Indian Patents. 263994:A PROCESS FOR PREPARATION OF MONTELUKAST SODIUM SALT

Title of Invention	A PROCESS FOR PREPARATION OF MONTELUKAST SODIUM SALT
Abstract	The present invention relates to a process for the preparation of [R-([E)J-1-[[[l-[3 --[2-(7- chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- I -methylethyl)phenyl] - propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt, i.e. Montelukast sodium by isolating crystallized salt with high purity, high yield and low residual solvent.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) As amended by the Patents (Amendment) Act, 2005 & The Patents Rules, 2003 As amended by the Patents (Amendment) Rules, 2005 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION A PROCESS FOR THE PREPARATION OF MONTELUKAST SODIUM 2. APPLICANTS Name : Melody Healthcare Private Limited Nationality : Indian Company Address : 505, Unique Tower, Behind Patel Petrol Pump, Off S.V.Road, Goregaon (West), Mumbai 400062 3. INVENTORS Names : Shetty Jayram Nationality : Indian National Address : Ostwal Empire, L-1 building, Flat no 101, Opp Hotel Madhur, Navapur Navapur Road, Boisar, Thane 401506, Maharashtra 4. PREAMBLE TO THE DESCRIPTION The following specification describes the nature of this invention and the manner in which it is to be performed: Technical field: The present invention relates to an improved process for the preparation of [R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy-1 -methylethyl)phenyl] -propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt of Formula (I); Formula I The present invention particularly relates to a process for the preparation of [R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl] -propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt by isolating crystallized salt with high purity and yield and low residual solvent. Prior Art: [R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl] - propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt is commonly known as Montelukast Sodium. It is an orally administered Leukotriene D-4 antagonist developed for the treatment of chronic asthma and allergic rhinitis. Montelukast was first developed by Merck and is disclosed in US 5,565,473. Montelukast Sodium is prepared by condensing 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenyl)3-(methanesulfonyloxy)methylethyl)phenyl)-2-propoxy) tetrahydropyran (II) with methyl-1- (acetylthiomethyl)cyclopropane acetate (III) in the presence of cesium carbonate to produce methyl-4-((l(R)- (3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)3-(2-(2-(2-tetrahydropyranyloxy)-2-methylethyl)phenyl)propyl)thio) cyclopropyl acetate (IV), which is deprotected in the presence of pyridinium-p-toluene sulfonate followed by conversion to Montelukast Sodium (I) in the presence of sodium base in a mixture of solvent i.e. Methanol and tetrahydrofuran. Scheme I demonstrates the schematic representation of the process. The above process requires tedious chromatographic purification of both intermediates and the final product which results into low yield. Thus the process is not commercially viable. US 5,614,632 discloses a process for the preparation of Montelukast Sodium. 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl) ethenyl)phenyl )3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) is condensed with anion of l-(mercaptomethyl) cyclopropaneacetic acid (VII) to obtain crude Montelukast. Montelukast is further converted into its dicyclohexylamine salt which is further converted into sodium salt upon treatment with sodium hydroxide. Scheme II demonstrates the schematic representation of the process. Condensation of 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenyl )3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) with l-(mercaptomethyl) cyclopropaneacetic acid (VII) in the presence of strong base n-butyl lithium results into undesired impurities. The removal of impurities is difficult and requires tedious purification. Thus major drawback is low yield and low purity of Montelukast. ♦ -XjC- m Na® or COOMe COOMe SCHEME! ♦ »AX^» vn COOH nc vm nc COOH .P IX S^N^^COOPS SCHEME-O Objects of the invention An object of the present invention is to provide a process for the preparation of Montelukast Sodium in crystallized form with high purity of 99 to 99.6 % and high yield of 80 to 82%. Another object of the invention is to provide a process for the preparation of Montelukast Sodium by eliminating steps of preparation of Montelukast dicyclohexylamine salt and further conversion into its free acid for purification, thereby process becomes cost-effective. Another object of the present invention is to provide a process for the preparation of Montelukast Sodium by crystallizing Montelukast Sodium in a mixture of toluene and n-Heptane followed by reacting Montelukast free acid with alkali salt of organic acid, thus avoiding highly hygroscopic chemical like sodium methoxide or sodium hydroxide for the preparation of Sodium salt thereby process becomes simple and easy to operate. Another object of the invention is to provide a process for the preparation of Montelukast Sodium where the process eliminates purification by chromatography