FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of [R- (E)-l-[[[l- [3-[2-[7-chloro-2-quinolinyl] ethenyl] phenyl]-3-[2-(l-hydroxy- 1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid, which is generically known as Montelukast. The present invention also relates to the process for the preparation of amine salts of Montelukast. The structure of the Montelukast can be depicted as Formula (1); the marketed form is Montelukast sodium and is marketed under brand name "Singulair" in US market.

BACK GROUND OF THE INVENTION
Montelukast sodium is a Leukotriene antagonist and useful in the treatment of Asthma as well as other conditions mediated by leukotrienes, such as inflammation and allergies. EP 480717 discloses certain substituted quinoline compounds including [R- (E)-l-[[[l- [3-[2-[7-chloro-2-quinolinyl] ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid (Montelukast), and its pharmaceutically acceptable salts, specifically claimed Sodium salt, methods of making and using them. The process for the preparation of Montelukast is described generically in many ways. The process, which is disclosed in the experimental section, comprises the condensation
of protected 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- methanesulfonyloxypropyl) phenyl)-2-propanol with an ester of l-(mercaptomethyl) cyclopropane acetic acid using hydrazine and cesium carbonate in acetonitrile. The resultant compound is further treated with pyridinium p-toluene sulfonate in presence of methanol produced Montelukast, which is further converted to sodium salt. The patent also disclosed the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium calcium, lithium magnesium, manganese, potassium, sodium and Zinc. Organic salts derived from primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, diethylamine, ethanolamine, purines, theobromine, triethylamine, trimethylamine and tripropylamine.
The patent doesn't describe the process for the preparation of Montelukast amine salts, however the patent has disclosed genetically along with various other pharmaceutically acceptable salts.
The WO patent 95/18107 specifically disclosed the process for the preparation of compound of Formula (1), which comprises the condensation of l-(mercaptomethyl) cyclopropaneacetic acid with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- methanesulfonyloxypropyl) phenyl)-2-propanol in tetrahydrofuran as a solvent using n- butyl lithium at a temperature of-5°C and further reaction work up to produce the free acid of Montelukast, thus obtained free acid was converted to its dicyclohexyl amine salt
in ethyl acetate as solvent and further isolated the solid by adding excess volume of hexane.
The prior art procedure involves the usage of n-butyl lithium, which is not environment friendly reagent on commercial scale, n-butyl lithium is highly reactive with water and liberates butane gas, which is highly inflammable, hence the usage of such reagents are not recommendable on commercial scale. The prior art processes are also involves the usage of more number of reagents and the tedious workup to isolate the Montelukast or its salts thus results in prolonged time cycle of the process, which in turn rendering the process more costly and less eco friendly.
Montelukast of Formula (1) can be easily converted into Montelukast sodium, which is useful in the treatment of Asthma, it is important to have a cost effective and commercially viable process for preparing the compound of Formula (1). Therefore, the main objective of the present invention is to prepare [R- (E)-l-[[[l-[3-[2- [7-chloro-2-quinolinyl] ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid in a commercially viable and environment friendly process. The present invention involves the usage of simple bases instead of n-butyl lithium for the preparation of Montelukast.
Another aspect of the present invention provides the process for the preparation of basic salts of Montelukast, which are the precursor for the preparation of Montelukast sodium. The bases are selected from amines comprising of primary, secondary and tertiary amines further it is converted into Montelukast sodium.
