WO2008049922A2

WO2008049922A2 - A new process for the preparation of montelukast

Info

Publication number: WO2008049922A2
Application number: PCT/EP2007/061552
Authority: WO
Inventors: Davor Kidemet; Vesna Kroselj; Renata Osolnik
Original assignee: Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority date: 2006-10-26
Filing date: 2007-10-26
Publication date: 2008-05-02
Also published as: EP2094664A2; WO2008049922A3; SI22382A

Abstract

The present invention describes a novel process for the preparation of montelukast acid, and its pharmaceutically acceptable salts and esters.

Description

A NEW PROCESS FOR THE PREPARATION OF MOOTELUKAST

Field of tliθ invention

Background of the invention

Montelukast sodium is a potent inhibitor of CysLTl , and it is used for chronic treatment and prevention of asthma in adult and pediatric patients.

Its chemical name is 1- [ [ [ [3- [ (IE) -2- {7-chloroquinoline-2- yl) ethenyl] phenyl] -3- [2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid monosodium salt, and it is represented by the following formula:

The empirical formula is CssHasClNNaChS, and its molecular weight is 608.18. Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water, and practically insoluble in acetonitrile . Montelukast sodium is a selective and orally active leucotriene receptor antagonist that inhibits the cysteinyl leucotriene CysL-Ti receptor. It is active as an anti-asthmatic, anti-allergic, antiinflammatory and a cryoprotective agent and is hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

Montelukast sodium is marketed in the form of film coated tablets, chewing tablets and granules under the trade name ΞINGULAIR^®. The commercially available film coated SINGULAIR^® tablets contain microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate and coating which comprises hyproxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red and yellow ferric oxide and carnauba wax.

It was first described in EP 480 717 Al. The preparation process of EP 480 717 is as disclosed in the following scheme 1 :

The mesylate is reacted with the methyl 1-

(mereaptomethy1 ) cyclopropaneacetate, which is in situ generated from methyl 1- ( acetylthiomethyl) cyclopropaneacetate with hydrazine. The ester obtained is hydrolyzed into the free acid and the free acid is transformed into montelukast sodium. The process disclosed is unsuitable for large-scale production due to the need for chromatographic purification which cannot be applied in industrial scale. Further on, when using the oxazaborolidine complex in earlier reaction steps, a partially over-reduced product is formed in an amount up to 10%.

An improved process is described in EP 737 186 wherein the dilithium salt of 1- (mercaptomethyl) cyclopropaneacetate is reacted with the mesylate derivative. The organic solution of montelukast is transformed to the dieyelohexylammonium salt of montelukast. The drawback of this route of synthesis is the use of n-butyl lithium which is highly reactive and difficult to handle on industrial scale.

WO 2006/05845 relates to a process for the preparation of montelukast wherein 2- [2- [3 (S) - [3- [ (IE) -2- (7-chloroquinoline- 2-yl) ethenyl] phenyl] -3-methylsulfonyloxypropyl] phenyl-2- propanol is reacted with 1- (mercaptomethyl) cyclopropaneacetic acid in the presence of a base, preferably an alkali hydroxide. The drawback of this process is that the resulting acid obtained by the acidification of the reaction mixture needs to be further purified before converting it to the sodium salt of montelukast.

WO 2006/008562 discloses a process for the preparation of montelukast by asymmetric transfer hydrogenation of the ketone intermediate by using chiral ruthenium or rhodium catalysts, in the presence of a hydrogen source.

Consequently, there still exists a need for an efficient synthesis of montelukast sodium, suitable for large-scale production. Summary of the invention

The present invention relates to an efficient process for the preparation of montelukast comprising the steps of:

a) asymmetric reduction of the ketone of formula (VI) to obtain the secondary alcohol of formula (V ) which can be optionally further converted to the secondary alcohol of formula (V) by reaction with CHj-Met,

b} conversion of the secondary alcohol of formula (V) or (V } to the compound of formula (IV) or (IV) respectively, following which compound (IV ) can be optionally further converted to the compound of formula (IV) ,

c) nucleophilic substitution of the compound of formula (IV) or (IV) with 2~ (1- {mercaptomethy1) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into the carboxylic acid to obtain an acetic acid derivative of formula (II) or (II') respectively, following which compound (II') can be optionally further converted to the compound of formula (II) ,

d} Heck coupling reaction of the acetic acid derivative of formula (II) or (II'} with vinylquinoline of formula (III) to obtain montelukast acid of formula (I) or to obtain the crude ester (I') respectively, following which compound (I') is further converted to montelukast acid of formula (I) ,

e) optional isolation of montelukast acid of formula (I),

f) optional conversion of montelukast acid to montelukast sodium or

g) optional conversion of montelukast acid to montelukast arginine salt and its optional conversion to montelukast sodium. This process is schematically depicted in the following scheme 2 , wherein

Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium;

R3 represents Ci-Cs alkyl;

R' represents a negative charge, hydrogen, alkyl, trifluoromethyl, C3-C8 cycloalkyl or a Cs-Cio aryl group;

L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group; and

Met represents a metal residue selected from -MgCl, -MgBr,

-MgI or -Li :

^RlτΛi^0OR3

(Vl) asymmetric reduction

According to another embodiment, the compound of formula (IV) or (IV)

wherein

Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate ;

R3 represents Ci-Ce alkyl, preferably methyl;

R' represents a negative charge, hydrogen, alkyl, trifluoromethy1, C3~Cs cycloalkyl or a CB-CIO aryl group;

L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group, preferably chlorine or a methylsulfonyloxy group ; is provided.

According to another embodiment, the compound of formula (II) or (II'}

wherein

Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate;

R3 represents Ci-Cs alkyl, preferably methyl; R' represents a negative charge, hydrogen, alkyl, trifluoromethyl , C3-Cs cycloalkyl or a C5-C10 aryl group; is provided.

Another embodiment of the present invention is montelukast arginine salt and the preparation thereof.

Brief Description of the Figures

Figure 1: Powder X-ray diffraction pattern of amorphous montelukast arginine salt.

Figure 2 : FTIR spectrum of amorphous montelukast arginine sale .

Description of the invention

Accordingly the present invention relates to an efficient process for the preparation of montelukast acid comprising the steps of:

a) asymmetric reduction of the ketone of formula (VI) to obtain the secondary alcohol of formula (V ) which can be optionally further converted to the secondary alcohol of formula (V) by reaction with CHs-Met,

b) conversion of the secondary alcohol of formula (V) or (V) to the compound of formula (IV) or (IV ) respectively, following which compound {IV} can be optionally further converted to the compound of formula (IV)

CH₃-MeI

c) nucleophilic substitution of the compound of formula (IV) or (IV) with 2™ (1- (mercaptomethyl ) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into the carboxylic acid to obtain an acetic acid derivative of formula (II) or (II') respectively, following which compound (II') can be optionally further converted to the compound of formula ( II} ,

CHu-Met

d) Heck coupling reaction of the acetic acid derivative of formula (II) or (II'} with vinylquinoline of formula (III) to obtain montelukast acid of formula (I) or to obtain the crude ester (I') respectively, following which compound (I') is further converted to montelukast acid of formula (I)

wherein

R: represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium;

R.3 represents Ci-Ce alkyl;

R' represents a negative charge, hydrogen, alkyl, trifluoromethyl , C3-Cs cycloalkyl or a C5-C10 aryl group;

Met represents a metal residue selected from -MgCl, -MgBr,

-MgI or -Li .

