% caustic solution. Refluxing is continued to get absence of MS-2B. Product is extracted in toluene at acidic pH. Toluene layer is washed and dried and concentrated azeotropically to a volume of 500 ml. It is added drop wise to 400 ml, 3M solution of of methyl magnesium chloride in THF and diluted with 200 ml toluene cooled at -5 to -10 deg. Stirring is continued till MS-2 content less than 5%. Mass is quenched by adding lltr, 10% acetic acid solution below 15 deg. Layers are separated, aqueous layer is re extracted with 200 ml toluene, combined toluene layers are washed with lltr 30% sodium bicarbonate solution. Washed organic layer is partially distilled azeotropically to remove moisture content. Mass is cooled to -5 to -10 deg and 200 ml, 3M solution of methyl magnesium chloride is added slowly. Stirring is continued for 3-4 hrs and work up is repeated as above to get washed organic layer. Toluene layer is charcolised at 60-70 deg and is concentrated to leave behind 200 ml residue. Dicyclohexylamine (0.22 mol) diluted with 200 ml toluene is added slowly at RT. Mass is seeded to get effective crystallization. 800 ml hexane is slowly added at 40 deg and mass is cooled slowly to 15-20 deg. Slurry is stirred for 2-3 hrs and filtered followed by washing with toluene-hexane mixture and hexane. Cake was dried to give 80g dried product. On requirement product can be recrystallized in toluene-hexane.

Example 25: Preparation of 2-[l-[l(R)-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(methoxycarbonyl) phenyl] propylsulfanylmethyl]cyclopropaneacetic acid [MS-2]

Potassium hydroxide (0.55 mol) is suspended in 300 ml DMF, cooled to -5 to -10 deg u/N2 arm. A solution of 1-mercaptomethyl cyclopropane acetic acid (0.26 mol) in 150 ml DMF is added slowly at -5 to -10 deg. MS-1 from example 14 is added lot wise to above mass at -5 to -10 deg. Mass is stirred overnight to get reaction completion at same temperature. Mass is diluted with 1 ltr toluene and quenched adding 1 ltr water. pH is adjusted to 7 with 25% tartaric acid solution (100 ml). After layer separation aqueous layer is extracted with 1 ltr toluene. Combined organic layer is washed with water, dried over sodium sulfate and charcolised at 40 deg. Organic layer is concentrated under vacuum to a mass (500 ml) containing title compound which is used as such for next step.

Example 26: Preparation of l-[{[(lR)-l-[3-[(lE)-2-(7- chloro-2-quinolinyl) ethenyl] phenyl]-3[2-(l-hydroxy-l-methylethyl) phenyl propyl] thio] methyl cyclopropane acetic acid dicyclohexylamine salt, DCHA Salt [MS-3]

MS-2 solution (500 ml) as obtained from Example 16 is added drop wise to 400 ml, 3M solution of methyl magnesium chloride in THF and diluted with 200 ml toluene cooled at -5 to -10 deg. Stirring is continued till MS-2 content less than 5%. Mass is quenched by adding 11tr, 10% acetic acid solution below 15 deg. Layers are separated, aqueous layer is re extracted with 200 ml toluene, combined toluene layers are washed with 11tr 30% sodium bicarbonate solution. Washed organic layer is partially distilled azeotropically to remove moisture content. Mass is cooled to -5 to -10 deg and 200 ml, 3M solution of methyl magnesium chloride is added slowly. Stirring is continued for 3-4 hrs and work up is repeated as above to get washed organic layer. Toluene layer is charcolised at 60-70 deg and is concentrated to leave behind 200 ml residue. Dicyclohexylamine (0.22 mol) diluted with 200 ml toluene is added slowly at RT. Mass is seeded to get effective crystallization. 800 ml hexane is slowly added at 40 deg and mass is cooled slowly to 15-20 deg. Slurry is stirred for 2-3 hrs and filtered followed by washing with toluene-hexane mixture and hexane. Cake was dried to give 80g dried product. On requirement product can be recrystallized in toluene-hexane.

