Process for preparation of montelukast sodium

1. A process for preparing montelukast sodium of Formula I,

comprising the steps of:

a) reacting 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxy propyl)phenyl)-2-propanol (diol compound) of formula

with methane sulfonyl chloride in an organic solvent in the presence of a base to obtain a solution of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol (mesylate compound)

b) reacting 1-(mercaptomethyl)cyclopropane acetic acid

with a base and an additional alkali source in a polar aprotic solvent to obtain a solution of dibase salt of 1-(mercaptomethyl)cyclopropane acetic acid;

c) reacting the mesylate compound of step a) with the dibase salt of 1-(mercaptomethyl)cyclopropane acetic acid of step b) at a temperature of about −20° C. to about 10° C. to obtain an montelukast intermediate;

d) converting the montelukast intermediate from step c) with an organic amine to obtain a montelukast amine salt; and

e) converting the montelukast amine salt from step d to montelukast sodium.

2. The process of claim 1 , wherein the organic solvent of step a) is selected from the group consisting of dimethylformamide, dimethyl sulphoxide, dimethyl acetamide, dichloro methane, toluene, xylenes, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, and combinations thereof.

3. The process of claim 1 , wherein the base of step a) is selected from the group consisting of triethylamine, triisobutylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, N-methylmorpholine, N-methylpyrrolidine, pyridine; and combinations thereof.

4. The process of claim 1 , wherein the base of step b) is selected from the group consisting of sodium hydride, lithium hydride, sodium hydroxide, sodium methoxide, lithium methoxide, butyl lithium, potassium tertiary butoxide, quarternary ammonium bases, and combinations thereof.

5. The process of claim 1 , wherein the alkali source of step b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium tertiary butoxide, potassium tertiary butoxide, and mixtures thereof.

6. The process of claim 1 , wherein the polar aprotic solvent of step b) is selected from the group consisting of dimethyl formamide, dimethyl acetamide, acetone, methanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, ethyl acetate, and combinations thereof.

7. The process of claim 1 , wherein the reaction of step c) is carried out by adding the solution of step a) to the solution of step b).

8. The process of claim 1 , wherein products of steps a) to c) are not isolated.

9. The process of claim 1 , wherein the reaction of step c) is carried out at a temperature of about −5° C. to about 0° C.

10. The process of claim 1 , wherein the organic amine is 1-methyl-3-phenylpropyl amine, and the montelukast amine salt is montelukast 1-methyl-3-phenylpropyl amine salt.

11. The process of claim 1 , further comprising the step of purifying the montelukast amine salt with an organic solvent after step d before step e.

12. The process of claim 10 , further comprising the steps of:

i) dissolving montelukast 1-methyl-3-phenylpropyl amine salt in an organic solvent at a temperature of about 25° C. to about reflux;

ii) stirring for about 30 minutes;

iii) cooling to about 25° C. to obtain a precipitate; and

iv) filtering the precipitate to obtain the montelukast 1-methyl-3-phenylpropyl amine salt.

13. The process of claim 12 , wherein the organic solvent is selected from the group consisting of C 1-4 alcohols, ketones, esters, ethers, aromatic hydrocarbons, cyclic hydrocarbons, water, and combinations thereof.

14. The process of claim 12 , wherein the organic solvent is ethyl acetate, toluene, n-hexane, n-heptane, cyclohexane and mixtures thereof.

15. A process for preparing montelukast sodium comprising the steps of:

a) reacting 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxy propyl) phenyl)-2-propanol (diol compound) of formula

with methane sulfonyl chloride in an organic solvent in the presence of a base to obtain a solution of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-methanesulfonyloxy propyl) phenyl)-2-propanol (mesylate compound)

b) reacting 1-(mercaptomethyl)cyclopropane acetic acid

with a base and an additional alkali source in a polar aprotic solvent to obtain a solution of dibase salt of 1-(mercaptomethyl)cyclopropane acetic acid;

c) reacting the mesylate compound of step a) with the dibase salt of 1-(mercaptomethyl)cyclopropane acetic acid of step b) at a temperature of about −20° C. to about 10° C. to obtain a montelukast intermediate;

d) converting the montelukast intermediate from step c) with 1-methy-3-phenylpropyl amine to obtain montelukast 1-methy-3-phenylpropyl amine salt;

e) neutralizing the montelukast 1-methy-3-phenylpropyl amine salt with an acid in a solvent to obtain montelukast;

f) treating the montelukast with an alcoholic sodium source; and

g) isolating the montelukast sodium.

16. The process of claim 15 , wherein the solvent in step e is selected from the group consisting of halogenated solvents and aromatic hydrocarbons.

17. The process of claim 15 , wherein the solvent in step e is selected from the group consisting of dichloromethane, chloroform, dichloroethane, and toluene.

18. The process of claim 15 , wherein the acid in step e is acetic acid.

19. The process of claim 15 , wherein the alcoholic sodium source in step f is ethanolic sodium hydroxide.