This process is schematically depicted in scheme 2 above.

According to the first aspect of the present invention, the secondary alcohol of formula (V ) is prepared hy asymmetric reduction of ketone of formula (VI) with a reducing agent, selected from sodium and lithium borohydride, in an inert solvent and a tartaric acid-derived boronate ester as a catalyst. The reaction is performed at a temperature between about -5O⁰C and about 100⁰C, preferably at a temperature between about 0 and about 3O⁰C, for approximately 2 to 4 hours . The inert solvents for the reaction can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are benzene, toluene, tetrahydrofuran, dioxane, dialkylether, acetonitrile, 2-methyltetrahydrofuran and/or diethoxymethane, preferably tetrahydrofurane.

The tartaric acid-derived boronate ester is prepared by reacting the (D) -tartaric acid with an appropriately substituted arylboronic acid in refluxing THF, and in the presence of CaH2. Substituted arylboronic acids are represented by the compound of formula (VII) :

(VIi)

wherein Rs and Rε independently represent hydrogen, halogen, trifluoromethyl , cyano or nitro. Preferably, 3- nitrophenylboronic acid is used.

According to the another aspect of the present invention, the secondary alcohol of formula (V ) is prepared by metal- catalysed transfer hydrogenation of compounds of the general formula (VI) by using a hydrogen donor in the presence of a metal catalyst based on ruthenium complexes of optically active N-sulfamoyl-1 , 2-diamine ligands of the general formula (VIII) :

(VIlI) wherein :

* represents an asymmetric carbon atom;

Rs and R7 independently represent a hydrogen atom, a linear or branched Ci-Cis alkyl group that is optionally substituted with a C5-C10 aryl group, or Re and R7 may be linked together to form with the nitrogen atom an optionally substituted 4 -

6 membered ring;

Rs and R9 independently represent a hydrogen atom, an optionally substituted Cs-Cio aryl group, or a C3-Ca cycloalkyl group, or Rs and Ra may be linked together to form a cyclohexane ring.

Preferably Rs and R7 are independently selected from the group consisting of methyl, isopropyl and cyclohexyl, or Rs and R7 are linked together to form a ring selected from the group consisting of pyrrolidyl, piperidyl, morpholyl and azepanyl .

The optically active N-sulfamoyl-1 , 2-diamine ligands used in the process of the present invention have an enantiomeric excess of more than 95%, preferably more than 99%.

The metal catalyst is prepared from a ruthenium metal precursor and an optically active N-sulfamoyl-1 , 2-diamine ligand of the general formula (VIII)

The ruthenium metal catalyst used in the process of the present invention is prepared from a precursor of the formula [RuX2 ()j⁶-arene) ] 2 , wherein η⁶-arene represents an arene group, selected from the group consisting of benzene, p-cymene, mesitylene, 1 , 3 , 5-triethylbenzene, hexamethylbenzene and anisole, and X is halide selected from the group consisting of chloride, bromide and iodide.

The hydrogen donor used in the process of the present invention is based on HCO2H. Examples for preferred hydrogen donors comprise HCO2H-Et3N, HCChH-iso-P^NEt , HCOsH-metal bicarbonates and HC02H-metal carbonates, wherein the metal is selected from ISJa, K, Cs, Mg and Ca.

The metal-catalysed transfer hydrogenation according to the present invention is conducted in a solvent selected from the group consisting of dichloroethane, acetonltrile, N, N- dimethyl formamide, N,N-dimethylacetamide, 1-methyl-2- pyrrolidinone (WMP), 1, 1 , 3 , 3-tetramethylurea, 1, 3-dimethyl-2- imidazolidinone, ISI, N' -dimethylpropyleneurea and mixtures thereof .

Starting ketone of formula (VI) used in an asymetric reduction according to the present invention can be prepared by any process known by the prior art, as for example disclosed in R. D. Larsen et al, J. Org, Chem. 1996, 61, 3398- 3405.

The secondary alcohol of formula (V) obtained by asymmetric reduction of ketone of formula (VI) can be used in the next step of the process according to the present invention or it can be optionally further converted to secondary alcohol of formula (V) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent. The reaction temperature is below the boiling temperature of the solvent used, preferably between about -78⁰C to boiling temperature of the solvent, more preferably between about -10⁰C to about 35°C. The organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium. Methylmagnesium iodide is preferably used. The inert solvents can be selected from a variety of known process solvents . Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2- methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene .

According to another aspect of the invention, the compound of formula (IV) or (IV) is prepared by the conversion of the OH-group in secondary alcohol of formula (V) or (V } to a leaving group L such as for example chlorine, bromine, iodine or a Ci-Cs alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group, preferably a chlorine atom and a methylsulfonyloxy group .

The reaction can be performed with an alkyl or aryl sulfonyl halide selected from the group consisting of methyl, ethyl, n-butyl, besyl or tosyl sulfonyl halide in an inert solvent In the presence of a base such as any organic tertiary non- nucleophilic base such as for example triethylamine, N- ethyldiisopropylamine, or similar. The suitable solvent may be selected from dichloromethane, tetrahydrofurane, 2- methyltetrahydrofurane, and N, N-dimethyIformamide . The reaction temperature is below the boiling temperature of the solvent used, preferably between about -78°C to boiling temperature of the solvent, more preferably between about - 10⁰C to about 35⁰C. Preferably methanesulfonyl chloride in dichlorometane is used.

Additionally, the reaction can be performed with a halogen acid or inorganic acid halide selected from the group consisting of HCl, HBr, HI, SOCI2, PCI3, POCIa, PBn in a suitable solvent. The suitable solvents may be selected from dichloromethane, tetrahydrofurane, 2-methyltetrahydrofurane, and N,N-dimethyIformamide. The reaction temperature is below the boiling temperature of the solvent used, preferably between about ™78°C to boiling temperature of the solvent, more preferably between about -10⁰C to about 35⁰C. Preferably, SOCI2 is used in dichloromethane as the solvent.

The compound of formula (IV ) obtained by the conversion of the secondary alcohol of formula (V ) can be used in the next step of the process according to the present invention or it can be optionally further converted to compound of formula (IV) by the reaction with organornetalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent. The reaction temperature is below the boiling temperature of the solvent used, preferably between about -78⁰C to boiling temperature of the solvent, more preferably between about -10⁰C to about 35⁰C. The organometalic reagent can be selected from the group consisting of methyimagnesium chloride, metylmagnesium bromide, methyimagnesium iodide or methyllithium. Methyimagnesium iodide is preferably used. The inert solvents can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2- methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene.

According to another aspect of the present invention, the nucleophilic substitution of the compound of formula (IV) or (IV) is performed by reacting the compound of formula (IV) or (IV) with 2- (1-mercaptomethyl) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into carboxylic acid, in the presence of a base and in a solvent to obtain the compound of formula (II) or (II'}-

The base can be selected from the group consisting of an alkali hydroxide, an alkaline earth hydroxide, alkali carbonate, alkali alkoxide, alkali hydride, alkyllithium or lithium hexamethydisilazide, preferrably sodium t-butoxyde, n-butyllithium, or caesium carbonate is used.

