WO2014118796A1

WO2014118796A1 - An in-situ process for the preparation of highly pure montelukast sodium

Info

Publication number: WO2014118796A1
Application number: PCT/IN2013/000312
Authority: WO
Inventors: Dayabhai Somabhai PATEL; Anil Balkrishna GHOGARE; Kishor Tukaram VISHE
Original assignee: Melody Healthcare Pvt. Ltd.
Priority date: 2013-01-31
Filing date: 2013-05-13
Publication date: 2014-08-07

Abstract

The present invention disclosed herein is a cost effective, in-situ process for the preparation of montelukast or its pharmaceutically acceptable salts of formula (1) by reacting optically pure (S)-1-{3-[2-(7-chloroquinolin-2-yl)ethylene]-phenyl}-3-[2-(1-hydroxy-1-methyl ethyl) phenyl]-propan-I-ol with methane sulfonyl chloride to afford mesylate derivative of formula (2) substantially free of impurities; followed by insitu condensing the same with disodium salt of mercapto-cyclopropyl acetic acid of formula (3) to afford montelukast free acid in good yield and purity, then converting the montelukast free acid into its substituted amine salt of formula (4). Further the montelukast substituted amine is converted into its pharmaceutically acceptable salt.

Description

"AN IN-SITU PROCESS FOR THE PREPARATION OF HIGHLY PURE

MONTELUKAST SODIUM"

FIELD OF THE INVENTION:

The present invention relates to a cost effective, in-situ process for the preparation of montelukast and its pharmaceutical acceptable salts of formula (l)comprises reacting optically pure (S)-\ - {3-[2-(7-chloroquinolin-2-yl)ethylene]-phenyl}-3-[2-( 1 -hydroxy- 1 - methyl ethyl) phenyl] -propan-l-ol with methane sulfonyl chloride to affordmesylate derivative of formula (2) substantially free of impurities; followed by condensing the same with disodium salt of mercapto-cyclopropyl acetic acid of formula (3) to afford montelukast free acid in good yield and purity, then converting the montelukast free acid into its substituted amine salt of formula (4).

Further the montelukast substituted amine is converted into its pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION:

Montelukast namely (R,E) - (l-{ l-{3-[2-(7-chloroquinolin-2-yl)ethenyl]-phenyl}-3-[2- (1 -hydroxy- l -methylethyl)phenyl]-propylthiomethyl} cyclopropyl) acetic acid has formula (1),

wherein in X is H, Na, Li, K

Montelukast sodium is a leukotriene D4 antagonist compound, widely used in prophylaxis and chronic treatment of asthma in adults and pediatric patients. Montelukast sodium is a useful anti-allergic agent for treating seasonal allergic rhinitis and perennial allergic rhinitis in adults and pediatric patients.

Montelukast sodium is optically active, highly hygroscopic compound and -is freely soluble in ethanol, methanol and water.

Montelukast sodium salt is available in a number of oral formulations including tablets, chewable tablets and oral granules. Accordingly, now a days it is widely used for treatment of pulmonary disorders including asthma and related obstructive airway diseases, allergies and allergic reaction, inflation and anti-inflammatory agent.

EP 480717 discloses a process for the synthesis of montelukast and its pharmaceutically acceptable salts especially sodium salt. The process for the preparation comprises of reacting[(E)-2-(2-(2-(3(S)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl-3-(methane sulfonyloxy)propyl)phenyl)-2-propoxy) tetrahydropyran with methyl -1 -(acetyl thiomethyl)cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as a solvent to get methyl ester of montelukast in pyran protected form. The protected compound is further reacted with pyridium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium.

WO/2004/108679 discloses a process for preparation of montelukast sodium salt. In the process as disclosed in WO/2004/108679, the dicyclohexylamine (DCHA) salt of montelukast acid is isolated, followed by purification using lengthy crystallization process in toluene and vacuum drying to get desired purityof 99% of montelukast acid. Further, the free montelukast acid is converted to highly viscous foamy .solid of montelukast sodium salt in presence of sodium hydroxide, which is further triturated in non-polar solvent i.e. C5 to C7 normal alkanes or cycloalkane to give montelukast sodium salt.

EP 0737186 discloses a process for preparation of montelukast and sodium salt thereof. The process comprises of generating the dilithium of l-(mercaptomethyl)cyclo- propaneacetic acid and reacting the said dilithium of l-(mercaptomethyl)cyclo- propaneacetic acid with sulfonate derivative of montelukast, followed by reaction with water soluble carboxylic acid giving free acid of montelukast which is then converted to dicyclohexylamine salt of montelukast. Further, the dicyclohexylamine salt of montelukast is converted to montelukast sodium in presence of sodium hydroxide.

US81 15004 discloses a process for preparation of montelukast sodium through intermediate diol compound; methyl ester of mercaptomethyl cyclopropane acetic acid and crystalline n-butyl amine salt of montelukast sodium, wherein sodium salt preparation is done by using alcoholic sodium hydroxide.

It is evident from the foregoing examples the preparation of montelukast sodium known in the art involves hazardous chemicals, tedious and cumbersome, lengthy process steps hence industrially and commercially not feasible.

Additionally the use of alcoholic sodium hydroxide in the preparation of montelukast sodium gives gummy or viscous foamy material of montelukast salt and hence difficult to isolate the desired product.

Furthermore, the purity of montelukast sodium obtained as per the prior art process is less due to the interference of couple of impurities in high extent such as montelukast methylstyrene/dehydro impurity, montelukast sulfoxide impurity, montelukast cis isomer impurity, montelukast methyl ketone impurity and montelukast michael adduct impurities. Further, to> improve the purity of final product needs several purification which may affects the yield of the final product.

