WO2008009970A2

WO2008009970A2 - Process for the preparation of montelukast

Info

Publication number: WO2008009970A2
Application number: PCT/GB2007/002790
Authority: WO
Inventors: Amir Avdagic; Juraj Jerkovic; Davorka Pavlicic
Original assignee: Pliva Hrvatska D.O.O.; Mcleish, Nicholas, Alistair, Maxwell
Priority date: 2006-07-21
Filing date: 2007-07-23
Publication date: 2008-01-24
Also published as: EP2046750A2; CA2658473A1; IL196602A0; WO2008009970A3; GB0614485D0

Abstract

A process of preparing montelukast, or a pharmaceutically acceptable salt thereof, which process comprises reacting a protected intermediate of formula (II) as defined in the specification with a cyclopropyl intermediate.

Description

PROCESS

The present invention is concerned with the preparation of montelukast, or a pharmaceutically acceptable salt thereof, in particular montelukast sodium.

Montelukast is the international non-proprietary name for l-[[[(lR)-l-[3-[(lE)-2-(7-Chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, having the following structural formula (I)

(I)

Montelukast is generally employed as its sodium salt and is a leukotriene antagonist. Montelukast, and its sodium salt, is thus useful as an anti-asthmatic, anti-allergic, antiinflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma.

Montelukast sodium and related compounds were first disclosed in EP 0480717B. The synthesis of montelukast sodium, as taught in EP 0480717B, involves the following key reaction steps

The above is followed by deprotection and hydrolysis of the resulting methyl ester so as to form montelukast as the free acid, which is followed by conversion of the free acid to a corresponding sodium salt.

Subsequent to above EP 0480717B, there have been several disclosures of possible routes of synthesis to montelukast, or a pharmaceutically acceptable salt thereof. Some examples are as follows.

EP 0737186B describes crystalline montelukast sodium and a process of preparing the same. The process involves the preparation of the dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid as an intermediate, followed by condensation thereof with 2-(2-(3- (S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2- propanol, to yield montelukast acid, according to the following key reaction step

The resulting montelukast acid is converted, via a corresponding amine salt, to montelukast sodium. The montelukast sodium is crystallized from a toluene/acetonitrile solution to obtain crystalline montelukast sodium. EP 0737186B confirms that montelukast as disclosed in EP 0480717B is amorphous montelukast sodium.

WO 05/105751 discloses a process of preparing a pharmaceutically acceptable salt of montelukast, where 2-(2-(3(S)-(2-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-((α- hydroxy)propyl)phenyl-2-propanol is activated with a benzylsulfonyl or mesyl group, the activated product is reacted with l-(mercaptomethyl)cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a co-solvent and a base, followed by hydrolysis. The above reaction step, where 2-(2-(3(S)-(2-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-((α- hydroxy)propyl)phenyl-2-propanol is activated with toluene sulfonyl, is as follows

US 2005/0234241 discloses a process of preparing montelukast, which comprises: (a) reacting 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-sulfonyloxypropyl)phenyl)-2- propanol with an alkali salt of a cyclopropyl intermediate shown below, wherein X = CN or CONH₂, according to the following key reaction step

and hydrolyzing the resulting compound to montelukast in the presence of a base selected from sodium hydroxide, sodium methoxide, sodium secondary butoxide, sodium tertiary butoxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium tertiary butoxide, or potassium carbonate, optionally in a solvent selected from a group consisting of methanol, ethanol, 1-proρanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, glycol; diethyl ether, diisopropyl ether, methyl isopropyl ether, tetrahydrofuran, diethylene glycol, 1,4-dioxan, methoxy ethanol; and toluene, cyclohexane, hexanes, n-heptane or mixtures of two or more miscible solvents.

WO 05/105749 describes intermediates useful in the synthesis of montelukast, namely 2-(2- (3(S)-{3-(2-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3(thio)ρropyl}phenyl}-2-propanol and 2-(2-(3(S)-{3-(2-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3(acetylthio)ρropyl}ρhenyl}-2- propanol.

