WO2012020271A1 - Process for the preparation of montelukast sodium - Google Patents

Abstract

The present invention relates to a process for the synthesis of Montelukast sodium of formula I the chemical name of which is [(R)-(E)]-1-[[[1-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl] -3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl]propyl] thio]methyl] - -cyclopropaneacetic acid sodium salt. The present invention further provides compounds of general formulae V, VI, VIb and VIII as new intermediates.

Description

Process for the preparation of Montelukast sodium

FIELD OF THE INVENTION

The present invention relates to a novel process for the synthesis of Montelukast sodium of formula I (chemical name: [(R)-(E)]-l-[[[l -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2- -(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid sodium salt).

I

The present invention provides compounds of general formulae V, VI, VIb and VIII as new intermediates of the process.

The present invention further provides a one-pot process for the preparation of cesium salt of formula Vila starting from the S-acetyl compound of formula VII. BACKGROUND OF THE INVENTION

Asthma is considered to be an endemic. Approximately 200 million people suffer from asthma around the world. The disease causes enormous direct medical expenditures and indirect costs globally. Asthma is responsible for inpatient hospitalizations, emergency room use, reduced productivity due to loss of school days, high medical expenditures, and for the deterioration of quality of life.

Leukotrienes cause contractions in the smooth muscles lining the trachea. The overproduction of leukotrienes is a major cause of inflammation in asthma and allergic rhinitis. Treatment and prevention of asthmatic and allergic symptoms is possible by inhibiting the production or activity of leukotrienes. Compound of formula I, also known by the name Montelukast sodium (chemical name: [(R)-(E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid sodium salt) is a selective leukotriene antagonist which is the active ingredient of commercially available oral pharmaceuticals (Singulair® from Merck Co.) Montelukast sodium is effective in preventing shortness of breath including the day and night symptoms of asthma attack. Furthermore it prevents the physical activity induced sudden constriction of respiratory tracts. Montelukast sodium is effective in the treatment of different seasonal forms of allergic diseases including the day and night symptoms as well.

The first synthesis of Montelukast and its related compounds is described in patent EP 0480717 Bl . This process became the basis of the later published processes that use very similar synthetic strategies with slight modifications. The aforementioned patent discloses a process shown on the scheme 2/A. At first the compound of formula Via (5)-l-{3-[(E)-2-(7-chloro- quinolin-2-yl)-vinyl]-phenyl } -3 - [2-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl] -propan- 1 -ol is synthesized. The secondary OH-group of compound of formula Via is silylated by tert.butyl- dimethylsilyl chloride (TBDMSC1), and then the tertiary OH-group is protected as tetrahydropyranyl ether by reacting with dihydropyrane (DHP). After cleavage of the silyl moiety using tetrabutyl-ammonium-fluoride (TBAF), the free secondary OH-group of compound of formula X is reacted with methanesulfonyl-chloride (MsCl). The thus obtained tetrahydropyranyl protected intermediate of formula XI is coupled with the cesium salt of formula Vila (R₂=CH₃) in the presence of a base. The cesium salt of formula Vila is prepared in two steps from 1-acetylmercaptomethyl-cyclopropaneacetic acid methyl ester of formula VII (R₂=CH₃). The formed protected Montelukast methyl ester of formula XII is treated with acid to remove tetrahydropyranyl (THP) protecting group then the formed ester of formula XIII was transformed to Montelukast sodium using alkaline hydrolysis. The product of formula I is isolated in amorphous form by freeze-drying.

Patent US 5614632 discloses an improved process as shown on the scheme 3/A. The secondary OH group of the (5)-l-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l- hydroxy-l-methyl-ethyl)-phenyl] -propan- l-ol intermediate of formula Via is converted in one step to good leaving mesyloxy group. The formed mesylate intermediate is reacted with 1- mercaptomethyl-cyclopropaneacetic acid dilithium salt of formula Vllb to obtain Montelukast acid of formula la. Montelukast acid is then crystallized as its dicyclohexylamine (DCHA) salt, then the DCHA salt is converted to sodium salt.

One of the drawbacks of these processes is the extreme condition (reaction temperature is below -25°C) that is required to prepare the appropriate mesylate intermediate. At higher temperatures the activated mesylate of formula XIV may be transformed to cyclic ether of formula XV side product.

XV

Due to its instability, mesylate ester of formula XIV must be stored below -18°C. The aforementioned patent disclose the synthesis of diol of formula Via starting from the methyl benzoate derivative of formula XVI using Grignard reaction, as shown on scheme 3/B. In this Grignard reaction ketone of formula XVII is formed in the first step. In the presence of Grignard reagent the ketone may be transformed into its enolate form, which is unreactive toward the second Grignard reagent. After work up side product of formula XVII (l-[2-((S)-3-{3-[(E)-2-(7- chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-phenyl]-ethanone) is formed as an impurity.

Patent US 5614632 discloses an improved process applying large excess of anhydrous

CeCl₃ in the Grignard reaction to decrease the amount of ketone impurity (XVII). This process, however, might be very costly.

Analogous process is described in international patent application WO 2005/105751 shown on scheme 3/C. Compound of formula XIV (methanesulfonic acid (-$)-1-{3-[(Ε)-2-(7- chloro-quinolin-2-yl)-vinyl] -phenyl } -3 -[2-( 1 -hydroxy- 1 -methyl-ethyl)-phenyl] -propyl ester) is reacted with 1-mercaptomethyl-cyclopropaneacetic acid methyl ester of formula VIIc in the presence of inorganic base (e.g. sodium hydroxide) to obtain Montelukast methyl ester of formula XIII. The formed ester is converted to the final product of formula I by alkaline hydrolysis followed by sodium salt formation.

The mentioned methanesulfonic acid ester of formula XIV is a common instable intermediate published in several patent application. (See e.g. US 2005/02434241, US2007/0208177 or WO 2006/058545)

To avoid the use of unstable intermediate international patent application WO 2006008751 discloses an other synthesis route as shown in scheme 4/A. Mesylate of compound of formula XVI is reacted with 1-mercaptomethyl-cyclopropaneacetic acid dialkali salt of formula Vllb, then the thus formed monoester of formula XVIII is treated with methyl magnesium bromide to obtain Montelukast acid of formula la. Patent EP 01693368 discloses an analogue process as well. All these analogous synthetic methods may produce the same ketone impurity of formula XIX. In the above summarized patents describe processes all in which 1 -mercaptomethyl- cyclopropaneacetic acid derivatives of formulae Vila, Vllb or VIIc are alkylated with corresponding active esters of formulae XIV or XVI. International patent application WO 2005/105749 discloses a process that somewhat differs from the above described methods (Scheme 4/B). Active ester derivatives of formulae XI, XIV and XVI are converted to the corresponding acetylthio derivatives of formulae XX, XXI or XXIV. Methyl benzoate of formula XXIV is reacted with methyl lithium to form the corresponding carbinol of formula XXI. Acetyl groups are removed by hydrazinolysis, and then the obtained thiol of formula XXII is alkylated with 1-halomethyl-cyclopropaneacetic acid or with 1-mesyloxymethyl- cyclopropaneacetic acid derivative to produce Montelukast ester of formula XIII. These processes do not avoid the use of instable intermediate; moreover, these include more chemical steps than the previously mentioned ones.