The solvent can be selected from the group consisting of benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, N, N-dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone.

Optionally, the compounds of formula (II) or (II') may be isolated as organic base salts by dissolving the residue in ethyl acetate or toluene after distilling the solvent, treating with organic amine such as diisopropylamine, dipropylamine, tributylamine, dibenzylamine, dicyclohexylamine, alpha-methylamine or L-arginine, at temperature about 1O⁰C to about 5O⁰C, adding hexane, heptane or acetonitrileto yield the organic base salt of the compound of formula (II) or (II').

Compound 2- ( 1-mercaptomethyl) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into carboxylic acid used in nucleophilic substitution of the present invention can be prepared by any process known by the prior art, as for example disclosed in EP 0480717, US 6320052.

The compound of formula (II') obtained by the nucleophilic substitution can be used in the next step of the process according to the present invention or it can be optionally further converted to compound of formula (II) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent. The reaction temperature is below the boiling temperature of the solvent used, preferably between about -78⁰C to boiling temperature of the solvent, more preferably between about -10⁰C to about 35⁰C. The organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium. Methylmagnesium iodide is preferably used. The inert solvents can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2™ methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene .

According to another aspect of the present invention, the compound of formula (I) or (I') is prepared by reacting the acetic acid derivative of formula (II) or (II') with the vinylquinoline of formula (III) in the presence of a catalyst and a base in an inert solvent under conditions known per se as Heck coupling reaction. The reaction is performed at a temperature between about 60 and about 200⁰C, preferably at a temperature between about 80 and about HO⁰C for approximately 7 to 15 hours at normal or elevated pressure and in an inert atmosphere, as for example under argon or nitrogen.

The catalyst used in the Heck coupling reaction can be selected from the group consisting of Pd source, such as palladium{II) acetate, palladium (II) chloride, palladium dibenzylideneacetone, dichlorobis (acetonitrile) palladium (II) , dichlorobis (benzonitrile) palladium (II) , dichlorodiamine palladium ( II ), palladium { II) acetylacetonate, palladium (II) bromide, palladium (II) cyanide, palladium (II) iodide, palladium oxide, palladium{ϊl) nitrate hydrate, palladium(II) sulfate dihydrate, palladium (II) trifluoroacetate, tetraamine palladium (II) tetrachloropalladate and tetrakis (acetonitrile) palladium (II) tetrafluoroborate; and a bidentate phosphorous or nitrogen ligand such as for example a phosphine such as triphenylphosphine, tris (o-tolyl) phosphine, 1,3- bis (diphenylphoεphino) propane, tri (t-butyl) phosphine, tris (p- tolyUphoshine, tricyclohexylphosphine, tris (p- chlorophenyl ) phosphine, tris (p-fluorophenyl) phosphine, tris (p-methoxyphenyl ) phosphine, tributylphosphine, tris (isopropyl) phosphine, Pd(OAc)2 is the preferred catalyst and tris (o-tolyl) phosphine is the preferred bidentate ligand. Less than six mole percent of catalyst is necessary to run the reaction, preferably the range of catalyst is from one to five mole percent.

Organic or inorganic bases may be used in the Heck coupling reaction. As organic bases primary, secondary or tertiary amines may be used, such as for example triethylamine or diisopropylethylamine . Inorganic bases may be carbonates, hydrogencarbonates, hydroxides and alkali metal alkoxides such as for example potassium carbonate, sodium carbonate, sodium hydrogencarbonate, caesium carbonate, thallium carbonate, potassium hydroxide, sodium hydroxide, thallium hydroxide, or the alkoxides of these alkali metals.

When an inorganic base insoluble in the organic solvent is used, dissolution in water may be necessary; the use of a phase-transfer catalyst such as for example tetra-n- butylammonium bromide or crown ether also facilitate the reaction. Organic solvent soluble bases such as tetra-n- butylammonium carbonate or tetra-n-butylammonium hydroxide, benzyltrimethylammonium carbonate, benzyltrimethylammonium methyl carbonate, benzyltrimethylammonium methoxide or benzyltrimethylammonium hydroxide, or other basic tetraalkylammonium compounds may be useful in certain cases. Preferably triethylamine is used.

The inert solvents used in the Heck coupling reaction may be selected from a variety of known process solvents. Illustrative of the coupling solvents that can be utilized either singly or in combinations are benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, N, N- dimethylformamide, N, N~dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran or diethoxymethane, N-methylpyrrolidinone, hexarnethylphosphoramide, supercritical CO2, and/or ionic liquids.

In the preferred embodiment, the acetic acid derivative of formula (II) or (II'} wherein Ri is Br and RJ is methyl reacts_^ with 2-ethenyl-7-chloroquinoline (compound of formula III) in the presence of Pd(OAc) 2, P(o-tolyl)- and Et--N, in a DMF solution or suspension.

Intermediate (III) used in Heck coupling reaction of the present invention can be prepared by any process known by the prior art, as for example disclosed in R. D. Larsen et al, J. Org. Chem. 1996, 61, 3398-3405, M.A.Fakhfakh et al , Synth. Coπimun. 2002, 32, 2863-2875, EP 0775694, WO 2004058742, and EP 1408033.

The compound of formula {!') obtained by the Heck coupling reaction is further converted to compound of montelukast acid of formula (I) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent. The reaction temperature is below the boiling temperature of the solvent used, preferably between about -78⁰C to boiling temperature of the solvent, more preferably between about -10⁰C to about 35°C. The organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium. Methylmagnesium iodide is preferably used. The inert solvents can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2- methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene. Preferably, montelukast acid of formula (I) is prepared by reacting the compound of general formula (I'} with methylmagnesium bromide activated by cerium(III) chloride in tetrahydrofuran .

Optionally, montelukast acid of formula (I) is isolated in the process according to the present invention. The purification and isolation of all intermediates and final product by methods known in the art should be considered as included in the scope of the invention. One of the standard purification method is the preparation of intermediates and final product in its solid state, by conventional crystallisation and recrystallisation techniques using solvents that a person skilled in the art considers to be the most suitable.

The process of the present invention represents a simple and economically viable way of the preparation of rnontelukast and its pharmaceutically acceptable salts and esters while the vinylquinoline building part of the molecule is introduced in the last step of the preparation of montelukast acid and the starting compound can be easily produced.

According to another embodiment, the compound of formula (IV) or (IV)

wherein

R3 represents Ci-Cβ alkyl, preferably methyl;

L represents a leaving group such as chlorine, bromine, iodine, a Ci-Ca alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group, preferably chlorine or a methylsulfonyloxy group ; is provided. According to another embodiment, the compound of formula (Ii; or (II')

wherein

Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate ; ϊb represents Ci-Ce alkyl, preferably methyl;

R' represents a negative charge, hydrogen, alkyl, trifiuoromethyi, C3-C8 cycloalkyi or a C5-C10 aryl group; is provided.