Example 27: Preparation of l-[[[(1R)-l-[3-[(1E)-2-(7- chloro-2-quinolinyl) ethenyl] phenyl]-3[2-(l-hydroxy-l-methylethyl) phenyl propyl] thio] methyl cyclopropane acetic acid, Montelukast free acid [MS-4]

MS-2 solution (500 ml) as obtained from Example 16 is added drop wise to 400 ml, 3M solution of methyl magnesium chloride in THF and diluted with 200 ml toluene cooled at -5 to -10 deg. Stirring is continued till MS-2 content less than 5%, Mass is quenched by adding lltr, 10% acetic acid solution below 15 deg. Layers are separated, aqueous layer is re extracted with 200 ml toluene, combined toluene layers are washed with 11tr 30% sodium bicarbonate solution. Washed organic layer is partially distilled azeotropically to remove moisture content. Mass is cooled to -5 to -10 deg and 200 ml, 3M solution of methyl magnesium chloride is added slowly. Stirring is continued for 3-4 hrs and work up is repeated as above to get washed organic layer. Toluene layer is charcolised at 60-70 deg and is concentrated to leave behind 200 ml residue. 50 ml heptane is slowly added at 40 deg and mass is cooled slowly to 15-20 deg. Slurry is stirred for 2-3 hrs and filtered followed by washing with toluene-heptane mixture and heptane. Cake was dried to give 65g dried product. On requirement product can be recrystallized in toluene-heptane or in methanol.

Example 28: Preparation of Montelukast sodium [MS-5] from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is suspended in a mixture of 500 ml water and 500 ml MDC. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT. Solution is stirred for 30 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml MDC. Combined organic layer is washed thoroughly with water. 5 g Sodium hydroxide dissolved in 50 ml methanol and 5 ml water is added to washed organic layer. Mass is refluxed for 30 minute followed by MDC recovery under vacuum. 200 ml toluene is added to get clear solution at 50 deg. Mass is charcolised and filtrate is concentrated under vacuum to remove toluene and traces of MDC. Mass is again dissolved in 150 ml toluene to get clear solution. Clear solution is slowly added to 500 ml n-heptane to get precipitation of product. Slurry is filtered and washed with 100 ml n-heptane. Cake is dried under vacuum at 50-60 deg. to get 72 g amorphous product.

Example 29: Preparation of Montelukast sodium [MS-5] from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is suspended in a mixture of 500 ml water and 700 ml toluene. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT. Solution is stirred for 15 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml toluene. Combined organic layer is washed thoroughly with water. 5 g Sodium hydroxide dissolved in 5 ml water is added to washed organic layer. Mass is refluxed for 30 minute followed by charcolization and solvent recovery under vacuum. 150 ml toluene is added to get clear solution. Clear solution is slowly added to 500 ml n-heptane to get precipitation of product. Slurry is filtered and washed with 100 ml n-heptane. Cake is dried under vacuum at 50-60 deg. to get 71.5 g amorphous product.

Example 30: Preparation of Montelukast sodium [MS-5] from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is suspended in a mixture of 500 ml water and 700 ml toluene. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT. Solution is stirred for 15 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml toluene. Combined organic layer is washed thoroughly with water. 5 g Sodium hydroxide dissolved in 5 ml water is added to washed organic layer. Mass is refluxed for 30 minute followed by charcolization and solvent recovery under vacuum. 150 ml toluene is added to get clear solution. Clear solution is slowly added to 500 ml acetonitrile to get precipitation of product. Slurry is filtered and washed with 100 ml acetonitrile. Cake is dried under vacuum at 50-60 deg. to get 70.8 g amorphous product.

Example 31: Preparation of Montelukast sodium [MS-5] from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is suspended in a mixture of 500 ml water and 700 ml ethyl acetate. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT. Solution is stirred for 15 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml ethyl acetate. Combined organic layer is washed thoroughly with water. 5 g Sodium hydroxide dissolved in 5 ml water is added to washed organic layer. Mass is refluxed for 30 minute followed by charcolization and solvent recovery under vacuum. 150 ml ethyl acetate is added to get clear solution. Clear solution is slowly added to 500 ml acetonitrile to get precipitation of product. Slurry is filtered and washed with 100 ml acetonitrile. Cake is dried under vacuum at 50-60 deg. to get 70.5 g amorphous product.