International patent application WO 2007/051828 describes a process according to which the carboxyl group of the side chain is built into the molecule at the end of the synthesis. See scheme 5/A. primary alcohol of formula XXV is converted to an activated ester of formula XXVI, then compound of formula XXVT is transformed to nitrile of formula XXVII. Nitrile of formula XXVII is then hydrolyzed to form Montelukast acid of formula la. The process is claimed to be cost efficient, however, it consist more reaction steps than the previously presented processes.

International patent application WO2008/009970 discloses a very similar synthetic route to that described in EP 0480717 Bl. (See scheme 2/B) The only difference is that ester of formula XII is hydrolyzed to obtain THP -protected Montelukast acid of formula XXVIII.

Different synthetic strategy for the construction of the skeleton of the molecule disclosed in patent EP 2053043 is shown on scheme 5/B. Montelukast acid of formula la is prepared by the reaction of 7-chloro-2-vinylquinoline of formula XXIX and compound of formula XXX using Pd-catalyzed coupling. Compound of formula la is purified in the form of cyclopropylamine salt. Preparation of compound of formula XXX is described in WO 2008/098965 patent application.

International patent application WO 2008/014703 discloses two synthetic routes for the preparation of Montelukast starting from compound of formula XXXI. (Scheme 6/ A) In one embodiment chloropropyl derivative of formula XXXI is reacted with thiol of formula Vlld, then the product of formula XVIII is reacted with ceriumchloride-methylmagnesiumbromide reagent to form the carbinol function. In another embodiment construction of chlorocarbinol of formula XXXII is followed by S-alkylation. Montelukast acid of formula la is purified in the form of its isopropylamine salt, and then the isopropylamine salt is transformed into Montelukast sodium of formula I. The same patent application describes the preparation of Montelukast acid by the reaction of chlorocarbinol of formula XXXII with dilithium salt of formula Vllb.

Scheme 6/B shows a synthetic route disclosed in WO 2008/032099 published international patent application. Ester of formula XVI is transformed into methylketone of formula XVII. Hydroxyl group of compound of formula XVII is transformed into good leaving group (L) and the thus obtained active ester of formula XXXIII is reacted with thiol of formula Vlld to prepare methylketone of formula XIX. Ketone function of compound of formula XIX is reacted again with Grignard reagent to yield acid of formula la.

International patent application WO 2009/016191 discloses the methylketone intermediate of formula XIX and the purification of formula XIX as its DCHA salt. The published process involves the use of sensitive Grignard reagent twice during the synthesis.

Scheme 2/C shows the process described in WO 2009/138993 published international patent application. Diol of formula Via is converted into a stable phosphoric acid ester of formula XXXIV then the phosphoric acid ester is reacted with thiolester of formula VIIc to prepare Montelukast ester of formula XIII. Final product of formula I is obtained from Montelukast ester using well known method. In this process formation of the active ester is performed at low temperature (between -40°C and -20 °C)

International patent application WO 2008/072872 discloses the use of phosphoric acid ester as active ester as well.

International patent application WO 2009/048236 publishes the reaction of mesylate of formula XIV with bis-alkali metal salt of thiol acid of formula Vlld in a solvent mixture of ionic liquid and dimethylsulfoxide (DMSO). During work-up conventional solvents (e.g. n-hexane, ethylacetate) are applied. Product of formula la is obtained with good chemical purity.

International patent application WO 2006/021974 discloses a process for the synthesis of Montelukast skeleton as shown on scheme 7. Aldehyde of formula XXXV is converted to alcohol of formula XXXVI with Grignard reaction, followed by Swern oxidation to yield methylketone of formula XXXVII. Reaction of methylketone of formula XXXVII and dimethylcarbonate yields β-oxoester of formula XXXVIII which is then alkylated with benzylbromide of formula XXXIX to obtain oxoester of formula XL. Decarboxylation of oxoester of formula XL yields ketone of formula XLI which is converted to alcohol of formula XVI by asymmetric reduction. Similar process is disclosed in patent application WO 2009/001374. The drawback of this process is the use of numerous chemical steps.

All of the aforementioned processes involve purification of crude Montelukast acid of formula la by crystallization. Since Montelukast acid contains a basic nitrogen atom, it may also form acid addition salts as well. Some examples of base addition salt of Montelukast acid are cyclopropylamine salt (EP 2053043), cyclooctylamine and cyclohexyl amine salts (US 2008/0188664), tris(hydroxymethyl)aminomethane salt, L-(+)-threo-2-amino-l-phenyl-l ,3- propanediol, L-(+)-a-phenylglycinol salt (WO 2008/017669), tert.octylamine and 4-amino- cyclohexanol salts (WO 2008/023044). Acid addition salts contain primarily strong mineral and organic acids such as HC1, HBr, HI (WO2009/098271), or 1,2-ethanedisulfonic acid (WO 2009/052625).

Considering the drawbacks of the reviewed processes our aim was to design a safe, cost effficient, industrially applicable process which comprises simple technological steps and the quality of the final product meets the pharmacopoeial requirements of pharmaceutically active compounds. We aimed to develop a process without difficult technological steps using extreme conditions. Furthermore it is also necessary that intermediates can be isolated efficiently, and purified with simple procedures. We planned to apply more expensive procedures are at the end of the process. We would like to avoid the above mentioned drawbacks with using a convergent synthetic strategy, thus the final product is constructed from preformed building blocks. To avoid the application of instable mesylate intermediate, tertiary hydroxyl group was protected by silyl protecting group. 2-Bromo-2'-hydroxypropylbenzene building block containing the carbinol moiety was prepared according to a method well known from the literature. Purified 2-bromo-2'- hydroxypropylbenzene building block was used for convergent synthesis of the molecule.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the synthesis of Montelukast sodium of formula I (chemical name: [(R)-(E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2~(l-hydroxy-l-methylethyl)phenyl]

ropyl]thio]methyl]cyclopropaneacetic acid sodium salt) , new intermediers of this process. The present invention further provides a one-pot process for the preparation of cesium salt of formula Vila starting from the S-acetyl compound of formula VII.

DETAILED DESCRIPTION OF THE INVENTION

We have surprisingly found that Heck-reaction of compound of formula III (chemical name: 2-bromo-2'-hydroxypropylbenzene, X = Br) with compound of formula II (l-{3-[(E)-2- (7-chloro-quinolin-2-yl)-vinyl]-phenyl}-l-hydroxy-propene) provided compound of formula IV (l- {3-[(E)-2-(7-chloro- quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-hydroxy-l-methyl-ethyl)-phenyl]- propane- 1 -on) in high yield. After silylation of compound of formula IV, the product compound of formula V (Rj = trimethylsilyl) was obtained in crystalline form. The ketone of formula V was reduced stereoselectivly in the presence of CBS-catalyst (Corey-Bakshi-Shibata catalyst) such as (R)-(+)-methyl-CBS-oxazaborolidine or (R)-(+)-n-butyl-CBS-oxazaborolidine or (R)-(+)-o- tolyl-CBS-oxazaborolidine - preferably in the presence of (R)-(+)-tolyl-CBS-oxazaborolidine - using catecholborane as reducing agent. The crude compound of formula VI ((S)-l-{3-[(E)-2-(7- chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l -mehyl-l-trimethylsilanyloxy-ethyl)-phenyl]- propan-l-ol) was obtained in surprisingly high enantiomeric purity (>98%), then it was purified by simple crystallization. The mesylate of formula Vic prepared from compound of VI proved to be a stable and easily preparable intermediate. The reaction of mesylate of formula VIc with 1 - mercaptomethyl-cyclopropaneacetic acid methyl ester cesium salt of formula Vila produced protected Montelukast of formula VIII in high yield. 1 -Mercaptomethyl-cyclopropaneacetic acid methyl ester cesium salt of formula Vila was prepared from (1-acetylsulfanylmethyl- cyclopropyl)-acetic acid methyl ester of formula VII in one step without using hydrazine hydrate. Montelukast acid was prepared from protected Montelukast of formula VIII by alkaline hydrolysis followed by purification in the form of its dicyclohexylamine salt of formula IX. Then the purified dicyclohexylamine salt was converted to Montelukast sodium of formula I according to a process known from literature.