thereby making the process economical and simple. Detailed Description According to the invention there is provided a process for the preparation of Montelukast Sodium, the process comprising the steps of a) preparing 2-(2-(3-(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)3- (methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) by dissolving 2- (2-(2-(3-(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl-3-hydroxy- propyl)phenyl)-2-propanol in a mixture of acetonitrile and toluene at 30 to 35° C , adding di-iso propylthylamine, cooling the reaction mixture to -20° C and adding slowly methane sulphonyl chloride at -20° to -10 °C, stirring the reaction mixture at -35 to -30°C to obtain compound of formula (VI); b) condensing the compound of formula (VI) with l-(mercaptomethyl) cyclopropaneacetic acid (VII) in the presence of N-Butyl lithium and solvent selected from tetrahydrofuran at temperature of -30 to -10° C to obtain condensed mixture comprising Montelukast free acid; c) stirring the condensed mixture at 0 to 5° C for at least 2 hours; d) quenching the reaction mass in sodium chloride solution and ethyl acetate at 10 to 30°C to obtain two phases; e) separating organic phase comprising Montelukast free acid from aqueous phase followed by washing with tartaric acid solution and subsequently with water; f) treating the organic layer comprising Montelukast free acid with activated charcoal and filter; g) distilling out ethyl acetate from the organic layer comprising Montelukast free acid under vacuum at 28 to 30°C; h) converting Montelukast free acid into Montelukast Sodium salt by treating it with alkali salt of free acid in the presence of ethyl acetate and i) Montelukast Sodium salt was crystallized by using solvent such as n-heptane, toluene, ethyl acetate or mixture thereof. The alkali salt of organic acid is alkali salt of propanoic acid, alkali salt of heptanoic acid, and alkali salt of octanoic acid. Most preferably sodium salt of heptanoic acid is used. The purity of Montelukast Sodium prepared by the above process is 99 % to 99.6%. The yield of Montelukast Sodium prepared by the above process is 80 to 82 % Thus the purity and yield is high and also eliminates the purification by chromatography. The purification is carried out by simple solvent treatment such as ethyl acetate. The process of the present invention eliminates steps of preparation of Montelukast dicyclohexylamine salt and further conversion into its free acid for purification. Montelukast dicyclohexylamine salt is not stable and very difficult to handle. The present process uses alkali salt of organic acid instead of highly hygroscopic chemical like sodium methoxide or sodium hydroxide to prepare Montelukast Sodium. Thus the present process is simple and easy to operate and cost-effective. The following example demonstrates the nature of the invention and is provided for illustrative purpose only and should be construed to limit the scope of the invention. Example: 100 gms of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl-3-hydroxy-propyl) phenyl)-2-propanol was dissolved in a mixture of acetonitrile (300 ml) and toluene (100 ml) at 30to 35°C. To this mixture, 40 gms di-isopropylethylamine was added and chilled to -20°C. To this chilled mixture, methane sulphonyl chloride (19.16 gms) was slowly added at -20 to -10°C and stirred it at -35 to -30°C. The reaction mixture is filtered to obtain 2-(2-(3-(S)-(3-(2-(7-chloroquinoli-2-yl) ethenyl) phenyl) 3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol. The product was condensed with l-(mercaptomethyl) cyclopropaneacetic acid in presence of 36.76 gms of n-butyl lithium salt and 300ml of tetrahydrofuran at temperature of-30 to -10°C. The condensed mixture was stirred at 0 to 5°C for 2 hours. The reaction mixture was quenched in sodium chloride solution at 10 to 30°C to obtain two phases. The organic layer was separated and washed with tartaric acid solution 5% and subsequently with water. The organic layer was treated with activated charcoal and filtered. The filtrate was treated with alkali salt of Heptanoic acid to obtain Montelukast Sodium. Montelukast Sodium was treated with molecular sieve and activated charcoal and filtered. The filtrate was treated with 400 ml of ethyl acetate and removed by vacuum distillation at 32 to 35°C. To the reaction mixture, 500 ml of toluene and 3000 ml n Heptane were added and stirred. The reaction mixture was filtered. The filtrate was vacuum distilled at 60 to 65° C and the product was dried. Yield: 80 gms.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005 PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PROCESS FOR THE PREPARATION OF MONTELUKAST SODIUM
2. APPLICANTS
Name : Melody Healthcare Private Limited
Nationality : Indian Company
Address : 505, Unique Tower, Behind Patel Petrol Pump, Off S.V.Road, Goregaon (West), Mumbai 400062
3. INVENTORS
Names : Shetty Jayram
Nationality : Indian National
Address : Ostwal Empire, L-1 building, Flat no 101, Opp Hotel Madhur, Navapur Navapur Road, Boisar, Thane 401506, Maharashtra
4. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and the manner in
which it is to be performed:

Technical field:
The present invention relates to an improved process for the preparation of [R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy-1 -methylethyl)phenyl] -propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt of Formula (I);

Formula I
The present invention particularly relates to a process for the preparation of [R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl] -propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt by isolating crystallized salt with high purity and yield and low residual solvent.
Prior Art:
[R-([E)]-l-[[[l-[3 ~[2-(7-chloroquinolin-2-yl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl] - propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt is commonly known as Montelukast Sodium. It is an orally administered Leukotriene D-4 antagonist developed for the treatment of chronic asthma and allergic rhinitis.
Montelukast was first developed by Merck and is disclosed in US 5,565,473. Montelukast Sodium is prepared by condensing 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenyl)3-(methanesulfonyloxy)methylethyl)phenyl)-2-propoxy) tetrahydropyran (II) with methyl-1-

(acetylthiomethyl)cyclopropane acetate (III) in the presence of cesium carbonate to produce methyl-4-((l(R)- (3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)3-(2-(2-(2-tetrahydropyranyloxy)-2-methylethyl)phenyl)propyl)thio) cyclopropyl acetate (IV), which is deprotected in the presence of pyridinium-p-toluene sulfonate followed by conversion to Montelukast Sodium (I) in the presence of sodium base in a mixture of solvent i.e. Methanol and tetrahydrofuran. Scheme I demonstrates the schematic representation of the process.
The above process requires tedious chromatographic purification of both intermediates and the final product which results into low yield. Thus the process is not commercially viable.
US 5,614,632 discloses a process for the preparation of Montelukast Sodium. 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl) ethenyl)phenyl )3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) is condensed with anion of l-(mercaptomethyl) cyclopropaneacetic acid (VII) to obtain crude Montelukast. Montelukast is further converted into its dicyclohexylamine salt which is further converted into sodium salt upon treatment with sodium hydroxide. Scheme II demonstrates the schematic representation of the process.
Condensation of 2-(2-(2-(3-(S)-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenyl )3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) with l-(mercaptomethyl) cyclopropaneacetic acid (VII) in the presence of strong base n-butyl lithium results into undesired impurities. The removal of impurities is difficult and requires tedious purification. Thus major drawback is low yield and low purity of Montelukast.

♦ -XjC-
m

Na®
or

COOMe
COOMe

SCHEME!