Hence, the process for the preparation of Montelukast and its amine salts of the present invention is simple, cost-effective and environment friendly.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of [R- (E)-l- [[[ 1 -[3-[2-[7-chloro-2-quinolinyl] ethenyl] phenyl]-3-[2-( 1 -hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid (Montelukast) of Formula (1) and its amine salts comprising of primary, secondary and tertiary amines. The amine salts of Montelukast are precursor for the preparation of Montelukast sodium. The improved process for the preparation of Montelukast and its amine salts comprises, mesylation of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol of Formula (2) with methane sulphonyl chloride using triethyl amine as a base, the resulted mesylated compound of Formula (3) is condensed with l-(mercaptomethyl) cyclopropane aceticacid of Formula (4) in the presence of simple base such as sodium hydroxide and sodium methoxide in a solvent to afford the Montelukast. The Montelukast is further converted into its amine salts in conventional methods. The process for the preparation of Montelukast and its amine salts of the present invention is simple, cost-effective and environment friendly. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Montelukast of Formula (1) and its amine salts, preferably primary, secondary and tertiary amines. The amine salts of Montelukast are further converted into Montelukast sodium, which is a known active ingredient for the treatment of Asthma. The process of the present invention is schematically depicted as follows:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol of Formula (2) is reacted with methane sulfonyl chloride in presence of organic base to get the mesylate of Formula (3). The mesylate is condensed with 1- (mercaptomethyl) cyclopropane aceticacid of Formula (4) using a safe and cheaper base such as alcoholic solutions of sodium hydroxide or sodium methoxide or powder sodium methoxide to afford the desired Montelukast of Formula (1). Thus, resulted Montelukast is further converted into its primary, secondary or tertiary amine salts of Formula (5).
Accordingly, an improved process for the preparation of Montelukast of Formula (1) and its amine salts comprises:
a) dissolving 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- hydroxypropyl) phenyl)-2-propanol of Formula (2) in halogenated solvents comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of benzene, toluene, ethyl benzene or xylene and accompanied by removal of water by azeotropic distillation;
b) further partly distilling the solvent from the reaction solution of step (a);
c) optionally diluting the reaction mass obtained in step (b) with halogenated solvent comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of benzene, toluene, ethyl benzene or xylene or polar solvent such as dimethylformamide, acetonitrile propionitrile or tetrahydrofuran;
d) adding methane sulphonyl chloride to the reaction mass of step (c) in presence of organic base comprising of triethylamine, tributylamine, tertiary butylamine or other tertiary alkyl amines at a temperature of-20 to +5°C;
e) stirring the mass of step (d) till the solid separates;
f) filtering the solid separated in step (e) by known methods to afford the mesylate of Formula (3);
g) dissolving l-(mercaptomethyl) cyclopropane aceticacid of Formula (4) in solvents such as tetrahydrofuran or toluene or dimethylformamide accompanied by cooling the solution to a temperature of-5 to +20° C;
h) adding the alkoxide powder or a solution of alkali or alkoxide in C1-C4 straight or branched chain alcohols to the reaction solution of step (g) followed by adding the solution of mesylate of Formula (3) in solvents such as tetrahydrofuran or toluene or dimethylformamide;
i) stirring the reaction mass obtained in step (h) at a temperature of 0-10°C for 5-30 hours;
j) adding aqueous sodium chloride solution and an ester solvent such as methyl acetate or ethyl acetate or aromatic hydrocarbon solvent such as toluene, ethybenzene or xylene or halogenated solvent such as chloroform, dichloromethane or dichloroethane;
k) separating the organic layer from the reaction solution of step (j);
1) distilling of the solvent from the reaction solution of step (k) to afford the Montelukast of Formula (1) as a residual mass;
m) optionally triturating the residual mass obtained in step (1) in aliphatic cyclic or alicyclic or acyclic hydrocarbon solvent such as n-hexane, n-heptane, pet. ether or cyclohexane or mixtures thereof to get the Montelukast of Formula (1) in solid form;
n) converting the Montelukast of Formula (1) into its amine salts of Formula (5), particularly with primary, secondary or tertiary amines in a known method. The alkali or alkoxide mentioned in step (h) comprising of sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium methoxide or sodium ethoxide and C1-C4 straight or branched chain alcohols comprising of methanol, ethanol, n-propanol, isopropanol, n- butanol, secondary butanol or tertiary butanol. The preferred alcoholic alkali or alkoxide
solution is methanolic sodium hydroxide or methanolic sodium methoxide solution. The sodium methoxide powder is also used in step (h) of the above process to get Montelukast.
The present invention hence provides a cost effective and eco-friendly process, which involves safe and cheaper base for condensing 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol and 1- (mercaptomethyl) cyclopropane aceticacid to afford the Montelukast. The Montelukast amine salts thus obtained in this process is having more than 99.0% purity with non- solvated and free flowing powder.
