Process for preparing montelukast and salts thereof

1. A process for preparation of Montelukast or a salt thereof, said process comprising the steps of:

reacting (S)-1-(3-(E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-isopropenyl phenyl]propan-1-ol with methane sulfonyl chloride or toluene sulfonyl chloride to obtain a hydroxy styrene mesylate salt or tosylate salt;

condensing the hydroxy styrene mesylate salt or tosylate salt with 1-(mercapto methyl)cyclopropane acetic acid followed by salification with an amine to obtain (1-[(R)-1-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanyl methyl]cyclopropyl]acetic acid styrene amine salt;

converting the styrene amine salt to Montelukast amine salt; and

converting the Montelukast amine salt to Montelukast free acid or an alkali or alkaline salt of Montelukast.

2. The process of claim 1 , wherein the reacting step is carried out in the presence of an organic solvent selected from one of chlorinated hydrocarbons, aromatic hydrocarbons, Tetrahydrofuran and mixtures thereof.

3. The process of claim 1 , wherein the condensing step is carried out in a polar solvent in the presence of a base.

4. The process of claim 3 , wherein said polar solvent is selected from one of N,N-dimethylformamide, dimethylsulphoxide, N,N-dimethylacetamide, N- methylpyrrolidine, methanol, THF and mixtures thereof.

5. The process of claim 3 , wherein said base is selected from one of metal alkoxides, metal hydrides, metal carbonates, alkyl lithium salts and mixtures thereof.

6. The process of claim 1 , wherein the styrene amine salt is dicyclohexylamine salt.

7. The process of claim 1 , wherein the first converting step further comprises treating said styrene amine salt with sulphuric acid; and isolating the obtained Montelukast as an amine salt.

8. The process of claim 1 , wherein the first converting step further optionally comprises converting said styrene amine salt to its free acid; treating said free acid with sulphuric acid; and isolating the obtained Montelukast as an amine salt.

9. The process of claim 1 , wherein said Montelukast amine salt is one of 1-methyl-3-phenylpropylamine, 1,2-cyclohexyl diamine salt and mixtures thereof.

10. The process of claim 1 , wherein the second converting step comprises converting said Montelukast amine salt to its free acid; treating the free acid with an alkali or alkaline base; and isolating the resultant alkali or alkaline salt of Montelukast.

11. The process of claim 1 , wherein the second converting step further comprises:

providing a solution of Montelukast free acid in one of a halogenated solvent, aromatic solvent, alkanols and mixtures thereof;

treating said solution with an alcoholic base to convert said Montelukast free acid to an alkali or an alkaline salt of Montelukast;

concentrating the reaction mass to dryness; and

adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said alkali or alkaline salt of Montelukast.

12. The process of claim 1 , wherein the second converting step further optionally comprises treating said Montelukast amine salt with an alkali or an alkaline base; and isolating Montelukast as its alkali or alkaline salt.

13. The process of claim 12 , wherein the second converting step further comprises:

providing a solution of Montelukast amine salt in one of a halogenated solvent, aromatic solvent, or mixtures thereof;

treating said solution with an alkali or an alkaline base to convert said Montelukast amine salt into a salt of Montelukast;

concentrating the reaction mass to dryness; and

adding a cyclic or acyclic hydrocarbon solvent to said solution to precipitate said alkali or alkaline salt of Montelukast.

14. The process of claim 13 , wherein the alkali or alkaline base is selected from one of sodium hydroxide, sodium methoxide and sodium ethoxide in an alcohol; and wherein the alcohol is selected from one of methanol, ethanol, propanol, butanol, 2-propanol and tert-butanol.

15. The process of claim 11 , wherein said hydrocarbon solvent is selected from one of cyclohexane, pentane, hexane, heptane and mixtures thereof.

16. The process of claim 13 , wherein said hydrocarbon solvent is selected from one of cyclohexane, pentane, hexane, heptane and mixtures thereof.

17. The process of clam 1 , wherein the reacting step is performed at a temperature of about −25° C. to about 50° C.

18. The process of claim 1 , wherein the condensing step is performed at a temperature of about −15° C. to about 60° C.

19. The process of claim 7 , wherein the first converting step is performed at a temperature of about −20° C. to about 50° C.

20. The process of claim 11 , wherein the halogentated solvent is selected from one of: chloroform, dichloromethane and dichloroethane.

21. The process of claim 11 , wherein the aromatic solvent is toluene.

22. A process for preparation of Montelukast or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

reacting a hydroxy styrene compound with a methane sulfonyl chloride in the presence of a tertiary amine, in a polar, a non-polar or a mixture of polar and non-polar organic solvent to obtain a reaction mass;

stirring the reaction mass until the reaction is substantially complete to obtain the mesylated compound of formula (V);

reacting the mesylated compound of formula (V) with 1-mercapto methyl cyclopropane acetic acid in a polar organic solvent or mixture of polar solvents, and in the presence of a base, and stirring until the reaction is substantially complete to obtain a styrene compound;

reacting with dicyclohexyl amine salt to afford an amine salt of the compound of formula (VI);

treating the dicyclohexyl amine salt of formula (VI) with sulphuric acid, wherein the sulphuric acid is either aqueous or concentrated;

stirring until the reaction is substantially complete, to isolate Montelukast acid;

further reacting the resultant Montelukast free acid with primary, secondary or tertiary amines to obtain an amine salt of the compound of formula (VII);

converting the amine salt of formula (VII) into its pharmaceutically acceptable salts by generating Montelukast free acid from the amine salt in a halogenated solvent or an aromatic hydrocarbon in the presence of an organic acid.

23. The process of claim 21 , further comprising the steps of:

converting to a sodium salt of Montelukast using sodium hydroxide, sodium methoxide or sodium ethoxide in an alcohol selected from one of methanol, ethanol, propanol, butanol, 2-propanol and tertbutanol;

distilling the alcohol under reduced pressure until a residue is formed;

dissolving the residue in methanol and treating with activated carbon;

distilling the methanol completely;

isolating the desired product by adding cyclohexane, n-pentane, n-heptane or a hexane; and

drying the isolated solid under vacuum.