Our further experiments showed that Montelukast acid can be purified using amine functionalized ion exchange resin instead of using crystallization.

In an alternative process, intermediate of formula VI ((S)-l-{3-[(E)-2-(7-chloro-quinolin-

2-yl)- vinylj-phenyl } -3 -[2-( 1 -mehyl- 1 -trimethylsilanyloxy-ethyl)-phenyl]-propan- 1 -ol) can be synthesized from compound of formula Via ((S)-l-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]- phenyl}-3-[2-(l-hydroxy-l-mehyl-ethyl)-phenyl]-propan-l-ol). According to this process , free hydroxyl groups of compound of formula Via were silylated with chlorotrimethylsilane to obtain the disilyl derivative of VIb. Surprisingly it has been found, that silyl protecting group of secondary OH group in disilyl derivative of VIb can be selectively removed by methanolic ammonia reagent. The obtained monosilyl intermediate of formula VI can be easily purified by simple crystallization.

According to the above, present invention relates to a process for preparing Montelukast sodium of formula I by removing the protecting group from protected Montelukast of formula VIII by in one step by alkaline hydrolysis, and then isolating Montelukast sodium, after purification if desirable.

According to a further embodiement of the invention the initial protected Montelukast of formula VIII is obtained by reacting methanesulfonic acid ester derivative of formula VIc with 1-mercaptomethyl-cyclopropaneacetic acid cesium salt of formula Vila.

According to a further embodiement of the invention the initial compound of formula Vila is directly obtained by reacting cyclopropane derivative of formula VII with cesium carbonate.

According to a further embodiement of the invention the initial methanesulfonic acid ester derivative of formula VIc is prepared from ether of general formula of VI.

According to a further embodiement of the invention the initial ether of general formula VI is prepared by reducing the compound of general formula V in the presence of a catalyst and an appropriate reducing agent.

According to the present invention CBS-catalyst (Corey-Bakshi-Shibata catalyst) is applied advantageously (R)-(+)-o-tolyl-CBS-oxazaborolidine or (R)-(+)-methyl-CBS- oxazaborolidine or (R)-(+)-n-butyl-CBS-oxazaborolidine is applied.

According to the present invention borane type reagents are used as reducing agents, advantageously borane-tetrahydrofuran complex, borane-dimethylsulfide complex, most preferably catecholborane.

In one embodiment the process further comprises silylating the ketocarbinol of formula IV to obtain compound of general formula of V.

In another embodiment the silanizing reagent is selected from the group consisting of chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, N,0-bis(trimethylsilyl) acetamide, N-trimethylsilylimidazole, 1,1,1,3,3,3-hexamethyldisilazane, chlorotriethylsilane tert.butyl-dimethylchlorosilane, tert.butyl-dimethylsilyl-trifluormethanesulfonate, chloro- triisopropylsilane. Preferably the silanizing reagent is chlorotrimethylsilane.

In one embodiment the process further comprises reacting allyl alcohol of formula II with carbinol of general formula of III to obtain ketocarbinol intermediate of formula IV.

In another embodiment the process further comprises converting compound of formula

VIb into the intermediate of general formula of VI using inorganic or organic base in organic solvent.

In another embodiment the process further comprises silylating compound of formula Via to obtain intermediate of formula VIb

The present invention also relates to compounds of general formulae V, VI, VIb and VIII as new intermediates.

The procedure of the present invention is illustrated on the Scheme 1/A and 1/B. The technological steps and are described in detail in the followings.

Step 1

According to Scheme 1/A allyl alcohol of formula II -synthesized by well known procedure (see e.g. EP0480717) - is reacted with the carbinol-derivative of formula III (X = halogen) in Heck-type reaction. 2-5 mol%, preferably 3-4 mol% of palladium (II) acetate is used as catalyst, 2-3 molar equivalent of sodium acetate and 2-3 molar equivalent of tetrabutylammonium bromide are used as base. Toluene, N-methyl-2-pyrrolidone, acetonitrile, N,N-dimethylacetamide or the mixture thereof is used as solvent, preferably mixture of toluene and N-methyl-2-pyrrolidone is used. The temperature of the reaction is 100-140°C, preferably 120°C. The product of formula IV is used in the next step without purification. The crude ketocarbinol of formula IV is dissolved in aprotic organic solvent, preferably in tetrahydrofuran, and 2 molar equivalents of imidazole are added to the solution. Thus, the palladium(II) content of the ketocarbinol is transformed into an insoluble precipitate. The precipitate (contains the insoluble complex of the palladium(II) catalyst) is filtered, and the resultant mother liquor is treated with suitable silylating agent such as chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, N,0-bis(trimethylsilyl)-acetamide, preferably with chlorotrimethylsilane. The silyloxy intermediate of formula V is purified by recrystallization from acetonitrile. Step 2

According to Scheme 1/A silyloxy-ketone of the general formula V is reduced in the presence of CBS-oxazaborolidine catalyst ((R)-(+)-o-tolyl-CBS-oxazaborolidine, (R)-(+)- methyl-CBS-oxazaborolidine, (R)-(+)-n-butyl-CBS-oxazaborolidine), preferably in the presence of (R)-(+)-o-tolyl-CBS-oxazaborolidine, using excess of borane-type reducing agent such as BH₃-THF, BH3-dimethylsulfide complex, catecholborane, preferably using 2-3 equivalent catecholborane. Aprotic solvent is used such as tetrahydrofuran, toluene, dichloromethane and mixture thereof, preferably is used dichloromethane. The temperature of the reduction is -78 to 0°C, preferably -40 to -50°C. The optical purity of the (S)-l - {3-[(E)-2-(7-chloro-quinolin-2-yl)- vinyl]-phenyl}-3-[2-(l-hydroxy-l-methyl-ethyl)-phenyl]-propan-l -ol silyl ether of formula VI is >98% ee. The crude product can be recrystallized using various organic solvents, preferably using acetonitrile. Step 2a

According to Scheme 1/A, (S)-l-{3-[(E)-2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2- (1 -hydroxy- l -methyl-ethyl)-phenyl]-propan-l-ol (Via) - synthesized by well known procedure - is solved in aprotic organic solvent (tetrahydrofuran, methyl tert-buthyl ether, toluene), preferably in tetrahydrofuran, then it was sylilated with suitable silylating agent such as chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, N,0-bis(trimethylsilyl)- acetamide, preferably with chlorotrimethylsilane, in the presence of organic base, preferably imidazole, to obtain the product of the general formula Vlb (Ri = trimethylsilyl). The temperature of the reaction is maintained between 0 and 30°C, preferably at 25°C.