To overcome the technical constraints , the present inventors have developed industrially and commercially feasible, cost effective, in-situ process for preparation of highly pure , stable montelukast sodium, with less impurity and hygroscopicity. Further, the instant process is easy to perform which enhances the product shelf life. Therefore the objective of the instant invention is to provide industrially viable, cost effective, in situ process for the preparation of highly pure, stable montelukast or its pharmaceutically acceptable salts of formula (1) by reacting mesylate derivative of formula (2) and disodium salt of mercapto cyclopropyl acetic acid of formula (3).

SUMMARY OF THE INVENTION:

The present invention provides industrially viable, cost-effective, in-situ process for the preparation of montelukast and its pharmaceutically acceptable salts, preferably sodium salt.

In an aspect, the present invention provides cost-effective, in-situ process for the preparation of stable, highly pure montelukast or its pharmaceutically acceptable salts of formula (1) which comprises:

formula (1)

a) reacting optically pure (5 -l-{3-[2-(7-chloroquinolin-2-yl)ethylene]-phenyl}-3-[2- (1 -hydroxy- 1 -methyl ethyl) phenyl]-propan-l-ol with methane sulfonyl chloride in presence of diisopropylethylamine and a solvent mixture consisting of acetonitrile: toluene in the ratio of 1 :1 to 3: 1 at temperature range of -35°C to -30°C, followed by extraction into a mixture of DMF and Hexane in the ratio of 1 : 1.1 to 1 : 1.5 to afford mesylate derivative of formula (2) substantially free of impurities;

in-situ condensing mesylate derivatives of formula (2) with disodium salt of mercapto-cyclopropyl acetic acid of formula (3) to afford montelukast free acid in good yield and purity,

formula (3)

wherein X is Na

c) converting montelukast free acid into its corresponding substituted amine salt in presence of organic solvent to obtain substituted amine salt of montelukast of formula (4); and

formula (4)

wherein Rl and R2 is independently selected from the group consisting of H, (C6- C12) aryl, ara-alkyl; and R3 is independently selected from H, (C1-C6) alkyl. . d) converting substituted amine salt of montelukast of formula (4) to its alkali salt in presence of milder source of sodium in non-aqueous solvent to obtain stable and highly pure montelukast alkali salt.

The another aspect of the present invention provides a process for the preparation of highly pure mesylate derivative of formula (2) substantially free from impurities comprises; reacting optically pure diol of ($-l -{3-[2-(7-chloroquinolin-2-yl) ethylene]- phenyl}-3-[2-(l -hydroxy- l -methylethyl)phenyl]-propan-l -ol with methane sulfonyl chloride in molar ratio in the range of 1 : 1.1 to 1 : 1.4, in presence of diisopropylethylamine in solvent mixture consisting of acetonitrile : toluene in the ratio of 2: 1 at temperature in the range of -35°C to -30°C. DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In preferred embodiment, the present invention provides industrially viable, cost- effective, in-situ process for the preparation of stable, highly pure montelukast or its pharmaceutically acceptable salts of formula (1) which comprises:

formula (1)

a) reacting optically pure (5^-l-{3-[2-(7-chloroquinolin-2-yl)ethylene]-ph¾nyl}-3-[2-(l- hydroxy-1 -methyl ethyl) phenyl]-propan-l-ol with methane sulfonyl chloride in presence of diisopropylethylamine and a solvent mixture consisting of acetonitrile: toluene in the ratio of 1 : 1 to 3: 1 at temperature range of -35°C to -30°C, followed by extraction into a mixture of DMF and Hexane in the ratio of 1 : 1.1 to 1 : 1.5 to afford mesylate derivative of formula 2) substantially free of impurities;

formula (2)

b) in-situ condensing mesylate derivatives of formula (2) with disodium salt of mercapto- cyclopropyl acetic acid of formula (3) to afford montelukast free acid in good yield and purity, xs- coox formula (3)

wherein X is Na

formula (4)

wherein Rl and R2 is independently selected from the group consisting of H, (C6- C12) aryl, ara-alkyl; and R3 is independently selected from H, (C1-C6) alkyl.

d) converting substituted amine salt of montelukast of formula (4) to its alkali salt in presence of milder source of sodium in non-aqueous solvent to obtain stable and highly pure montelukast alkali salt.

The montelukast alkali salt is preferably sodium salt of montelukast in amorphous solid form.

According to the present invention, the diol compound and methane sulfonyl chloride react together in suitable condition to obtain mesylate derivative product of compound of formula (2) in higher conversion which is more than 85%.

The diol is starting material which is optically pure ( -l-{3-[2-(7-chloroquinolin -2- yl)ethylene]-phenyl } -3-[2-( 1 -hydroxy- 1 -methylethyl)pheny l]-propan- 1 -ol (ee>99.8%); wherein optically pure ( -l-{3-[2-(7-chloroquinolin -2-yl)ethylene]-phenyl}-3-[2-(l- hydroxy- l-methylethyl)phenyl]-propan-l-ol (ee>99.8), in presence of diisopropylethylamine in suitable aprotic organic solvent at temperature in the range of -

20°C to -40°C particularly -35°C to -30°C is reacted with methane sulfonyl chloride, which substantially reduced the methyl styrene impurity below 0.6%.

However, temperature in the range of -10°C to -15°C resulted in high impurity level though rate of reaction was fast but the impurity level of methyl styrene was as high as 8-

10%.

The suitable aprotic organic solvent is selected from the group consisting of acetonitrile, toluene, xylene, either alone or combination thereof, particularly acetonitrile: toluene in the ratio of 1 : 1 to 3: 1. The molar ratio of diol compound to methane sulfonyl chloride is changed from 1 : 1.1 to 1 : 1.4 with equivalent proportion of diisopropylethylamine (DIP A). Most preferred molar ratio of diol compound to methane sulfonyl chloride is 1 : 1.1 to 1 : 1.3, which leads to complete conversion of diol compound to mesylate derivative of formula (2). The rate of addition is critical beside the temperature of addition is critical. Further, the addition time of diol compound to methane sulfonyl chloride is selected from the range of 20 min to 180 min and most preferred addition time is selected at 60-150 min.

