FIELD OF INVENTION:
This invention relates to an improved processes for preparation of Montelukast acid and salt
thereof.
Particularly the invention relates to an economical and industrially feasible process leading to
a title compound with enhanced purity.
BACKGROUND OF THE INVENTION
Montelukast sodium is chemically known as [R-(E)-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)
ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl]cyclopropane
acetic acid sodium salt and is represented by the formula (II).
Montelukast is leukotriene antagonists and is useful agent in the treatment of asthma,
inflammation and allergic diseases.
It is orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene Cys
LT1 receptor. Leukotrienes are associated with the inflammation and constriction of airway
muscles and the accumulation of fluid in the lungs.
(Formula Removed)
US pat. No. 5,565,473 describes a process for Montelukast sodium, wherein the compound is obtained as oil that is then dissolved in water and freeze dried. The process is lengthy as well as tedious since it requires chromatographic purification of intermediates and Montelukast acid. Additionally, the process of freeze drying is very time consuming and costly.
US pat. No. 5,614,632 discloses a method for preparation of Montelukast sodium by reacting mesylate with dilithium anion of the l-(mercaptomethyl) cyclopropane acetic acid. The
process employs n-butyl lithium to prepare dilithium anion of 1 -(mercaptomethyl) cyclopropane acetic acid. Because butyl lithium is a dangerous reagent, the process becomes unfriendly to the environment and user. Furthermore the mesylate has limited stability as it undergoes decomposition particularly when isolated, therefore resulting in a need for a process without isolating this unstable intermediate. The process for preparation of Montelukast sodium (II) described in this US Patent is also very tedious and time consuming. Furthermore, the product obtained is not of high purity.
WO 2004/108697 describes a simpler method for the preparation of amorphous Montelukast sodium, but employs flammable and dangerous reagent n-butyl lithium in the coupling stage thereby proving to be unfit for industrial application and limits its use.
US 2005/0256156Alreported the coupling of mesylate with 1 (mercaptomethyl) cyclopropane acetic acid methyl ester using metal hydrides, hydroxides, alkoxides and quarternary ammonium bases. However, the purity of product claimed by this process is very low. Besides this, the salts formed during mesylation reactions are filtered off. Since mesylate is an unstable intermediate, it is not advisable to expose this solution of this intermediate in order to minimize the decomposition. The product formed by this process needs repeated purification in organic solvents thus adding to the cost of production. Moreover, the product purity achieved is only 97%.
It is apparent from the above discussion, that several drawbacks are encountered in prior art processes like, tedious and lengthy procedure, involving development of unstable intermediate compound, using hazardous reagent like n-butyl lithium. Therefore, there is a need for developing methodologies, which overcome the above mentioned drawbacks.
SUMMARY OF THE INVENTION
The main object of this invention is to provide a process for the preparation of montelukast acid and salt thereof avoiding at least some of the drawbacks associated with the existing processes.
The other object of this invention is to provide a process for the preparation of montelukast acid and salt thereof that is cost effective and industrially feasible.
Another object of this invention is to provide a process for the preparation of montelukast acid and salt thereof that is environment and user friendly.
Yet another object of this invention is to provide a process for the preparation of montelukast acid and salt thereof that leads to a title product of higher purity.
Still another object of this invention is to provide a simple process for the preparation of montelukast acid and salt thereof, which eliminates using hazardous compound like n-butyl lithium, avoids isolation of unstable intermediate compound of formula IV and employ reactants that helps smoother reaction and eliminates tedious and time consuming steps.
BRIEF DESCRIPTION OF THE FIGURES
Schemes A, B, C, and D depict processes for the preparation of Montelukast sodium (II) according to the present invention.
SCHEME A
(Scheme Removed)
SCHEME B
(Scheme Removed)
SCHEME C
(Scheme Removed)
SCHEME D
(Scheme Removed)
STATEMENT OF THE INVENTION
Accordingly the present invention provides a n improved process for preparation of Montelukast acid and salt thereof which comprises:
(a) preparing a compound of general formula 1A
(Formula Removed)
Where in R1 is represented by OH or a compound of formula(Formula Removed)
if so desired
by reacting Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl] Benzoate with magnesium halide in organic solvent such as herein described,
(b) then reacting with sulfonyl chloride in organic solvent in presence of base to obtain
mesylate,
(c) coupling l-(mercaptomethyl) cyclopropane derivative of formula(Formula Removed)

wherein R represents CN, COOCH3, CONH2 or OH,
with mesylate so obtained in organic solvent in presence of base to obtained a compound of formula
(Formula Removed)

Wherein R1 has the meaning as given above, deprotecting of dihydropyran ring when r is other than OH and Rl is(Formula Removed)

(d) recovering Montelukast acid by mere quenching the reaction when R is OH or
subjecting to alkali hydrolyzing of the product obtained in step (c) followed by washing
with water immiscible organic solvent and isolating by conventional methods when R
is other than OH ,
(e) optionally purifying and converting to amine salt by conventional methods such as herein described and, reconverting to acid by reacting with acetic acid in organic solvent to get purified Montelukast acid, then
(f) transforming to its sodium salt by conventional alkali metal treatment.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the present invention is to provide a process for preparing Montelukast acid (I) and salt thereof (II) which comprises:
b) reacting the compound of formula (III) with methane sulphonyl chloride in organic solvent in presence of base to obtain mesylate of formula (IV).
c) coupling l-(mercaptomethyl) cyclopropane derivative of formula (Xa/ Xc/ Xd) with mesylate (IV) in in-situ reaction mass of (IV) of step (a) or on isolation in organic solvents in the presence of a base to form compound of formula (Va/ Vc/ Vd).
d) hydrolyzing the product of step (b) by conventional methods followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after pH adjustment, extraction in water immiscible organic solvent followed by solvent recovery.
e) optionally preparing amine salt of formula (VI) of product of step (c) for its purification, optionally repurifVing and converting the amine salt (VI) back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization.
f) converting pure Montelukast acid (I) into Montelukast sodium (II) using conventional methods.