Thus, the usage of hazardous raw material n-butyl lithium is avoided as mentioned in the prior art references for the similar condensation to afford Montelukast. The Montelukast obtained in the above process is further converted into its amine salts preferably primary, secondary and tertiary amines. These amine salts are precursors for the preparation of Montelukast sodium in a high purity, which is a known active ingredient for treating asthma.
It is noteworthy to mention that the process for the conversion of Montelukast amine salts to Montelukast sodium is disclosed in our co-pending Indian Patent application vide No. 94/MAS/2002. The starting material of the present invention 2-(2-(3(S)-(3-(2-(7-chloro- 2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2-propanol is prepared as per the procedure disclosed in EP 480717 Example No. 140 step (iii).
The following examples illustrate the invention but do not limit the effective scope of the claims in any way.
Preparation of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-
methanesulfonyloxypropyl) phenyl)-2-propanol (Formula 3):
Example-1:
Method-A:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol (50.0 g) was added to toluene (100.0 ml), heated to reflux and water was removed by azeotropic distillation. Approximately 50.0 ml of toluene was distilled off and the reaction mass was cooled to a temperature of 25-35°C. Then, the reaction mass was further cooled to a temperature of -15 to -10°C followed by acetonitrile (500.0 ml), triethylamine (22.8ml) were added under nitrogen atmosphere and stirred for 15-30 minutes. Methanesulfonyl chloride (9.3 ml) was then added slowly to reaction mass at a temperature of -15 to -10°C and stirred till the reaction is substantially complete. The separated solid was filtered, washed "with chilled acetonitrile (50.0 ml) under nitrogen atmosphere and suck dried under vacuum to afford the title compound (Weight: 58.5 g). Method-B:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol (50.0 g) was added to toluene (500.0 ml), heated to reflux and water was removed by azeotropic distillation. Approximately 100.0 ml of toluene was distilled off and the reaction mass was cooled to a temperature of 25-35°C. Then, the reaction mass was further cooled to a temperature of -15 to -10°C followed by dimethyl formamide (10.0 ml), triethylamine (22.8ml) were added under nitrogen atmosphere and stirred for
15-30 minutes. Methanesulfonyl chloride (9.3 ml) was then added slowly to reaction mass at a temperature of -15 to -10°C and stirred till the reaction is substantially complete. The separated solid was filtered, washed with chilled toluene (50.0 ml) under nitrogen atmosphere and suck dried under vacuum to afford the title compound. (Weight: 58.0 g). Method-C:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol (100.0 g) was added to methylene chloride (500.0 ml), heated to reflux and water was removed by azeotropic distillation. Approximately 400 ml of methylene chloride was distilled off and the reaction mass was cooled to a temperature of 25-35°C. Then, the reaction mass was further cooled to a temperature of -15 to -10°C followed by tributyl amine (62.5 ml) was added under nitrogen atmosphere and stirred for 15-30 minutes. Methanesulfonyl chloride (18.6 ml) was then added slowly to reaction mass at a temperature of-15 to -10°C and stirred till the reaction is substantially complete. The separated solid was filtered, washed with chilled methylene chloride (25.0 ml) followed by hexane (100 ml) under nitrogen atmosphere and suck dried under vacuum to afford the title compound (Weight: 100.0 g). Method-D:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol (50.0 g) was added to toluene (100.0 ml), heated to reflux and water was removed by azeotropic distillation. Approximately 50.0 ml of toluene was distilled off and the reaction mass was cooled to a temperature of 25-35°C. Then, the reaction mass was further cooled to a temperature of -15 to -10°C followed by acetonitrile (500.0 ml), -ibutylamine (39 ml) were added to under nitrogen atmosphere and stirred for 15-30 minutes. Methanesulfonyl chloride (9.3 ml) was then added slowly to reaction mass at a temperature of-15 to -10°C and stirred till the reaction is substantially complete. The separated solid was filtered, washed with chilled acetonitrile (50.0 ml) under nitrogen atmosphere and suck dried under vacuum to afford the title compound (Weight: 41.8 g). Method-E:
2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxypropyl) phenyl)-2- propanol (100.0 g) was added to methylene chloride (250.0 ml), heated to reflux and water was removed by azeotropic distillation. Approximately 50.0 ml of methylene chloride was distilled off and the reaction mass was cooled to a temperature of 25-35°C. Then, the reaction mass was further cooled to a temperature of -15 to -10°C followed by acetonitrile (200.0 ml), tributylamine (62.5 ml) were added under nitrogen atmosphere and stirred for 15-30 minutes. Methanesulfonyl chloride (18.6 ml) was then added slowly to reaction mass at a temperature of -15 to -10°C and stirred till the reaction is substantially complete. The separated solid was filtered, washed with chilled acetonitrile (100.0 ml) followed by hexane (100.0 ml) under nitrogen atmosphere and suck dried under vacuum to afford the title compound (Weight: 85.0 g). Preparation of Montelukast of Formula (1): Example-2: Method-A:
l-(mercapto methyl) cyclo propane acetic acid (6.8 grams) was added to tetrahydrofuran (250 ml) and stirred for 10-15 minutes at a temperature of 25-30°C. Sodium hydroxide flakes (3.73 grams) were dissolved in methanol (112 ml) and the resulting methanolic
sodium hydroxide solution was added to the reaction mass at a temperature of -5 to 0° C. Then, the reaction mass was stirred for 15 to 30 minutes followed by solution of 2-(2-(3- (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-sulfonyloxypropyl) phenyl)-2- propanol (25 grams) in tetrahydrofuran (125 ml) was added. Further, the reaction mass stirred at same temperature till the reaction is substantially complete. Aqueous sodium chloride solution (25 grams in 250 ml of water) was added at a temperature of 5-10°C and the compound was extracted into ethyl acetate (250 ml). The organic layer thus separated was washed with aqueous tartaric acid solution (25 grams in 250 ml of water) and followed by water (3 X 250 ml). The organic layer was dried over sodium sulfate and the solvent was distilled off under vacuum at a temperature of below 50° C. Acetonitrile (50 ml) was added to the residue and the resulting solution was washed with hexane (3 X 100 ml). The solvent acetonitrile was distilled off under vacuum to afford the Montelukast in residual mass (Weight: 25 grams).
The residual mass was triturated with hexane (250 ml) for about 10-12 hours to crystallize the solid mass. The solid mass was filtered, washed with hexane (25 ml) and dried at a temperature of 40°C to a constant weight to afford the title compound in solid form.
(Weight: 15.8 grams). Method-B:
l-(mercapto methyl) cyclo propane acetic acid (3.8 grams) was added to toluene (25 ml) and stirred for 10-15 minutes at a temperature of 25-30°C. Sodium methoxide powder (3.6 grams) was added to the reaction mass and stirred for 15 to 30 minutes. Dimethyl formamide (25.0 ml) followed by 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-sulfonyloxypropyl) phenyl)-2-propanol (15.6 grams) were added and stirred at same temperature till the reaction is substantially complete. Aqueous sodium chloride solution (6.0 grams in 60 ml of water) was added at a temperature of 0-5°C and the compound was extracted into ethyl acetate (75 ml). The organic layer thus separated was washed with aqueous tartaric acid solution (6.0 grams in 60 ml of water) and followed by water (3 X 50 ml). The organic layer was dried over sodium sulfate and the solvent was distilled off under vacuum at a temperature of below 50° C to afford Montelukast in residual mass (Weight: 13 grams). Example-3
Preparation of Montelukast dicyclohexyl amine salt:
Montelukast (13.0 grams, obtained as per Example-2 Method-B) was dissolved in ethyl acetate (60 ml) and dicyclo hexyl amine (6.5 ml) was added and stirred at a temperature of 20-35°C for 6-8 hours to crystallize the solid mass. Acetonitrile (30 ml) was added and the solid mass was filtered, washed with chilled acetonitrile (30 ml) and dried at 50- 55°C to a constant weight to result the title compound. (Weight: 6.0 grams) Example-4
Preparation of Montelukast tertiary butyl amine salt:
Montelukast (72.0 grams, prepared as per Example-2 Method-A) was dissolved in acetone (125 ml) and stirred for clear solution. The solvent acetone was distilled of completely under vacuum at a temperature of below 50°C. Acetone (310 ml) was added to the resulting residual mass and tertiary butyl amine (9.7 ml) was added and stirred at a temperature of 25-35°C for 6-8 hours to crystallize the solid mass. The solid mass was
ltered, washed with acetone (30 ml). The wet material was suspended in a mixture of toluene (62 ml) and hexane (248 ml) and stirred for 1-2 hours at a temperature of 25-35°C. The material was filtered, washed with hexane (30 ml) and dried at 50-55°C to a constant weight to result the title compound. (Weight: 25.9 grams)

We claim:
1. An improved process for the preparation of Montelukast and its amine salts, which comprises:
a. dissolving 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- hydroxypropyl) phenyl)-2-propanol of Formula (2) in halogenated solvents comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of benzene, toluene, ethyl benzene or xylene and accompanied by removal of water by azeotropic distillation;
b. further partly distilling the solvent from the reaction solution of step
(a);
c. optionally diluting the reaction mass obtained in step (b) with halogenated solvent comprising of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride or aromatic hydrocarbon solvents comprising of benzene, toluene, ethyl benzene or xylene or polar solvent such as dimethylformamide, acetonitrile propionitrile or tetrahydrofuran;
d. adding methane sulphonyl chloride to the reaction mass of step (c) in presence of organic base comprising of triethylamine, tributylamine, tertiary butylamine or other tertiary alkyl amines at a temperature of- 20 to +5°C;
e. stirring the mass of step (d) till the solid separates;
f. filtering the solid separated in step (e) by known methods to afford the mesylate of Formula (3);
g. dissolving 1 -(mercaptomethyl) cyclopropane aceticacid of Formula (4) in solvents such as tetrahydrofuran or toluene or dimethylformamide accompanied by cooling the solution to a temperature of-5 to +20° C;
h. adding the alkoxide powder or a solution of alkali or alkoxide in Cl- C4 straight or branched chain alcohols to the reaction solution of step (g) followed by adding the solution of mesylate of Formula (3) in solvents such as tetrahydrofuran or toluene or dimethylformamide;
i. stirring the reaction mass obtained in step (h) at a temperature of 0- 10°C for 5-30 hours ;
j. adding aqueous sodium chloride solution and an ester solvent such as methyl acetate or ethyl acetate or aromatic hydrocarbon solvent such as toluene, ethybenzene or xylene or halogenated solvent such as chloroform, dichloromethane or dichloroethane;
k. separating the organic layer from the reaction solution of step 0);
1. distilling of the solvent from the reaction solution of step (k) to afford the Montelukast of Formula (1) as a residual mass;
m. optionally triturating the residual mass obtained in step (1) in aliphatic cyclic or alicyclic or acyclic hydrocarbon solvent such as n-hexane, n- heptane, pet. ether or cyclohexane or mixtures thereof to get the Montelukast of Formula (1) in solid form;
n. converting the Montelukast of Formula (1) into its amine salts of Formula (5), particularly with primary, secondary or tertiary amines in a known method.

Where R1 and R2 = H or C1-C4 alkyl group individually or together
2. The process according to claim 1 step (a), wherein the said halogenated solvent is methylene chloride.
3. The process according to claim 1 step (a), wherein the said aromatic hydrocarbon solvent is toluene.
4. The process according to claim 1 step (c), wherein the said polar solvent is acetonitrile.
5. The process according to claim 1 step (d), wherein the said organic base is either triethyl amine or tri butyl amine.
6. The process according to claim 1 step (h), wherein the said alcoholic alkali solution is methanolic sodium hydroxide.
7. The process according to claim 1 step (h), wherein the said alcoholic alkoxide solution is methanolic sodium methoxide.
8. The process according to claim 1 step (h), wherein the said metal alkoxide is sodium methoxide powder.
9. The process according to claim 1 step (j)> wherein the said ester solvent is ethyl acetate.
10. The process according to claim 1 step (m), wherein the said aliphatic hydrocarbon solvent is n-hexane.
11. The process according to claim 1 step (n), wherein the primary amine salt of Montelukast is tertiary butyl salt.
12. The process according to claim 1 step (n), wherein the secondary amine salt of Montelukast is dicyclohexyl amine salt.
13. The improved process for the preparation of Montelukast and its amine salts is substantially as herein described and exemplified.