To the reaction mixture of mesylate derivative of formula (2), the mixture of polar aprotic solvent and non-polar solvent is added for extraction, wherein polar aprotic solvent is THF, DMF, ethyl acetate, DCM , ACN or mixtures thereof preferably DMF and non-polar solvent is selected from hexane, pentane, toluene, chloroform, cyclohexane, diethyl ether either alone or mixtures thereof, preferably hexane. The extraction is preferably carried out in presence of mixture of DMF and hexane in ratio ranges from 1 :1.1 to 1 : 1.5. The organic polar solvent i.e. DMF layer containing mesylate derivative is taken directly in solution for further condensation reaction for the preparation of montelukast free acid.

Further, the isolation of mesylate derivative is eliminated to prevent degradation of mesylate derivative. Thus, the methyl styrene impurity is controlled by keeping the mesylate derivative in solution. The solid mesylate derivative product is not isolated because the methyl styrene impurity content is enhanced due to atmospheric exposure and the solid mesylate derivative product changes color appearance due to the atmospheric impact and storage below -10°C is required. Also, the methyl styrene impurity is formed due to further dehydration reaction of tertiary alcoholic function due to acidity present in isolated mesylated derivative.

To the clear solution of dianion salt of (l-mercaptomethyl-cyclopropyl)acetic acid of formula (3), the organic phase containing mesylate derivative of formula (2) is added at temperature in the range of 0 to -10°C, wherein the anion is alkali metal such as Na, K, Li. The reaction mixture is stirred initially below 0°C, preferably 0°C to -5°C for 2hrs and subsequently the temperature is gradually raised to 0°C to 10°C, preferably 0°C to 5°C and the reaction mixture mass is stirred for 4-6 hrs till reaction is completed. After complete conversion of the reagents, the reaction mixture is diluted with an inert organic solvent organic solvent such as toluene, ethyl acetate, methyl isobutyl ketone orfrom the mixtures thereof and is saturated with aqueous solution of the sodium chloride. The organic solvent is separated after work-up by distillation under reduced pressure giving degass reaction mass which is directly taken for preparation amine salt of montelukast. The montelukast free acid is in-situ or without isolation converted to its amine salt.

The amine salt is added to the degass reaction mass of montelukast free acid in presence of suitable organic solvents such as ethyl acetate, THF, acetone, methanol, ethanol, water, butanol, acetonitrile to obtain desired amine salt of montelukast of formula (4).

formula(4)

wherein Rl and R2 is independently selected from the group consisting of H, (C6-C12) aryl, ara-alkyl; and R3 is independently selected from H, (C1-C6) alkyl. Particularly the amine salt is selected from (diphenyl methyl) amine/2-amino diphenyl methane, N-methyl benzyl amine, or related benzyl amine salt, where the steric hindrance of benzyl ring of amine salt resulted in controlling the cis isomer and hence -a highly pure compound of formula (1) with desired quality in regards of purity and impurity content is obtained.

Accordingly, the present invention encompasses the crude amine salt of montelukast of formula (4), substantially devoid of impurities, wherein the impurity levels such as dehydro/methyl styrene is found less than 0.6%, sulfoxide impurity is less than 0.7%, cis isomer impurity less than 0.4%, methyl ketone impurity less than 0.5%, optionally Michael adduct impurity is present.

Alternatively, the purification of crude amine salt of montelukast of formula (4) is accomplished by treatment of organic solvent at elevated temperature, further the seeding of the amine salt of montelukast is done to precipitate the pure mass of amine salt, followed by drying under vacuum at elevated temperature. The suitable solvent used in purification is selected from high boiling point non-polar solvent, preferably toluene and the temperature is maintained in the range of 40°C-95°C, preferably 50°C-80°C.

Furthermore, the amine salt of montelukast is purified and is further reacted with milder source of sodium in presence of non-aqueous solvents giving compound of formula (1).

According to the invention, montelukast salt of compound of formula (1) is made from the mild source of alkali which consists of alkali preferably sodium salt of C5-C7 organic acids such as sodium pentanoic acid, sodium hexanoic acid or sodium heptanoic acid. The said alkaline or alkali metal salt of C5-C7 organic acids like sodium pentanoic acid, sodium hexanoic acid or sodium heptanoic acid is added to pure 2-amino diphenyl methane salt of montelukast at ambient condition under nitrogen atmosphere. Optionally the mild source of alkali can be selected from the alkoxides of alkali metal such as sodium methoxide, sodium ethoxide, sodium butoxide etc. Then, the reaction mixture is stirred with dehydrating agents preferably dehydrating molecular sieve and carbon treatment is given to the resulting solution after and the reaction mass so obtained is filtered. The filtered solution is first distilled under reduced pressure and then crystallized in non aqueous solvents, hexane, pentane, toluene, chloroform, cyclohexane, diethyl ether either like hexane, heptane, toluene or mixture thereof or solvent mixture comprising toluene/hexane, toluene/heptane, toluene/diethyl ether, ethyl acetate/hexane or acetone/hexane. The solvent ratio and isolation condition is measured to obtain high purity of the product of compound of formula (1). Further, the product of compound of formula (1) is filtered, washed and dried under vacuum not exceeding temperature above 60-65°C. Purity of product montelukast sodium of compound of formula (1) obtained is 99% and above and yield is 42-45% from starting material i.e. optically pure (S) -l -{3-[2- (7-chloroquinolin-2-yl)ethylerie]-phenyl}-3-[2-(l-hydroxy-l -methylethyI)phenyl]-propan -l-ol (ee>99.8%).

In aft another embodiment, the invention provides a process for the preparation highly pure mesylate derivative of formula (2), with isolation or without isolation from the reaction mixture comprises reacting diol compound with methane sulfonyl chloride in presence of diisopropylethylamine in suitable organic solvent to afford mesylate derivative of formula (2).

