This invention relates to Salts of Montelukast and Process therefor.
The invention particularly relates to amine salts of montelukast having formula II
(Formula II Removed)
where B represents ammonia, benzyl amine, or phenyl hydrazine. The invention also provides a process for preparing these amine salts and sodium salt with increased purity, and solubility and reduced toxicity. The process further is cost effective, environment friendly, and easily scale up to commercial level. The invention also provides a process for conversion of these amine salts to montelukast acid with high purity at a reduced cost and its further conversion to sodium salt
BACKGROUND OF THE INVENTION
The biosynthesis of leukotrienes, which are produced in living system from arachidonic acid, begins with the action of enzyme 5-lipoxygenase on arachidonic acid and epoxide known as Leukotriene A4 (LTA4) is produced. These leukotriene A4 are converted into other leukotrienes by enzymatic process. The compound of formula (I) is leukotriene antagonists and useful agent in the treatment of asthma, inflammation and allergic diseases.
European patent No. 480,717 describes certain quinoline compounds, including Montelukast. The reported synthesis of compound of formula (I) as described in U.S. Pat. No. 5,565,473 proceeds through corresponding methyl ester which is formed by coupling of methyl-l-(mercaptomethyl) cyclopropane acetate with mesylate of formula (III) generated in situ.
(Formula III Removed)
The free acid (I) is obtained by hydrolysis of its methyl ester and is converted directly to its sodium salt.
This process requires tedious chromatographic purification of methyl ester intermediate and/ or the final product. Furthermore, the yield of product is quite low. Therefore, this process is not suitable for large scale production.
Furthermore, U.S. pat. No. 5,614,632 discloses the preparation of DCHA salt of Montelukast having formula (IV) for its purification which is ultimately converted into its sodium salt after neutralization of DCHA.

(Formula IV Removed)
Acetic acid Where A is Dicyclohexylamine (DCHA).
U.S. pat. No. 0107612 discloses the preparation of tertiary butylamine and phenylethylamine salt of the compound of formula (I).
Although certain processes of its preparation and purification are known, still an improved and efficient process is required for preparation and purification of compound of formula (I) which can be utilized in the scale-up of the product having appropriate yield and quality.
SUMMARY OF THE INVENTION
The first aspect of this invention is to get new amine salts (organic amines and inorganic
amines based) of Montelukast.
According to another aspect of the invention there is provided a process for the
preparation of salts of Montelukast of formula (II), which comprises,
a) preparing solution/ suspension of the Montelukast free acid of formula I in an organic solvent like C1-C5 ester solvents e.g. ethyl acetate, isopropyl acetate etc; aromatic hydrocarbons like toluene, benzene, xylene etc; ether solvents like tetrahydrofuran, diethyl ether, diisopropyl ether etc; halogenated hydrocarbons like
dichloromethane, chloroform etc; ketone solvents like acetone, methyl isobutyl ketone etc. or a mixture thereof
b) reacting with amines preferably ammonia, benzylamine or phenyl hydrazine
c) isolating the amine salt of formula (II) by adding optionally another antisolvent
e.g. hexane, heptane, toluene or a mixture thereof
d) optionally drying amine salt of formula (II) at 40-45°C under vacuum.
In accordance with the other aspect of this invention there is provided a process for preparing Montelukast acid and/or montelukast sodium salt from amine salt comprising lowering pH of aqueous solution of amine salt to pH 5.0 + 0.5 in order to get montelukast acid, raising pH above 8.0 using source of sodium ion, purifying if so desired, reconverting to acid by acidification and crystallizing acid so obtained by conventional methods
In accordance with another aspect of the invention there is provided a process for the preparation of amine salt of Montelukast of formula (II) and hence of Montelukast free acid of formula (I) in pure form, by hydrolysis of Montelukast methyl ester (V).
(Formula V Removed)
Thus, according to this invention, there are provided new salts of Montelukast of formula (II) having distinct XRD profile and process along with use of these amine salts. It resulted in the increased purity of the salts of Montelukast of formula (II). These salts were converted into Montelukast free acid of formula (I) of high purity by treatment with acids in toluene-water or water.
BRIEF DESCRIPTION OF THE FIGURES:
FIG.l depicts the X-ray powder diffraction pattern of ammonium salt of Montelukast of formula II.
(Formula II Removed)
FIG.2 depicts the X-ray powder diffraction pattern of Benzylamine salt of Montelukast of formula II.
FIG.3 depicts the X-ray powder diffraction pattern of Phenyl hydrazine salt of Montelukast of formula II.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of this invention is to get new salts (organic amines and inorganic amines base) of Montelukast having X-ray powder diffraction pattern as shown in figures 1 to 3 accompanying this specification.
According to another aspect, this invention provides a process for the preparation of
ammonium, benzylamine and phenyl hydrazine salt of Montelukast of formula (II) which
comprises,
a) dissolving/ suspending the Montelukast free acid of formula I in an organic solvent b)
reacting with amines
c) isolating the amine salt of formula (II)
The organic solvents used for dissolution or suspension include (1) C1-C4 ester solvents
selected from ethyl acetate, isopropyl acetate; (2) aromatic hydrocarbons selected from
toluene, benzene, xylene; (3) ether solvents selected from tetrahydrofuran, diethyl ether,
diisopropyl ether, (4) halogenated hydrocarbons selected from dichloromethane,
chloroform; (5) ketone solvents selected from acetone, methyl isobutyl ketone etc. or a
mixture of two or more solvents
The amines employed are selected from ammonia, benzylamine or phenyl hydrazine.
Amine salts are isolated by seeding or cooling or by adding another anti solvent selected
hexane, heptane, toluene or a mixture thereof or by crystallization. The salts so obtained
are dried at 40-45°C under vacuum.
The salts (II), thus obtained, have the advantage that they resulted in the increased purity of the product e.g. the amine salt of formula (II) having purity >99% are obtained using ammonia, benzylamine or phenyl hydrazine starting from Montelukast free acid of formula (I) having HPLC purity even <80%. Out of three salts of formula (II), although all salts afford high purity of compound of formula (II), ammonium salt gives best results
as far as yield and quality of compound of formula (II) is concerned. The ammonium salt of formula (II) has also following advantages over known DCHA, t-butylamine and phenylethylamine salts of Montelukast:
1. Use of ammonia to get ammonium salt is comparatively safer over use of DCHA
to prepare DCHA salt, due to less toxicity. LD50 of DCHA is 373 mg/kg whereas
LC50 of ammonia is 2000 ppm/ 4H. Thus Ammonia is less toxic than DCHA.
2. Ammonia is highly water soluble and there is no possibility of its carryover, to
final product when ammonium salt is cleaved with acid to get Montelukast free
acid in water or water-organic solvent mixture. Whereas possibility of DCHA
carryover is more when DCHA salt is cleaved using above process to get
Montelukast free acid due to DCHA being sparingly soluble in water.
3. On burning of DCHA there is formation of highly toxic gases like carbon mono
oxide and carbon dioxide whereas no such gases are produced on burning
ammonia.
4. DCHA is cancer suspect chemical whereas ammoia has no such evidence.
5. The ammonium salt of formula (II) of Montelukst can easily be used as API.
Thus, it is apparent that though t-butylamine and phenylethylamine salts of Montelukast are advantageous over DCHA, ammonium salt is far superior to t-butylamine and phenylethylamine salts with regard to yield. Furthermore, ammonium salt is more environmental friendly, less toxic and cost effective in comparison to other salts.
The readily isolable amine salts of formula (II) resulted in the effective purification of a compound of formula (I) in presence of acids in water or toluene-water mixture.
The ammonium salt of formula (II) has a unique advantage over DCHA, benzyl or phenyl hydrazine salts that it affords Montelukast free acid of formula (I) simply by heating or by acidification in water in comparatively higher yield than other amine salts (in water or toluene-water) whereas other salts including DCHA salt are not completely converted to Montelukast free acid of formula (I) in water and requires a mixture of toluene or other water immiscible organic solvents and water. Accordingly, another aspect of the present invention provides a process for the preparation of sodium salt of Montelukast acid of formula (I) from its amine salt of formula (II) which comprises,
a) reacting the suspension of amine salt of formula (II) in water or water immiscible
organic solvents like toluene, methyl isobutylketone, ethyl acetate etc. and water mixture
with acids
b) isolating the solid obtained in water or separating water immiscible solvent layer
from water and crystallizing the product just by raising pH to above 8.0 using souece of
sodium ion.
c) drying the sodium salt of Montelukast acid of formula (I).
The other aspect of the present invention provides a process for the preparation of Montelukast acid of formula (I) from its ammonium salt of formula (II) which comprises,
a) stirring a suspension of Montelukast acid ammonium salt (II) in an organic solvent
like toluene, ethyl acetate etc or water, converting to sodium salt in a known manner,
b) isolating the product by filteration.
c) drying the sodium salt of Montelukast free acid of formula (I).
The other aspect of the present invention provides a process for the preparation of Montelukast acid of formula (I) from its ammonium salt of formula (II) which comprises,
a) heating of Montelukast acid ammonium salt (II) directly or in a suitable organic
solvent like C\-C* ester solvents e.g. ethyl acetate, isopropyl acetate etc; aromatic
hydrocarbons like toluene, benzene, xylene etc; ether solvents like tetrahydrofuran,
diethyl ether, diisopropyl ether etc; halogenated hydrocarbons like dichloromethane,
chloroform etc; ketone solvents like acetone, methyl isobutyl ketone etc. or a mixture of
two or more solvents
b) drying the Montelukast free acid of formula (I) as such or after filtration.
EXAMPLE I
To a solution of lOOg of Montelukast acid (I) in ethyl acetate (600ml) with stirring at 20-25°C, ammonia gas was purged for 1 hr. or ammonical ethyl acetate( 17-20%, 25ml) was added. Then hexane (600ml) was slowly added with continuous stirring. After complete addition of hexane, the slurry was further stirred for 10-15 hr. at 20-25 °C. The solid, thus
obtained was filtered and was given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (100gm; 97%)
EXAMPLE II
To a suspension of ammonium salt (II) of Montelukast (100g) in water (500ml.) at 25-30°C, acetic acid (10g) was added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture was stirred at 25-30°C for 5-6 hr. The solid, thus obtained, was filtered and washed with water (100ml.) and material was suck dried. Then the product was dried at 40-45 °C for 5-6 hr. under vacuum. (87.3g; 90%)
EXAMPLE III
To a solution of lOOg of Montelukast (I) in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) was added drop wise with continuous stirring. The reaction mixture was stirred for 1 hr. Then Hexane (600ml) was slowly added with continuous stirring at 20-25°C. After complete addition of hexane, the reaction mixture was further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained was filtered and was given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (112g;95%) EXAMPLE IV
To a suspension of benzylamine salt (II) of Montelukast (100g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (lOg) was added drop wise with continuous stirring. After complete addition of acetic acid, the reaction mixture was stirred at 25-30°C for 5-6 hr. The toluene layer was separated and washed with water (100ml.). The toluene layer was stirred at 25-30°C for 7-8 hr. The solid, thus obtained was filtered and dried at 40-45°C for 5-6 hr under vacuum. (68g; 81%)
EXAMPLE V
To a solution of lOOg of Montelukast (I) in ethyl acetate (600ml) with stirring at 20-25°C, phenylhycirazine (23.80g) was added drop wise with continuous stirring. The reaction mixture was stirred for 1 hr. Then hexane (600ml) was slowly added with continuous stirring at 20-25 °C. After complete addition of hexane, the reaction mixture was further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained, was filtered and was given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (60gm;51%)
EXAMPLE VI
To a suspension of phenylhydrazine salt (II) of Montelukast (60g) in toluene (300ml.) and water (300ml.) at 25-30°C, acetic acid (6g) was added drop wise with continuous stirring. After complete addition of acetic acid, the reaction mixture was stirred at 25-30°C for 5-6 hr. The toluene layer was separated and washed with water (100ml.). The toluene layer, thus obtained, was stirred at 25-30°C for 7-8hrs. The solid was filtered and dried at 40-45 °C for 5-6 hr under vacuum. (43. Ig; 85%)
EXAMPLE VII
To a suspension of 100g of Montelukast methyl ester (V) in methanol (400ml) and THF (400ml), one molar aq. caustic solution (347ml) is added at 25-30°C and the reaction mixture is stirred at 25-30°C for 24hr.The progress of reaction is monitored by HPLC. After completion of reaction, methanol-THF is recovered at reduced pressure and a mixture of water (1000ml) and methanol (400ml) is added and pH of solution is adjusted to 8-9 using acetic acid. The reaction solution is washed with toluene (3 x100ml) and aq. layer is separated. The pH of aq. layer is adjusted to 5.0-5.5 using acetic acid and product is extracted in ethyl acetate (3 x 200ml) followed by washing of ethyl acetate layer with water (2 x 100ml). Organic layer is dried over anhydrous Na2SO4,
To the above ethyl acetate layer with stirring at 20-25°C, ammonia gas was purged for 1 hr. or ammonical ethyl acetate (17-20%, 25ml) was added. Then hexane (600ml) was slowly added with continuous stirring. After complete addition of hexane, the slurry was further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained was filtered and was
given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (90g; 92.15%)
Example VIII
To a suspension of 100g of Montelukast methyl ester (V) in methanol (400ml) and THF (400ml), one molar aq. caustic solution (347ml) is added at 25-30°C and the reaction mixture is stirred at 25-30°C for 24hr.The progress of reaction is monitored by HPLC. After completion of reaction, methanol-THF is recovered at reduced pressure and a mixture of water (1000ml) and methanol (400ml) is added and pH of solution is adjusted to 8-9 using acetic acid. The reaction solution is washed with toluene (3 x 100ml) and aq. layer is separated. The pH of aq. layer is adjusted to 5.0-5.5 using acetic acid and product is extracted in ethyl acetate (3 x200ml) followed by washing of ethyl acetate layer with water (2x 100ml). Organic layer is dried over anhydrous Na2SO4, To the above ethyl acetate layer at 20-25°C, benzylamine (23.58g) was added drop wise with continuous stirring. The reaction mixture was stirred for 1 hr. Then Hexane (600ml) was slowly added with continuous stirring at 20-25°C. After complete addition of hexane, the reaction mixture was further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained was filtered and was given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (92.5g; 94%)
Example IX
To a suspension of 100g of Montelukast methyl ester (V) in methanol (400ml) and THF (400ml), one molar aq. caustic solution (347ml) is added at 25-30°C and the reaction mixture is stirred at 25-30°C for 24hr.The progress of reaction is monitored by HPLC. After completion of reaction, methanol-THF is recovered at reduced pressure and a mixture of water (1000ml) and methanol (400ml) is added and pH of solution is adjusted to 8-9 using acetic acid. The reaction solution is washed with toluene (3 x100ml) and aq. layer is separated. The pH of aq. layer is adjusted to 5.0-5.5 using acetic acid and product is extracted in ethyl acetate (3 x 200ml) followed by washing of ethyl acetate layer with water (2 x 100ml). Organic layer is dried over anhydrous Na2SO4,
To the above ethyl acetate layer at 20-25°C, phenylhydrazine (23,80g) was added drop wise with continuous stirring. The reaction mixture was stirred for 1 hr. Then hexane (600ml) was slowly added with continuous stirring at 20-25°C. After complete addition of hexane, the reaction mixture was further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained, was filtered and was given slurry washing with hexane (100ml) and material was suck dried. The product was dried at 40-45°C for 5-6 hr. (58g, 50%)
Example X
To a suspension of ammonium salt (II) of Montelukast in toluene is stirred at 50-60°C for 6hrs and the Montelukast acid, thus obtained, is filtered and washed with toluene. The product is dried at 40-45°C for 5-6 hr under vacuum.
ADVANTAGES
1. The main advantage of isolable amine salts of formula (II) of Montelukast is that they
resulted in the increased purity of amine salt of formula (II) and hence of Montelukast
free acid of formula (I).
2. The ammonium salt of formula (II) of Montelukast is readily convertible to
Montelukast in water these use of solvent can be avoided. Furthermore, the process of
ammonium salt of Montelukast of formula (II) is cost effective, echo-friendly and
suitable for scale-up.
3. The ammonium salt of formula (II) of Montelukst can easily be used as API.
4. All the new amine salts described herein, specially ammonium salt resulted in the
increased yield of Montelukast free acid of formula (I).
5. The amine salt of Montelukast acid (II) can be converted directly into Montelukast
acid (I) by stirring at higher temperature.

WE CLAIM: 1. Novel salts of m ontelukast having formula II
(Formula II Removed)
where B represents ammonia, benzyl amine or phenyl hydrazine having X-ray powder diffraction pattern as depicted in the drawing accompanying this specification.
2. A process for the preparation of salts of Montelukast acid formula (II) as claimed in claim 1, which comprises
a) dissolving/ suspending the Montelukast free acid of formula (I) in an organic
solvent.
b) reacting with an amine.
c) isolating the amine salt so produced.

3. The process as claimed in claim 2, wherein the organic solvent used in step (a)
include C1-C4 aliphatic esters; aromatic hydrocarbons; cyclic or acyclic ethers;
halogenated hydrocarbons; aliphatic ketones or a mixture thereof
4. The process as claimed in claim 3, wherein the C1-C4 aliphatic esters used is
selected from ethyl acetate, isopropyl acetate.
5. The process as claimed in claim 3, wherein the aromatic hydrocarbons used is
selected from toluene, benzene, xylene.
6. The process as claimed in claim 2, wherein the cyclic or acyclic ethers used is
selected from tetrahydrofuran, diethyl ether, diisopropyl ether.
7. The process as claimed in claim 2, wherein the halogenated hydrocarbons used is
selected from dichloromethane, chloroform; aliphatic ketones preferably selected
from acetone, methyl isobutyl ketone or a mixture thereof.
8. The process as claimed in claim 2, wherein the amines used in step (b) are
selected from benzylamine, phenylhydrazine and ammonia.
9. The process as claimed in claim 2, wherein the isolation is carried out by adding
anti-solvent comprising aromatic hydrocarbons selected from toluene, benzene,
xylene; C5-C8 aliphatic straight or branched chain hydrocarbons selected from
hexane, heptane or a mixture thereof.
10. The process as claimed in claim 2, wherein the isolation is carried out by
crystallization.
11. The process as claimed in claim 11, wherein the crystallization is carried out by
seeding.
12. A process for the preparation of sodium salt of Montelukast acid of formula (I),
which comprises:

(a) lowering pH of aqueous solution of amine salt of montelukast having formula II
wherein 'B" has the meaning as defined herein above in claim 1, to 5.0±0.5,
(b) raising pH to above 8.0 using source of sodium ion, and
(c) isolating the sodium salt by crystallization.
13. A process for the preparation of sodium salt of Montelukast acid of formula (I),
which comprises
a) reacting the suspension of amine salt of formula (II) in water or water
immiscible organic solvents with acid.
b) isolating the Montelukast free acid so obtained in water or separating water
immiscible solvent layer from water converting to its sodium salt by
conventional method and crystallizing the product.
14. A process as claimed in claim 15, wherein the organic solvents used in step (a)
comprising aromatic hydrocarbons selected firm toluene, benzene, xylene;
aliphatic esters selected from ethyl acetate, isopropyl acetate; aliphatic ketones
selected from acetone, methyl isobutyl ketone etc , water or a mixture thereof.
15. A process as claimed in claim 15, wherein the acid used in step (a) is selected
from acetic acid, tartaric acid, sulfuric acid , hydrochloric acid or a mixture
thereof.
16. A process as claimed in claim 15, wherein the organic solvents used in step (b)
for crystallization are selected from aromatic hydrocarbons like toluene, benzene,
xylene etc; aliphatic esters like ethyl acetate, isopropyl acetate etc ; halogenated
hydrocarbons like dichloromethane, chloroform etc , water or a mixture thereof.
17. A process for the preparation of sodium salt of Montelukast acid of formula (I) , which comprises
a) stirring a suspension of Montelukast acid ammonium salt (II) in an organic
solvent.
b) isolating the Montelukast acid (I) by filtration.
c) drying the Montelukast free acid of formula (I).

18. A process as claimed in claim 17, wherein the organic solvent used in step (a) is
selected from aromatic hydrocarbons like toluene, benzene, xylene etc; aliphatic
esters like ethyl acetate, isopropyl acetate etc ; C5-C8 straight or branched chain
aliphatic hydrocarbons like, hexane, heptane etc or water or a mixture thereof.
19. A process as claimed in claim 17, wherein the stirring is carried out at a
temperature ranging from 20-100°C , more preferably 30-80°C; most preferably
50-70°C.
20. A process as claimed in claim 1 7, wherein the isolation is conducted at a temperature ranging from 10-60°C, more preferably 20-40°C; most preferably
25-35°C.
21. The invention substantially such as herein described.