Example 32: Preparation of Montelukast sodium [MS-5J from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is suspended in a mixture of 500 ml water and 700 ml ethyl acetate. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT. Solution is stirred for 15 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml ethyl acetate. Combined organic layer is washed thoroughly with water. 5 g Sodium hydroxide dissolved in 5 ml water is added to washed organic layer. Mass is refluxed for 30 minute followed by charcolization and solvent recovery under vacuum. 150 ml ethyl acetate is added to get clear solution. Clear solution is slowly added to 500 ml n-heptane to get precipitation of product. Slurry is filtered and washed with 100 ml n-heptane. Cake is dried under vacuum at 50-60 deg. to get 70.5 g amorphous product.

Example 33: Preparation of Montelukast sodium [MS-5] from, DCHA Salt [MS-3]

MS-3 (100 g, 0.13 mol) is $uspended in a mixture of 500 ml water and 500 ml MDC. Mass is stirred at RT to get solution. 12 ml acetic acid is slowly added at RT, Solution is stirred for 30 minutes at RT. Layers are separated. Aqueous layer is extracted with 100 ml MDC. Combined organic layer is washed thoroughly with water. MDC is recovered under vacuum to get residue which is dissolved in 200 ml methanol. 5 g Sodium hydroxide dissolved in 100 ml methanol is added to washed organic layer. Mass is stirred for 30 minute followed by charcolization and solvent recovery under vacuum. 150 ml methanol is added to get clear solution. Clear solution is slowly added to 500 ml acetonitrile to get precipitation of product. Slurry is filtered and washed with 100 ml acetonitrile. Cake is dried under vacuum at 50-60 deg. to get 72 g amorphous product.

Example 34: Preparation of Montelukast sodium [MS-5] from, Montelukast free acid [MS-4]

MS-4 (100 g, 0.17 mol) is suspended in 500 ml MDC. Mass is stirred at RT to get solution. 6.8 g Sodium hydroxide dissolved in 50 ml methanol and 5 ml water is added to washed organic layer.

Mass is refluxed for 30 minute followed by MDC recovery under vacuum. 200 ml toluene is added to get clear solution at 50 deg. Mass is charcolised and filtrate is concentrated under vacuum to remove toluene and traces of MDC. Mass is again dissolved in 150 ml toluene to get clear solution. Clear solution is slowly added to 500 ml n-heptane to get precipitation of product. Slurry is filtered and washed with 100 ml n-heptane. Cake is dried under vacuum at 50-60 deg. to get 97 g amorphous product.
Advantages:

1) Process is simplified and involves lesser operations and less production equipments

2) Coupling step of 7-chloroquinaldine with isophthaldehyde gives lesser quantity of undesired dimmer reaction product leading to higher yield and simpler operations

3) Reaction of vinyl magnesium bromide at cryogenic condition < -55 deg results is cleaner product less formation of benzyl alcohol derivative impurity

4) Chiral reduction step using DIP chloride is done at room temperature and above unlike traditional chilling temperature conditions, thus saving refrigeration cost.

5) Mesylating CMC-4 is advantageous over mesylating CMC-5 like traditional processes due to mono hydroxy in CMC-4 and so lesser impurities in API, in comparison to CMC-5 where 2-hydroxy groups present in molecule compete for mesylation leading to impurities generation.

CLAIMS:

We claim

1) A process involving, a) reacting 7-chloroquinaldine with isophthaldehyde in molar excess of isophthaldehyde in presence of acetic anhydride or acetic acid in reaction conditions minimizing formation of undesired dimmer/ disubstituted impurity. Molar excess is 1.1-3, precisely 1.1-2, more precisely 1.1-1.8 and even most precisely 1.1-1.5, anti-solvent is added slowly to reaction mass at high temperature, cooling to RT and filter the slurry. Cake is treated with aqueous solution of sodium meta bisulfite or sodium bi sulfite to extract out excess isophthaldehyde. Optinally cake is extracted with anti-solvent. Excess isophthaldehyde is recovered from bisulfite solution adduct or from anti-solvent solution. Anti-solvent may be water, methanol, ethyl acetate, toluene or a mixture thereof. b) reacting step a) product with vinyl magnesium bromide in organic solvent at cryogenic conditions to avoid impurity formation. Organic solvent may be toluene, THF, MeTHF or a mixture thereof. Cryogenic temperature may be -55 to -80 deg and more accurately -60 to -75 deg. c) quenching reaction mass b) with NH4C1 or other acidic solution and as such is concentrated under vacuum to get residue. d) diluting residue with triethylamine and optionally with 1-3 volumes of organic solvent. Organic solvent may be toluene, THF, MeTHF, acetonitrile, methanol or a mixture therof. e) reacting diluted mass with methyl-2-iodo benzoate or 2-iodo benzoic acid in presence of palladium acetate under reflux condition, concentrating the mass under vacuum to remove excess solvent and triethylamine and crystallizing the product in methanol-water mixture, acetonitrile or acetonitrile-water mixture. f) reacting step e) product with DIP chloride in organic sovents at elevated temperatures to accelerate the reaction and to yield anhydrous polymorphic form 2, which converts to hydrate in aqueous based recrystallization in organic solvents. Organic solvents may be toluene, dichloromethane, THF, methanol or a mixture thereof. Elevated temperature may be 40 deg to reflux temperature and more preferably 5 deg below to reflux temperature of solvents. g) reacting step f) product with methyl magnesium chloride in traditional reaction conditions but taking optionally polymorphic form 2.

