FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"PROCESS FOR THE PREPARATION OF MONTELUKAST FREE ACID AND ITS STRONTIL SALT'
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Murnbai Maharashtra, India. Pin Code; 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR THE PREPARATION OF MONTELUKAST FREE ACID AND ITS STRONTIUM SALT

FIELD OF THE INVENTION

The present invention relates to Strontium salt of montelukast free acid [R - (E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1 methyl ethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid and methods for their preparation.

BACKGROUND OF THE INVENTION

Montelukast sodium is described chemically as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy-1 -methylethyl)phenyl]propyl]thio] methyl]cyclopropaneacetic acid, monosodium salt having the structural Formula I, and is known from U.S. Patent No. 5,565,473.

Formula I

The proprietary name of montelukast sodium is Singulair and is indicated for the prophylaxis and chronic treatment of asthma, for prevention of exercise-induced bronchoconstriction and for relief of symptoms of allergic rhinitis in adults.

U.S. Patent No. 5,565,473 discloses a process for preparing montelukast sodium by reacting 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyI) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1-(acetylthiomethyl) cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of montelukast in pyran protected form, which is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium of Formula (I). This process is not suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and / or the final product with low yield.

Montelukast and its pharmaceutically acceptable salts are obtained by complex synthetic procedures which cause the formation of several by-products due to competing side reactions. These processes need tedious workups to isolate the montelukast and its intermediates and thus results in excess time cycle, which in turn rendering the process more costly and less eco friendly.

Montelukast and its precursors are unstable to oxygen and light causing a fast degradation. For the above reasons, montelukast is generally obtained with a low degree of chemical and optical purity.

Some processes for the purification of montelukast have been described in the art which are based on the formation of its salts.

U.S. Patent No. 5,614,632 describes a process for the preparation of montelukast, which comprises reacting the dilithium dianion of l-(mercaptomethyl)-cyclopropane acetic acid with 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol to afford montelukast acid. The crude montelukast acid is purified through the formation of its dicyclohexyl amine salt.

U.S. Patent Publication No. 2005/0234241 describes a process for the purification of montelukast via the formation of an amine salt using the amine NR1R2R3, wherein R1 = R2 = R3 = H or C1-5 alkyl, preferably R1= (CH3)3C- and R2= R3= H.

U.S. Patent Publication No. 2005/107612 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as, tert butyl amine salt and phenyl ethylamine.

PCT Publication no. 2006/008751 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as diisopropylamine, dipropylamine, tributylamine, dibenzylamine, dicyclohexylamine, and alpha-methylbenzylamine.

U.S. Patent Publication No. 2007/0078158 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as di-n-propyl amine.

U.S. Patent Publication No. 2007/0213365 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as cyclopentyl amine, cyclohexyl amine, cycloheptyl amine, cyclododecyl amine, dicyclohexyl amine, phenethyl amine and cyclooctyl amine.

PCT Application no. 2008/017669 describes a process for the purification of montelukast via the formation of an amine salt using the amine selected from the group consisting of tris-(hydroxymethyl) aminomethane, L-(+)-threo-2-amino-l-phenyl-l,3-propanediol, and L-(+)-α-phenylglycinol, in the presence of an appropriate solvent.

PCT Application no. 2008/062478 describes a process for the purification of montelukast via the formation of an amine salt using the amine selected from cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, pyrrolidine or morpholine or alkyl amines such as methyl amine, isopropyl amine, diisopropyl amine, tert-butyl amine, n-butyl amine, isobutyl amine, sec-butyl amine and n-methyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine.

PCT Application no. 2008/023044 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as trans-4-aminocyclohexanol, cyclohexylamine, dicyclohexylamine, tertiary octylamine.

PCT Application no. 2008/015703 describes a process for the purification of montelukast via the formation of an amine salt using the amine such as isopropyl amine and cyclohexyl amine.

U.S. Patent No. 7,446,116 describes a process for the purification of montelukast via the formation of an amantadine salt of montelukast.

U.S. Patent Publication No. 2009/0005413 describes a process for the purification of montelukast via the formation of tert-butyl amine salt of montelukast.

PCT Application no. 2009/098271 describes a process for the purification of montelukast via the formation of montelukast tert-amylamine salt.

Indian Patent Application No. 2406/MUM/2008 describes a process for the purification of montelukast via the formation of montelukast di-n-butyl amine salt.

PCT Publication no. 2009/117381 describe that montelukast can be purified via alkali metal or alkaline earth metal salt of montelukast such as lithium, sodium, potassium, cesium, magnesium, calcium or strontium.

The prior-art processes for purifying montelukast sodium involve the formation and isolation of montelukast amine salt. Montelukast amine salts are sparingly soluble in organic solvents such as toluene, diisopropyl ether and ethyl acetate hence resulting in low yield of purified montelukast sodium.