According to other aspect of the present invention, there is provided a process for the preparation of Montelukast free acid of formula (I) or salt thereof (II) comprising:
a) reacting the compound of formula (VII) with methane sulphonyl chloride in organic solvent in presence of base to obtain mesylate of formula (VIII).
b) coupling compound of formula (Xa/ Xc/ Xd) with mesylate (IV) in in-situ reaction mass of (VIII) of step (a) or on isolation in organic solvents in the presence of a base to form compound of formula (IXa/ IXc/ IXd).
c) deprotecting of dihydropyran ring of the product of step (b) by using conventional method to get compound (Va/ Vc/ Vd) and hydrolysing the compound (Va/ Vc/ Vd) by conventional methods followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after pH adjustment, extraction in water immiscible organic solvent followed by solvent recovery,
d) preparing amine salt (VI) of product of step (d) for its purification, optionally repurifving and converting the amine salt (VI) back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization,
e) converting pure Montelukast acid (I) of step (d) into Montelukast sodium (II) by conventional methods.
According to yet another aspect of the present invention there is provided a process for the preparation of Montelukast acid (I) and salt thereof (II) which comprises,
a) reacting the compound of formula (III) with methane sulphonyl chloride or p-toluene sulfonyl chloride in organic solvent in presence of base to obtain mesylate of formula (IV).
b) coupling of formula (Xb) with mesylate (IV) in in-situ reaction mass of (IV) of step (a) or on isolation in organic solvents in the presence of a base.
c) quenching the reaction mass of step (b) with water, basification followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after acidification, extraction in water immiscible organic solvent followed by solvent recovery.
d) optionally preparing amine salt of Montelukast acid (I) from step (b) for its purification, optionally repurifving and converting the amine salt back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization.
e) converting pure Montelukast acid (I) of step (d} into Montelukast sodium (II) using conventional methods.
According to one of the embodiments of this invention, the organic solvent used in step (a) and (b) may be such as aliphatic nitriles; cyclic or acyclic aliphatic ethers; aromatic hydrocarbons; halogenated hydrocarbons, aliphatic amides or a mixture thereof.
The organic solvent particularly used in step (a) & (b) may be acetonitrile, propionitrile, tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether, diethyl ether; dichloromethane, chloroform; N,N-dimethyl formamide, N,N-dimethyl acetamide, benzene, toluene, xylenes or a mixture thereof.
According to other embodiment of the present invention, the base used in step (a) may be selected from tertiary amines preferably N,N-diisopropyl ethylamine, triethylamine, while the one employed in step (b) may be such as alkali or alkaline earth metal carbonates like Cs2CO3, K2CO3, Na2CO3 , CaCO3, Li2CO3. Specifically Cs2CO3 is more preferred when R is ester.
According to other embodiment of the present invention, the molar ratio of methane sulfonyl chloride or p-toluene sulfonyl chloride with reference to compound of formula (III) in step (a) is in the range of 0.8 to 3.0, while molar ratio of base used in step (a) ranges from 1.0 to 5.0.
According to yet other embodiment, the molar ratio of the base with reference to compound of formula (IV) in step (b) may be in the range of is 1.0 to 10.0, while molar ratio of compound of formula (Xa/ Xc/ Xd) in step (b) w.r.t. of formula (IV) may range from 1 to 6.
According to yet another embodiment, the reaction temperature in step (a) ranges from -40°C to +30°C and that in the reaction temperature in step (b) ranges from -35°C to +40°C.
According to still another embodiment of the invention, the amines used for salt formation in step (d) may be such as NH3, benzylamine, phenyl hydrazine, tris-(hydroxymethyl)amino methane, α,α-diphenyl-4-piperidinemethanol, dicyclohexylamine etc.
According to still another embodiment of the present invention, the organic solvents used in step (d) may be selected from aliphatic esters preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate; aromatic hydrocarbons preferably toluene, xylene, benzene; C5 - C7 aliphatic hydrocarbons like pentane, hexane, heptane, C1-C4 aliphatic alcohols like methanol, ethanol, propanol, butanol; halogenated hydrocarbons like methylene chloride, chloroform; cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
l-(mercaptomethyl) cyclopropane derivatives of formula (Xa-d) used in the process are prepared by:
(a) reacting cyclopropane dimethanol with thionyl chloride to form cyclic sulphite.
(b) cyanating the product of step (I) using sodium or potassium cyanide.

(c) reacting product of step (II) with methane sulphonyl chloride in the presence of a base like triemylamine or diisopropylethylamine in methylene chloride followed by its reaction with thiolacetic acid in the presence of a base to form l-(acetylthiomethyl) cyclopropane acetonitrile.
(d) partially hydrolyzing the product of step (III) in biphasic medium containing aq. solution of caustic and an immiscible organic solvent or monophasic medium containing aqueous solution of caustic & a water miscible organic solvent to get compound of formula Xa which on further hydrolysis gives 1-(mercaptomethyl) cyclopropaneacetic acid (Xb).
(e) reacting the product Xb in methanol in the presence of an acid or thionyl chloride to form 1-(mercaptomethyl) cyclopropaneacetic acid methyl ester of formula (Xc). Xb and Xc may further be converted to Xd by known methods.
According to one aspect of the present invention, the solvent used in step (a) is aliphatic or aromatic halogenated or non-halogenated hydrocarbon like methylene chloride, chloroform, carbobtetrachloride, toluene, benzene, xylenes etc or a mixture thereof.
According to another aspect of the present invention, cyanide used in step (b) is sodium cyanide or potassium cyanide.