The diol is optically pure (S) -l-{3-[2-(7-chloroquinolin -2-yl)ethylene]-phenyl}-3-[2-(l- hydroxy-l-methylethyl)phenyl]-propan-l-ol (ee>99.8%); is reacted with methanesulfonyl chloride, in the presence of diisopropylethylamine (DIPA) at temperature below -25°C. The molar ratio of diol compound to methane sulfonyl chloride is changed from 1 : 1.1 to 1 : 1.4 preferably 1 : 1.1 with equivalent proportion of diisopropylethylamine (DIPA) wherein the impurity levels mainly dehydro/methyl styrene is found less than 0.8% leads to complete conversion of diol to mesylate derivative of formula (2).

In yet another embodiment of the invention, the dianion of (1-mercaptomethyl- cyclopropyl)acetic acid is selected from the dialkali salt such as dilithium, dipotassium, disodium salt etc. preferably disodium salt of (l-mercaptomethyl-cyclopropyl)acetic acid of formula (3). The disodium salt of (l-mercaptomethyl-cyclopropyl)acetic acid of formula (3) is prepared by reaction of l -(mercapto methyl)cyclopropane acetic acid with pre-cooled mixture of polar aprotic solvent, sodium alkoxide and lower alcohol at temperature -5°C to 0°C, wherein sodium alkoxide is selected from (C1-C6) alkoxide such as methoxide, ethoxide or butoxide but most preferred is sodium methoxide and lower alcohol is (Cl- C6) alcohols such as methanol, n-propanol, ethanol, isopropanol, butanol; preferably methanol.

The polar aprotic solvent, used in the preparation of dianion salt of formula (3) is preferably selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), or tetrahydrofuron (THF) either alone or mixtures thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising montelukast or its pharmaceutically acceptable salts, along with pharmaceutically acceptable excipients or carriers, for the treatment of prophylaxis, chronic asthma, related obstructive airway diseases, allergies and allergic reaction, seasonal allergic rhinitis and perennial allergic rhinitis in a mammal. Further - the composition may be formulated into preparations like solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, syrup, solutions, injections, gels and microspheres etc.

The pharmaceutically acceptable salts of montelukast include, but are not limited to, sodium, lithium, potassium.

Generally, the quantity of active compound will range between 0.5% to 90% by weight of the composition. Normally, the effective amount of dosage of montelukast sodium component will be in the range of about 0.1 to about 100 mg/kg, more preferably about 1.0 mg to about 50 mg/kg of body weight/day.

The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and in another embodiment, the present invention relates to administering 'an effective amount' of the 'composition of invention ' to the subject suffering from prophylaxis, chronic asthma, related obstructive airway diseases, allergies and allergic reaction, seasonal allergic rhinitis and perennial allergic rhinitis. Accordingly, compound of the invention and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation,^* oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

The invention will now be illustrated with help of examples. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art. All such modifications may be construed to fall within the scope and limit of this invention as defined by the appended claims.

Examples

1- (mercapto methyl) cyclopropane acetic acid & sodium methoxide niele ratio, to- control Micheal impurity

Example 01:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yI) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanol (mesylated mass)

2- (2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypr- opyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5 gm, 0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methane sulfonyl chloride (7.0gm, 0.060 mole) was added slowly to the reaction mixture over a period of lhr at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to -30° C. After completion of the reaction, dimethylformamide (75ml) was added at same temperature. Further, hexane(lOOml) was added at -5°C to - 10°C.The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfony- loxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step- II). Mesylated mass conversion by HPLC- 94.91%.

Step-II

Preparation of 2-amino diphenyl methane salt of montelukast from mesylated mass in organic phase (In-situ process)

9.5grams(0.065 mole ) of l-(mercapto methyl)cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 6.8 grams (0.12 mole ) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C. The reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and extract in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane (12.35gm, 0.067 mole) were added at 35-40°C. The degass mass was stirred at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 89.79%.

Yield: 32.00gm (Crude 2-amino diphenyl methane salt)

HPLC Purity: 97.16, Sulfoxide: 0.07%, MethylStyrene: 0.48%

Cis Isomer: 0.07%, Michael adducts: 1.67%, Methyl Ketone: 0.16%

Step-III

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm, 0.032 mole) (Crude 2-amino diphenyl methane salt) was taken in toluene (150ml) and was further heated to 70-75°C; a clear solution was obtained which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25- 30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°C and was further heated to 70- 75°C and a clear solution was obtained which was further allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). The solid mass was dried under vacuum at 50-55 °C and title compound (Pure2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.00gm. (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.50%, Sulfoxide: 0.03%, MethylStyrene: 0.09%

Cis Isomer: ND, Michael adducts: 0.21 %, Methyl Ketone: ND

Step-IV

Preparation of montelukast sodium from pure 2-amino diphenyl methane salt of montelukast

Compound obtained in Step-III (15gm, 0.019 mole) (2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.065gm, 0.019 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was further filtered under nitrogen atmosphere and subsequently washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75 °C for 18-20 hrs and title compound was obtained.

(Montelukast Sodium)

Yield: 12.50gm (Montelukast Sodium)

HPLC Purity: 99.54%, Sulfoxide: 0.09%, MethylStyrene: 0.13%

Cis Isomer: ND Michael adducts: 0.14%, Methyl Ketone: 0.03%

Example 02:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanol (mesylated mass) 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropy^'l) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction mixture over a period of lhr at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethyl formamide (75ml) was added at same temperature. Further, hexane (100ml) was added at -5°C to - 10°C. The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step. (i.e. Step- II). Mesylated mass conversion by HPLC- 94.47%.