WO 05/105750 also describes intermediates useful in the synthesis of montelukast, namely methyl 2-((3R)-acetylsulfanyl)-3-{3-[(E)-2-(7-chloro-2-quinolinyl)-ethenyl]-ρhenyl}-proρyl)- benzoate and a cyclopropylacetate intermediate. US 2005/0107612 discloses preparation of montelukast, or a salt thereof, by reacting a late intermediate compound which is 2-[l-[l-R-3-[2-(7-chloroquinolin-2-yl)vinyl [phenyl] -3- [2- methoxycarbonylphenyl]propylsulfonylmethyl]cyclopropyl]acetic acid or a salt thereof with methyl magnesium chloride or methyl magnesium bromide in an organic solvent. There is also disclosed a process for preparation of montelukast Na comprising: (i) providing a solution of starting montelukast free acid in a halogenated solvent, aromatic solvent, or mixtures thereof; (ii) treating said solution with an alcoholic base to convert said montelukast free acid into a sodium salt of montelukast; (iii) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said sodium salt of montelukast.

US 2006/0004204 discloses montelukast free acid in solid form and processes of preparing the same.

WO 06/021974 also discloses processes of preparing various intermediates useful in the preparation of montelukast sodium.

Despite the considerable research that has been carried out in trying to devise RoS for montelukast, or a pharmaceutically acceptable salt thereof, montelukast remains a difficult compound to prepare. For example, we have found that an unprotected mesylate intermediate as shown above with reference to EP 0737186B, WO 05/105751 and US 2005/0234241, is highly unstable and this instability is a considerable problem to the processes described in these documents. EP 0480717B, on the other hand, does employ a protected form of the above referenced intermediate, but this process is also not suitable for industrial application, as it requires numerous purification steps and finishes with harsh reaction conditions employing highly flammable butyl lithium at extremely low temperatures. The process of EP 0480717B is also undesirable in that it employs the commercially unavailable di-ester of 1- (mercaptornethyi)cyclopropaneacetic acid.

There remains a need, therefore, for improved processes of manufacturing montelukast, or a pharmaceutically acceptable salt thereof, which can be efficiently used on an industrial scale. This is now provided by the present invention, whereby there is provided a process that (i) employs stable intermediates, (ii) avoids the use of numerous purifications, (iii) applies mild reaction conditions and (iv) employs a simple, economic precursor to create the mercaptomethylcyclopropane side chain of montelukast.

According to the present invention, there is, therefore, provided an improved process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a protected intermediate of formula (II) with a cyclopropyl intermediate of formula (III)

where:

P₁ represents a hydroxy protecting group;

L represents a leaving group, such as arylsulfonyl, typically selected from benzenesulfonyl or toluene sulfonyl, or C_1-4 alkylsulfonyl;

X represents a monovalent cation, for example Na⁺ or Li⁺;

Y represents -CN or -CO₂X, where X is as above;

and converting the reaction product to the free acid form of montelukast of formula (I)

(I) or a pharmaceutically acceptable salt thereof, especially the sodium salt.

Generally, it is preferred that L represents C_1-4 alkylsulfonyl, especially methanesulphonyl. Generally, it is also preferred that X represent Na⁺. In a first preferred embodiment, there is provided a process for the preparation of montelukast of formula (I)₅ or a pharmaceutically acceptable salt thereof, which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (Ilia)

wherein Ms represents methanesulphonyl (mesyl); and P₁ is a hydroxy protecting group as above;

(I) or a pharmaceutically acceptable salt thereof, especially the sodium salt.

In a second preferred embodiment, there is provided a process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (UIb)

(I) or a pharmaceutically acceptable salt thereof, especially the sodium salt.

In a third preferred embodiment, there is provided a process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (HIc)

(I) or a pharmaceutically acceptable salt thereof, especially the sodium salt.

Suitably, a cyclopropyl intermediate of formula (III), and as such any of intermediates (Ilia), (HIb) and (IHc). is added to a reaction medium for intermediates (II) and (III), as a precursor compound of formula (IV)

OV)

where Y' represents -CN or -CO₂H and wherein the reaction medium also includes a source of the monovalent cation X as present in formula (III). Typically, the source of the monovalent cation is a strong base, such as an alkali metal alkoxide, preferably an alkali metal C_1-4 alkoxide, such as sodium or lithium C_1-4 alkoxide, for example sodium or lithium methoxide.