The rαontelukast acid prepared and isolated according to the process by the present invention can be used in the pharmaceutical composition as the active substance together with other pharmaceutically acceptable excipients or it can be further converted without isolation into any known pharmaceutical acceptable salt as for example disclosed in EP 480717 Bl, WO 0006585, WO 2006008751, WO 2006043846, WO 2006064269, WO 2007096875, WO 2007107297. Preferably the pharmaceutical acceptable salt is sodium salt prepared by any method known in the art and being in amorphous or crystalline form as disclosed in for example EP 737186 Bl, WO 03066598, WO 2004091618, WO 2004108679, WO 2005075427, WO 2005074893, WO 2007005965, WO 2007012075, WO 2007059325, WO 2007116240. Preferably the sodium salt of montelukast is prepared from montelukast acid prepared by the process of the present invention by reacting the pure montelukast acid in a polar protic solvent with a source of sodium ions followed by evaporation of the solvent and triturating of the residue with a non-polar solvent to obtain the sodium salt of montelukast . The polar protic solvent may be selected form the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, methanol, acetonitrile, toluene, and the any mixture thereof. Preferably toluene is used. The source of sodium ion may be selected from the group consisting of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, preferably sodium hydroxide. The non-polar solvent may be selected from n-hexane, n- heptane, cyclohexane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether. Preferably, n-heptane is used.

The present inventors surprisingly found a new salt of montelukast, montelukast arginine, obtained in high yield and characterized by the improved properties . The main advantages of this salt are that it is prepared from natural occurring amino acid, that it has an active role in metabolism of mammals and that it is easily metabolized in mammals.

Thus another aspect of the present invention is the conversion of montelukast acid into montelukast arginine salt and optionally its further conversion into sodium salt comprising the steps of: a} obtaining the arginine salt of montelukast by adding L- arginine to the crude montelukast acid, b) optional purifying and converting the arginine salt of montelukast to montelukast acid and reacting the pure montelukast acid in a polar protic solvent with a source of sodium ions, followed by evaporation of solvent and crystallizing the pure sodium montelukast.

The process for preparing the crystalline solid comprising montelukast arginine salt according to the present invention comprises the following steps: a) providing a mixture of montelukast acid in an organic solvent while stirring and optionally heating to elevated temperature; b} adding L- arginine dissolved in water and distilling the water-solvent azeotrope; c) adding an anti-solvent upon cooling; d) stirring for sufficient time to allow crystallization; e} obtaining the crystals by filtering and washing; and f) optionally drying the obtained crystals .

The organic solvent can be selected from the group consisting of toluene, diisopropyl ether, tetrahydrofuran (THF) , ethyl acetate, acetone, methyl ethyl ketone {MEK} , methanol, isopropanol, acetonitrile, m-xylene, 2-methoxyethyl ether, isobutyl acetate, t-butyl alcohol, n-amyl alcohol and mixtures thereof.

The anti-solvent can be selected from the group consisting of n-hexane, cyclohexane, n-heptane, methyl t-butyl ether (MTBE) , diisopropyl ether, ethoxymethyl ether, ethyl acetate, acetonitrile and mixtures thereof.

The obtained montelukast arginine salt is in amorphous form and further characterized in Figures 1 and 2.

It is important to control size of particles of montelukast sodium during its preparation. Average particle size of particles prepared and used in our work is 5 to 200 μm, preferably below 100 μm. If unstirred, crystallization from organic solvents, or their mixtures with water might also yield bigger particles, e.g. with an average diameter of above 200 μm which need to be milled or processed in any other way which reduces particle size, prior to their application in pharmaceutical formulations. When milling, particles of less then 3 μm average diameter may be produced. For this purpose air jet mills, ball mills or hammer mills are commonly used as milling equipment. However, it is not enough to control only the average size of particles, but also particle size distribution. Average particle size and particle size distribution is important to assure that the technological process is industriable, i.e. does not cause segregation of ingredients of tabletting mixture if it is not tabletted/compressed just after preparation of tabletting mixture.

Generally a pharmaceutical composition according to the present invention includes at least one of the substances montelukast acid or montelukast arginine or montelukast sodium as an active ingredient and optionally an additional active substance. The pharmaceutical composition according to the present invention can be in any conventional form, preferably an oral dosage form such as a capsule, tablet, pill, liquid, emulsion, granule, suppositories, powder, sachet, suspension, solution, injection preparation and the like. The formulations/compositions can be prepared using conventional pharmaceutically acceptable excipients. Such pharmaceutically acceptable excipients and additives include fillers/diluents, binders, disintegrants, glidants, lubricants, wetting agents, preservatives, stabilizers, antioxidants, flavouring agents, coloring agents, emulsifier.

A pharmaceutical composition according to the present invention may include ingredients as disclosed in WO 2007/077135 and may be prepared by a process comprising the steps of preparing montelukast acid, montelukast arginine salt and/or montelukast sodium salt according to the process of the present invention and mixing a therapeutically effective amount thereof with one or more pharmaceutically acceptable excipients and optionally with one or more further active substances.

The pharmaceutical composition according to the present invention can be used to treat respiratory diseases such as asthma and allergic rhinitis in a mammal by administering a therapeutically effective amount of the active substance to a mammal in need.

The present invention is illustrated by the following Examples without being limited thereto.

EXAMPLES

Example 1 s

(S) -Methyl 2- (3- (3-hromophenyl) -3-hydroscypropyl)benzoate (V₁ RioBr, Ra=CHa)

An oven dried 50 mL round bottom flask was cooled under argon and charged with methyl 2- { 3- ( 3-bromophenyl) -3-oxopropγl) benzoate (4.17 g, 12 mmol) and TarB-N02 (50 mL of a 0.5 M solution in THF, 24 mmol) and allowed to stir for 10 min. NaBH* (0.908 g, 24 mmol) was added in a single portion to the ketone/TarB~Nθ2 solution, causing rapid evolution of H2 gas. The reaction was allowed to stir for 30 min. Water was added dropwise to quench the reaction until gas evolution ceased. The mixture was brought to pH 12 with 5M NaOH and stirred. The solution was extracted with ethyl acetate (3 x 30 mL) and the organic layer washed with 3M NaOH (30 mL) , brine (30 mL} , and dried over Na2SO4. Evaporation under reduced pressure gave (S) -methyl 2- (3- (3-bromophenyl) -3-hydroxypropyl ) benzoate (4.05 g, 96.6%) .

¹H HMR (300 MHz, CDCI3} δ/ppm: 7.88 (dd, IH), 7.50 (t, IH), 7.46-7.33 (m, 2H), 7.28-7.14 (m, 4H), 4.64 (t), 3.87 (s, 3H), 3.16-2.97 (m, 3H), 2.06-1.97 (m, 2H).

TarB-HCh s An oven-dried 50 mL round bottom flask with a sidearm was equipped with a magnetic stirring bar and reflux condenser, and cooled to room temperature under argon. The flask was charged with 3-nitrophenylboronic acid (4 g, 24 mmol), (D) -tartaric acid (3.63 g, 22.4 mmol), and CaH2 (2.06 g, 49 mmol), and subsequently purged with argon. Anhydrous THF (50 mL) was added via syringe, and the suspension heated to reflux for 1 h. The reaction mixture was cooled to room temperature, transferred to a fritted funnel using a double- ended needle, and carefully filtered under argon. The filtrate was collected into an oven-dried 100 mL round bottom flask, sealed with a septum, and used without further purification.