Step-II

9.5grams (0.065 mole) of l-(mercapto methyl) cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 6.8grams (0.12 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C. The reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was further extracted- in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane(12.35gm,0.067 mole) were added to degass mass at 35-40°C and the degass mass was stirred at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 93.44%.

Yield: 30.00gm (Crude 2-amino diphenyl methane salt)

HPLC Purity: 97.84% Sulfoxide: 0.04% MethylStyrene: 0.50% Cis Isomer: ND Michael adducts: 1.24% Methyl Ketone: O.Q6%

Step-Ill

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm, 0.032 mole) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C, a clear solution was obtained which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in Toluene (135ml) at 25-30°C and heated to 75- 80°C and clear solution was obtained, which was further allowed to cool to 25-30°C.

The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). The solid mass was further dried under vacuum at 50- 55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.00gm (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.58% Sulfoxide: 0.01% MethylStyrene: 0.12%

Cis Isomer: 0.01% Michael adducts: 0.08% Methyl Ketone: 0,07%

Step-IV

Preparation of montelukast sodium from pure 2-amino diphenyl methane salt of montelukast using sodium methoxide

Compound obtained in Step-Ill (15gm, 0.019 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.02gm, 0.019 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was filtered and further added in n-Heptane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was filtered under nitrogen atmosphere and further washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 12.00gm (Montelukast Sodium)

HPLC Purity: 99.53% Sulfoxide: 0.08% MethylStyrene: 0.11%

Cis Isomer: 0.08% Michael adducts: 0.07% Methyl Ketone: 0.02%

Step-IV

Preparation of montelukast sodium from pure 2-amino diphenyl methane salt of montelukast using sodium 2-ethyl hexanoate.

Compound obtained in Step-III (15gm, 0.019 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium 2-ethyl hexanoate (3.15 gm, 0.019 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and a clear reaction mass was obtained, to which further activated charcoal treatment was given. The reaction mass was filtered and was further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was further filtered under nitrogen atmosphere and washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 12.50gm (Montelukast Sodium)

HPLC Purity: 99.44% Sulfoxide: 0.09% MethylStyrene: 0.16%

Cis Isomer: 0.13% Michael adducts: 0.01% Methyl Ketone: 0.07%

Example 03:

The Step I for the preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyl)- 3-(methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanol (mesylated mass) and Step II for the preparation of 2-amino diphenyl methane salt of montelukast from mesylated mass in organic phase (In-situ process) were performed as disclosed in the Example 02.

Step-III

Preparation of extra pure 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm, 0.032 mole) (Crude 2-amino diphenyl methane salt of Montelukast) was taken in toluene (150ml) and was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C.The seeding of 2- amino diphenyl methane salt of Montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°C and furtherheated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25r30°C and the precipitate mass was filtered and further the solid was washed by toluene (25ml). Wet material was again taken in toluene (120.00ml) and was heated to 65-70°C and subsequently methanol (10% of Toluene) was slowly added and was stirred for reprecipitation for 4-5 hrs at room temperature. The mass was filtered and washed by hexane. The solid mass was dried under vacuum at 50-55°C and title compound was obtained. (Pure 2-amino diphenyl methane salt of montelukast)

Yield: 12.50gm (Extra pure 2-amino diphenyl methane salt of montelukast) HPLC Purity: 99.81% Sulfoxide: 0.04% MethylSryrene: 0.08%

Cis Isomer: 0.02% Michael adducts: 0.01% Methyl Ketone: 0.02%

Step-IV

Preparation of extra pure montelukast sodium from pure 2-amino diphenyl methane salt of montelukast using sodium 2-ethyl hexanoate

Compound obtained in Step-III (15gm, 0.019 mole) (Pure 2-amino diphenyl methane Salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.02gm, 0.019 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was. filtered and further was added in n-Heptane (450ml) under high agitation, a precipitate mass of montelukast Sodium was obtained, which was filtered under nitrogen atmosphere and then washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Y ield: 12.00g m (Montelukast Sodium)

HPLC Purity: 99.78% Sulfoxide: 0.03% MethylSryrene: 0.08%

Cis Isomer: 0.05% Michael adducts: ND Methyl Ketone: ND Following experiments were conducted to control dehydro impurity by addition of methanesulfonyl chloride in 30.0min, 45.0min, 60.0min, 90.0min & 120.0min and the results were analysed.

Example 04:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyI)-2-propanoI (mesylated mass) 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction mixture over a period of 30min at -30°C to -25°C and the reaction mixture was stirred for 2 hr to -35°C to-30° C. After completion of the reaction, dimethylformamide (75ml) was added at same temperature. Further, hexane (100ml) was added- at -5°C .to - 10°C. The organic layer and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3- (methanesulfonyloxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step-II).

Mesylated mass conversion by HPLC- 90.01%

Step-II

13.5grams( 0.092 mole) of l-(mercapto methyl)cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C and the reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid "content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane (12.50 gm, 0.068 mole) were added at 35-40°C. The degass mass was. stirred at

50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 88.30%

Yield: 31.00gm (Crude 2-amino diphenyl methane salt)

HPLC Purity: 96.55% Sulfoxide: 0.02% MethylStyrene: 0.49%

Cis Isomer: 0.04% Michael adducts: 2.47% Methyl Ketone: 0.03%

Step-III

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C.The seeding of 2-Amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml).Wet material was again added in toluene (135ml) at 25-30°C and was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25- 30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C and the precipitate mass was filtered and subsequently the solid was washed by toluene (25ml). The solid mass was further dried under vacuum at 50-55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.00gm (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.44% Sulfoxide: 0.03% MethylStyrene: 0.32%

Cis Isomer: ND Michael adducts: 0.03% Methyl Ketone: 0.08% Step-IV

Preparation of montelukast sodium from pure 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-III (15gm, 0.022 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.23gm, 0.022 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was siven. The reaction mass was filtered and further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was filtered under nitrogen atmosphere and subsequently was washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 11.25gm (Montelukast Sodium)

