The present invention relates to a process for the preparation of amorphous Montelukast sodium.
Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-
quinolinyl)ethenyl]phenyl]-3-[2-(1 -hydroxy-1 -
methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
(Figure Removed)

Montelukast is selective, orally active leukotriene receptor antagonist that inhibits cysteinyl leukotirene CycLTi receptor. Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older.
US Patent No 5,565,473 provides a process for preparing amorphous montelukast sodium, wherein the process involves freeze-drying of an aqueous solution containing montelukast sodium. PCT Publication WO 03/066598 provides a process for preparing amorphous montelukast sodium, wherein the process involves the use of montelukast free acid as a starting material and sodium salt is generated in situ in toluene medium. The starting montelukast free acid is prepared by neutralizing the dicyclohexylamine salt of montelukast with acetic acid. PCT Publication No WO 04/108679 provides a process for preparing amorphous montelukast sodium, wherein the process involves montelukast free acid as a starting material and sodium salt is generated in situ in alcoholic medium. The starting montelukast free acid is prepared by neutralizing the dicyclohexylamine salt of montelukast with acetic acid. PCT Publication No WO 05/074893 provides a process for preparing amorphous montelukast sodium, wherein the process involves dissolving montelukast sodium in aqueous or alcoholic solution and subsequent spray drying or lyophilization. The process also involves the use of lactose in order to obtain a co-precipitate.
The present inventors have developed a novel process for the preparation of amorphous montelukast sodium. The present process is simple and does not require neutralization of amine salt of montelukast and subsequent isolation of montelukast free acid. By employing the present invention, an amine salt of montelukast can be directly converted into montelukast sodium and it can be isolated as an amorphous solid from the reaction mixture. Thus the present process reduces the steps involved in the preparation of amorphous montelukast sodium and improves process economics.
A first aspect of the present invention provides a process for the preparation of montelukast sodium, wherein the said process comprises
a) treating an amine salt of montelukast with an organic solvent,
b) treating the reaction mixture obtained in step a) with a source of sodium ion, and
c) isolating amorphous montelukast sodium,
characterized by the fact that montelukast free acid is not isolated at any step.
An amine salt of montelukast can be prepared by the processes known in the prior art. The amine salt is preferably a di- or trialkylamine salt, more preferably dicyclohexylamine or tertiary butylamine salt. The amine salt of montelukast is treated with an organic solvent at a temperature of about 20° to about 50°C. The organic solvent is selected from a group comprising of aromatic hydrocarbons, halogenated hydrocarbons, esters and alcohols. The reaction mixture is treated with a source of sodium ion at a temperature less than or equal to about 20°C. Sodium hydroxide or a sodium alkoxide can be used as a source of sodium ion. The reaction mixture is optionally stirred for about 10 minutes to about 5 h. The reaction mixture is subsequently treated with a second organic solvent optionally at a temperature more than about 25°C. The second organic solvent is selected from a group comprising of aliphatic hydrocarbons. The amorphous montelukast sodium can be isolated from the reaction mixture by filtration or by removal of the solvent.
Figure 1 depicts XRPD of amorphous montelukast sodium.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1 PREPARATION OF AMORPHOUS MONTELUKAST SODIUM:
Dicyclohexylamine salt of montelukast was prepared as per the method provided in US 6,320,052. Dicyclohexylamine salt of montelukast (100 g) added into toluene (800 ml) at 25° to 30°C. The slurry so obtained was cooled to 10° to 12°C with stirring. Sodium methoxide (7 g) was added in four equal lots into the slurry at 10° to 20°C in 30 minutes time. The reaction mixture was stirred for 30 minutes at 20°C to obtain a clear solution. Molecular sieves (4A, 20 g) were added to the said clear solution followed by the addition of activated carbon (10 g). The reaction mixture was stirred for 30 minutes at 20°C and filtered through Celite bed, followed by washing with toluene (100 ml). The reaction mixture was added drop-wise into n-heptane (3 L) at 30°C in 2 h time under constant stirring. The stirring was continued for further 30 minutes. The reaction mixture was filtered and washed with n-heptane (100 ml X 2). The solid obtained was dried at 40° to 45°C for 30 h to obtain the title compound.
Yield: 72

WE CLAIM:
1. A process for the preparation of montelukast sodium, wherein the said process
comprises
a) treating an amine salt of montelukast with an organic solvent,
b) treating the reaction mixture obtained in step a) with a source of sodium ion,
and
c) isolating amorphous montelukast sodium,
characterized by the fact that montelukast free acid is not isolated at any step.
2. A process as claimed in claim 1, wherein the amine salt is a di- or trialkylamine salt.
3. A process as claimed in claim 2, wherein the amine salt is dicyclohexylamine or
tertiary butylamine salt.
4. A process as claimed in claim 1, wherein the organic solvent is selected from a group
comprising of aromatic hydrocarbons, halogenated hydrocarbons, esters and alcohols.
5. A process as claimed in claim 4, wherein the organic solvent is toluene.
6. A process as claimed in claim 1, wherein step a) is carried out at a temperature of
about 20° to about 50°C.
7. A process as claimed in claim 1, wherein step b) is carried out at a temperature less
than or equal to about 20°C.
8. A process as claimed in claim 1, wherein step b) is accompanied by stirring for about
10 minutes to about 5 h.
9. A process as claimed in claim 1, wherein step b) further comprises treating with a
second organic solvent.

10. A process as claimed in claim 9, wherein the second organic solvent is selected from a group comprising of aliphatic hydrocarbons.