Example 2 i

( S ) -Methyl 2 - ( 3 - ( 3 -brσmophenyl ) - 3 -hydroxypropyl ) bexxzoat e

)

The Ru-complex was prepared from [RuCl2 (mesitylene) ] 2 (2.1 mg, 7.2 μmol Ru at.) and { IS, 2S) -N-piperidylsulfamoyl-1 , 2- diphenylethylenediamine (3.2 mg, 8.9 μmol) by heating in (CHsCDa (0.5 ml) at 80 ⁰C for 30 min. The Ru-complex solution and HCO₂H-Et₃N (5:2, 210 μl) were then added in portions over 24 h to (S) -methyl 2- (3- (3-bromophenyl} -3- oxopropyl} benzoate (128 mg, 0.37 mmol) in (CH2CD2 (0.5 ml} stirred at 40 ⁰C. The mixture was partitioned between ethyl acetate {5 ml) and water (5 ml} , the organic layer washed with brine (5 ml) , dried over Na2SO4, and filtered through a bed of silica gel. The residue of concentration (120 mg) was recrystallized from ethyl acetate/hexane (1:1) to afford the product (S) -methyl 2- (3- (3-bromophenyl} -3-hydroxypropyl) benzoate.

Example 3 s

(S) -1- (3-bromophenyl) -3- (2- (2-Iaya.ro3cypropan~2-yl) phenyl) propan-1-ol (V,

To (S) -methyl 2- (3- (3-bromophenyl ) -3-hydroxypropyl) benzoate (1.502 g, 4.30 mmol) in THF (9 mL} and toluene (9 mL) was added MeMgBr (2.78 M in Et.O, 8.5 mL, 23.4 mmol) in a rapid dropwise fashion at 1O⁰C. The solution was stirred at rt for 3.5 hr after the addition was complete, then quenched by slow addition of saturated aq. NH4CI . The resulting mixture was poured over EtϊO (50 mL) and brine (25 mL) . The organic phase was dried over NasSCk, and chromatographed to provide (S)-I- (3-bromophenyl) -3- (2- (2-hydroxypropan-2-yl) phenyl) propan-1-ol (1.39 g, 93%) as a white to off-white solid. ¹H NMR (300 MHz, CDCIs) δ/ppm: 7.49 (s, IH) , 7.37-7.31 (m, 2H) , 7.26-7.09 {m, 5H) , 4.61 (dd, IH) , 3.26-3.14 (m, IH), 3.12-3.01 (m, IH), 2.21 (br s, 1H} , 2.15-1.95 (m, 3H) , 1.67 (s, 3H} , 1.64 (s, 3H) .

Example 4 i

(S) -Methyl 2- ( 3- (3-brσmophenyl) -3-methylsulfonylpropyl) benzoate (IV',

R₃-CH₃)

(S) -Methyl 2- (3- ( 3 -bromophenyl ) -3-hydroxγpropyl) benzoate (10.2 g, 29.2 mmol) was dissolved in dichloromethane (100 mL) and cooled to -10⁰C. To the reaction mixture, N- diisopropylethylamine (7.5 mL, 43.8 mmol) was added. Within 30 min, MsCl (2.84 mL, 36.5 mmol) was added dropwise. The reaction mixture was stirred further for 2 hrs at 0⁰C. The mixture was poured over water/ice mixture (100 mL) and layers separated. Organic layer was washed with sat. solution of NaHCO₃ (100 mL) , brine (100 mL) , and dried over Na₂SO₄. The solvent was evaporated in vacuo, to provide crude product (12.6 g, ~ 100%) .

Example 5 :

(S) -Methyl 2- ( 3- {3-bromophenyl) -3-chlor©propyl ) bβnsoate

(S) -Methyl 2- (3™ ( 3 -bromophenyl ) -3-hydroxypropyl) benzoate

(5.83 g, 16.7 mmol) was dissolved in dichloromethane (50 mL) and N, N-dimethyIformamide (2 mL) , and cooled to -10⁰C. To the reaction mixture, SOCI2 (2 mL, 27.6 mmol) in dichloromethane

(20 mL) was added dropwise during 1 hr. The reaction mixture was stirred further for 10 hrs at -1O⁰C and than for 10 hrs at room temperature . The mixture was poured over saturated solution of NaHCθ3 (20 mL) and extracted with EtOAc (3 x 20 mL) . Organic layer was washed with a sat. solution of NaHC03

(50 mL) , brine (50 mL) , and dried over Na2SO4. The solvent was evaporated in vacuo, to provide crude product (5.63 g, 91.7%) . Example 6 s

( S) -2- (2- ( 3 - ( 3 -bromophenyl } ~3 ~chloropropyl ) phenyl )propan~2-ol

To (S) -methyl 2- (3- ( 3 -bromophenyl ) -3-chloropropyl) benzoate (2.81 g, 7.64 mmol) in toluene (20 mL) was added MeMgI (3M in Et2θ, 10 mL, 30 mmol) in a rapid dropwise fashion at 10⁰C. The solution was stirred at rt for 3.5 hr after the addition was complete, then quenched by slow addition of saturated aq. NHdCl. The resulting mixture was poured over EtOAc (50 mL) and brine (25 mL) . The organic phase was dried over Na2SO4, and chromatography to provide (S) -2- (2- (3- (3-bromophenyl) -3- chloropropyl) phenyl )propan-2-ol {2.09 g, 74.4%). 1H NMR (300 MHz, CDCIs) δ/ppm: 7.49 (s, IH), 7.37-7.31 (m, 2H), 7.26-7.09 (m, 5H), 4.08 (dd, IH), 3.21-3.11 (m, IH), 2.93-2.83 (m, IH), 2.42-2.13 (m, 3H)₇ 1.72 (br s, IH), 1.64 (s, 3H) , 1.63 (s, 3H) .

Eκample 7 Ϊ

(R) -2- (1- ( (1- (3-bromophenyl) -3- (2- (methoκycarbonyl) phenyl)propylthio) methyl) cyclopropyl) acetic acid (II',

DMF (30 mL} was placed in a 250 mL three-neck flask. Sodium t-butoxide (8.42 g, 87.6 mmol) was added under continuous stirring. Under vigorous stirring 1- (mercaptomethyl) - cyclopropaneacetic acid (6.4 g, 43.7 mmol) in DMF (20 mL) was added to this solution at room temperature for 30 min. Within 30 min, a solution of methyl 2- (3- (3 -bromophenyl) -3- chloropropyl) benzoate (12.1 g, 32.9 mmol) in 20 mL DMF was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 48 hrs, and than quenched by pouring into water (200 mL) and ethyl acetate (50 mL) . The pH of the mixture was brought to pB=7 by addition of 20% tartaric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL) . Combined organic layers were washed with 5% solution of tartaric acid (100 mL) , water (2 x 100 mL) , than dried over Na2SO4 and solvent evaporated, to provide crude (R) -2- (1- { (1- (3- bromophenyl) ~3~ (2~ (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (14.47 g, 92.1%). 1H tMR (300 MHz, CDCl₃) δ/ppm: 7.89 (dd, IH), 7.52-7.16 (m, 7H), 3.90-3.80 (m, 4H), 3.12-2.83 {m, 2H), 2.51-2.44 (m, 3H), 2.17-2.06 (m, 3H), 0.57-0.39 (m, 4H).