According to still another aspect of the present invention, the solvent used in step (b) is selected from aliphatic amide like N,N-dimethyl formamide etc; aromatic hydrocarbons like benzene, toluene, xylenes etc or a mixture thereof.
According to yet another aspect of the present invention, the solvents used in step (c) are selected from halogenated aliphatic or aromatic hydrocarbons like methylene chloride, chloroform, carbontetra chloride etc.; benzene, toluene, xylenes etc.; aliphatic amide like N,N-dimethyl formamide etc. or a mixture thereof.
According to still another aspect of the present invention, the solvent used in biphasic medium in step (d) is selected from aromatic hydrocarbons like benzene, toluene, xylenes etc. or a mixture thereof.
According to yet another aspect of the present invention, the solvents used in monophasic medium in step (d) is selected from aliphatic alcohols like methanol, ethanol, propanol, butanol etc. glycols like monoethylene glycol, diethylene glycol etc. or a mixture of two or more thereof.
According to yet another aspect of the present invention, the reaction temperature in step (d) is from 0°C to reflux temperature.
According to still another aspect of the present invention, the acid used in step (d) is selected from hydrochloric acid, sulphuric acid etc or a mixture thereof.
The compound [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy
propyl]-phenyl]-2- Propanol (III) used in the process is prepared by
(A) reacting the compound of formula (XV) with methyl magnesium halide.
(B) further reacting the product of step (A) with methyl magnesium halide in order to further react the intermediate into product.
(C) isolating the product and purifying to get compound (III) of high purity.
According to one aspect of the invention, the grignard reagent used in step (A&B) are selected from methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide or a mixture thereof.
According to another aspect of the present invention, the organic solvent used in step (A&B) is selected from cyclic or acyclic ethers like tetrahydrofuran, dioxane, monoglyme, diisopropylether, tert-butylmethyl ether, diethyl ether etc. or aromatic hydrocarbons like benzene, toluene, xylenes etc. or a mixture thereof.
According to yet another aspect of the invention, the reaction temperature in step (A&B) is preferably between -30°C to +50°C, more preferably -20°C to +40°C and most preferably -15°C to+25°C.
According to still another aspect of the present invention, the molar ratio of methyl magnesium halide with respect to compound of formula (XV) in step (A&B) is 2.0 to 15.0.
According to yet another aspect of the present invention, the solvents used in step (C) for purification of compound (III) are selected from aromatic hydrocarbons like benzene, toluene, xylenes; C4-C8 aliphatic hydrocarbons like butane, pentane, hexanes, heptanes etc. or a mixture thereof.
According to still another aspect of the present invention, highly pure product of formula (III) is obtained by resubmission of product of step (A) with methyl magnesium halide.
It may be pertinent to mention here that the mesylate, which is a sensitive and unstable intermediate on its isolation gets decomposed during subsequent handling. The present invention minimizes its decomposition by reacting the said mesylate in-situ, and reduces
involvement of machinery like filtration kit, centrifuge, dryer etc required in handling the mesylate on isolation.
Further, employing water immiscible organic solvents for washing of reaction solution helps in improving purity of Montelukast due to removal of non carboxylic impurities. Reaction solution having as low as 40% Montelukast before washing gets converted into a mass having Montelukast of purity as high as 85% which upon further processing and purification yields Montelukast acid and its salt of purity > 99.80% with all impurities <0.10%.
Reaction is cleaner and faster when alkali or alkaline earth metal carbonates specially CS2CO3 is used as base in step (b) compared to prior art bases.
According to still another aspect of the present invention, the using of 0.5-10% of sulphur compounds preferably compounds of formulae Xa to Xd, thiophenol, P2S5 or a mixture thereof in step (b),(c), (d) and (e) results in control and removal of sulphoxide and sulfone impurity in the product.
According to yet another aspect of the present invention, the process results in exceptionally good control on the impurity formation and thereby results in highly pure Montelukast acid and its salts.
The invention is further illustrated by non-limiting examples. Thus the following examples should not construe the scope of the protection sought in this invention.
EXAMPLE 1
To a solution of cyclopropanedimethanol XI (100g) in dichloromethane (21tr), triethyl amine (203g) and thionyl chloride (116g) is added at 0 to -5°C, the reaction mixture is stirred for 3-5hr at 0 to -5°C. After completion of reaction, reaction mixture is quenched in sodium bicarbonate solution followed by extraction of product with dichloromethane (600ml). The solvent is removed at reduced pressure and product was crystallized in hexane to obtain cyclopropane dimethanol cyclic sulphite (XII). (yield = 125g)
EXAMPLE 2
To a solution of cyclopropanedimethanol cyclic sulphite XII (100g) of Example I in N,N-dimethylformamide (3201tr), potassium iodide and sodium cyanide are added. The reaction mixture is stirred at 90 to 95°C for 10-12hr. After completion of reaction, reaction mixture is quenched by addition of water (18ml) and toluene (l.lltr) is added. The reaction mixture is filtered through hyflo bed and the toluene is recovered at reduced pressure. The product 1-hydroxymethyl cyclopropane acetonitrile (XIII) is obtained using high vacuum distillation. (yield = 45g)
EXAMPLE 3
To a solution of 1-hydroxymethyl cyclopropane acetonitrile XIII (100g) of Example 2 in MDC (500ml), triethylamine (99g) and methanesulfonyl chloride (108g) is added under nitrogen atmosphere at 0° to -5°C. The reaction mixture is stirred for l-2hr at 0° to -5°C. After completion of reaction, reaction mixture is quenched by addition of water (400ml). The product is extracted in MDC and washed with water (800ml). The solvent is removed at reduced pressure to obtain the mesylate intermedialte.