Accordingly there is a need in the art to develop a purification process of montelukast acid and its pharmaceutically acceptable salts such as montelukast sodium, which produces purified montelukast sodium in high yield.

SUMMARY OF THE INVENTION:

A first aspect of the present invention is to prepare substantially pure montelukast sodium of formula I comprising the steps of:
a. reacting 1-(mercaptomethyl) cyclopropane acetic acid compound of formula IV with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V to get montelukast acid of formula II,

b. reacting montelukast acid of formula II with a source of strontium to get montelukast strontium salt of formula III and

c. converting montelukast strontium salt of formula III into substantially pure montelukast sodium of formula I.

A second aspect of the present invention is to provide montelukast strontium salt of formula III.

DETAILED DESCRIPTION OF THE INVENTION:

2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V may be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,565,473; 5,523,477; 5,614,632; 7,501,517 and 7,528,254, which are incorporated herein by reference only.
2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V may be prepared in-situ by reacting 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)-phenyl)-3-hydroxypropyl) phenyl)-2-propanol compound of formula VI with methane sulfonyl chloride in an organic solvent in the presence of an organic base.

The examples of organic solvent may include toluene, acetonitrile, dichloromethane, xylene, tetrahydrofuran, cyclopentyl methyl ether, 2-methyl tetrahydrofuran or mixture(s) thereof.

The examples of organic base may include sodium methoxide, sodium ethoxide, triethyl amine, N, N-diisopropyl ethyl amine, diethyl amine, benzyl amine or tertiary butyl amine.

The reaction of 1-(mercaptomethyl) cyclopropane acetic acid compound of formula IV with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V may be carried out in aprotic polar solvent in the presence of base at a temperature in the range of -15°C to 0°C for a period of 4 hours to 15 hours to get montelukast acid of formula II .

The examples of aprotic polar solvent may be selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl acetamide or mixture(s) thereof.

The examples of base may include diethylamine, triethyl amine, sodium methoxide, strontium hydroxide, sodium ethoxide, N, N-diisopropyl ethyl amine, benzyl amine, tertiary butyl amine or lithium hydroxide.

The montelukast acid of formula II may be reacted with a source of strontium in organic solvent at a temperature in the range of 0°C to 60°C to get montelukast strontium salt of formula III.

The examples of source of strontium may include strontium chloride hexahyadrate, strontium carbonate or strontium hydroxide.

The example of organic solvent may include alkyl acetate solvents such as methyl acetate, ethyl acetate, diisopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or propyl acetate and alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol or pentanol.

Montelukast strontium salt of formula III may be isolated by the steps of precipitation, filtration, centrifugation, washing, drying or the combination thereof.

Montelukast strontium salt of formula III may be dried at a temperature in the range of 50°C to 80°C under reduced pressure.

Montelukast strontium salt of formula III may be desaltify with an inorganic acid such as hydrochloric acid and then resulting montelukast acid may be reacted with sodium methoxide in an organic solvent to get substantially pure montelukast sodium of formula I. The term “substantially pure montelukast sodium of formula I” described herein refers to montelukast sodium having less than 0.1% weight / weight of montelukast sulfoxide impurity of formula VII; montelukast styrene impurity of formula VIIII and montelukast cyclic ether impurity of formula IX.

The reaction of montelukast acid of formula II with sodium methoxide may be carried out at a temperature in the range of 25°C to 40°C.

The examples of organic solvent may include toluene, heptane, acetone, methanol, acetonitrile, xylene, tetrahydrofuran, ethanol, isobutanol or mixture(s) thereof.

The substantially pure montelukast sodium of formula I obtained by the present invention may be dried at a temperature in the range of 40°C to 90°C for a period of 6 hours to 18 hours.

The substantially pure montelukast sodium of formula I obtained by the present invention may be amorphous or crystalline in nature.

The limit of detection for montelukast sulfoxide impurity of formula VII; montelukast styrene impurity of formula VIIII and montelukast cyclic ether impurity of formula IX is 0.001% weight / weight.

The limit of quantitation for montelukast sulfoxide impurity of formula VII; montelukast styrene impurity of formula VIIII and montelukast cyclic ether impurity of formula IX is 0.01% weight / weight.