HPLC Purity: 99.56% Sulfoxide: 0.04% MethylStyrene: 0.26%

Cis Isomer: 0.03% Michael adducts: 0.02% Methyl Ketone: ND

Example 05:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyf)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanoI (mesylated mass)

2-(2-(3(S)-(3-(2-(7-Chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypr- opyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction mixture over a period of 45 min at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethyl formamide (75ml) was added to the reaction mixture at same temperature. Further, hexane( 100ml) was added at -5°C to -10°C and the organic layer was separated and 2-(2-(3(S)-(3-(2-(7- chloroquinolin-2-yl) ethenyl)phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2- propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step-II). Mesylated mass conversion by HPLC- 90.70% Step-II

13.5grams( 0.092 mole) of l -(mercapto methyl)cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C and the reaction mixture was stirred for 10 - 12 hours at -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction riiass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and was further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-Amino diphenyl methane (12.50 gm ,0.068 mole) were added in degass mass at 35-40°C and the degass mass was stirred at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained. Montelukast free acid conversion by HPLC- 90.20%

Yield: 30.00gm (Crude 2-amino diphenyl methane salt)

HPLC Purity: 96.86% Sulfoxide: 0.03% MethylStyrene: 0.32%

Cis Isomer: ND Michael adducts: 1.54% Methyl Ketone: ND

Step-ffl

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°C and heated to 75- 80°C and clear solution was obtained, which was allowed to cool to 25-30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). The solid mass was dried under vacuum at 50-55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.00gm (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.52% Sulfoxide: 0.04% MethylStyrene: 0.24%

Cis Isomer: ND Michael adducts: 0.06% Methyl Ketone: 0.05%

Step-IV

Compound obtained in Step-III (15gm,0.022 mole) (Pure 2-amino diphenyl" methane. salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.23gm, 0.022 mole) was charged under nitrogen atmosphere and the reaction mxiture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was filtered was further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was further filtered under nitrogen atmosphere and subsequently washed with cyclohexane (30ml).Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 11. lOgm (Montelukast Sodium)

HPLC Purity: 99.56% Sulfoxide: 0.11% MethylStyrene: 0.12%

Cis Isomer: 0.09% Michael adducts: 0.01 % Methyl Ketone: ND ...

Example 06:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinoIin-2-yl) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanol (mesylated mass)

2-(2-(3(S)-(3-(2-(7-Chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50° C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction mixture over a period of 60 min at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethylformamide (75ml) was added at same temperature. Further, hexane(lOOml) was added at -5°C to - 10°C.The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step- II). Mesylated mass conversion by HPLC- 87.54%

Step-II

13.5grams( 0.092 mole) of l-(mercapto methyl)cyclopropane acetic acid was .added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C and the reaction mixture was stirred for 10 - 12 hours at -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-Amino diphenyl methane (12.50 gm^* ,0.068 mole) were added in degass mass at 35-40°C and the degass mass was stirred at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 89.80%

Yield: 30.00gm (Crude 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 97.81% Sulfoxide: 0.10% MethylStyrene: 0.23%

Cis Isomer: 0.15% Michael adducts: 1.30% Methyl Ketone: 0.04%

Step-III

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C and clear solution was obtained, which was further allowed to cool to 25-30°C. The seeding of 2- amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and subsequently the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°C and heated to 75-80°C, a clear solution was obtained, which was allowed to cool to 25- 30°C.The seeding of 2-amino diphenyl methane salt of montelukast was done and the reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and subsequently the solid was washed by toluene (25ml). The solid mass was dried under vacuum at 50-55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.50gm . (Pure 2-amino diphenyl methane salt of montelukast) HPLC Purity: 99.51% Sulfoxide: 0.08% MethylStyrene: 0.19%

Cis Isomer: 0.02% Michael adducts: 0.02% Methyl Ketone: 0.06%^'

Step-IV

Compound obtained in Step-ΠΙ (15gm,0.022 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.23gm, 0.022 mole) was charged under nitrogen atmosphere and the reaction mixture wasstirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was filtered and further was added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was filtered under nitrogen atmosphere and subsequently washed with cyclohexane (30ml). Wet material was further dried under vacuum at 70-75 °C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 11.25gm (Montelukast Sodium)

HPLC Purity: 99.51% Sulfoxide: 0.11% MethylStyrene: 0.14%

Cis Isomer: 0.12% Michael adducts: 0.01% Methyl Ketone: ND Example 07:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) pnenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanoI (mesylated mass)

2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3-(hydroxypropyl)phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50°C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0gm,0.060 mole) was added slowly to the reaction mixture over a period of 90 min at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethyl formamide (75ml) was added at same temperature. Further, hexane( 100ml) was added at -5°C to - 10°C.The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2-prop'anor (mesyl derivative) in organic layer was obtained, which is further used in next step.(i.e.Step-II). Mesylated mass conversion by HPLC- 83.89%

Step-II

13.5grams( 0.092 mole) of l-(mercapto methyl) cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C. The reaction mixture was stirred for 10 - 12 hours -5 tp 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane (12.50 gm ,0.068 mole) were added in degass mass at 35-40°C and the degass mass at 50-55°C for 10-12 hrs The precipitate mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 89.46%

Yield: 32.00gm (Crude 2-Amino diphenyl methane Salt)

HPLC Purity: 96.21% Sulfoxide: 0.66% MethylStyrene: 0.13%

Cis Isomer: 0.38% Michael adducts: 1.53% Methyl Ketone: ND

Step-III

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm) (Crude 2-amino diphenyl methane salt of montelukast) was taken in toluene (150ml) and was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C.The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°C and* was further heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25- 30°C. The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). The solid mass was further dried under vacuum at 50-55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 20.00gm (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.65% Sulfoxide: 0.03% MethylStyrene: 0.18%