Compound of the general formula Vlb (Ri = trimethylsilyl) is dissolved in polar solvent such as C1 -C4 alcohols, acetonitrile, preferably in methanol, and the silyl protecting group is selectively removed from the secondary hydroxyl group applying suitable organic or inorganic base such as potassium-carbonate, ammonia solution, triethylamine, pyridine, preferably using ammonia solution at 30 to 60°C, preferably at 50°C. The crude product of formula VI can be recrystallized using organic solvent, preferably acetonitrile.

Step 3 According to Scheme 1/A, S-acetyl derivative of formula VII (wherein the meaning of R₂ is Ci-C₄ alkyl) - synthesized by well known procedure - is dissolved in alcohol selected from the group of C]-C₄ alcohols, and then dry cesium carbonate is added under inert atmosphere, at 0 to 30°C, preferably at 20 to 25°C . The alcoholic solution is concentrated in vacuum and cesium- salt of formula Vila is readily obtained.

Step 4

According to Scheme 1/B, compound of the general formula VI - wherein the meaning of Ri is trimethylsilyl - is reacted with a sulfonic acid derivative such as methanesulfonyl chloride, p-toluenesulfonyl chloride, preferably with methanesulfonyl chloride, in anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, toluene, preferably in toluene, in the presence of base selected from the group of diisopropyl-ethylamine, triethylamine, pyridine, preferably triethylamine at -25 to 25°C, preferably at 0°C to obtain the product of the general formula Vic wherein the meaning of Ri is trimethylsilyl and R₃ is methyl.

The compound of the general formula Vic - wherein R_\ is trimethylsilyl and R₃ is methyl

- is dissolved in anhydrous solvent such as toluene, tetrahydrofuran, acetonitrile, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide or the mixture thereof, preferably in N-methyl-2-pyrrolidone, then it is reacted with the solution of the salt of formula Vila - the solvent of which is selected from the list of toluene, tetrahydrofuran, acetonitrile, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, Ν,Ν-dimethylformamide or mixtures thereof, preferably N-methyl-2-pyrrolidone - at 0 to 25°C.

After workup, compound of general formula VIII is purified by chromatography. Alternatively, crude compound of formula VIII is used in the next reaction step without purification.

Step 5

According to Scheme 1/B, chromatographically purified compound of the general formula VIII - wherein R_\ is trimethylsilyl, R₂ is methyl - is stirred in the mixture of a completely or partially water miscible organic solvent such as C1-C4 alcohol, acetonitrile, tetrahydrofuran, 2 -methyl -tetrahydrofuran, preferably methanol and an alkaline solution of sodium carbonate or sodium hydroxide, preferably methanolic sodium hydroxide, under inert atmosphere, at 25 to 80°C, preferably at 70 to 80°C. Montelukast sodium of formula I is readily obtained after extractive workup. Crude Montelukast sodium is dissolved in toluene and precipitated by addition of an apolar organic solvent selected from C₅-C₇ alkanes and mixtures thereof, preferably heptane. The obtained amorphous precipitate can be easily filtered. Step 5a

According to Scheme 1/B crude compound of the general formula VIII - wherein R_\ is trimethylsilyl, R₂ is methyl - obtained in Step 4 is used in the next hydrolysis reaction without further purification. Details of the hydrolysis are as follows.

The hydrolysis is carried out under inert atmosphere in the mixture of an organic solvents selected from the list of Q-C4 alcohol, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran and mixtures thereof, preferably mixture of 2-methyl-tetrahydrofuran and methanol, and an alkaline solution of sodium carbonate or sodium hydroxide, preferably aqueous sodium hydroxide solution, at 25 to 80°C, preferably at 70 to 80°C. After the reaction is complete, the reaction mixture is diluted with water immiscible solvent, preferably with 2-methyl- tetrahydrofuran. Organic phase containing Montelukast sodium is treated with organic or inorganic acid selected from the group consisting of acetic acid, citric acid, potassium dihydrogen phosphate solution, sodium dihydrogen phosphate solution, preferably with potassium dihydrogen phosphate solution to obtain Montelukast acid of formula la. Crude Montelukast acid oil of formula la is isolated as an oil by evaporating organic phase.

The crude Montelukast acid is purified via the dicyclohexylamine salt of formula IX to produce Montelukast sodium of formula I according to procedure well known from literature.

The DHCA salt of formula IX is recrystallized as follows. The salt is dissolved in appropriate solvent, preferably in ethylacetate and 1-5 mol%, preferably 2 mol% dicyclohexylamine is added to the homogenous solution. The crystallization is performed by addition of apolar solvent such as C5-C-7 alkanes, cycloalkanes or mixture thereof, preferably by addition of n-hexane, at room temperature. The precipitated DCHA salt of formula IX is easily filtered and washed using said solvents or mixtures thereof.

Montelukast sodium of formula I is produced from the DCHA salt, according to procedure known from literature. BRIEF DESCRIPTION OF THE SCHEMES

The process according to present invention is demonstrated on the following schemes:

Scheme 1: illustrates the process of the present invention, all steps are presented. In the general formulae of Scheme 1, the meaning of X is halogen, such as Br or I; Ri means silyl, such as trimethyl silyl, tert.butyl-dimethylsilyl; R₂ means Ci-C₄ alkyl; R₃ means methyl, phenyl or substituted phenyl.

Scheme 1/A: illustrates the 1-3 steps of the process of present invention.

Scheme 1/B: illustrates the 4-5 steps of the process of present invention

Scheme 2/A : illustrates the process disclosed in EP0480717

Scheme 2/B: illustrates the process disclosed in WO2008/009970

Scheme 2/C: summarizes the process disclosed in WO2009/138993

Schemes 3/A and 3/B: illustrate the process disclosed in US5614632

Scheme 3/C: illustrates the process disclosed in WO2005/105751

Scheme 4/A: illustrates the process disclosed in WO2006/008751

Scheme 4/B: illustrates the process disclosed in WO2005/105749

Scheme 5/A: illustrates the process disclosed in WO2007/051828

Scheme 5/B: illustrates the process disclosed in EP2053043

Scheme 6/A: illustrates the process disclosed in WO2008/014703

Scheme 6/B: illustrates the process disclosed in WO2008/032099

Scheme 7: illustrates the process disclosed in WO2006/021974

Advantages of the present invention are summarized in the followings. a) The present invention provides a process for the synthesis of compound of formula I wherein the key intermediate of formula VI is produced applying few synthetic steps. The key intermediate can be purified effectively using simple crystallization due to its good crystallization ability.

b) The protected mesylate of formula VIc obtained by mesylation of the key intermediate of formula VI is stable, its handling and storage do not require extreme conditions.

c) The cesium salt of formula Vila, which is further transformed with mesylate of formula VIc, is prepared readily from the S-acetyl derivative of formula VII without use of hydrazine. d) Alternatively the key intermediate of formula VI can be prepared from diol of formula Via through a single intermediate of formula VIb. With this procedure the selective protecting of the two different type hydroxyl groups of compound of formula Via can be avoided.

e) The carbinol part of the molecule of formula I is built in using convergent synthesis. This synthetic procedure applies building blocks one of which already contains the carbinol function. Using this strategy the formation of the ketone side product of formula XVII is avoided. Moreover, application of the expensive anhydrous cerium chloride, or other environmentally hazardous heavy metal salts, can also be avoided.

f) The protecting groups can be removed from the protected Montelukast of formula VIII applying a single synthetic step to prepare Montelukast sodium of formula I.

g) Montelukast acid of formula la can be obtained by hydrolyzing of the protected Montelukast of formula VIII, which without isolation is transformed to DCHA salt. The salt is effectively purified by simple crystallization.

h) In another embodiment of the present invention Montelukast acid of formula la is purified effectively using basic ion exchange resin to remove non-acid type impurities.