To the solution of mesylate intermediate in toluene (400ml) and N,N-dimethyl formamide (200ml), triethylamine (99g) and potassium thiolacetate (162.5g) is added and reaction mixture is stirred for 10-12hr, After completion of reaction, reaction mixture is quenched in water (750ml). The product is extracted in toluene (600ml). The solvent was recovered at reduced pressure to obtain the product, l-(acetylthiomethyl) cyclopropane acetonitrile (XIV). (yield = 100g)
EXAMPLE 4
To a solution of l-(acetylthiomethyl) cyclopropane acetonitrile XIV (100g) of Example 3 in toluene(300ml), 5N NaOH solution (11tr) is added at 0 - 5°C. The reaction mixture is stirred for 12-15hr at 25 - 30°C to get compound Xa. The aqueous layer containing Xa is separated and refluxed for 3-5hr. The reaction mixture is cooled to 10°C and washed with toluene (500ml). The pH (2-2.5) is adjusted with 8N-HC1 at 0°C to 5°C. The product is extracted with toluene (lltr) and washed with water (11tr). The toluene layer is charcolized and filter
through hyflo. The solvent is recovered at reduced pressure and product is crystallized in hexane to obtain 1-(mercaptomethyl) cyclopropaneacetic acid (Xb). (yield = 50g)
EXAMPLE 5
To a solution of 1-(mercaptomethyl) cyclopropaneacetic acid Xb (100g) of Example 4 in methanol (500ml), hydrochloric acid (25ml) is added at 20 to 30°C. The reaction mixture is stirred for 2-3hr at 65 to 70°C. After completion of reaction, the reaction mixture is quenched in water (2.51tr). The pH 8-8.5 is adjusted with sodium bicarbonate solution followed the extraction of product in MDC (1.51tr). The solvent is recovered at reduced pressure to get product. 1-(mercaptomethyl) cyclopropaneacetic acid methyl ester of formula Xc. (yield = 100g)
EXAMPLE 6
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in toluene (250ml) and acetonitrile (750ml) at 15 to 20°C, diisopropylethylamine (56ml) is added and the reaction mixture is cooled to -35 to -30°C. Then methane sulphonyl chloride (20ml) is added at -35 to -30°C and the reaction mixture is stirred at same temperature for 3hr. The product (IV) is filtered and used in the next step. (yield = 100g)
EXAMPLE 7
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, Cs2CO3 (215g) is added followed by addition of compound of formula IV of Example 6 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml).
The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 8
To a solution of compound Vc of Example 7 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I), (yield = 90g)
EXAMPLE 9
To a solution of 100g of crude Montelukast (I) of example 8 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield =* 112g)
EXAMPLE 10
To a suspension of benzylamine salt VI of Montelukast (100g) of Example 9 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 11
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol) of example 10 is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 12
To a solution of [(S)-(E)]-2-t3[-3-[2-(7-chloro-2-quinolinyl) ethenyl]-3-[2-[2-(tetrahydro pyranyl)-2-oxy)-2-propyl] phenyl]-1- Propanol (100g) of formula VII in toluene (500ml) at -25°C to -30°C, N,N Diisopropyl ethylamine (41.6g) is added at stirring followed by slow addition of methane sulphonyl chloride (29.6g). The reaction is stirred at -25°C to -30°C for 2hr and then at -10°C to -15°C for l-2hr. After completion of reaction, the above reaction mixture is added to a mixture of l-(mercaptomethyl) cyclopropane acetic acid methyl ester (58.8g), toluene (300ml) and sodium hydride (11.52g) at -25°C to -30°C. The resulting reaction mixture is stirred at -25°C to -30°C for l-2hr and then at 20°C to 30°C for 16-18hr. After completion of reaction, the reaction mixture is quenched is water (500ml) followed by extraction of product in toluene (300ml). The organic layer is washed with water (100ml), brine (100ml) and solvent is removed at reduced pressure to obtain the product (IXc). (yield = 120g)
EXAMPLE 13
To a solution of [( R )-(E)-l[[[-l-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)-phenyl]propyl]thio]methyl]cyclopropane methyl acetate (100g) of formula IXc of example 12 in MeOH (600ml) and THF (200ml), Pyridinium p-toluene sulfonate (1 lg) is added at 20°C to 30°C. The reaction mixture is refluxed for 20-24hr. After completion of reaction, the reaction mixture is cooled to 10-15°C and quenched in water (31tr) followed by extraction of product in ethyl acetate (lltr). The organic layer is washed with water (500ml), brine (500ml) and solvent is removed at reduced pressure to obtain the product. [( R )-(E)-l[[[-l-[3-[2-(7-chloro-2-qumolinyl) ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl) phenyl]propyl]thio]methyl]cyclopropane methyl acetate of formula Vc. (yield = 90g)
EXAMPLE 14
To a solution of compound of formula Vc from Example 13 (100g) in MeOH (600ml), 4M NaOH aq. solution (250ml) is added at 10°C to 30°C, the reaction mixture is stirred for 16-18hr at 20°C to 30°C. After completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml), The pH of aq. layer is adjusted to 5,0 - 5.5 with acetic acid at 10°C to 15°C and product is extracted with ethyl acetate (lltr). The organic layer is washed with water (500ml), brine (500ml) and dried over sodium sulphate. The solvent is recovered at reduced pressure to obtain crude product (I), (yield = 90g)
EXAMPLE 15
To a solution of 100g of crude Montelukast acid (I) of Example 14 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture was stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and was given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 16
To a suspension of benzylamine salt VI of Montelukast acid (100g) of Example 15 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained, is filtered and dried at 40-45°C for 5-6 hr under vacuum to obtain pure product (I). (yield = 68g)
EXAMPLE 17
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol) of example 16 is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain Montelukast sodium (I) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light, (yield = 50g)
EXAMPLE 18
To a suspension of Xb (70g) in acetonitrile (400ml) at 0 - 5°C, Cs2C03 (430g) is added followed by addition of compound of formula IV from Example 6 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. After completion of reaction, the reaction mixture is quenched in water (700ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml). The crude product was obtained by recovery of ethyl acetate from organic layer at reduced pressure to obtain crude Montelukast acid (I), (yield = 120g)
EXAMPLE 19 To a solution of 100g of crude Montelukast (I) of example 18 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. yield = 110g)
EXAMPLE 20
To a suspension of benzylamine salt of Montelukast (100g) of Example 19 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added drop wise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried at 40-45°C for 5-6 hr under vacuum to obtain pure Montelukast acid (I), (yield = 68g)
EXAMPLE 21
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol) from example 20 is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield =50g)
EXAMPLE 22
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in toluene (500ml) and acetonitrile (500ml) at 15 to 20°C, DIPEA (56ml) is added and the reaction mixture is cooled to -35 to -30°C. Then methane sulphonyl chloride (20ml) is added at -35 to -30°C and the reaction mixture is stirred at same temperature for 3hr. The reaction solution is used as such in the next step of Example 23.