Cis Isomer: 0.01% Michael adducts: 0.01% Methyl Ketone: 0.04%

Step-IV

Compound obtained in Step-III (15gm, 0.022 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.23gm, 0.022 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and clear reaction mass was obtained, to which activated charcoal treatment was given.. The reaction mass was filtered and was further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast sodium was obtained, which was further filtered under nitrogen atmosphere and subsequently washed with cyclohexane (30ml). Wet material was dried under vacuum at 70-75°C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 11.20gm (Montelukast Sodium)

HPLC Purity: 99.53% Sulfoxide: 0.07% MethylStyrene: 0.11%

Cis Isomer: 0.10% Michael adducts: 0.01% Methyl Ketone: ND

Example 08:

Step-I

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yI) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyI)-2-propanol (Mesylated mass) 2-(2-(3(S)-(3-(2-(7-Chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50°C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0 gm,0.060 mole) was added slowly to the reaction mixture over a period of 120 min at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to-30° C. After completion of the reaction, dimethyl formamide (75ml) was added at same temperature. Further, hexane(lOOml) was added at -5°C to - 10°C.The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyIoxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step- II). Mesylated mass conversion by HPLC- 90.13%

Step-II

13.5grams( 0.092 mole) of l-(mercapto methyl)cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C and the reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at .0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and further was washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-Amino diphenyl methane (12.50 gm ,0.068 mole) were added in degass mass at 35-40°C and the degass mass was stirred at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was further dried at 50-55°C and title compound was obtained. Montelukast free acid conversion by HPLC- 92.32%

Yield: 30.00gm (Crude 2-Amino diphenyl methane Salt)

HPLC Purity: 97.45% Sulfoxide: 0.39% MethylStyrene: 0.06%

Cis Isomer: 0.18% Michael adducts: 1.08% Methyl Ketone: ND

Step-Ill

Purification of 2-amino diphenyl methane salt of montelukast.

Compound obtained in Step-II (25gm) (Crude 2-amino diphenyl metHane' salt of montelukast) was taken in toluene (150ml) and was heated to 75-80°C and clear solution was obtained, which was allowed to cool to 25-30°C.The seeding of 2-amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25- 30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). Wet material was again added in toluene (135ml) at 25-30°Cand was heated to 75-80°C and a clear solution was obtained, which was allowed to cool to 25-30°C.The seeding of 2- amino diphenyl methane salt of montelukast was done. The reaction mass was stirred for 8-10 hrs at 25-30°C. The precipitate mass was filtered and the solid was washed by toluene (25ml). The solid mass was further under vacuum at 50-55°C and title compound (Pure 2-amino diphenyl methane salt of montelukast) was obtained.

Yield: 21.00gm (Pure 2-amino diphenyl methane salt of montelukast)

HPLC Purity: 99.70% Sulfoxide: 0.02% MethylStyrene: 0.07%

Cis Isomer: 0.009% Michael adducts: 0.03% Methyl Ketone: 0.07% Step-IV

Compound obtained in Step-III (15gm, 0.022 mole) (Pure 2-amino diphenyl methane salt of montelukast) was taken in toluene (75ml) and sodium methoxide (1.23gm, 0.022 mole) was charged under nitrogen atmosphere. The reaction mixture was stirred at 30-35°C and a clear reaction mass was obtained, to which activated charcoal treatment was given. The reaction mass was filtered and was further added in cyclohexane (450ml) under high agitation, a precipitate mass of montelukast Sodium was obtained, which was filtered under nitrogen atmosphere and subsequently washed with cyclohexane (30ml). Wet material was further dried under vacuum at 70-75 °C for 18-20 hrs and title compound was obtained. (Montelukast Sodium)

Yield: 11.25gm (Montelukast Sodium)

HPLC Purity: 99.67% Sulfoxide: 0.08% MethylStyrene: 0.10%

Cis Isomer: 0.06% Michael adducts: 0.01% Methyl Ketone: ND

Following example is explained in which reaction proceeded with l-(mercapto methyl) cyclopropane acetic acid & sodium methoxide without nitrogen atmosphere, and the result was analysed, concluding that sulfoxide impurity and- cis isomer impurity is increased.

Example 09:

Step-1

Preparation of 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyl)-3- (methanesulfony-l-oxy) methyl ethyl) phenyl)-2-propanol (Mesylated mass)

2-(2-(3(S)-(3-(2-(7-Chloroquinolin-2-yl) ethenyl) phenyl)-3-(hydroxypropyl) phenyl)-2- propanol (25gm, 0.054 mole) was dissolved in toluene (50 ml) and acetonitrile (100 ml) mixture under nitrogen atmosphere at 45-50°C temperature. Diisopropylethylamine (10.5 gm,0.081 mole) was added to the reaction mixture and the temperature was lowered to - 35° C. to -30° C. Methanesulfonyl chloride (7.0 gm,0.060 mole) was added. slowly to the reaction mixture over a period of 120 min at -30°C to -25°C and the reaction mixture was stirred for 2 hrs to -35°C to -30° C. After completion of the reaction, dimethyl formamide (75ml) was added at same temperature. Further, hexane (100ml) was added at -5°C to - 10°C. The organic layer was separated and 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethenyl) phenyl)-3-(methanesulfonyloxy) methyl ethyl) phenyl)-2-propanol (mesyl derivative) in organic layer was obtained, which was further used in next step.(i.e.Step- II). Mesylated mass conversion by HPLC- 89.94%

Step-II

13.5grams( 0.092 mole) of l-(mercapto methyl)cyclopropane acetic acid was added to the pre cooled mixture of 100ml of dimethyl formamide and 9.75 grams(0.18 mole) of sodium methoxide and methanol solution at -5 to 0° C. The reaction mixture was stirred for one hour at -5 to 0° C. The above obtained reaction mass was added lot wise to the reaction mixture at -5 to 0° C and the reaction mixture was stirred for 10 - 12 hours -5 to 0° C. The montelukast free acid content was analysed by HPLC. The reaction mass was quenched into saturated solution of sodium chloride (160gm) and was extracted in ethyl acetate (200ml) at 0 to 5°C. The ethyl acetate layer was washed by 25% tartaric acid solution and was further washed with purified water (100ml*3T). The ethyl acetate layer was concentrated under reduced pressure. The ethyl acetate (125ml) and 2-amino diphenyl methane (12.50 gm ,0.068 mole) were added in degass mass at 35-40°C and the degass mass at 50-55°C for 10-12 hrs. The precipitate mass was filtered and solid was obtained, which was dried at 50-55°C and title compound was obtained.