In summary, the present invention relates to a process designed for the economic industrial scale production of Montelukast sodium of formula I. The quality of the final product produced by the process of the present invention meets the strict pharmacopoeial requirements of pharmaceutically active compounds.

EXAMPLES

The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way as many variations and equivalents that are encompassed by present invention will become apparent to those skilled in the art upon reading the present disclosure.

Example 1

Preparation of l-{3-[ (E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-methyl-l- trimethylsilanyloxy-ethyl)-phenyl]-propan-l-one (V, Rj - trimethylsilyl) 0.8 g (0.0037 mol) of palladium(II) acetate, 20.5 g (0.25 mol) of sodium acetate, 64.5 g (0.20 mol) of tetrabutylammonium bromide were placed under an argon atmosphere and 23.7 g (0.1 1 mol) of bromo-carbinol (III, X=Br) dissolved in 170 cm³ of toluene was added. The mixture was heated to 120°C and then 32.2 g (0.10 mol) of chloroquinaldine-alcohol (II) dissolved in 70 cm³ of N-methyl-2-pirrolidone (NMP) was added. The mixture was stirred at 120 °C until the reaction was complete. 100 cm³ of saturated NaHC0₃ solution, 100 cm³ of distilled water and 200 cm³ of ethyl acetate were then added. The mixture was stirred for 5 minutes. The layers were separated. The organic phase was washed three times with 200 cm³ of distilled water and with 200 cm³ of brine. The organic solution was dried over 30 g of sodium sulfate. The drying agent was filtered, washed with 200 cm³ of ethyl acetate and the filtrate was evaporated in vacuum. Yield: 54.7 g crude 1-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-hydroxy-l- methyl-ethyl)-phenyl]-propan-l-one (IV) as a brown oil. A small amount of the product was purified by chromatography; the structure was checked by NMR spectroscopy: 1H NMR (DMSO-i/₆) δ 1.57 (s, 6H, Me₂C), 3.26-3.35 (m, 2H, CH₂Ar), 3.40-3.48 (m, 2H, CH₂CO), 5.04 (s, 1H, OH), 7.11-7.22 (m, 2H), 7.27-7.32 (m, 1H), 7.36-7.42 (m, 1H), 7.55-7.64 (m, 3H), 7.89-8.04 (m, 6H), 8.32-8.36 (m, 1H), 8.41 (d, 1H, J= 8.6 Hz) ppm.

¹³C NMR (DMSO-i¾ δ 28.5 (CH₂Ar), 2 31.8 ( e₂C), 41.7 ( H₂CO), 72.0 (Me₂Q, 120.3, 125.5, 125.5, 125.6, 126.5, 126.8, 127.0, 127.2, 128.0, 129.3, 129.4, 129.7, 131.4, 131.5, 134.1, 134.4, 136.6, 136.6, 137.3, 139.8, 146.8, 148.0, 156.6, 199.6 (CO) ppm.

26.7 g (0.06 mol) of the evaporation residue (IV) was dissolved in 100 cm³ of dry tetrahydrofuran and 8.0 g (0.12 mol) of imidazole was added. The mixture was stirred until imidazole was dissolved. An off-white substance precipitated while the imidazole was dissolving. The precipitate was filtrated. 9.8 cm³ (0.08 mol) of chlorotrimethylsilane was added dropwise to the filtrate and the mixture was stirred at room temperature until the reaction was complete. Then 200 cm³ of toluene and 100 cm³ of distilled water was wadded to the mixture. It was stirred for 5 minutes, the layers were separated. The organic layer was washed four times with 200 cm distilled water (to neutral pH) and was dried over sodium sulfate. The drying agent was filtered, washed with 100 cm³ of toluene and the filtrate was evaporated in vacuum. 140 cm³ of acetonitrile was added to the evaporation residue (28 g) and the suspension was stirred for 12 hours at room temperature. The precipitate was filtered, washed twice with 50 cm³ of acetonitrile. The product was dried under vacuum keeping the temperature below 40 °C

Yield: 16,8 g crystalline (65 % based on II)

If necessary, the product is purified by recrystallization. The product was dissolved in 84 cm³ of dichloromethane and 16,8 g of silica gel was added. The mixture was stirred for 15 minutes at room temperature. The silica gel was filtered and washed three times with 8.5 cm³ of dichloromethane. 168 cm of acetonitrile was added to the filtrate and the solution was concentrated to obtain 84 g residue. 168 cm³ of acetonitrile was added to the residue and the solvent was evaporated again to 84 g. The evaporation residue was stirred for 30 minutes at room temperature and at 0 °C for 30 minutes. The precipitate was filtrated. The crystals were dried under vacuum at 40 °C.

Yield: 12.6 g crystalline (49 % related to compound II).

1H NMR (CDC1₃) δ 0.06 (s, 9H, SiMe₃), 1.72 (s, 6H, Me₂C), 3.35-3.42 (m, 2H, CH₂Ar), 3.44-3.50 (m, 2H, CH₂CO), 7.13-7.19 (m, 1H), 7.19-7.29 (m, 2H), 7.35-7.40 (m, 1H), 7.40 (d, 1H, J_tra = 16.2 Hz), 7.44 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz), 7.49 (t, 1H, J = 7.8 Hz), 7.61 (d, 1H, J = 8.6 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.75 (d, 1H, J_lrans = 16.2 Hz), 7.80 (dm, 1H, J = 7.8 Hz), 7.93 (dm, 1H, J= 7.8 Hz), 8.07 (d, 1H, J= 2.1 Hz), 8.10 (d, 1H, J= 8.6 Hz), 8.23 (m, 1H) ppm. ¹³C NMR (CDC1₃) 6 2.5 (SiMe₃), 27.8 (CH₂Ar), 32.3 (Me₂C), 42.0 (CH₂CO), 76.5 (Me₂Q, 119.8, 125.3, 125.7, 126.7, 127.0, 127.2, 128.1, 128.2, 128.7, 129.1, 129.5, 131.4, 131.5, 134.0, 135.6, 136.2, 136.8, 137.5, 140.0, 146.4, 148.6, 156.4, 199.3 (CO) ppm.

Example 2

Preparation of (S)-l-{3-[ (E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-methyl-l- trimethylsilanyloxy-ethyl)-phenyl]-propan-l-ol (VI, Rj - trimethylsilyl)

24.0 g (0.045 mol) of V (Ri = trimethylsilyl) was dissolved in 130 cm³ of dichloromethane and the solution was placed under argon atmosphere. 18.3 cm³ (0.009 mol) of (/?)-(+)-o-tolyl-CBS- oxazaborolidine 0.5 M toluene solution was evaporated under vacuum. The evaporation residue was dissolved in 25 cm³ of dry dichloromethane and was added to the solution of V (Ri = trimethylsilyl) under stirring. The mixture was cooled to (-50H-40) °C and 14.5 cm³ (0.135 mol) of catecholborane was added dropwise. The mixture was stirred at (-40)-(-50) °C. After the reaction was complete, the solution was added to 50 cm of dichloromethane and 200 cm of 10 % NaOH solution under intensive stirring. The mixture was stirred for 10 minutes at room temperature. The layers were separated. The organic phase was extracted three times with 50 cm³ of 1M NaOH solution then washed with 50 cm³ of 10 % NaHC0₃ solution finally with 50 cm brine. The organic solution was dried over sodium sulfate and 25 g silica gel. The mixture was stirred for 15 minutes. The drying agent and the silica gel were filtered, washed with dichloromethane and the filtrate was concentrated in vacuum to obtain 40 g residue. The evaporation residue was dissolved in 100 cm³ of acetonitrile. The solvent was evaporated again under vacuum to get 75 g residue. The evaporation residue was stirred at room temperature and was seeded with crystals of compound of formula VI (Rj = trimethylsilyl) The suspension was stirred for 2 hours at room temperature and 1 hour at 0°C. The precipitate was filtered, washed with acetonitrile and dried under vacuum at 40 °C.