Example 8s

(R) -2- (1- ( (1- (3-bromophenyl) -3- (2- (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (II',

R₃=CH₃)

DMF (30 mL) was placed in a 250 mL three-neck flask. Sodium t-butoxide (8.42 g, 87.6 mmol) was added under continuous stirring. Under vigorous stirring 1- (mercaptomethyl) - cyclopropaneacetic acid (6.4 g, 43.7 mmol) in DMF (20 mL) was added to this solution at room temperature for 30 min. Within 30 min, a solution of methyl 2- (3- (3-bromophenyl) -3- chloropropyl) benzoate (12.6 g, 29.2 mmol) in 20 mL DMF was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 48 hrs, and than quenched by pouring into water (200 mL) and ethyl acetate (50 mL) . The pH of the mixture was brought to pH=7 by addition of 20% tartaric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL) . Combined organic layers were washed with 5% solution of tartaric acid (100 mL) , water (2 x 100 mL) , than dried over Na2SO4 and solvent evaporated, to provide crude (R) -2~ (1- ( <1- (3- bromophenyl ) -3 - ( 2 -

(methoxycarbonyl ) phenyl ) propylthio) methyl ) cyclopropyl ) acetic acid (12.20 g, 87.5%) . Example 9 :

(R)-2-(l-({l-(3-bromopheny1) -3- {2- (methoxycarbony1) phenyl) propylthio) methyl) cyclopropyl) acetic acid dieyelohexylamine salt (II^f DCHA salt,

Crude (R)-2-(l-((l~ ( 3 -bromophenyl ) -3- (2- (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (12.20 g 25.6 mmol} was dissolved in toluene (100 mL) , stirred for 10 min and dicyclohexylamine was added (6 mL) . The solution was concentrated under vacuum to about 50 mL . The concentrate was maintained at rt and n-hexane (100 mL} was added. The suspension vas stirred at rt for 18 hrs, filtered through a sinter funnel under argon. The product was washed with n- hexane (20 mL} , and dried under vacuum to provide title product (9.80 g, 58.2%)

Example 10:

(R) -2- {1- ( {l^»(3^»bromophenyl)-3- (2- (2-hydroκypropan-2-yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (II, Ra=Br)

To (R) -2- (1- { (1- (3-bromopheny1 ) -3- (2- (methoxycarbonyl) phenyl) propylthio) methyl} cyclopropyl) acetic acid (4.07 g, 8.53 mmol} in toluene (50 mL) was added MeLI ( 1.6M in Et2θ, 20 mL, 32 mmol) dropwise at -5°C for 30 min. The solution was stirred at O⁰C for 3.5 hr after the addition was complete, then quenched by slow addition of saturated aq. NHiCl. The resulting mixture was poured over EtOAc (50 mL) and brine (25 mL) . The organic phase was dried over Na2SO4, and chromatographed to provide (R) -2- ( 1- ( (1- (3-bromophenyl) -3- (2- (2-hydroxypropan-2-yl) phenyl) propylthio) methyl} cyclopropyl) acetic acid (3.65 g, 89.6%).

Example 11:

(R) -2- (l-( (l-(3~bromophenyl)-3-(2-(2~hydroxypropan-2-yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (II,

Ri=Br) DMF (10 mL) was placed in a 100 mL three-neck flask. Sodium t-butoxide (2.78 g, 29.0 mmol} was added under continuous stirring. Under vigorous stirring 1- (mercaptomethyl) - cyclopropaneacetic acid (2.05 g, 14 mmol) in DMF (5 mL) was added to this solution at room temperature for 30 min. Within 30 min, a solution of (S) -2- (2- (3- ( 3 -bromophenyl } -3- chloropropyl) phenyl )propan-2-ol (3.67 g, 10 mmol} in DMF (5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 48 hrs, and than quenched by pouring into water (100 mL) and ethyl acetate {20 mL) . The pH of the mixture was brought to pH=7 by addition of 20% tartaric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL) . Combined organic layers were washed with 5% solution of tartaric acid (50 mL) , water (2 x 50 mL) , than dried over Na2SO4 and solvent evaporated, to provide crude (R) -2- (1- { (1- (3- bromophenyl ) -3- (2-

(methoxycarbonyl ) phenyl ) propylthio) methyl } cyclopropyl ) acetic acid (3.24 g, 67.8%) .

Example 12 :

(Ξ)-2-(l^»((l~(3-(2-{7-chloroquinolin-2-yl)vinyl)phenyl)-3-{2- (methostycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (I', Ib=CH3)

2~{i-( (l- (3-Bromophenyl) -3- (2- (methoxycarbonyl) phenyl) propylthio} methyl) cyclopropyl) acetic acid (265 mg 0.527 mmol) was added to Pd(OACh (7 mg, 0.031 mmol), P(o-tolyl)₃ (28 mg, 0.092 mmol), 2-ethenyl-7-chloroquinoline (III) (100 mg, 0.555 mmol) in DMF (3 mL) . The dark mixture was degassed three times using the freeze-pump-thaw technique, and then Et3N (0.2 mL, 1.437 mmol) was added. The reaction was heated to 100 ⁰C for 4 hr, then cooled to rt . The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with 20 mL of brine, and dried over Na2Sθ4. The solvent was evaporated in vacuo. The crude mixture was chromatographed on silica column using EtOAc :n~hexane=l : 2 + 1% AcOH as eluent, affording the title product (191 mg, 61.8%).

¹H INMR (300 MHz, CDCl₃), δ/ppm: 8.2-7 (m, 15H), 3.95 {t, IH), 3.8 (s, 3H), 3.2-2.8 (m, 2H), 2.7-2.2 (m, 4H), 2.2 (m, 2H), 0.5 (d, 4H) .

Example 13 : Montelukast acid (I)

To { (E)-2-(l-( { l-(3-(2- (7-chloroqu.inolin-2-yl) vinyl) phenyl )- 3- (2- (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl} acetic acid (2.92 g, 4.98 mmol) in toluene {20 mL) was added MeMgI (3M in Et∑O, 10 mL, 30 mmol} in a rapid dropwise fashion at 10⁰C. The solution was stirred at rt for 3.5 hr after the addition was complete, then quenched by slow addition of saturated aq, NH4CI . The resulting mixture was poured over EtOAc (50 mL) and brine {25 mL} . The organic phase was dried over KfeSCu, and chromatographed to provide

(S)-2-(2-(3- ( 3 -bromophenyl ) -3 -chloropropyl) phenyl ) propan-2-ol

(2.09 g, 71.6%} .

Example 14 : Montelukast acid (I)

(R) -2- (1- { {1- (3-bromophenyl) -3- (2- {2-hydroxypropan~2~yl} phenyl) propylthio) methyl} cyclopropyl) acetic acid (475 mg 0.994 mmol) was added to Pd(OAch {15 mg, 0.067 mmol), P(o- tolylb (90 mg, 0.296 mmol), 2~ethenyl-7-chloroquinoline

(III) (190 mg, 1.002 mmol} in DMF (5 mL) . The dark mixture was degassed three times using the freeze-pump-thaw technique, and then Et:sN {0.34 mL, 2.443 mmol) was added. The reaction was heated to 100 ⁰C for 4 hr, then cooled to rt . The mixture was poured into water (10 mL) and extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with 20 mL of brine, and dried over Na2SO4. The solvent was evaporated in vacuo . The crude mixture was chromatographed on silica column using EtOAc :n-hexane=l : 2 + 1% AcOH as eluent, affording the title product (394 mg, 67.6%).