♦ »AX^»
vn

COOH
nc

vm

nc

COOH

.P

IX
S^N^^COOPS

SCHEME-O

Objects of the invention
An object of the present invention is to provide a process for the preparation of Montelukast Sodium in crystallized form with high purity of 99 to 99.6 % and high yield of 80 to 82%.
Another object of the invention is to provide a process for the preparation of Montelukast Sodium by eliminating steps of preparation of Montelukast dicyclohexylamine salt and further conversion into its free acid for purification, thereby process becomes cost-effective.
Another object of the present invention is to provide a process for the preparation of Montelukast Sodium by crystallizing Montelukast Sodium in a mixture of toluene and n-Heptane followed by reacting Montelukast free acid with alkali salt of organic acid, thus avoiding highly hygroscopic chemical like sodium methoxide or sodium hydroxide for the preparation of Sodium salt thereby process becomes simple and easy to operate.
Another object of the invention is to provide a process for the preparation of Montelukast Sodium where the process eliminates purification by chromatography thereby making the process economical and simple.
Detailed Description
According to the invention there is provided a process for the preparation of Montelukast
Sodium, the process comprising the steps of
a) preparing 2-(2-(3-(S)-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)3-
(methanesulfonyloxy) methylethyl) phenyl)-2-propanol (VI) by dissolving 2-
(2-(2-(3-(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl-3-hydroxy-
propyl)phenyl)-2-propanol in a mixture of acetonitrile and toluene at 30 to 35° C , adding di-iso propylthylamine, cooling the reaction mixture to -20° C and

adding slowly methane sulphonyl chloride at -20° to -10 °C, stirring the reaction mixture at -35 to -30°C to obtain compound of formula (VI);
b) condensing the compound of formula (VI) with l-(mercaptomethyl) cyclopropaneacetic acid (VII) in the presence of N-Butyl lithium and solvent selected from tetrahydrofuran at temperature of -30 to -10° C to obtain condensed mixture comprising Montelukast free acid;
c) stirring the condensed mixture at 0 to 5° C for at least 2 hours;
d) quenching the reaction mass in sodium chloride solution and ethyl acetate at 10 to 30°C to obtain two phases;
e) separating organic phase comprising Montelukast free acid from aqueous phase followed by washing with tartaric acid solution and subsequently with water;
f) treating the organic layer comprising Montelukast free acid with activated charcoal and filter;
g) distilling out ethyl acetate from the organic layer comprising Montelukast free acid under vacuum at 28 to 30°C;
h) converting Montelukast free acid into Montelukast Sodium salt by treating it with alkali salt of free acid in the presence of ethyl acetate and
i) Montelukast Sodium salt was crystallized by using solvent such as n-heptane, toluene, ethyl acetate or mixture thereof.
The alkali salt of organic acid is alkali salt of propanoic acid, alkali salt of heptanoic acid, and alkali salt of octanoic acid. Most preferably sodium salt of heptanoic acid is used. The purity of Montelukast Sodium prepared by the above process is 99 % to 99.6%. The yield of Montelukast Sodium prepared by the above process is 80 to 82 %
Thus the purity and yield is high and also eliminates the purification by chromatography. The purification is carried out by simple solvent treatment such as ethyl acetate. The process of the present invention eliminates steps of preparation of Montelukast dicyclohexylamine salt and further conversion into its free acid for purification. Montelukast dicyclohexylamine salt is not stable and very difficult to handle. The present

process uses alkali salt of organic acid instead of highly hygroscopic chemical like sodium methoxide or sodium hydroxide to prepare Montelukast Sodium. Thus the present process is simple and easy to operate and cost-effective.
The following example demonstrates the nature of the invention and is provided for illustrative purpose only and should be construed to limit the scope of the invention.
Example:
100 gms of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl-3-hydroxy-propyl) phenyl)-2-propanol was dissolved in a mixture of acetonitrile (300 ml) and toluene (100 ml) at 30to 35°C. To this mixture, 40 gms di-isopropylethylamine was added and chilled to -20°C. To this chilled mixture, methane sulphonyl chloride (19.16 gms) was slowly added at -20 to -10°C and stirred it at -35 to -30°C. The reaction mixture is filtered to obtain 2-(2-(3-(S)-(3-(2-(7-chloroquinoli-2-yl) ethenyl) phenyl) 3-(methanesulfonyloxy) methylethyl) phenyl)-2-propanol. The product was condensed with l-(mercaptomethyl) cyclopropaneacetic acid in presence of 36.76 gms of n-butyl lithium salt and 300ml of tetrahydrofuran at temperature of-30 to -10°C. The condensed mixture was stirred at 0 to 5°C for 2 hours. The reaction mixture was quenched in sodium chloride solution at 10 to 30°C to obtain two phases. The organic layer was separated and washed with tartaric acid solution 5% and subsequently with water. The organic layer was treated with activated charcoal and filtered. The filtrate was treated with alkali salt of Heptanoic acid to obtain Montelukast Sodium. Montelukast Sodium was treated with molecular sieve and activated charcoal and filtered. The filtrate was treated with 400 ml of ethyl acetate and removed by vacuum distillation at 32 to 35°C. To the reaction mixture, 500 ml of toluene and 3000 ml n Heptane were added and stirred. The reaction mixture was filtered. The filtrate was vacuum distilled at 60 to 65° C and the product was dried. Yield: 80 gms.