Yield: 18 g ivory-white crystalline.

Preparation of the second crystalline fraction: The filtrate of the precipitate was evaporated to approx. 20 cm³. The residue was seeded with crystals of compound of formula VI (Ri = trimethylsilyl). The suspension was stirred for 12 hours. The precipitate was filtrated, washed three times with 1-2 cm³ acetonitrile. The precipitate was dried under vacuum at max. 40 °C. Yield: 3 g ivory-white crystalline.

Combined yield: 21 g (88%), enantiomeric purity 98%ee.

1H NMR (DMSO-<¾ δ -0.06 (s, 9H, SiMe₃), 1.55 + 1.57 (2 * s, 2 * 3H, Me₂C), 1.89-2.06 (m, 2H, CH₂CO), 2.86-2.97 + 3.02-3.13 (2 x m, 2 ^χ 1H, CH₂Ar), 4.68-4.75 (m, 1H, CHO), 5.39 (brm, 1H, OH), 7.03-7.10 (m, 1H), 7.12-7.19 (m, 1H), 7.19-7.24 (m, 1H), 7.27-7.32 (m, 1H), 7.35-7.44 (m, 2H), 7.47 (d, 1H, J_trans = 16.3 Hz), 7.58 (dd, 1H, J= 8.7 Hz, J = 2.1 Hz), 7.61 (dm, 1H, J - 7.4 Hz), 7.73-7.77 (m, 1H), 7.89 (d, 1H, J_trans = 16.3 Hz), 7.92 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J= 8.7 Hz), 8.02 (d, 1H, J= 2.1 Hz), 8.39 (d, 1H, J= 8.6 Hz) ppm.

¹³C NMR (DMSO-<¾ δ 2.2 (SiMe₃), 28.9 (CH₂Ar), 32.0 ( ¾C), 41.9 ( H₂CO), 72.5 (CHO), 75.8 (Me₂Q, 120.3, 124.8, 124.9, 125.0, 125.6, 125.9, 126.7, 126.7, 126.8, 127.2, 128.1 , 128.6, 129.8, 130.8, 134.3, 135.3, 135.7, 136.6, 140.8, 145.4, 146.8, 148.0, 156.9 ppm. Example 3

Preparation of (1 -{(R)- 1 -{3-[ (E)-2-(7-Chloro-quinolin-2-yl)-vinylJ -phenyl}-3-[2-(l -methyl-1 - trimethylsilanyloxy-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid methyl ester (VIII, R] = trimethylsilyl, R2 = methyl)

Preparation of cesium salt (Vila, R2— methyl)

12.8 g (39.3 mmol) of dry cesium carbonate was dissolved in 105 cm³ of dry methanol. 7.9 g (39.2 mmol) of 1-acetylmercaptomethyl-cyclopropaneacetic acid methyl ester (VII, R₂ = methyl) was added to the cesium carbonate solution under inert atmosphere. The mixture was stirred at room temperature. After the reaction was complete, the methanol was evaporated under vacuum. 100 cm water- and oxygen free toluene was added to the evaporation residue, and the toluene was evaporated under vacuum. The residue Vila was dissolved in 135 cm³ of NMP. Preparation of mesylate (Vic, Ri = trimethylsilyl, R3 = methyl)

13.9 g (26.2 mmol) of VI (Ri = trimethylsilyl) was dissolved in 135 cm³ dry dichloromethane in ice-water bath and 7.3 cm³ (52.1 mmol) triethylamine was added to the solution. 2.5 cm³ (32.7 mmol) methanesulfonyl chloride was added dropwise to the mixture. The solution was stirred at 0-5 °C for 30 minutes. The mixture was washed with 140 cm³ 4 % NaHC0₃ solution, and with 100 cm³ brine. The organic layer was dried over sodium sulfate. The drying agent was filtered, washed with dichloromethane. The filtrate was concentrated under vacuum. The evaporation residue (Vic, R_\ = trimethylsilyl, R₃ = methyl) was dissolved in NMP.

Preparation of VIII (Ri = trimethylsilyl, R₂ - methyl)

Cesium salt of formula Vila (R₂ = methyl) dissolved in NMP was cooled in ice-water bath under nitrogen atmosphere. The solution of compound of formula Vic in NMP was added to the Vila cesium salt solution over 5 minutes. The mixture was stirred at 0-5°C for 2 hours and it was allowed to warm to room temperature. After the reaction was complete, the mixture was poured into a mixture of 890 cm³ distilled water and 450 cm³ cyclohexane with intensive stirring at 0-5 °C. 450 cm³ of brine was added to the mixture. After 5 minutes stirring the phases were separated. The water phase was extracted with 450 cm³ cyclohexane. The combined organic phase was washed with 150 cm³ brine. The organic solution was dried over 50 sodium sulfate. The drying agent was filtered, washed twice 30 cm cyclohexane. The filtrate was evaporated to dryness.

Yield: 20.7 g (thick yellowish brown oil) Purification of Crude VIII (where Rj is trimethylsilyl and R2 is methyl) with normal phase high performance liquid chromatography (HPLC)

510 g silica-gel (ZEOPREP C-GEL C-490L, 15-35 μιη particle size) was packed into a 5 cm I.D. axial compression HPLC column, using slurry packing method. The column was compressed and then it was conditioned with eluent (cyclohexane - dichloromethane -tert.butyl methyl ether 87 : 10 : 3 v.%). The length of the compressed packing was approx. 60 cm. 6,0 g of crude compound of formula VIII (where R_\ is trimethylsilyl and R₂ is methyl) was dissolved in 75 ml eluent. After filtration the solution was injected onto the column.

Elution was performed with flow rate of 80 ml/min. The separation was monitored by UV detection. After the elution of apolar impurities, the detector signal increased significantly. Pure fraction was collected from this point. The volume of the pure fraction was approx. 1250 ml. The pure material was recovered by evaporation. The weight of compound of formula VIII (where R_\ is trimethylsilyl and R₂ is methyl) was 5.65 g with max. 3.0% total impurities. Yield was 94%. 1H NMR (DMSO- 6 -0.09 (s, 9H, SiMe₃), 0.31-0.53 (m, 4H), 1.49 + 1.56 (2 ^χ s, 2 3H, Me₂C), 2.03-2.24 (m, 2H, CH₂CS), 2.35 + 2.44 (2 d, 2 x 1H, J_gem = 15.9 Hz, CH₂CO), 2.48-2.52 (m, CH₂S), 2.77-2.89 + 3.02-3.14 (2 x m, 2 x 1H, CH₂Ar), 3.53 (s, 3H, OMe), 3.96-4.04 (m, 1H, CHS), 7.04-7.12 (m, 1H), 7.14-7.23 (m, 2H), 7.25-7.31 (m, 1H), 7.37 (dm, 1H, J = 7.7 Hz), 7.42 (t, 1H, J = 7.7 Hz), 7.50 (d, 1H, J_trans = 16.4 Hz), 7.59 (dd, 1H, J = 8.6 Hz, J = 2.1 Hz), 7.64 (dm, 1H, J = 7.7 Hz), 7.72-7.76 (m, 1H), 7.89 (d, 1H, J_trans = 16.4 Hz), 7.93 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J = 8.6 Hz), 8.01 (d, 1H, J = 2.1 Hz), 8.40 (d, 1H, J = 8.6 Hz) ppm.