Example 15 ;

Montelukast arginine salt

Solution of montelukast acid (5.1 g) prepared by the processes as disclosed in the previous examples or by any processes known from the prior art in toluene (50 mL) is completely distilled off under reduced pressure at below 5O⁰C. The obtained residue is dissolved in toluene (100 mL) and solution of L-arginine (1.67 g) in water (15 mL) was added and the mixture stirred at 5O⁰C for 30 min and than concentrated to -50 mL at normal pressure. The solution was cooled to rt and hexane (100 mL) was added dropwiεe, and stirred at rt for 18 hrs . The product is filtered under nitrogen and washed with hexane (50 mL) , and dried under vacuum at 40⁰C for 12 hrs to yield amorphous form of montelukast arginine (6.89 g) .

¹H NMR (300 MHz, DMSO-ds} δ/ppm: 8.37 (d, IH), 8.01-7.08 (m, 14H), 4.00 (t, 3H), 3.25 (m, IH), 3.04 (m, 3H), 2.77-2.60 (m, 2H}, 2.28-2.05 <s, 4H), 1.72-1.57 (m, 3H), 1.41 (s, 6H), 0.41-0.21 (m, 4H)

The X-ray powder diffraction pattern was obtained by Philips PW3040/60 X' Pert powder diffTactometer, X'celerator detector at CuKa radiation, 1.54178 A, 3²<2#<30^a.

FT-IR spectra of KBr discs were recorded over the wave number range of 4000-400 cm ^l on Perkin Elmer FT-IR spectrometer Spectrum GX at a resolution 4 cm^'1.

Fig 1: Powder X-ray diffraction pattern of amorphous montelukast arginine salt

Fig 2 : FTIR spectrum of amorphous montelukast arginine salt Example 16: Montelukast sodrαm

Montelukast arginine salt (4.14 g) was dissolved in toluene (100 mL) . Acetic acid (1 mL) in water {100 mL) was added. The mixture was stirred at rt for 30 min, and layers separated. To organic layer, solution of sodium hydroxide (218 mg) in methanol (12 mL) was added, and stirred at rt for 1 hr . The solvent is completely disstiled off under vacuum at below 50⁰C to afford the residue. The residue is dissolved in toluene (40 mL} and charcoal was added and stirred at 40⁰C for 2 hrs . The reaction mixture was filtered, and concentrated under vacuum to -20 mL. The mixture was dropwise added to hexane (60 mL) and stirred under nitrogen 18 hrs. The product is filtered under nitrogen and washed with hexane (20 mL) , and dried under vacuum at 4O⁰C for 12 hrs to yield amorphous form of montelukast sodium (2.07 g) .

Example 171 Montelukast sodium

To the solution of montelukast acid (2.5 g) prepared by the processes as disclosed in the previous examples or by any processes known from the prior art in toluene (50 mL) solution of sodium hydroxide (218 mg) in methanol (12 mL) was added, and stirred at rt for 1 hr. The solvent is completely disstiled off under vacuum at below 50⁰C to afford the residue. The residue is dissolved in toluene (40 mL) and charcoal was added and stirred at 40⁰C for 2 hrs. The reaction mixture was filtered, and concentrated under vacuum to -20 mL. The mixture was dropwise added to hexane (60 mL) and stirred under nitrogen 18 hrs. The product is filtered under nitrogen and washed with hexane (20 mL) , and dried under vacuum at 40⁰C for 12 hrs to yield amorphous form of montelukast sodium (1.95 g) . Example 18 s Chewable tablets 5 mg

* corresponds to 5.00 mg of montelukast free acid

A 1 kg batch was prepared. Manitol, aspartame, iron oxide red, microcrystalline cellulose, and croscarmellose sodium were mixed in a granulator and granulated with a solution of Klucel EF. The obtained granulate was dried and then, montelukast sodium, croscarmellose sodium, mictocrystalline cellulose, aroma cherry black, and magnesium stearate were admixed, and the obtained mixture was pressed into tablets using round, slightly biconvex punches to a target hardness of approx. 20 - 90 N. The same compression mixture was used for the preparation of 4 mg tablets with target weight 240 mg.

Claims

1. A process for the preparation of montelukast acid comprising the steps of: a) asymmetric reduction of the ketone of formula (VI) to obtain the secondary alcohol of formula (V } which can be optionally further converted to the secondary alcohol of formula (V) by reaction with CH3-Met,

b) conversion of the secondary alcohol of formula (V) or (V to the compound of formula (IV) or (IV) respectively, following which compound (IV) can be optionally further converted to the compound of formula (IV)

c) nucleophilic substitution of the compound of formula (IV) or (IV) with 2- ( 1- (mercaptomethyl) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into the carboxylic acid to obtain an acetic acid derivative of formula (II) or (II') respectively, following which compound (II') can be optionally further converted to the compound of formula (II) ,

CH₃-Met

d) Heck coupling reaction of the acetic acid derivative of formula (II) or {II') with vinylquinoline of formula (III) to obtain montelukast acid of formula (I) or to obtain the crude ester (I') respectively, following which compound (I'} is further converted to montelukast acid of formula (I)

wherein

R3 represents Ci-Cs alkyl;

R' represents a negative charge, hydrogen, alkyl, trifluoromethyl , C3~Cs cycloalkyl or a Cs-Cio aryl group;

L represents a leaving group such as chlorine, bromine, iodine, a Ci-Ce alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group; and

Met represents a metal residue selected from -MgCl, -MgBr,

-MgI or -Li.

2. The process according to claim 1 wherein Ri is bromine or trifluoromethanesulfonate, R3 is methyl and L is chlorine or methylsulfonyloxy .

3. The process according to claims 1 and 2 wherein the secondary alcohol of formula (V) is prepared by asymmetric reduction of ketone of formula (VI) with a reducing agent, selected from sodium and lithium borohydride, in an inert solvent and a tartaric acid-derived boronate ester as a catalyst.

4. The process according to claim 3 wherein the tartaric acid-derived boronate ester is prepared by reacting (D) - tartaric acid with a substituted arylboronic acid of formula (VII)

(Vl!)

wherein Rs and Rs independently represent hydrogen, halogen, trifluoromethyl , cyano or nitro, in refluxing THF and in the presence of CaH2.

5. The process according to claim 4 wherein the substituted arylboronic acid is 3-nitrophenylboronic acid.

6. The use of a tartaric acid-derived boronate ester according to claims 4 and 5 in the asymmetric reduction of ketone of formula (VI) .

7. The process according to any previous claim wherein the secondary alcohol of formula (V ) is prepared by metal- catalysed transfer hydrogenation of compound of the general formula (VI) by using a hydrogen donor in the presence of a metal catalyst based on ruthenium complexes of optically active N~sulfamoyl-1, 2-diamine ligands of the formula (VIII):

(VIIi) wherein:

* represents an asymmetric carbon atom;

Re and Rv independently represent a hydrogen atom, a linear or branched C1-C15 alkyl group that is optionally substituted with a C5-C10 aryl group, or R6 and R7 may be linked together to form with the nitrogen atom an optionally substituted 4 -

6 membered ring;

Rs and Rs independently represent a hydrogen atom, an optionally substituted C5-C10 aryl group, or a C3-C8 cycloalkyl group, or Rs and R9 may be linked together to form a cyclohexane ring.