Documents:

320-MUM-2008-ABSTRACT(12-2-2009).pdf

320-MUM-2008-CLAIMS(12-2-2009).pdf

320-MUM-2008-CLAIMS(AMENDED)-(7-7-2014).pdf

320-MUM-2008-Claims-211114.pdf

320-MUM-2008-CORRESPONDENCE 1(12-2-2009).pdf

320-MUM-2008-CORRESPONDENCE(11-12-2009).pdf

320-MUM-2008-CORRESPONDENCE(12-2-2009).pdf

320-MUM-2008-CORRESPONDENCE(13-2-2008).pdf

320-MUM-2008-CORRESPONDENCE(19-5-2014).pdf

320-MUM-2008-Correspondence-211114.pdf

320-mum-2008-correspondence-received.pdf

320-mum-2008-description (provisional).pdf

320-MUM-2008-DESCRIPTION(COMPLETE)-(12-2-2009).pdf

320-mum-2008-digram.doc

320-MUM-2008-FORM 1(12-2-2009).pdf

320-MUM-2008-FORM 1(13-2-2008).pdf

320-MUM-2008-FORM 1(20-2-2013).pdf

320-MUM-2008-FORM 18(11-12-2009).pdf

320-mum-2008-form 2(12-2-2009).pdf

320-MUM-2008-FORM 2(TITLE PAGE)-(12-2-2009).pdf

320-MUM-2008-FORM 2(TITLE PAGE)-(20-2-2013).pdf

320-MUM-2008-FORM 2(TITLE PAGE)-(PROVISIONAL)-(13-2-2008).pdf

320-MUM-2008-FORM 26(11-12-2009).pdf

320-MUM-2008-FORM 26(12-2-2009).pdf

320-MUM-2008-FORM 26(13-2-2008).pdf

320-MUM-2008-FORM 3(12-2-2009).pdf

320-MUM-2008-FORM 3(13-2-2008).pdf

320-MUM-2008-FORM 5(12-2-2009).pdf

320-MUM-2008-FORM 9(12-2-2009).pdf

320-mum-2008-form-1.pdf

320-mum-2008-form-2.doc

320-mum-2008-form-2.pdf

320-mum-2008-form-26.pdf

320-mum-2008-form-3.pdf

320-MUM-2008-OTHER DOCUMENT(20-2-2013).pdf

320-MUM-2008-REPLY TO EXAMINATION REPORT(20-2-2013).pdf

320-MUM-2008-REPLY TO HEARING(7-7-2014).pdf

320-MUM-2008-SPECIFICATION(AMENDED)-(20-2-2013).pdf

« Previous Patent

Next Patent »

Patent Number

263994

Indian Patent Application Number

320/MUM/2008

PG Journal Number

49/2014

Publication Date

05-Dec-2014

Grant Date

28-Nov-2014

Date of Filing

13-Feb-2008

Name of Patentee

MELODY HEALTHCARE PRIVATE LIMITED

Applicant Address

505, UNIQUE TOWER, BEHIND PATEL PETROL PUMP, OFF S.V. ROAD, GOREGAON(WEST), MUMBAI.

Inventors:

#	Inventor's Name	Inventor's Address
1	SHETTY JAYRAM	OSTWAL EMPIRE, L-1, BUILDING, FLAT-101, OPP. HOTEL MADHUR, BOISAR, DIST-THANA.

PCT International Classification Number

C07D215/18

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA