Process for preparing Montelukast and salts thereof

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

condensing styrene mesylate of formula (V)

with 1-(mercaptomethyl)cyclopropane acetic acid with an amine to obtain (1-[(R)-1-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanylmethyl]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 condensing step is carried out in a polar solvent in the presence of a base.

3. The process of claim 2 , wherein said polar solvent is selected from the group consisting of N,N-dimethylformamide, dimethylsulphoxide, N,N-dimethylacetamide, N-methylpyrrolidine, methanol, THF and mixtures thereof.

4. The process of claim 2 , wherein said base is selected from the group consisting of metal alkoxides, metal hydrides, metal carbonates, alkyl lithium salts and mixtures thereof.

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

6. The process of claim 1 , wherein the first converting step comprises the steps of:

treating said styrene amine salt with sulphuric acid; and

isolating the obtained Montelukast as an amine salt.

7. The process of claim 1 , wherein the first converting step comprises the steps of:

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.

8. The process of claim 1 , wherein said Montelukast amine salt is selected from the group consisting of 1-methyl-3-phenylpropylamine, 1,2-cyclohexyl diamine salt and mixtures thereof.

9. The process of claim 1 , wherein the second converting step comprises the steps of:

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.

10. The process of claim 1 , wherein the second converting step comprises the steps of:

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 by drying; and

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

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

treating said Montelukast amine salt with an alkali or an alkaline base; and isolating Montelukast as its alkali or alkaline salt.

12. The process of claim 1 , wherein the second converting step comprises the steps of:

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.

13. The process of claim 12 , wherein the alkali or alkaline base is selected from the group consisting of sodium hydroxide, sodium methoxide and sodium ethoxide in an alcohol; and wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, 2-propanol and tert-butanol.

14. The process of claim 10 , wherein said hydrocarbon solvent is selected from the group consisting of cyclohexane, pentane, hexane, heptane and mixtures thereof.

15. The process of claim 12 , wherein said hydrocarbon solvent is selected from the group consisting of cyclohexane, pentane, hexane, heptane and mixtures thereof.

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

17. The process of claim 1 , wherein the first converting step is performed at a temperature of −20° C. to 50° C.

18. The process of claim 10 , wherein the halogenated solvent is selected from the group consisting of chloroform, dichloromethane, and dichloroethane.

19. The process of claim 10 , wherein the aromatic solvent is toluene.

20. A method for making 1-methyl-3-phenylpropylamine salt of Montelukast comprising the steps of

condensing styrene mesylate of formula (V)

with 1-(mercaptomethyl)cyclopropane acetic acid and 1-methyl-3-phenylpropylamine to obtain (1-[(R)-1-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanylmethyl]cyclopropyl]acetic acid styrene 1-methyl-3-phenylpropylamine salt;

treating the styrene 1-methyl-3-phenylpropylamine salt with sulfuric acid to produce Montelukast 1-methyl-3-phenylpropylamine salt.