FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE MANUFACTURE OF MONTELUKAST SODIUM"

APPLICANT (S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS

GLADE ORGANICS. PVT. LTD.
India
19, Crystal, 1st Floor, Juhu Road, Santacruz (W),
Mumbai 400 054, Maharashtra, India

FIELD OF THE INVENTION
The present invention relates to an improved process for the manufacture of 1-[[[(1R)-l-[3-[(lE)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid, sodium salt I, which is known as Montelukast sodium.

I
The compound of the formula I is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLTi receptor. These compounds are effective in the treatment of asthmatic disorders, etc. Several processes for the manufacture of the same are reported.
PRIOR ART
The European Patent No. 480717 discloses a class of novel anti-asthmatic compounds including montelukast sodium of structural formula I, having activity as leukotriene antagonists and to methods for their preparation. This patent provided a process for the preparation of the title compound I, which comprises of converting an alcohol of the formula II to a mesylate of the formula III. The mesylate is then condensed, in presence of cesium carbonate, with methyl (1-acetylthiomethyl) cyclopropaneacetate of the formula IV, after treatment of the latter with hydrazine, to obtain a compound of the formula V

(II)

(III)


o.
SCOCH3V—0CH3


(IV)

(V)


(VI)
Finally the acid of the formula VI was prepared by hydrolysis of the methyl ester V in presence of pyridinium p-toluenesulphonate. The acid VI was, then, taken up in ethanol, treated with an equivalent amount of NaOH and the resultant oil was freeze dried to afford

the compound of the formula I. This process afforded the title compound in low yields and purities and required purification by chromatography at intermediate stages.
European Patent No. 500360 relates to quinoline-containing ketoacids having activity as leukotriene antagonists and to methods for their preparation. This patent again provides processes as exemplified in EP 480717 and hence suffers from the same drawbacks.
VII III
The European Patent No. 737186 relates to a process for the preparation of a compound of the formula I which comprises of reacting the dilithium dianion of 1-(mercaptomethyl) cyclopropaneacetic acid (VII) "'ith methanesulphonyloxy compound of the formula III to afford after suitable workup the acid VI which was in situ converted to its dicyclohexyl amine (DCHA) salt having the formula VIII.


VIII
The dicyclohexylamine salt was purified by leaching with solvents and dried. The dried salt VIII was taken up in toluene and treated with acetic acid to generate free acid VI, the toluene solution of which was subsequently treated with an equivalent quantity of sodium hydroxide

and the sodium salt so formed (I) was crystallized from a solvent mixture comprising of toluene-acetonitrile. This process suffers from multiplicity of steps involving formation of VI, conversion of the latter to its dicyclohexylamine salt, purification of the dicyclohexylamine salt, regeneration of acid VI before it is converted to montelukast sodium which is crystallized, making it very tedious and industrially unattractive.
The provisional patent application WO 03/066598 discloses an anhydrous amorphous form of montelukast sodium of the formula I which comprises of preparing the montelukast free acid from montelukast dicyclohexylamine salt by acidification, dissolving the free acid of montelukast in a C1-C2 halogenated solvent or in C7-Cg aromatic hydrocarbon solvent and converting the dissolved acid to the corresponding alkali salt using an alkaline metal hydroxide/an alkaline metal alkoxide/alcoholic alkaline metal hydroxide/ alcoholic alkaline metal alkoxide in presence of C1-C4 straight or branched chain alcohol and isolating amorphous form of montelukast alkali salt by adding a C5-C7 acyclic or Cs-Cs cyclic hydrocarbon. This process affords the compound of the formula in yields less than 70% of theory which renders the process unattractive.
The provisional patent application WO 04/108679 relates to an improved method for the preparation of montelukast acid sodium salt in an amorphous form which comprises of generating the dilithium dianion of l-(thiomethyl)cyclopropaneacetic acid (VII) and coupling said dianion with wet mesylate of the formula III to get montelukast acid VI in crude form followed by conversion of the latter to its DCHA salt, purifying the DCHA salt and converting the DCHA salt to montelukast acid in the pure form and finally reacting the pure montelukast acid with a sodium base followed by evaporation of the solvent and triturating the residue with nonpolar water immiscible solvent to obtain the title compound, I. This long drawn procedure affects the overall yield of the final product.

The US application US2005/0187245 discloses a stable non-hygroscopic amorphous form of the compound of the formula I which comprises of dissolving the montelukast sodium in a solvent/ a combination of solvents followed by spray drying the resultant solution. As a comparative example the patent also reports that a product prepared according to the process disclosed in EP 480717 which comprises of freeze drying an aqueous solution of montelukast sodium, provides an amorphous form as confirmed by the X-ray Diffraction data of the product. The patent does not disclose the yields obtained by following the procedure and is thus not clear.
SUMMARY
The object of the present invention is to provide a process for the manufacture of the compound of formula I in good yields by reducing the number of steps while still achieving good purities.
Another objective of the present invention is to utilize the ease of isolation of metal carboxyl ate salts wherein an ester compound of the formula IX is hydrolytically converted to a monometal salt of the formula X which can be isolated by filtration and thereafter can be dried to desired limits. These mono metallides can thereafter be converted to the dimetallides by use of a metal hydride, alkyi lithio derivatives etc. This step serves the function of converting the mercapto end of l-(mercaptomethyl)-cyclopropane acetate metal salt, X to its dimetal salt, XI. Thus the process of the present invention utilizes lesser n-butyl lithium.
Another objective of the present invention is convert an alcohol derivative and of the formula II to alkyl sulfonate compounds of the formula III which are reacted irw

situ with the compound of the formula XI. It is well known to those conversant in the art that compounds of the formula III are relatively unstable and their isolation by operations such as filtration etc becomes an industrially critical operation which need special handling systems and hence the process of the present invention provides an efficient and hitherto unreported method of utilizing in-situ the thus obtained alkyl sulfonate which thereby affords much improved yields and also makes the process industrially easy to carry out. Thus the process for the manufacture of the compound of the Formula I is rendered simple, easy and convenient to carry out on a large scale.
Yet another objective of the present invention is to provide the synthetic utility of the chirally pure bases such as a-methyl benzylamine, brucine, strychnine, quinine, cinchonidine, ephedrine, amphetamine etc. These chiral bases afford the title compound in better efficiencies and purities which thereby affords a process for the manufacture of the compound of the formula I that is highly economical and commercially advantageous.
DETAILED DESCRIPTION
In an attempt to devise a more efficient process for montelukast sodium (I), it was conceived that the ester of the formula IX which has been reported in EP480717 can be readily converted to metal salts (X). These metal salts of the formula X apart from protecting the carboxylic acid can also be isolated as stable crystalline salts which can be characterized. These mono metal lides can be reacted with anhydrous metallide forming reagents affording the dimetallide derivatives which can have potential uses for onward coupling with suitable substrates.

HO
CH3
(II)
RS02X
(R=Me, Et, Pr; X=C1, Br, I)

CHs (R=Me, Et, Pr)
(III)

SH COO Me SH COO'M,

► ►


§ M 2 COO M 1

IX

X XI
(M,=Na, K, Ca, Mg; M2=Li, Na, K)


CH3
XII
According to the invention there is provided a process for the manufacture of the compound of the formula I consisting of converting methyl l-(mercaptomethyl)-

cyclopropane acetate of the formula IX to metal salts of the formula X in a suitable solvent at 0 to 50°C wherein Mi can be alkali metal or an alkaline earth metal such as Na+, K+, Ca+2, Mg+2 etc. The compounds of the formula X are dried and characterized. These are then converted to the dimetal salt of the formula XI in a suitable solvent at 0 to -50°C wherein Mi is as described above and M2 is an alkali metal such as Li+, Na+, K+ etc. The process is so carried out that simultaneously as XI is being synthesized, a compound of the formula II is converted to compounds of the formula III. This alkyl sulfonation affords compounds of the formula III which is monitored by HPLC (herein described in the examples) which without isolation are condensed "in-situ" with the simultaneously prepared compounds of the formula XI in a suitable solvent at 0 to -50°C. This reaction is again monitored by HPLC. After the specified limits are achieved the reaction mass is quenched and extracted with a suitable solvent. The organic layer is thereafter treated with a suitable chirally pure base. This affords the crystallization of montelukast salt (XII) with the chirally pure base which is isolated by filtration. The compound of the formula XII is then purified by crystallization from a suitable solvent. It was important to establish that during the in-situ condensation of alkyl sulfonate HI with the dimetalide XI, complete inversion occurs at the carbon carrying the alkyl sulfonate group, to give the desired enantiomer XII and that the proportion of the undesired enantiomer XIII does not increase as compared to the standard procedure reported in EP 737186. This was done by preparing XII where the chiral base used is (R)-(+)-a-methylbenzyl amine and also preparing (R)-(+)-a-methylbenzyl amine salt of montelukast obtained according to the procedure described in EP 737186 wherein instead of adding DCHA as prescribed in the process a-methyl benzylamine was added.
To obtain montelukast sodium (I), the purified salt XII is dissolved in a suitable solvent and treated with a stoichiometric amount of a sodium base at 0 to 50°C followed by

trituration of the resultant solution in an antisolvent. An amorphous powder of pure montelukast sodium (I) is obtained.
As a suitable solvent for the saponification of the compound of the formula IX affording X one can use methanol, ethanol, n- or isopropanol, preferably methanol. As a suitable solvent for the isolation of compound of the formula X one can utilize the hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, THF, acetonitrile, preferably toluene.
As a suitable base for the saponification of the compound of the formula IX affording
X one can use sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium
hydroxide, preferably sodium hydroxide.
The saponification of the compound of the formula IX affording X is carried out at -10 to 80°C preferably 50°C.
As a suitable solvent for the dimetallation of the compound of the formula X affording XI one can utilize the hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, THF, acetonitrile, preferably THF.
As a suitable base for the dimetallation of the compound of the formula X affording
XI one can use n-butyl lithium, sodium hydride, sodium methoxide, potassium hydride,
potassium methoxide, calcium hydride, magnesium oxide, phenyl sodium, preferably n-butyl
lithium. The molar quantity of the base used for dimetallation can be varied between 1.0
andl .5 but preferably 1.1 moles with respect to the compound of the formula IX.
The temperatures employed for the dimetallation of the compound of the formula X affording XI is carried out at -20 to 20°C preferably -10°C.
As a suitable solvent for the conversion of the compound of the formula II to the compound of the formula III, one can utilize the ethers such as dialkyl ethers, where alkyl

connotes methyl, ethyl, n- & iso propyl, cyclic ethers such as THF, 1,4-dioxane, etc. More preferred ones are the cyclic ethers like tetrahydrofuran and 1,4-dioxane.
As a suitable reagent for the conversion of the compound of the formula II to the compound of the formula III, one can utilize the routinely available alkyl sulfonyl halide such as methanesulfonyl chloride, ethane sulfonyl chloride, propane sulfonyl chloride; methanesulfonyl bromide, ethane sulfonyl bromide, propane sulfonyl bromide; methanesulfonyl iodide, ethane sulfonyl iodide, propane sulfonyl iodide. More preferred ones are the methanesulfonyl chloride, ethane sulfonyl chloride.
The molar quantity of the alkyl sulfonyl halide used for the conversion of the compound of the formula II to the compound of the formula III can be varied between 1.0 and 1.5 but preferably 1.1-1.2 moles with respect to the compound of the formula II.
The temperatures employed for the conversion of the compound of the formula II to the compound of the formula III is carried out at -50 to 20°C preferably -20°C.
The reaction temperatures employed for the condensation between the compound of the formula III with the compound of the formula XI is carried out at -50 to 20°C preferably -10°C.
The molar quantity of the dimetallide XI used with respect to the compound of the formula III can be varied between 1.0-2.0 moles but preferably 1.4 to 1.5 moles with respect to the compound of the formula III.
As a suitable chiral base for the conversion of the compound of the formula XI affording XII one can use the commercially available chirally pure bases such as a-methyl benzylamine, brucine, strychnine, quinine, cinchonidine, ephedrine, amphetamine etc. The molar quantity of the base used for this salt formation can be varied between 1.0 to 1.5 moles but preferably 1.1 -1.2 moles with respect to the compound of the formula II.

As an organic solvent for purification of the compound of the formula XII one can utilize halogenated organic solvents, ethers, alkyl acetates, aromatic hydrocarbons, etc. More preferred are the alkyl acetates preferably ethyl acetate.
The organic solvent for dissolving the purified compound of the formula XII is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone or esters such as methyl acetate, ethyl acetate or n-butyl acetate. More preferred one is toluene.
As a base for generating the sodium salt one can utilize the alkali metal hydroxides such as sodium hydroxide, the alkali metal carbonates such as sodium carbonate, the alkali metal bicarbonates such as sodium bicarbonate, alkali metal acetates such as sodium acetate, or alkali metal alkoxides such as sodium methoxide. More preferred one is sodium methoxide.
The suitable antisolvent for precipitating the compound of the formula I is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone or esters such as methyl acetate, ethyl acetate or n-butyl acetate, preferably n-heptane.
The process does not proceed via the dilithio salt. The process of the present invention does not utilize any isolated mesylate. The process of the present invention does not employ the dicyclohexylamine salt as an intermediate. The process of the present invention does not utilize any freeze dryer for the isolation of the compound of the formula I. The process of the present invention does not proceed via the montelukast free acid.
The process of the invention does not utilize solvents such as acetonitrile during the final stages of crystallization, which have a stringent limit in ICH.

All the above collectively make the process economically more viable providing high yields and high purities for the final product.
The following examples are illustrative of the invention but not limitative to the scope thereof.
EXPERIMENTS
HPLC method for reaction monitoring:
Column: Cosmosil silica, 250 x 4.6 mm, 5.0 \i; wavelength: 280 n.m; injection volume: l0uL; Column temperature: 30°C; Run time: 30 min; Mobile phase: Hexane, dioxane & THF in the ratio of 85:15:2 and degassed.
EXAMPLE 1
Sodium l-(mercaptomethvl)-cyclopropane acetate:
A solution of methyl l-(mercaptomethy:)-cyclopropane acetate (50 gm, 0.31 mol) (IX) in toluene (250 ml) was treated with sodium hydroxide solution (12.4 gm in 100 ml distilled water) and stirred at 45°C for 2hrs. The hydrolysis was monitored by TLC and the reaction mass was concentrated to a residual mass which was again dried by distilling out 200 ml toluene. The residue containing (X) was slurried in cyclohexane and filtered under nitrogen atmosphere, washed with cyclohexane (50 ml x 2) and dried under vacuum at 35°C to afford 44.61 gm of sodium l-(mercaptomethyl)-cyclopropane acetate. Yield = 85% (of theory)
NMR (CDC13): 5 2.13-2.32 (m,4H), 0.27-0.44 (m, 4H) XRD:Asperfig-l
Montelukast a-methyl benzyl amine salt
A suspension of 17 gm sodium l-(mercaptomethyl)-cyclopropane acetate (X) (0.101 mol) in 75 ml THF was cooled to -40°C. To this 69 ml of n-butyl lithium (0.106 mol) was

added followed by maintaining the reaction mass at -20 to -40°C for an additional 30 min to provide a mass of XL
Simultaneously in another assembly the alcohol (II) (33 gm, 0.072 mol) was dissolved in 330 ml methylene chloride. To this N-methyl morpholine (10.91 gm, 0.108 mol) was added and the reaction mass was thereafter cooled to -25°C. Mesyl chloride (III) (9.76 gm, 0.085 mol) dissolved in 20 ml methylene chloride was added to the reaction mass and the reaction was stirred at -15 to -20°C for 2 hrs. The reaction mass was monitored by HPLC to check that the unreacted II was below 1%. Thereafter the reaction mass was further cooled to -40°C, filtered and the filtrate was concentrated in vacuum and the residue was dissolved in 600 ml THF. The resultant clear solution was cooled to -45°C. To this the simultaneously prepared XI mass was added and the reaction was maintained at -10 to -15°C for 12 hrs and the reaction was again monitored by HPLC to check that the unreacted III was below 2%. The reaction mass was thereafter poured in a mixture of 1000 ml each of ethyl acetate and water and acidified with acetic acid to pH of 3.5. The layers were separated and the organic layer was washed with 200 ml water followed by 100 ml of 20% sodium chloride. The ethyl acetate solution was treated with charcoal, filtered through celite and treated with (R)-(+)- a-methylbenzyl amine (9.6 gm, 0.079 mol) to afford the crude salt. The resultant salt was filtered and purified by crystallization from 200 ml ethyl acetate to afford 43.8 gm of the a-methylbenzyl amine salt of montelukast.
Yield: 86% (of theory)
M.P: 126-7°C.
IR: 3336, 1604, 1541, 1496
NMR: 5 8.12-8.14 (d, 1H), 8.04-8.05 (d, 1H), 7.81 (s, 1H), 7.61-7.64 (bs, 1H), 7.70-
7.74 (dd, 2H), 7.60-7.64 (d, 1H), 7.10-7.52 (m, 13H), 4.12-4.13 (q, 1H), 4.01-4.04 (t,

1H), 3.11-3.13 (m, 1H), 2.92-2.95 (m, 1H), 2.64-2.68 (d, 1H), 2.20-2.65 (m, 5H),
1.60-1.62 (2s, 6H), 1.40-1.41 (d, 3H), 0.46-0.55 (m, 4H)
Assay (by HPLC): 98.4%
Water content (by Karl Fisher): 0.12%
XRD: As per Fig-2 Montelukast sodium salt
The above a-methyl benzyl amine salt (30 gm, 0.042mol) was dissolved in 240 ml toluene and to the resultant solution 2.4 gm of sodium methoxide (0.044mol) was added and the contents stirred for 30 min at 25-30°C followed by addition of 1.5 gm charcoal. The mass was stirred at 25-30°C for 1 hr and filtered through celite. The clear filtrate was added drop-wise into 900 ml n-heptane. The product mass was stirred for an additional 10 min at 25-30°C and filtered. The product was dried at 50°C under vacuum to get 24 gm of montelukast sodium.
Yield: 93% (of theory)
Water content (by Karl Fisher): 1.3%
Assay (by HPLC): 99.6%
SOR: + 98.12
XRD: As per Fig-3

We claim:
1. A process for preparing l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2-
quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methyl ethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid, sodium salt [montelukast sodium (I)], the said process comprising steps of-


CH,
(I)
(a) treating methyl 1-(mercaptomethyl)-cyclopropane acetate of formula IX, in 2-10 volumes of a suitable solvent with alkali metal or alkaline earth metal hydroxide at a temperature ranging from 20 to 80°C affording the monometallide salt of the structure X, which is isolated by concentrating the saponified mass followed by dehydrating the water by using a suitable base.

SH COO Me


(IX)

SH COOM ,


(X)

s M"2 COO M ",


(XI)

(M,=Na, K, Ca, Mg; M2=Li, Na, K)
(b) treating the compound of the formula X with one molar equivalent of a metalide forming substance to get the dimetallide derivative of the formula XI, at a temperature ranging from -50 to 0°C,

(c) treating the compound of the formula II with an alkylsulfonyl halide in a suitable solvent in presence of a base at a temperature ranging from -50 to 0°C followed by filtration and redissolution of the residue in a suitable solvent,

CH3 (II)
RS02X (R=Me, Et, Pr; X=C1, Br, I)

0

(III) (R=Me,Et,Pr)
(d) mixing a solution of 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl-3-alkylsulphonyloxypropyl)phenyl)-2-propanol (III) with a suspension of 1.1 to 1.5 moles of XI cooled to -20 to 0°C and maintained at that temperature for 8-20 hrs,
(e) extracting out the active substance, after adjusting the pH between 2-6, from the reaction mass by using a suitable solvent,
(f) reacting the montelukast solution with a suitable chirally pure base in the molar equivalents of 1.0-2.0 molar to afford the montelukast salt (XII)


(g) purifying XII by crystallization from 3 to 5 volumes of a suitable solvent at 50-80°C
and cooling to ambient temperature, (h) dissolving purified XII in 8-10 volumes of a suitable solvent and treating it with an
equivalent quantity of sodium base at 25 to 50°C, (i) adding 25-50 volumes of an antisolvent and keeping the contents at 25 to 50°C,
2. A process as claimed in claim 1, wherein in step (a) the suitable solvent for saponification of the compound of the formula IX to a monometallide salt of formula X is selected from methanol, ethanol, n- or isopropanol, preferably methanol.
3. A process as claimed in claim 1, wherein in step (a) the suitable solvent for the isolation of compound of the formula X is selected from the hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, THF, acetonitrile, preferably toluene.
4. A process as claimed in claim 1, wherein in step (a) the suitable base for the saponification of the compound of the formula IX affording X is selected from the group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, preferably sodium hydroxide.
5. A process as claimed in claim 1, wherein in step (a) the saponification of the compound of the formula IX affording X is carried out at 20 to 80°C preferably 50°C.
6. A process as claimed in claim 1, wherein in step (b) the suitable solvent for the dimetallation of the compound of the formula X affording XI is selected from the

hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, THF, acetonitrile, preferably THF.
7. A process as claimed in claim 1, wherein in step (b) the suitable reagent for the dimetallation of the compound of the formula X affording XI is selected from lithium forming substances such as n-, sec- & tert-butyl lithium, lithium hydride, sodium forming substance such as sodium hydride, sodium methoxide, phenyl sodium, potassium forming substance such as potassium hydride, potassium methoxide, calcium forming substance such as calcium hydride, magnesium forming substance such as magnesium oxide, preferably n-butyl lithium.
8. .A process as claimed in claim 1, wherein in step (b) the temperatures employed for the dimetallation of the compound of the formula X affording XI is carried out at -20 to20°C, preferably-10°C.
9. A process as claimed in claim 1, wherein in step (c) the suitable solvent for the conversion of the compound of the formula II to the compound of the formula III is selected from the ethers such as dialkyl ethers, where alkyl connotes methyl, ethyl, n-& iso propyl, cyclic ethers such as THF, 1,4-dioxane, preferably the cyclic ethers like tetrahydrofuran and 1,4-dioxane.
10. A process as claimed in claim 1, wherein in step (c) the suitable alkyl sulfonyl halide for the conversion of the compound of the formula II to the compound of the formula III is selected from methanesulfonyl chloride, ethane sulfonyl chloride, propane sulfonyl chloride; methanesulfonyl bromide, ethane sulfonyl bromide, propane sulfonyl bromide; methanesulfonyl iodide, ethane sulfonyl iodide, propane sulfonyl iodide, preferably methanesulfonyl chloride or ethane sulfonyl chloride.
11. A process as claimed in claim 1, wherein in step (c) the molar quantity of the alkyl sulfonyl halide used for the conversion of the compound of the formula II to the

compound of the formula HI can be varied between 1.0 and 1.5, preferably 1.1-1.2 moles with respect to the compound of the formula II.
12. A process as claimed in claim 1, wherein in step (c) the temperatures employed for the conversion of the compound of the formula II to the compound of the formula III is carried out at -50 to 20°C, preferably -20°C.
13. A process as claimed in claim 1, wherein in step (d) the reaction temperatures employed for the condensation between the compound of the formula HI with the compound of the formula XI is carried out at -50 to 0°C, preferably -10°C.
14. A process as claimed in claim 1, wherein in step (d) the molar quantity of XI employed is 1.0-2.0 moles with respect to the compound of the formula II, preferably 1.4 to 1.5 moles with respect to the compound of the formula II.
15. A process as claimed in claim 1, wherein in step (e) the suitable solvent for extracting out the active substance, after adjusting the pH, from the reaction mass is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, or esters such as methyl acetate, ethyl acetate or n-butyl acetate, preferably ethyl acetate.
16. A process as claimed in claim 1, wherein in step (e) the suitable pH for adjustment is selected from 2 to 6 units, preferably 3.5.
17. A process as claimed in claim 1, wherein in step (f) the suitable chiral base for the conversion of the compound of the formula II affording XII is selected from the chirally pure bases such as a-methyl benzylamine, brucine, strychnine, quinine, cinchonidine, ephedrine, amphetamine, preferably a-methyl benzylamine.
18. A process as claimed in claim 1, wherein in step (f) the molar quantity of the base used for this salt formation can be varied between 1.0 to 1.5 moles with respect to the

compound of the formula II, preferably 1.1-1.2 moles with respect to the compound of the formula II.
19. A process as claimed in claim 1, wherein in step (g) the organic solvent for purification of the compound of the formula XII is selected from halogenated organic solvents, ethers, alkyl acetates, aromatic hydrocarbons, preferably alkyl acetates, most preferably ethyl acetate.
20. A process as claimed in claim 1, wherein in step (h) the suitable solvent for dissolving the purified compound of the formula XII is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone or esters such as methyl acetate, ethyl acetate or n-butyl acetate, preferably toluene.
21. A process as claimed in claim 1, wherein in step (h) the suitable base for converting the purified compound of the formula XII to the sodium salt is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide, where alkoxide connotes methoxide, ethoxide, n- & iso- propoxide, preferably sodium methoxide.
22. A process as claimed in claim 1, wherein in step (i) the suitable antisolvent for precipitating the compound of the formula I is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene, ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone or esters such as methyl acetate, ethyl acetate or n-butyl acetate, preferably n-heptane.
23. A process for the preparation of l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]

methyl] cyclopropane acetic acid, sodium salt [montelukast sodium(I)] essentially as described and with particular reference to the examples. 24. A process for the preparation of l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio] methyl] cyclopropane acetic acid, sodium salt [montelukast sodium(I)] whenever prepared by the process of any of the claims 1-23.

Dated this 3™ day of April, 2006

RAJESHWARI.H OF K&S PARTNERS AGENT FOR THE APPLICANTS

ABSTRACT
The present invention relates to an improved process for the manufacture of 1-[[[(1R)-1-[3-[(lE)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid, sodium salt I, which is known as Montelukast