¹³C NMR (DMSO-<¾ δ 2.1 (SiMe₃), 11.8, 12.1, 16.7, 31.0 (CH₂Ar), 2 ^χ 32.0 (Me₂C), 38.4 (CH₂S), 38.9 ( H₂CS), 39.0 (CH₂CO), 49.6 (CHS), 51.1 (OMe), 75.7 (Me₂Q, 120.3, 124.9, 125.3, 125.6, 126.0, 126.7, 126.7, 126.8, 127.2, 128.3, 128.4, 129.0, 129.8, 130.8, 134.3, 135.0, 136.2, 136.6, 140.0, 143.4, 145.4, 148.0, 156.8, 171.9 (COO) ppm. Example 4

Preparation of (l-{(R)-l-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-hydroxy-l- methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid dicyclohexylamine salt (IX)

20.5 g (0.0305 mol) of VIII (Rj = trimethylsilyl, R₂ = methyl) was dissolved in 200 cm³ of 2- methyltetrahydrofuran then 24.4 cm of 40 % NaOH solution and 30 cm of methanol were added. The mixture was stirred for 2 hours at 70-80 °C under nitrogen atmosphere. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. 100 cm³ of water and 100 cm³ of 2-methyltetrahydrofuran were added to the solution. The phases were separated. The organic layer was extracted with 100 cm³ of water, then with 150 cm³ 0,2 of M KH₂P0₄ followed by 100 cm³ of 0,2 M KH₂P0₄ solution. The organic layer was dried over sodium sulfate. The drying agent was filtered. The filtrate was evaporated to dryness under vacuum.

Yield: 15.6 g (0.0266 mol) crude Montelukast acid of formula la (87%).

14.9 g (0.0255 mol) of crude Montelukast acid of formula la was dissolved in 120 of cm³ ethyl acetate at room temperature and 5.1 cm³ (0.0255 mol) of dicyclohexylamine (DCHA) was added dropwise. 240 cm³ of n-hexane was added dropwise in 30 minutes to the previously obtained solution of Montelukast acid DCHA salt. The suspension was stirred at room temperature for 15- 20 hours under inert atmosphere. The precipitate was filtered, washed with n-hexane, dried under vacuum below 40 °C. Yield: crude crystalline Montelukast DCHA salt (IX): 14.4 g (74%)

Recrystallization:

14.9 g (0.0255 mol) crude Montelukast DCHA salt (IX) was dissolved in 60 cm³ ethyl acetate under inert atmosphere and 1 cm³ (0.005 mol) dicyclohexylamine was added dropwise at room temperature. 60 cm³ of n-hexane was added dropwise to the obtained solution. The mixture was stirred for 30 minutes at room temperature then additional 60 cm³ n-hexane was added. The suspension was stirred for 2 hours under inert atmosphere. The precipitate was filtered, washed with n-hexane-ethyl acetate mixture (V/V = 2/1) and twice with 10 cm³ of n-hexane. The precipitate was dried under vacuum at 40 °C. The recrystallization was repeated until the desired purity was reached.

Yield: crystalline Montelukast DCHA salt (IX): 10.4 g (70%)

Ή NMR (DMSO-<¾ 5 0.26-0.51 (m, 4H), 0.96-1.31 (m, 10H, cyclohexyl), 1.43 (s, 6H, Me₂C), 1.49-1.61 (m, 2H, cyclohexyl), 1.61-1.72 (m, 4H, cyclohexyl), 1.76-1.88 (m, 4H, cyclohexyl), 2.03-2.24 (m, 2H, CH₂CS), 2.21 + 2.28 (2 ^χ d, 2 ^χ 1H, J_gem = 15.5 Hz, CH₂CO), 2.49 + 2.58 (2 d, 2 x 1H, CH₂S), 2.57-2.67 (m, 2H, cyclohexyl), 2.70-2.82 + 2.99-3.1 1 (2 m, 2 x 1H, CH₂Ar), 3.97-4.05 (m, CHS), 7.03-7.16 (m, 3H), 7.33-7.45 (m, 3H), 7.50 (d, 1H, J_trans = 16.3 Hz), 7.59 (dd, 1H, J = 8.8 Hz, J = 2.2 Hz), 7.63 (dm, 1H, J = 7.4 Hz), 7.70-7.75 (m, 1H), 7.89 (d, 1H, J_trans = 16.3 Hz), 7.94 (d, 1H, J= 8.6 Hz), 8.00 (d, 1H, J= 8.8 Hz), 8.02 (d, 1H, J= 2.2 Hz), 8.41 (d, 1H, J= 8.6 Hz) ppm.

Example 5

Purification of (l-{(R)-l-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-hydroxy- l-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid (la) on benzylamine resin

20.0 g of Amberlyst- A21 resin was washed three times with 100 cm³ of isopropyl alcohol and twice with 100 cm³ of acetonitrile. 4.12 g of crude la Montelukast acid (intermediate of Example 4) was dissolved in 200 cm³ of dichloromethane. The pre-treated resin was added to the solution of Montelukast acid. 100 cm³ of acetonitrile was added to the suspension. The solvent was concentrated under vacuum to a final volume of approx. 50 cm³. The residue was filled into a

3 3 column. The resin was washed five times with 60 cm of acetonitrile and five times with 60 cm of dichloromethane/acetic acid mixture (V/V=95/5). Acetonitrile fractions were enriched in non- acidic impurities. The acidic dichloromethane fractions contain the desired Montelukast acid. Dichloromethane fractions were combined and concentrated to a volume of approx. 40 cm . The evaporation residue was diluted with 80 cm³ dichloromethane and was washed with water to neutral pH. The organic layer was dried over sodium sulfate, filtered and evaporated.

Yield: 2.8 g (68%) la Montelukast acid Example 6

Preparation of (1 -{(R)-l -{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl] -phenyl}-3-[2-(l -hydroxy- l-methyl-ethyl)-phenyl]-propylsulfanylmethyl}-cyclopropyl)-acetic acid sodium salt (I)

2.00 g (0.00284 mol) Montelukast DCHA salt (IX) was dissolved in a mixture of 50 cm³ of dichloromethane and 40 cm (0.0258 mol) of 1 M potassium-dihydrogen-phosphate solution. The mixture was stirred for 15 minutes at room temperature, and then the layers were separated. To organic layers was added 40 cm³ (0.04 mol) of 1M sodium hydroxide and the layers was stirred for 15 minutes, and then separated. The organic layer was dried over sodium sulfate. The drying agent was filtered, washed with 10 cm of dichloromethane and the filtrate was evaporated in vacuum.

The obtained 1.8 g evaporation residue was diluted with 5.6 cm of toluene and 22.4 cm of n- heptane was slowly added under the stirring. The crystalline product was filtered, washed with 2x4 cm³n-heptane. The product was dried in vacuum at 40 °C.