2) Use of molar excess of isophthaldehyde over 7-chloroquinaldine to minimize formation of undesired dimmer impurity.

3) Recovery and recycling of isophthaldehde from reaction mass and product cake using various organic solvents and or sodium bisulfite or sodium meta bisulfite adduct followed by its cleavage

4) We also claim, a) reacting Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl] Benzoate with methane sulfonyl chloride in suitable organic solvent at suitable temperature to get its mesylate or with p-toluene sulfonyl chloride in presence of suitable base to get its tosy late. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyi -2- pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; nitrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo romethane etc. and a mixture thereof. Suitable base may be trithyl amine, diisopropylethylamine. Suitable temperature may be -50 to +50 deg, preferably -40 to 10 deg and more preferably -30 to -10 deg. b) reacting mesylate or tosylate with 1-mercaptomethylcyclopropane acetonitrile/ 1-
mercaptomethyl cyclopropane acetamide/ 1-mercaptomethyl cyclopropane acetic acid/ 1-
mercaptomethyl cyclopropane acetate ester to get corresponding condensation product, in
presence of suitable base in a suitable solvent. Suitable base may be butyl lithium, sodium hydride, potassium hydride, potassium-t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyl pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; ritrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo fomethane etc. and a mixture thereof. c) reacting condensation product of step b) with methyl magnesium halide to get tertiary alcohol derivative. Halide may be chloride or bromide. Optionally hydrolyzing tertiary alcohol derivative in basic conditions in presence of suitable solvents followed by suitable amine salts preparation to get Montelukast amine salt. Suitable solvents may be hydrocarbon solvents like, benxene, toluene, xylene, hexane, heptane; ketonic solvents like, methyl ethyl ketone, methyl isobutyl ketone, acetone, N-methyl pyrolidone; amide solvents like dimethyl formamide, dimethylacetamide; ethereal solvents like, THF, MeTHF, methyl-t-butyl ether, diisopropyl ether; nitrile solvents like acetonitrile etc, halogenated hydrocarbons like dichlo romethane etc. and a mixture thereof. Suitable amines may be ammonia, benzyl amine, dicyclohexyl amine, Propylamine. 2-Propylamine. Methylamine. Dimethylamine. Trimethvlamine. Aniline. 4-Methylaniline. 2-Nitroaniline. 3-Nitroaniline. 4-Nitroaniline. 2,6-Dimethylmorpholine, 2,6-Xylidine, 1,3-Diaminopropane (1,3 DAP), 2-Phenylethylamine etc. d) converting amine salts to Montelukast sodium by in-situ extracting Montelukast free acid in suitable organic solvent from acidic water. Organic solvents may be toluene, ethyl acetate, dichloromethane. Contacting the solution with sodium hydroxide solution in water or alcohol (methanol or ethanol), concentrating resultant solution. Re-dissolving the mass in suitable solvent and precipitating the product by pouring this solution in suitable anti-solvent Suitable solvents may be toluene, ethyl acetate, dichloromethane, methanol etc. and suitable anti-solvent may be heptane, hexane, acetonitrile, disopropyl ether, methyl-t-butyl ether.

5) We also claim following new intermediates, their amine salts and their processes of preparations:

A) MS-1, when R: -CH3,any alkyl or
MS-1A, when R: p-C6H5-

B) MS-2 (-COOH), MS-2A (-CN), MS-2B (-CONH2)

R may be -CM, -CONH2, -COOH,-COO alkyl

C) R= (-CN), (-CONH2), and-COO alkyl