EXAMPLE 23
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, CS2CO3 (215g) is added followed by addition of an in-situ solution of compound of formula IV of Example 22 in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml). The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 24
To a solution of compound Vc of Example 23 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I), (yield = 90g)
EXAMPLE 25
To a solution of 100g of crude Montelukast (I) of example 24 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g), The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 26
To a suspension of benzylamine salt VI of Montelukast (100g) of Example 25 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 27
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) of Example 26 (50 g, 0. 085 mol) of example 26 is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder
and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 28
To a solution of l-(acetylthiomethyl) cyclopropane acetonitrile XIV (100g) of Example 3 in monoethylene glycol (300ml), 5N NaOH solution (lltr) is added at 0 - 5°C. The reaction mixture is stirred for 12-15hr at 25 - 30°C to get compound Xa. Then the reaction mixture is stirred at 90-100°C. The aqueous layer containing Xa is separated. The reaction mixture is cooled to 10°C and washed with toluene (500ml). The pH (2-2.5) is adjusted with 8N-HC1 at 0°C to 5°C. The product is extracted with toluene (lltr) and washed with water (lltr). The toluene layer is charcoalized and filter through hyflo. The solvent is recovered at reduced pressure and product is crystallized in hexane to obtain l-(mercaptomethyl) cyclopropaneacetic acid (Xb). (yield = 50g)
EXAMPLE 29
To a solution of l-(mercaptomethyl) cyclopropaneacetic acid Xb (100g) of Example 28 in methanol (500ml), hydrochloric acid (25ml) is added at 20 to 30°C. The reaction mixture is stirred for 2-3hr at 65 to 70°C, After completion of reaction, the reaction mixture is quenched in water (2.51tr). The pH 8-8.5 is adjusted with sodium bicarbonate solution followed the extraction of product in MDC (1.51tr). The solvent is recovered at reduced pressure to get product, l-(mercaptomethyl) cyclopropaneacetic acid methyl ester of formula Xc. (yield = 95g)
EXAMPLE 30
To a solution of l-(acetylthiomethyl) cyclopropane acetonitrile XIV (100g) of Example 3 in methanol (300ml), 5N NaOH solution (lltr) is added at 0 - 5°C. The reaction mixture is stirred for 12-15hr at 25 - 30°C to get compound Xa. The resulting reaction mixture containing Xa is refluxed for 3-5hr. The reaction mixture is cooled to 10°C and washed with toluene (500ml). The pH (2-2.5) is adjusted with 8N-HC1 at 0°C to 5°C. The product is
extracted with toluene (lltr) and washed with water (lltr). The toluene layer is charcolized and filter through hyflo. The solvent is recovered at reduced pressure and product is crystallized in hexane to obtain l-(mercaptomethyl) cyclopropaneacetic acid (Xb). (yield = 50g)
EXAMPLE 31
To a solution of l-(mercaptomethyl) cyclopropaneacetic acid Xb (100g) of Example 30 in methanol (500ml), hydrochloric acid (25ml) is added at 20 to 30°C. The reaction mixture is stirred for 2-3hr at 65 to 70°C. After completion of reaction, the reaction mixture is quenched in water (2.51tr). The pH 8-8.5 is adjusted with sodium bicarbonate solution followed the extraction of product in MDC (1.51tr). The solvent is recovered at reduced pressure to get product, l-(mercaptomethyl) cyclopropaneacetic acid methyl ester of formula Xc. (yield = 100g)
EXAMPLE 32
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in tetrahydrofuran (200ml) and methylene chloride (50ml) at 15 to 20°C, DIPEA (56ml) is added and the reaction mixture is cooled to -25 to -20°C. Then methane sulphonyl chloride (20ml) is added at -25 to -20°C and the reaction mixture is stirred at same temperature for 3hr. Then acetonitrile (600ml) is added to the reaction mixture at -25 to -20°C and the product, thus crystallized, was filtered and used in the next step. The product (IV) is filtered and used in the next step. (yield-100g)
EXAMPLE 33
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, Cs2CO3 (215g) is added followed by addition of compound of formula IV of Example 32 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction
mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml).
The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 34
To a solution of compound Vc of Example 33 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I), (yield = 90g)
EXAMPLE 35
To a solution of 100g of crude Montelukast (I) of example 34 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45 °C for 5-6 hr. (yield = 112g)
EXAMPLE 36
To a suspension of benzylamine salt VI of Montelukast (100g) of example 35 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water
(100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 37
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 36) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 38
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in tetrahydrofuran (200ml) and 1,4-dioxane (100ml) at 15 to 20°C, DIPEA (56ml) is added and the reaction mixture is cooled to -35 to -30°C. Then methane sulphonyl chloride (20ml) is added at -35 to -30°C and the reaction mixture is stirred at same temperature for 3hr. Then acetonitrile (600ml) is added to the reaction mixture at -35 to -30°C and the product (IV) thus precipitated is filtered and used in the next step. (yield = 100g)
EXAMPLE 39
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, Cs2CO3 (215g) is added followed by addition of compound of formula IV of Example 38 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml).