In a fourth embodiment, there is provided a process for the preparation of montelukast of formula (T), or a pharmaceutically acceptable salt thereof, which process comprises the following reaction steps

where L and P₁ are substantially as hereinbefore described, and R represents C_1-4 alkyl, preferably methyl, and converting a compound of formula (XII) to the free acid form of montelukast of formula (I)

(I) or a pharmaceutically acceptable salt thereof, especially the sodium salt.

Preferably, there is provided according to the fourth embodiment of the present invention a process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises the following reaction steps

where P₁ and Ms are substantially as hereinbefore described, and converting a compound of formula (XII) to the free acid form of montelukast of formula (I)

(D or a pharmaceutically acceptable salt thereof, especially the sodium salt.

Typically P₁ in formula (II) (and as such (Ha)) can represent any suitable hydroxy protecting group, for example alkyl, such as methyl, methoxyniethyl or methoxyethoxymethyl; aralkyl, such as benzyl, diphenylmethyl, or triphenylmethyl; heterocyclic groups, such as tetrahydropyranyl or tetrahydrofuranyl; acyl, such as acetyl or benzoyl; and silyl groups, such as trialkylsilyl, for example tert-butyldimethylsilyl. In a preferred embodiment P₁ represents tetrahydropyranyl.

Preferably conversion of the reaction product to the free acid form of montelukast of formula (I) is subject to deprotection and where required conversion of moiety Y as present in the reaction product to the free acid. Suitably, deprotection can be by hydrolysis under basic or acidic conditions. Pyridinium p-toluensulfonate can be used in the deprotection and the reaction is often heated over several hours, typically in the presence of a C_1-4 alcohol and a suitable inert organic solvent, such as tetrahydrofuran. By "inert organic solvent" is meant an organic solvent, which under the reaction conditions employed, does not enter into any appreciable reaction with either the reactants or the products. Conversion of a cyano moiety Y, namely -CN, to the free acid, can typically be carried out by acid or base hydrolysis, for example hydrolysis in the presence of an alkali metal hydroxide, such as sodium hydroxide.

Suitably conversion of the free acid of formula (I) to a corresponding pharmaceutically acceptable salt is by way of treatment with a base of the salt forming species, for example treatment with a pharmaceutically acceptable alkali metal hydroxide or C_1-4 alkoxide. Typically a pharmaceutically acceptable salt of montelukast of formula (I), such as montelukast sodium, thus obtained is an amorphous solid. In a preferred embodiment, montelukast free acid of formula (I) may initially be converted to an intermediate amine salt, such as the dicyclohexylamine or adamantylamine salt, prior to conversion to a pharmaceutically acceptable salt, such as the sodium salt. This intermediate amine salt formation can be advantageous in offering a simple and efficient method for purification of montelukast. Typically the salt forming amine is added to a solution of the montelukast free acid of formula (I) in a suitable solvent, such as ethyl acetate, followed by crystallization. For example, crystallization can be by hexane addition to effect crystallization of the required amine salt. It is particularly preferred that an adamantylamine salt is employed, specifically 1 -adamantylamine.

Preferably, therefore, there is provided a process of preparing a pharmaceutically acceptable salt of montelukast of formula (I), in particular the sodium salt, which process comprises treating the l-adamantylarnine salt of montelukast of formula (I) with an acid, treating the product thus obtained with a source of the pharmaceutically acceptable salt forming species, typically a source of sodium ions, and crystallizing the resulting pharmaceutically acceptable salt of montelukast of formula (I), typically montelukast sodium. In a particularly preferred embodiment, therefore, there is provided a process of preparing montelukast sodium, which process comprises treating the 1 -adamantylamine salt of montelukast of formula (I) with an acid, treating the product thus obtained with a source of sodium ions, and crystallizing the resulting montelukast sodium.

Suitably a compound of formula (II) is prepared from a corresponding hydroxy compound of formula (V)

by reacting a compound of formula (V) with an appropriate C_1-4 alkyl or aryl sulfonyl halide, in particular methanesulfonyl chloride, to yield in particular the corresponding mesylate intermediate for subsequent reaction with a compound of formula (III). In the case where a compound of formula (II) is a mesyl protected intermediate, it is preferred that mesylation of a compound of formula (V) is carried out in an inert organic solvent, such as methylene chloride, suitably in the presence of a tertiary amine base, such as diisopropylethylamme, and at a temperature of <0°C, preferably at a temperature in the range of about -15 to -5°C.