Montelukast free acid conversion by HPLC- 89.67%

Yield: 31.25gm (Crude2-Amino diphenyl methane Salt of Montelukast)

HPLC Purity: 95.92% Sulfoxide: 0.66% MethylStyrene: 0.11%

Cis Isomer: 0.40% Michael adducts: 1.56% Methyl Ketone:ND

The Step III for the purification of 2-amino diphenyl methane salt of montelukast and Step IV for the preparation of montelukast sodium from pure 2-amino diphenyl methane salt of montelukast were performed as disclosed in the Example 08.

Claims

We claim,

1. A cost-effective, in-situ process for preparation of stable, highly pure montelukast and its pharmaceutically acceptable salts of formula (1) which comprises:

formula (1)

a) reacting optically pure (^-l-fS-P-iT-chloroquinolin^-y ethyleneJ-phenylJ-S-P- (1 -hydroxy- 1 -methyl ethyl) phenyl]-propan-l-ol with methane sulfonyl chloride in presence of diisopropylethylamine and a solvent mixture consisting of acetonitrile: toluene in the ratio of 1 :1 to 3: 1 at temperature range of -35°C to -30°C, followed by extraction into a mixture of DMF and Hexane in the ratio of 1 : 1.1 to 1 :1.5 to afford mesylate derivative of formula 2) substantially free of impurities;

formula (2)

formula (3)

whereto. X is Na

c) converting montelukast free acid into its corresponding substituted amine salt in presence of organic solvent to obtain amine salt of montelukast to obtain substituted amine salt of montelukast of formula (4); and

formula (4)

wherein Rl and R2 is independently selected from the group consisting of H, (C6- C12) aryl, ara-alkyl; and R3 is independently selected from H, (C1-C6) alkyl. d) converting substituted amine salt of montelukast of formula (4) to its alkali salt in presence of milder source of sodium in non-aqueous solvent to obtain stable and highly pure montelukast alkali salt.

2. The process according to claim 1, wherein the montelukast or its pharmaceutically acceptable salts of formula (1) is highly pure, stable sodium salt of montelukast in amorphous form.

3. The process according to claim 1 step (a), wherein the molar ratio of optically pure l-{3-[2-(7-chloroquinolin-2-yl)ethylene]-phenyl}-3-[2-(l-hydroxy-l -methyl ethyl) phenyl]-propan-l-ol to methane sulfonyl chloride is in the range of 1 :1.1 to 1 : 1.4 with equivalent proportion of diisopropylethylamine (DIP A).

4. The process according to claim 1 step (c), wherein the conversion of montelukast free acid into its corresponding substituted amine salt is followed by optional purification to obtain highly pure substituted amine salt of montelukast of formula (4).

5. The process according to claim 1 step (c), wherein the amine salt is selected from the group consisting of 2-amino diphenyl methane, N-methyl benzyl amine.

6. The process according to claim 1 step (d), wherein the milder source of sodium is selected from the group consisting of sodium salts of organic acids such as sodium pentanoic acid, sodium hexanoie acid sodium heptanoic acid.

7. The process according to claim 1 step (d), wherein the milder source of sodium is sodium alkoxide.

8. The process according to claim 1 step (d), wherein the non-aqueous solvent is selected from group consisting of heptane, cyclohexane, toluene, ether, hexane, chloroform, ethyl acetate either alone or mixtures thereof.

9. The process according to claim 1 step (a), wherein the highly pure mesylate derivative of formula (2) substantially free from impurities is prepared by under kinetically controlled process conditions which comprises; reacting optically pure diol of (5)-l- {3-[2-(7-chloroquinolin-2-yl)ethylene]-phenyl}-3-[2-(l-hydroxy-l-methylethyl) phenyl]-propan-l-ol with methane sulfonyl chloride in molar ratio in range of 1 :1 to 1 : 1.4, in presence of diisopropylethylamine in mixture of acetonitrile and toluene in the ratio of 2:1 at tem erature in the range of -35°C to -30°C.

ormu a

10. A process for the preparation of montelukast and its acceptable salts comprises of reacting 2-(2-(3(S)-(3-(2-(7-chloroquinolin-2-yl) ethyl) phenyl)-3-(methanesulfony-l- oxy) methyl ethyl) phenyl)-2-propanol of formula (2) with disodium salt of mercapto- cyclopropyl acetic acid derivative of formula (3).

11. The process according to claim 10, wherein the disodium salt of mercapto-cyclopropyl acetic acid derivative of formula (3) is prepared by reacting l-(mercapto methyl)cyclopropane acetic acid with pre-cooled mixture of DMF, sodium methoxide and methanol at temperature -5° to 0°C.

fornmla (3) wherein X is Na

12. An amine salt of montelukast of formula (4) is;

formula (4)

wherein Rl and R2 is independently selected from the group consisting of H, (C3-C8) (C6-C12) aryl; and R3 is independently selected from H, (C1-C6) alkyl.

13. The amine salt of montelukast of formula (4) according to claim 12, wherein the amine is selected from the group consisting of 2-amino diphenyl methane or N-methyl benzyl amine.