The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 40
To a solution of compound Vc of Example 39 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I). (yield - 90g)
EXAMPLE 41
To a solution of 100g of crude Montelukast (I) of example 40 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 42
To a suspension of benzylamine salt VI of Montelukast (100g) of example 41 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 43
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 42) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield =50g)
EXAMPLE 44
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in tetrahydrofuran (200ml) and N,N-dimethyl formamide (100ml) at 15 to 20°C, DIPEA (56ml) is added and the reaction mixture is cooled to -35 to -30°C. Then methane sulphonyl chloride (20ml) is added at -35 to -30°C and the reaction mixture is stirred at same temperature for 3hr. Then acetonitrile (600ml) is added to
the reaction mixture at -35 to -30°C and the product (IV) thus crystallised is filtered and used in the next step. (yield =100g)
EXAMPLE 45
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, Cs2CO3 (215g) is added followed by addition of compound of formula IV of Example 44 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml).
The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 46
To a solution of compound Vc of Example 45 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I), (yield = 90g)
EXAMPLE 47
To a solution of 100g of crude Montelukast (I) of example 46 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus
obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 48
To a suspension of benzylamine salt VI of Montelukast (100g) of example 47 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 49
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 48) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 50
To a solution of [(S)-(E)]-2-[3-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl]-phenyl]-2- Propanol III (100g) in N,N-dimethyl formamide (250ml) at 15 to 20°C,
DIPEA (56ml) is added and the reaction mixture is cooled to -35 to -30°C. Then methane sulphonyl chloride (20ml) is added at -35 to -30°C and the reaction mixture is stirred at same temperature for 3hr. The reaction solution of product (IV) is used as such in the next step. (yield = 100g)
EXAMPLE 51
To a suspension of l-(mercaptomethyl)cyclopropane acetic acid methyl ester of formula Xc (70g) in acetonitrile (400ml) at 0-5°C, Cs2CO3 (215g) is added followed by addition of compound of formula IV of Example 50 (100g) in acetonitrile (200ml) and the reaction mixture is stirred. The progress of reaction is monitored by TLC. After 5hr, the reaction mixture is quenched in water (500ml) and product is extracted in ethyl acetate (500ml) followed by washing with water (300ml).
The product (Vc) was obtained by recovery of ethyl acetate from organic layer at reduced pressure, (yield = 120gm)
EXAMPLE 52
To a solution of compound Vc of Example 51 (100g) in methanol (600ml), aq. solution of 4M NaOH (250ml) is added at 10-30°C and the reaction mixture is stirred at 20-30°C for 16-18hr after completion of reaction, the reaction mixture is quenched in water (1500ml) and aq. layer is washed with toluene (500ml). Then pH of aq. layer is adjusted to 5.0 - 5.5 using acetic acid at 10-15°C and the product is extracted in ethyl acetate (500ml) followed by washing of ethyl acetate layer with water (500ml) and dried over Na2SO4. The solvent is removed at reduced pressure to obtain the crude product i.e. Montelukast acid (I), (yield == 90g)
EXAMPLE 53
To a solution of 100g of crude Montelukast (I) of example 52 in ethyl acetate (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then
toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 54
To a suspension of benzylamine salt VI of Montelukast (100g) of example 53 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 55
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 54) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 56
To a solution of 100g of crude Montelukast acid (I) of Example 34 in toluene (600ml) with stirring at 20-25°C, benzylamine (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 10-15 hr. at 20-25°C. The solid, thus obtained is filtered and was given slurry washing with toluene (100ml) and material is suck dried. The product (VI) is dried at 40-45°C for 5-6 hr. (yield =100g)
EXAMPLE 57
A suspension of benzylamine salt VI of Montelukast acid (100g) of Example 56 and compound Xc (5.0g) in toluene (800ml.) is stirred at 50-80°C for complete dissolution of material and the reaction mixture is stirred for 1 hr. Then the reaction mixture is cooled to 20-25°C and stirred for 10-12 hr. The solid, thus obtained, is filtered and dried at 40-45°C for 5-6 hr under vacuum to obtain pure product (VI). (yield = 85g)
EXAMPLE 58
To a suspension of methyl magnesium chloride in Tetrahydrofuran (350ml) at -20°C to -15°C, a solution of Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]benzoate (100g) in toluene (500ml) is added and the reaction mixture is stirred for 2 hr. Then the reaction mixture is quenched with ammonium chloride and toluene layer is separated and washed with water followed by drying over anhydrous sodium sulfate. To a suspension of methyl magnesium chloride (180ml) in tetrahydrofuran at -20°C to -15°C, above dried toluene layer is added and the reaction mixture is stirred for 2 hr. Then the reaction mass is quenched with ammonium chloride and toluene layer is separated followed by water washing. Toluene is partially removed at reduced pressure & product is crystallized by adding hexanes to get pale yellow solid. (Yield =85.0g)
EXAMPLE 59
The benzyl amine salt (VI) of Montelukast 100gm of example 48 dissolved in Methanol (200ml), followed by addition of acetic acid (12gm) and is stirred for l-2hrs. Water (600ml) is added and heated to 50°C under stirring. Then cooled to 20-30°C, filtered and dried at 40-45°C to obtained pure product (I). (Yield = 78.0g)
EXAMPLE 60
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 59) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 61