Yield: 1.51 g of white powder (87%)

1H NMR DMSO-d₆) δ 0.15-0.30 (m, 2H), 0.33-0.48 (m, 2H), 1.44 + 1.45 (2 s, 2 3H, Me₂C), 2.05-2.17 + 2.17-2.28 (2 x m, 2 x 1H, CH₂CS), 2.01 + 2.14 (2 d, 2 x 1H, Jgem = 14.3 Hz, CH₂CO), 2.55 + 2.71 (2 x d, 2 x 1H, J_gem = 12.6 Hz, CH₂S), 2.70-2.81 + 3.03-3.15 (2 x m, 2 x 1H, CH₂Ar), 3.99-4.07 (m, CHS), 5.14 (br, 1H, OH), 7.03-7.16 (m, 3H), 7.33-7.45 (m, 3H), 7.51 (d, 1H, J_trans = 16.3 Hz), 7.59 (dd, 1H, J= 8.7 Hz, J= 2.1 Hz), 7.63 (dm, 1H, J = 6.9 Hz), 7.71-7.76 (m, 1H), 7.90 (d, 1H, J_trans = 16.3 Hz), 7.95 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J= 8.7 Hz), 8.04 (d, 1H, J= 2.1 Hz), 8.41 (d, 1H, J= 8.6 Hz) ppm.

Example 7

Preparation of 7-Chloro-2-[(E)-2-(3-{(S)-3-[2-(l-methyl-l-trimethylsilanyloxy-ethyl)-phenyl]-l- trimethylsilanyloxy-pr opylj -phenyl) -vinyl] -quinoline (VIb, Rj - trimethylsilyl)

7.11 g (15.53 mmol) of Via was dissolved in 75 cm³ of tetrahydrofuran and 3.06 g (44.95 mmol) of imidazole was added. The mixture was stirred at room temperature and 5.06 cm³ (40.00 mmol) of chlorotrimethylsilane was added dropwise. The reaction mixture was stirred at room temperature for one hour, and then toluene and water was added under stirring. The layers were separated and the organic layer was washed with water then with brine. The organic solution was dried over sodium sulfate. The drying agent was filtered, washed with toluene and the filtrate was evaporated in vacuum.

Yield: 9.35 g (quant.). 1H NMR (DMSC -0.07 (s, 9H), 0.07 (s, 9H, Me), 1.58 (s, 6H), 1.95 (m, 2H), 2.87 (m, 1 H), 3.17 (m, 1H), 4.88 (t, 1H), 7.06 (t, 1H), 7.1 1 -7.26 (ol, 3H), 7.29 (d, 1H), 7.34-7.43 (ol, 2H), 7.47 (d, 1H, J_trans = 16.3 Hz ,), 7.58 (dd, 1H,), 7.61 (dm, 1H,), 7.72 (m, 1 H), 7.87 (d, 1 H, J_trans = 16.3 Hz), 7.92 (d, 1H), 8.00 (d, 1H), 8.39 (d, 1H, J = 8.6 Hz) ppm.

Example 8

Preparation of (S)-l-{3-[ (E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(l-methyl-l- trimethylsilanyloxy-ethyl)-phenyl]-propan-l-ol (VI, R = trimethylsilyl) from intermediate VIb (Rj = trimethylsilyl)

9.35 g (15.53 mmol) of VIb (Ri = trimethylsilyl) was dissolved in 95 cm³ of methanol. 9.50 cm³ of cc. ammonia solution was added and the reaction mixture was stirred at 50°C for 12 hours. The mixture was evaporated in vacuum and the evaporation residue was dissolved in the mixture of toluene and water. The organic layer was washed with water then brine, dried on sodium sulfate. The drying agent was filtered, washed with toluene and the filtrate was evaporated in vacuum. The evaporation residue was crystallized from n-hexane.

Yield: 4.89 g (94%).

The spectral properties of the product corresponded to that of product of Example 2.

Claims

1. A process for the preparation of Montelukast sodium of formula(I), the chemical name of which is [(R-(E)]-1 -[[[ 1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l -hydroxy-1 - methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid sodium salt wherein the protecting groups from protected Montelukast of general formula (VIII), wherein Ri is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert.butyldimethylsilyl group and meaning of R₂ is C1-C4 alkyl group are removed in one step with basic hydrolysis, then

Montelukast sodium is isolated, after purification if desirable.

Montelukast sodium

2. A process according to claim 1, wherein the initial compound is protected Montelukast (VIII), which is obtained from the reaction of sulfonic acid derivative of general formula (Vic), wherein R_\ is the same as in claim 1, and R₃ is methyl, trifiuoromethyl, 4- methylphenyl, with 1-mercaptomethyl-cyclopropaneacetic acid alkyl ester cesium salt derivative of general formula (Vila) wherein R₂ is the same as in claim 1.

3. A process according to claim 2 wherein the initial compound is cesium salt of formula (Vila), which is obtained directly from the reaction of cyclopropane derivative of general formula (VII), wherein R₂ is the same as in claim 1 and cesium carbonate.

4. A process according to any of claims 2 to 3 wherein the initial compound is sulfonic acid derivative of the formula (Vic), which is produced from ether derivative of general formula (VI), wherein R_\ is the same as in claim 1.

5. A process according to claim 4 wherein the initial compound is ether of the formula (VI) which is obtained from reduction of compound of formula (V), wherein Ri is the same as in claim 1 , in the presence of reducing agent and catalyst.

6. A process according to claim 5, wherein said catalyst is CBS-oxazaborolidine, preferably (R)-(+)-o-tolyl-CBS-oxazaborolidine, (R)-(+)-methyl-CBS-oxazaborolidine or (R)-(+)-n- butyl-CBS-oxazaborolidine.

7. A process according to any of claims 5 to 6, wherein said reducing agent is a borane, preferably borane-tetrahydrofuran complex, borane-dimethylsulfide complex or catecholborane, most preferably reducing agent is catecholborane.

8. A process according to any one of claims 5 to 7 wherein the initial compound is compound of formula (V) which is obtained from silylation of ketocarbinol of formula (IV).

A process according to claim 8 wherein the initial compound is ketocarbinol of formula (IV) which is obtained from the reaction of allyl alcohol of the formula (II) and carbinol derivative of formula (III) wherein X is chloro-, bromo-, iodo-.

10. A process according to claim 4 wherein the initial compound is ether derivative of the formula (VI) which is prepared regioselectively from compound of formula (VIb), wherein R_\ is the same as in claim 1, in an organic solvent, using organic or inorganic base.

11. A process according to claim 10 wherein the initial compound is intermediate of formula (Vlb) which is obtained from silylation of compound of formula (Via).

Via Vlb

12. A process according to any of claims 8 and 11 , wherein silylating agent is chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, Ν,Ο-bis- (trimethylsilyl)-acetamide, N-trimethylsilyl-imidazole, 1,1,1 ,3,3 ,3-hexamethyl-disilane, chlorotriethylsilane, tert.butyl-dimethyl-chlorosilane, tert.butyl-dimethylsilyl- trifluoromethanesulfonate, chlorotriiso-propylsilane, preferably chlorotrimethylsilane.

13. The compound of general formula (V),

wherein R_\ is silyl protecting group.

14. The compound of general formula (VI),

wherein Ri is silyl protecting group.

15. The compound of general formula (VIb),

wherein Ri is silyl protecting group.

16. The compound of general formula (VIII),

wherein R_\ is silyl protecting group, R₂ is Q-C4 alkyl group.