Suitably a compound of formula (V) can be prepared by selective deprotection of a protected derivative of formula (VI)

where P₁ is a hydroxy protecting group substantially as hereinbefore described; and P₂ is a second hydroxy protecting group, which is different from P₁;

wherein P₁ and P₂ are respectively such that P₂ can be selectively removed in preference to P₁ so as to yield a compound of formula (V). In a preferred embodiment, P₁ represents a heterocycle, such as tetrahydropyranyl, and P₂ represents a silyl group, such as trialkylsilyl, for example tert-butyldimethylsilyl, dimethylisopropylsilyl, tert-butyldiphenylsilyl or the like. A suitable deprotecting agent can be a hydrated alkylammonium halide, such as tetra-n- butylammonium fluoride trihydrate which can be used in the selective removal of a silyl protecting group.

A compound of formula (VI) is typically prepared by the stepwise protection of the corresponding di-hydroxy compound of formula (VII)

wherein P₁ and P₂ are respectively selcected and introduced so that P₂ can be preferentially removed to yield a compound of formula (V) as described above. In a preferred embodiment, P₂ is first introduced as a protecting group for the secondary hydroxy group substituted on the propylene chain and P₁ is subsequently introduced as a protecting group for the tertiary hydroxy group substituted on the phenyl ring, although it is of course appreciated that the above protecting steps could be carried out in the reverse order with P₁ introduction followed by P₂ introduction.

A compound of formula (VII) is suitably prepared from a corresponding hydroxy ester of formula (VIII)

wherein R₁ is a lower alkyl, namely C_1-4 alkyl, typically methyl or ethyl. Typically, a solution of a compound of formula (VIII) is initially formed under reflux and the hydroxy ester of formula (VIII) is then converted to the di-hydroxy compound of formula (VII) under Grignard conditions. Suitably, a Grignard reagent such as methyl magnesium chloride in the presence of cerium chloride is employed. The reaction can be carried out under anhydrous conditions, preferably using anhydrous cerium chloride, the hydroxy ester of formula (VIII) and solvents. A suitable solvent is tetrahydrofuran.

A compound of formula (VIII) is suitably prepared from a compound of formula (IX)

by asymmetric transfer hydrogenation, preferably using a chiral ruthenium or rhodium catalyst, in the presence of a hydrogen source. Suitably, the chiral ruthenium or rhodium catalyst is prepared in situ by reaction of a ruthenium or rhodium catalyst precursor and a chiral N-sulfamoyl-l,2-diamine type ligand. Typically, the hydroxy ester of formula (VIII) is thus prepared in the form of a monohydrate. With reference to the above described process steps starting with a compound of formula (IX), for the above described first preferred embodiment of the present invention, where a protected intermediate of formula (Ha) is reacted with a cyclopropyl intermediate of formula (Ilia)

the overall reaction scheme can be specifically represented by following Scheme 1.

Scheme 1:

It should also be appreciated that montelukast free acid, shown as molecule 10 of above Scheme 1, may not necessarily be prepared in a process according to the present invention. For example, in the case of basic hydrolysis with NaOH, the sodium salt shown as molecule 11 of above Scheme 1 can be a direct product obtained from molecule 9.

Similarly, for the above described second preferred embodiment, where a protected intermediate of formula (Ha) is reacted with a cyclopropyl intermediate of formula (HIb)

the overall reaction scheme can be specifically represented by following Scheme 2.

Scheme 2:

Again it should also be appreciated that the sodium salt, shown as molecule 10 of above Scheme 2, can be a direct product obtained from molecule 8, in the case of basic hydrolysis, for example with NaOH.

Similarly, for the above described fourth preferred embodiment, where a protected intermediate of formula (Ha) is reacted with methyl- l-(thiomethyl)-cyclopropane acetate of formula (HIe)

the overall reaction scheme can be specifically represented by following Scheme 3. Scheme 3:

Again it should also be appreciated that the sodium salt, shown as molecule 11 of above Scheme 3, can be a direct product obtained from molecule 9, in the case of basic hydrolysis, for example with NaOH.