To a solution of 100g of crude Montelukast (I) of example 40 in ethyl acetate (600ml) with stirring at 20-25°C, dicyclohexyl amine (52g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25°C. The solid, thus obtained, is filtered and is given slurry washing with toluene (100ml). The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 112g)
EXAMPLE 62
The dicyclohexyl amine salt (VI) of Montelukast 100gm of example 61 is dissolved in Methanol (200ml), followed by addition of acetic acid (12gm) and is stirred for l-2hrs. Water (600ml) is added and heated to 50°C under stirring. Then cooled to 20-30°C, filtered and dried at 40-45°C to obtained pure product (I). (Yield = 70.0g)
EXAMPLE 63
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 62) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 64
To a solution of 100g of crude Montelukast (I) of example 52 in ethyl acetate (600ml) with stirring at 20-25°C, tris-(hydroxymethyl)amino methane (25.0g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-25°C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-
25°C. The solid, thus obtained is filtered and is given slurry washing with toluene (100ml). The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 60g)
EXAMPLE 65
To a suspension of tris-(hydroxymethyl)amino methane salt VI of Montelukast (100g) of example 64 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained, is filtered and dried to obtain pure product (I), (yield = 68g)
EXAMPLE 66
To a stirred and cooled (0 to -5°C) solution of sodium hydroxide (3.6 g, 0.09 mol. ) in methanol (250 ml), pure Montelukast acid (I) (50 g, 0. 085 mol of example 65) is slowly added in small lots. After stirring at 0 to -5°C for 30 minutes, the temperature of the reaction mixture is raised to +25 to +35°C and stirred for 30 minutes. Activated charcoal (1.25 g) is added to the clear pale yellow solution and after stirring for 1 hour at +25 to +35°C, the mixture is filtered through a high-flow-bed and washed with methanol (50 ml). Methanol is then carefully evaporated under vacuum < 40°C and the residue is stirred with n-heptane (400 ml) for 1.5 hr at +25 to +35°C. The white solid is carefully filtered under nitrogen gas atmosphere, washed with n-heptane (100 ml) and dried at +35 to +40°C under vacuum to obtain amorphous Montelukast sodium (II) as a very hygroscopic white powder and stored in closed contained under nitrogen gas atmosphere away from exposure of light. (yield = 50g)
EXAMPLE 67
To a solution of 100g of crude Montelukast (I) of example 40 in ethyl acetate (600ml) with stirring at 20-25°C, α,α-diphenyl-4-piperidine methanol (23.58g) is added dropwise with continuous stirring followed by addition of compound Xc (5.0g). The reaction mixture is
stirred for 1 hr. Then toluene (600ml) is slowly added with continuous stirring at 20-2 5 °C. After complete addition of toluene, the reaction mixture is further stirred for 10-15 hr. at 20-25 °C. The solid, thus obtained, is filtered and is given slurry washing with toluene (100ml), The product (VI) is dried at 40-45°C for 5-6 hr. (yield = 110g)
EXAMPLE 68
To a suspension of α,α-diphenyl-4-piperidine methanol salt VI of Montelukast (100g) of example 67 and compound Xc (5.0g) in toluene (500ml.) and water (500ml.) at 25-30°C, acetic acid (10g) is added dropwise with continuous stirring. After complete addition of acetic acid, the reaction mixture is stirred at 25-30°C for 5-6 hr. The toluene layer is separated and washed with water (100ml.). The toluene layer is stirred at 25-30°C for 7-8 hr. The solid, thus obtained, is filtered and dried to obtain pure product (I), (yield = 68g)
ADVANTAGES
1. The process leads to Montelukast free acid (I), >99% purity and Montelukast sodium salt (II), >99% with purity
2. The process is high yielding.
3. The process is cost effective, environment and user friendly.

We Claim:
1. An improved process for preparation of Montelukast acid and salt thereof which comprises:
(a) preparing a compound of general formula 1A
(Formula Removed)
Where in R1 is represented by OH or a compound of formula(Formula Removed)
if so desired
by reacting Methyl-[E]-2-[3S-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-hydroxy propyl] Benzoate with magnesium halide in organic solvent such as herein described,
(b) then reacting with sulfonyl chloride in organic solvent in presence of base to obtain
mesylate,
(c) coupling l-(mercaptomethyl) cyclopropane derivative of formula(Formula Removed)

wherein R represents CN, COOCH3, CONH2 or OH,
with mesylate so obtained in organic solvent in presence of base to obtained a compound of formula
(Formula Removed)

Wherein R1 has the meaning as given above, deprotecting of dihydropyran ring when r is other than OH and R1 is(Formula Removed)

(d) recovering Montelukast acid by mere quenching the reaction when R is OH or
subjecting to alkali hydrolyzing of the product obtained in step (c) followed by washing
with water immiscible organic solvent and isolating by conventional methods when R
is other than OH ,
(e) optionally purifying and converting to amine salt by conventional methods such as herein described and, reconverting to acid by reacting with acetic acid in organic solvent to get purified Montelukast acid, then
(f) transforming to its sodium salt by conventional alkali metal treatment.

2. An improved process as claimed in claim 1 wherein magnesium halide used is methyl magnesium halide preferably methyl magnesium chloride, bromide, iodide or mixture thereof.
3. An improved process as claimed in claim 1 wherein the organic solvent used in step (a) is selected from cyclic or acyclic ethers like tetrahydrofuran, dioxane, monoglyme, diisopropylether, tert-butylmethyl ether, diethyl ether or aromatic hydrocarbons like benzene, toluene, xylenes or a mixture thereof.
4. An improved process as claimed in claim 1 wherein the reaction temperature in step (a) is preferably between -30°C to +50°C, more preferably -20°C to +40°C and most preferably -15°Cto+25°C.
5. An improved process as claimed in claim 1 wherein sulfonyl chloride used is methane sulfonyl chloride or p-toluene sulfonyl chloride or methane sulphonic anhydride.