8. The process according to claim 7 wherein Rs and R7 are independently selected from the group consisting of methyl, iso-propyl and cyclohexyl, or Re and R7 are linked together to form a ring selected from the group consisting of pyrrolidyl, piperidyl, morpholyl and azepanyl.

9. The process according to claims 7 or 8 wherein the optically active N-sulfamoyl-1, 2-diamine ligands of the formula (VIII) have an enantiomeric excess of more than 95%, preferably more than 99%.

10. The process according to claims 7 to 9 wherein the ruthenium metal catalyst is prepared from a precursor of the formula [RuX2 (ϊ?⁶-arene) ] 2, wherein τ/⁶-arene represents an arene group, selected from the group consisting of benzene, p-cyπiene, mesitylene, 1 , 3 , 5-triethylbenzene, hexamethylbenzene and anisole, and X is halide selected from the group consisting of chloride, bromide and iodide.

11. The process according to claims 7 to 10 wherein the hydrogen donor is selected from HCO2H-Et3Kf, HC02H-iso-Pr2NEt, HCChH-metal bicarbonates and HCChH-metal carbonates, wherein the metal is selected from Na, K, Cs, Mg and Ca.

12. The use of metal catalyst based on ruthenium complexes of optically active N-sulfamoyl-1, 2-diamine ligands of the formula (VIII) as defined in claims 7 to 9 in the asymmetric reduction of the ketone of formula (VI) as defined in claim 1.

13. The process according to any previous claim wherein the conversion of the secondary alcohol is performed with an alkyl or aryl sulfonyl halide selected from the group consisting of methyl, ethyl, n-butyl, besyl or tosyl sulfonyl halide in an inert solvent selected from the group consisting of dichloromethane, tetrahydrofurane, 2- methyltetrahydrofurane, and N, N-dimethylformamide in the presence of a base selected from the group consisting of organic tertiary non-nucleophilic base such as for example triethylamine , ISJ-ethyldiisopropylamine .

14. The process according to any previous claim wherein the conversion of the secondary alcohol is performed with a halogen acid or inorganic acid halide selected from the group consisting of HCl, HBr, HI, ΞOCI2, PCIa, POCIs, PBrs in a suitable solvent selected from the group consisting of dichloromethane, tetrahydrofurane, 2-methyltetrahydrofurane, and N, N~dimethylformamide.

15. The process according to any previous claim wherein the nucleophilic substitution is performed in the presence of a base selected from the group consisting of an alkali hydroxide, an alkaline earth hydroxide, alkali carbonate, alkali alkoxide, alkali hydrde, alkyllithium or lithium hexamethydisilazide, preferrably sodium t-butoxyde, n- butyllithium, or caesium carbonate and in a solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, N, N- dimethylformamide, N, N-dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone .

16. The process according to any previous claim wherein Heck coupling reaction is performed in the presence of a catalyst selected from the group consisting of Pd source, such as palladium{II) acetate, palladium(II) chloride, palladium dibenzylideneacetone, dichlorobis (acetonitrile} palladium(II) , dichlorobis (benzonitrile) palladium(II) , dichlorodiamine palladium (II) , palladium (II) acetylacetonate, palladium(II) bromide, palladium{II) cyanide, palladium(II) iodide, palladium oxide, palladium(II) nitrate hydrate, palladium (II) sulfate dihydrate, palladium ( II) trifluoroacetate, tetraamine palladium (II) tetrachloropalladate and tetrakis (acetonitrile) palladium (II) tetrafluoroborate; and a bidentate phosphorous or nitrogen ligand such as for example a phosphine such as triphenylphosphine, tris (o-tolyl) phosphine, 1,3- bis (diphenylphosphino) propane, tri (t-butyl) phosphine, tris(p- tolyl ) phoshine, tricyclohexylphosphine, tris (p- chlorophenyl) phosphine, tris (p-fluorophenyl) phosphine, tris (p-methoxyphenyl) phosphine, tributylphosphine, tris (isopropyl) phosphine, preferably Pd (OAc) 2 is the catalyst and tris { o-tolyl} phosphine is the bidentate ligand and a base selected from the group consisting of primary, secondary or tertiary amines, such as for example triethylamine or diisopropylethylamine, carbonates, hydrogencarbonates , hydroxides and alkali metal alkoxides such as for example potassium carbonate, sodium carbonate, sodium hydrogencarbonate, caesium carbonate, thallium carbonate, potassium hydroxide, sodium hydroxide, thallium hydroxide, or the alkoxides of these alkali metals in an inert solvent.

17. The process according to claim 16 wherein the acetic acid derivative of formula (II) or (II') wherein Ri is Br and R3 is methyl reacts with 2-ethenyl-7-chloroquinoline in the presence of Pd(OAc)2, P(o-tolyl>3 and EtsN in a DMF solution or suspension.

18. The process according to any previous claim wherein montelukast is isolated as montelukast acid of formula (I).

19. The process according to any previous claim wherein the montelukast acid in a polar protic solvent reacts with a source of sodium ions followed by evaporation of the solvent and triturating of the residue with a non-polar solvent to obtain the sodium salt of montelukast.

20. A process for the preparation of montelukast sodium comprising the steps of: a} preparing the rnontelukast acid according to the process of claims 1 to 17 , ta) converting the montelukast acid to montelukast arginine salt, c) converting the montelukast arginine salt to montelukast sodium salt, d) isolating the montelukast sodium salt.

21. A process for the preparation of montelukast arginine salt comprising the step of obtaining the arginine salt of montelukast by adding L~arginine to the crude montelukast acid.

22. Montelukast arginine salt.

23. Amorphous montelukast arginine salt.

24. Montelukast arginine salt prepared according to any of the preceding claims for use in a method for treating respiratory diseases such as asthma and allergic rhinitis.

25. A process for the preparation of a pharmaceutical composition comprising the steps of preparing montelukast acid, montelukast arginine salt and/or montelukast sodium salt according to any of the preceding claims and mixing a therapeutically effective amount thereof with one or more pharmaceutically acceptable excipients and optionally with one or more further active substances .

26. The compound of formula (IV) or (IV

wherein

R3 represents Ci-Ce alkyl;

R' represents a negative charge, hydrogen, alkyl, trifluoromethyl, Cs-Ca cycloalkyl or a Cs-Cio aryl group; and

L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group.

27. The compound of formula (IV) or (IV)

wherein

Ri represents bromine or trifluoromethanesulfonate, R3 represents methyl and L represents chlorine or a methylsulfonyloxy group.

28. The compound of formula (II) or (II'

wherein

R3 represents Ci-Ce alkyl; and

R' represents a negative charge, hydrogen, alkyl, trifluoromethyl, C3-Cs cycloalkyl or a Cs-Cio aryl group.

29. The compound of formula (II) or (II')

wherein

Ri represents bromine or trifluoromethanesulfonate and

R3 represents methyl.