There is also provided by the present invention an intermediate compound useful in the preparation of montelukast, or a pharmaceutically acceptable salt thereof, said intermediate compound being of formula (X)

where P₁ is a hydroxy protecting group substantially as hereinbefore described; and

T represents -CN, -CO₂H or -CO₂X₅ where X represents a monovalent cation, for example

Na⁺ or Li⁺ substantially as hereinbefore described.

There is also provided use of an intermediate of formula (X) as described above, in the preparation of montelukast, or a pharmaceutically acceptable salt thereof.

There is also provided a process of preparing montelukast, or a pharmaceutically acceptable salt thereof, which process employs an intermediate of formula (X) as described above.

Adamantylamine salts of montelukast of formula (I) substantially as hereinbefore described also represent novel compounds according to the present invention. Specifically, therefore, the present invention provides 1 -adamantylamine salt of montelukast of formula (I).

Similar to prior art montelukast sodium forms, montelukast, or a pharmaceutically acceptable salt thereof, as prepared according to the present invention is generally useful for the preparation of pharmaceutical compositions, where montelukast, or a pharmaceutically acceptable salt thereof, is an active ingredient. Generally, a pharmaceutical composition provided by the present invention includes montelukast, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

A pharmaceutical composition which includes montelukast prepared by a process as described herein generally includes, in addition to the carrier or diluent, such components as antibacterial agents, antioxidant agents, binding agents, buffering agents, bulking agents, coloring agents, diluents, disintegrants, emulsifying agents, excipients, flavoring agents, glidants, lubricants, skin penetration enhancers, sweetening agents, viscosity modifying agents and any combination thereof, which provide the composition with desired characteristics.

Montelukast as prepared by a process as described herein is typically in amorphous form. However, a pharmaceutical composition according to the present invention can include, in addition to montelukast, or a pharmaceutically acceptable salt thereof, as prepared by a process as described herein, an additional form of montelukast sodium, and / or an additional active ingredient other than montelukast.

A pharmaceutical composition of the present invention can be formulated in various forms. These include, without limitations, an aerosol, a bolus, a capsule, a cream, a delayed release capsule, a dispersion, a dissolvable powder, drops, a gel capsule, granules, an injection, an inhalable form, a liposome, an ointment, a patch, a pill, a powder, a suppository, a suspension, a syrup, a tablet, a tincture and a topical cream. Preferably montelukast is administered orally and as such preferred pharmaceutical compositions include solid dosage forms for oral administration such as, but not limited to, tablets (including chewable tablets), capsules, powders and granules.

The pharmaceutical compositions including montelukast as prepared by a process as described herein, or a pharmaceutically acceptable salt thereof, may in turn be manufactured by processes well known in the art, for example by means of conventional mixing, dissolving, granulating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions suitable for use in context of the present invention include compositions where the active ingredients are contained in a therapeutically effective amount so as to achieve a required therapeutic purpose. More specifically, a therapeutically effective amount means an amount of active ingredient effective to cure a condition, treat a condition, prevent a condition, treat symptoms of a condition, cure symptoms of a condition, ameliorate symptoms of a condition, treat effects of a condition, ameliorate effects of a condition, and prevent results of a condition. The pharmaceutical compositions according to the present invention are particularly useful with regard to conditions in which treatment by montelukast sodium is known to be beneficial. Such conditions include, but are not limited to, allergic rhinitis, asthma, and any related conditions.

A pharmaceutical composition of the present invention is useful in implementing a method of treating a medical condition in which administration of a leukotriene antagonist is beneficial. Accordingly, the present invention provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a leukotriene antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of montelukast, or a pharmaceutically acceptable salt thereof, prepared by a process as described herein. Preferably, the administering is effected orally. Further preferably, the pharmaceutical composition is formulated in a solid dosage form.

The present invention also provides use of montelukast, or a pharmaceutically acceptable salt thereof prepared by a process as described herein, in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a leukotriene antagonist. As described above such disease states or conditions include, but are not limited to, allergic rhinitis, asthma, and any related conditions.

The following intermediates and examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.