In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way

EXAMPLE-1: PREPARATION OF SUBSTANTIALLY PURE MONTELUKAST SODIUM OF FORMULA I

Step 1: Preparation of montelukast acid of formula II

A solution of 2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl)-phenyl)-3- hydroxypropyl) phenyl)-2-propanol (100gm) in tetrahydrofuran (400 ml) was added di-diisopropylethylamine (56.3gm) at -15°C to -10°C and then resulting reaction mixture was agitated for 10 minutes at the same temperature and then methane sulfonyl chloride (37.4gm) was added dropwise in a period of 2.5 hours at -15 °C to -10°C. The resulting reaction mixture was agitated for 60 minutes at -15 °C to -10°C and then it was diluted with N, N-dimethylformamide (300 ml) and then 1-(mercaptomethyl) cyclopropaneacetic acid (51gm) was added at -15°C to -10° in 15 minutes. The resulting reaction mixture was agitated for 15 minutes to -5°C to 0°C for 30 minutes and then the solution of sodium methoxide (165gm) in methanol (550ml) was added and resulting reaction mixture was agitated at 0°C to -5°C for 5 hours. The reaction mixture was quenched with water (1500ml) and diisopropyl ether (1000ml) at 25°C to 30°C and then aqueous layer was separated and treated with sodium chloride (100gm) and ethyl acetate (1000ml). The organic layer (ethyl acetate layer) was separated, dried under reduced pressure to get crude montelukast acid of formula II.
Yield: 120gm

Step 2: Preparation of montelukast strontium salt of formula III

A solution of montelukast acid obtained in step 1 (100gm) in ethyl acetate (1000ml) was added a solution of strontium chloride hexahyadrate (46gm) in methanol (200ml) at 25-30°C and then resulting reaction mixture was agitated for 24 hours at the same temperature and then it was diluted with water (1000ml) and then resulting solids were filtered, washed with water (50ml) and dried under reduced pressure to get montelukast strontium salt of formula III
Yield: 200gm

Step 3: Preparation of substantially pure montelukast sodium of formula I

A solution of montelukast strontium salt of formula III (100gm) in a mixture of toluene (500ml) was acidified up to pH 5.5 with hydrochloric acid and then it was diluted with water (250ml). The organic layer was separated, washed with water (2x100ml) and then sodium methoxide (10gm) was added and resulting reaction mixture was agitated for 2 hours and then it was filtered on hyflow-bed. The filtrated was concentrated up to 50ml volume and then it was added dropwise into n-heptane (300ml) and then resulting solids were filtered, washed with toluene (25 ml) and dried at 80°C under reduced pressure.
Yield: 42gm
Purity: 99.95%
Montelukast sulfoxide impurity of formula VII: 0.01%
Montelukast styrene impurity of formula VIIII: 0.01%
Montelukast cyclic ether impurity of formula IX: 0.02%

Dated this (27th) day of October, 2010

(Signed)____________________
Dr. B.V. Siva Kumar

Chief Scientific Officer
(Enaltec Labs Private Limited)

WE CLAIM:

1. A process for preparing substantially pure montelukast sodium of formula I comprising the steps of:
a. reacting 1-(mercaptomethyl) cyclopropane acetic acid compound of formula IV with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V to get montelukast acid of formula II,

b. reacting montelukast acid of formula II with a source of strontium to get montelukast strontium salt of formula III and

c. converting montelukast strontium salt of formula III into substantially pure montelukast sodium of formula I.
2. The process according to claim 1, wherein reaction of 1-(mercaptomethyl) cyclopropane acetic acid compound of formula IV with 2-(2-(2(S)-(3-(2-(7- chloro-2-quinolinyl)-ethenyl) phenyl)-3-methane sulfonyloxypropyl) phenyl)-2-propanol compound of formula V is carried out in an aprotic polar solvent in the presence of base at a temperature in the range of -15°C to 0°C for a period of 4 hours to 15 hours to get montelukast acid of formula II .
3. The process according to claim 2, wherein aprotic polar solvent is selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, acetonitrile, dimethyl acetamide or mixture(s) thereof.

4. The process according to claim 2, wherein base is selected from the group comprising of diethylamine, triethyl amine, sodium methoxide, strontium hydroxide, sodium ethoxide, N, N-diisopropyl ethyl amine, benzyl amine, tertiary butyl amine or lithium hydroxide.

5. The process according to claim 2, wherein montelukast acid of formula II is reacted with a source of strontium in organic solvent at a temperature in the range of 0°C to 60°C to get montelukast strontium salt of formula III.

6. The process according to claims 1 and 5, wherein source of strontium is strontium chloride hexahyadrate, strontium carbonate or strontium hydroxide.

7. The process according to 5, wherein organic solvent is selected from the group comprising of alkyl acetate solvents such as methyl acetate, ethyl acetate, diisopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or propyl acetate and alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol or pentanol.

8. The process according to claim 1, wherein montelukast strontium salt of formula III is desaltify with hydrochloric acid to get montelukast acid, which is reacted with sodium methoxide to get substantially pure montelukast sodium of formula I.

9. The process according to claim 1, wherein “substantially pure montelukast sodium of formula I contain less than 0.1% weight / weight of montelukast sulfoxide impurity of formula VII; montelukast styrene impurity of formula VIIII and montelukast cyclic ether impurity of formula IX.

10. A process for the preparation of substantially pure montelukast sodium of formula I as herein described in specification and example.