6. An improved method as claimed in claim 1 comprising:

(a) reacting the compound of formula (III) with methane sulphonyl chloride in organic solvent in presence of base to obtain mesylate of formula (IV)
(b) coupling l-(mercaptomethyl) cyclopropane derivative of formula (Xa/ Xc/ Xd) with mesylate (IV) in in-situ reaction mass of (IV) of step (a) or on isolation in organic solvents in the presence of a base to form compound of formula (Va/ Vc/ Vd),
(c) hydrolyzing the product of step (b) by conventional methods followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after pH adjustment, extraction in water immiscible organic solvent followed by solvent recovery.
(d) optionally preparing amine salt of formula (VI) of product of step (c) for its purification, optionally repurifying and converting the amine salt (VI) back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization.
(e) converting pure Montelukast acid (I) into Montelukast sodium (II) using conventional methods.
7. An improved process as claimed in claim 1 comprising:
a) reacting the compound of formula (VII) with methane sulphonyl chloride in organic solvent in presence of base to obtain mesylate of formula (VIII).
b) coupling compound of formula (Xa/ Xc/ Xd) with mesylate (IV) in in-situ reaction mass of (VIII) of step (a) or on isolation in organic solvents in the presence of a base to form compound of formula (IXa/ IXc/ IXd).
c) deprotecting of dihydropyran ring of the product of step (b) by using conventional method to get compound (Va/ Vc/ Vd) and hydrolysing the compound (Va/ Vc/ Vd) by conventional methods followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after pH adjustment, extraction in water immiscible organic solvent followed by solvent recovery,
d) preparing amine salt (VI) of product of step (d) for its purification, optionally repurifying and converting the amine salt (VI) back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization,
e) converting pure Montelukast acid (I) of step (d) into Montelukast sodium (II) by conventional methods.
8. An improved process as claimed in claim 1 comprising:
a) reacting the compound of formula (III) with methane sulphonyl chloride or p-toluene sulfonyl chloride in organic solvent in presence of base to obtain mesylate of formula (IV).
b) coupling of formula (Xb) with mesylate (IV) in in-situ reaction mass of (IV) of step (a) or on isolation in organic solvents in the presence of a base.
c) quenching the reaction mass of step (b) with water, basification followed by washing of reaction solution with water immiscible organic solvents optionally to get Montelukast acid (I) after acidification, extraction in water immiscible organic solvent followed by solvent recovery.
d) optionally preparing amine salt of Montelukast acid (I) from step (b) for its purification, optionally repurifying and converting the amine salt back to pure Montelukast acid (I) by reaction with acetic acid in an organic solvent and water mixture and isolating (I) by crystallization.
e) converting pure Montelukast acid (I) of step (d) into Montelukast sodium (II) using conventional methods.
9. An improved process as claimed in preceding claims wherein organic solvent used for
reaction with sulfonyl chloride and coupling is selected from aliphatic nitriles such as
acetonitrile, propionitrile; cyclic or acyclic aliphatic ethers such as tetrahydrofuran, dioxane,
diisopropyl ether, methyl tert-butyl ether , diethyl ether; aromatic hydrocarbons such as
benzene, toluene, xylenes; halogenated hydrocarbons such as methylene chloride,
chloroform, carbontetra chloride; aliphatic amides such as N,N-dimethyl formamide, N,N-
dimethyl acetamide or a mixture thereof.
10. An improved process as claimed in preceding claims wherein the molar ratio of methane sulfonyl chloride or p-toluene sulfonyl chloride with reference to compound of formula (1A/III/VII) is in the range of 0.8 to 3.0.
11. An improved process as claimed in preceding claims wherein the base used in step reaction with sulfonyl chloride is selected from tertiary amines preferably N,N-diisopropyl ethylamine, triethylamine.
12. An improved process as claimed in preceding claims wherein molar ratio of base used in reaction with sulfonyl chloride with reference to compound of formula (1A/III/VII) is ranging from 1.0 to 5.0.
13. An improved process as claimed in preceding claims wherein the base used in coupling is selected from alkali or alkaline earth metal carbonates like CS2CO3, K2CO3, Na2CO3 , CaCO3, Li2CO3. Specifically CS2CO3 is more preferred when R is ester.
14. An improved process as claimed in preceding claims wherein the molar ratio of the base with reference to compound of formula (IV) in step (b) may be in the range of is 1.0 to 10.0, while molar ratio of compound of formula (Xa/ Xc/ Xd) in step (b) w.r.t. of formula (IV) may range from 1 to 6.
15. An improved process as claimed in preceding claims wherein the reaction temperature in step (a) ranges from -40°C to +30°C and that in the reaction temperature in coupling ranges from -35°C to +40°C.
16. An improved process as claimed in preceding claims wherein the water immiscible solvents used for washing of reaction solution is selected from aromatic hydrocarbons such as benzene, toluene, xylenes; aliphatic esters like methyl acetate, ethyl acetate, propyl acetate, butyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform, carbontetra chloride; aliphatic ethers like diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
17. An improved process as claimed in preceding claims wherein the amines used for salt formation is NH3, benzylamine, phenyl hydrazine, tris-(hydroxymethyl)aminomethane, α,α-diphenyl-4-piperidinemethanol, dicyclohexylamine.
18. An improved process as claimed in preceding claims wherein the organic solvents used for preparation and purification of amine salt and conversion to free Montelukast acid, is selected from aliphatic esters preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate; aromatic hydrocarbons preferably toluene, xylene, benzene; C5 - C7 aliphatic hydrocarbons like pentane, hexane, heptane, C1-C4 aliphatic alcohols like methanol, ethanol, propanol, butanol; halogenated hydrocarbons like methylene chloride, chloroform; cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, ter-butyl methyl ether or a mixture thereof.
19. An improved process for preparation of Montelukast acid and salt thereofsubstantially such as herein described.