Intermediates

Intermediate 1 - Preparation of (S-(E^)-2-(3-(2-(7-chloro-quinolinyl)-ethenyl)phenylV3- hvdroxypropyD benzoic acid methyl ester (Compound 2, Scheme 2)

In a IL reactor with mechanical stirring [RuCl₂(mesitylene)]₂ (1.32g, 0.46mol, 2.1eq.) and (lS,2S)-piperidyl-N-sulfonyl-l,2-diphenylethylendiamine (1.68g, 0.46mol, 2.1eq.) were suspended in DMF (60OmL). The mixture was degassed with nitrogen and heated at 80⁰C for 45 minutes. The clear orange-red solution was cooled to 40⁰C and 2-(3-(2-(7-chloro- quinolinyl)-ethenyl)phenyl)-3-oxoproρyl) benzoic acid methyl ester (compound 1, Scheme 2) (10Og, 0.219mol) and a mixture of HCOOH and Et₃N (HOmL, 2:lmol) were added. The reaction mixture was stirred at 4O⁰C for 24 hours, cooled down to room temperature and then partitioned between methylene chloride (1.2L) and water (1.0L). The organic layer was further washed with water (2^χlL) and 10% sodium bicarbonate solution (LOL), dried over magnesium sulfate and concentrated. To the residual oil (129.7g) i-PrOAc (70OmL) and water (15mL) were added under stirring. After 15 minutes n-hexane (10OmL) was slowly added and stirred for an additional 1 hour at room temperature and 1 hour at 0-5⁰C. The precipitated product was filtered off, washed with n-hexane / i-PrOAc (7:3) and dried in vacuum at 40⁰C to give a light beige powder. The title compound (83.9g, 83%, 96 area% by HPLC) was prepared as the monohydrate: > 99.8e.e.

Intermediate 2 - Preparation of 2-(2-(3-(S)-(3-2-(7-chloro-quinolinyl)-ethenyl)phenyl-3- hvdroxyproρyDphenyl-2-propanol (Compound 3, Scheme 2)

In a 25OmL flask with mechanical stirrer and distillation head a suspension of Intermediate 1 (12. Ig, 0.026mol) in toluene (16OmL) was heated to reflux. AU solids were dissolved to afford a clear brown solution. Toluene : water azeotrope mixture (~40mL) was removed by distillation at atmospheric pressure (Ty 85-110⁰C). The clear solution of Intermediate 1 (~120mL) was cooled to room temperature. Step 2:

In a 4-neck 25OmL reactor with a mechanical stirrer and reflux condenser anhydrous CeCl₃ (3.4g, 0.014mol) was suspended in anhydrous THF (6OmL). The grey suspension was degassed with nitrogen and heated at 45°C for 2 hours and the resulting white suspension was cooled to -5 to 0⁰C. A solution of methyl magnesium chloride (3M in THF, 45mL, 0.135mol) was added dropwise over 30 minutes to the CeCl₃ suspension, whilst maintaining the temperature under 0°C. The solution was aged at 0°C for 2 hours. The solution of Intermediate 1 in toluene from step 1 was added dropwise over 2 hours whilst maintaining the temperature at 3 to 5°C. The reaction mixture was aged for 15 minutes after the addition was complete. The reaction was then quenched by cautious addition of the obtained reaction mixture to a mixture of ice water (30OmL), toluene (30OmL) and acetic acid (8OmL) whilst maintaining the temperature under 25 °C. The yellow solution was stirred for 15 minutes and the layers were separated. The organic layer was washed with water and 5% sodium carbonate solution, dried over sodium sulfate and concentrated in vacuum. The title compound was obtained as yellow oil (12.7g, 103%, 94.5 area% by HPLC).

Intermediate 3 - Preparation of 2-(2-(3-(S^')-(3-2-r7-chloro-quinolinvD-ethenyl)phenyl)-3- fdimemyl-f2-methyl-2-propyl)silyloxy)propyDρhenyl-2-propanol (Compound 4, Scheme 2)

A 50OmL flask, with a mechanical stirrer, reflux condenser and nitrogen inlet, was charged with a solution of Intermediate 2 (30.Og, 0.065mol) in toluene (18OmL). Imidazole (13.9g, 0.214mol) was added to the solution and the mixture was heated to 55⁰C. To the resulting solution tert-butyldimethylsilyl chloride (14.9g, 0.099mol) was added. The reaction mixture was heated to 70⁰C. Upon completion of the 5 hours reaction period, the reaction mixture was cooled to room temperature, washed with water, 1% HCl and 5% NaHCO₃, dried over Na₂SO₄ and concentrated under vacuum to ~ 80 mL. The resulting solution was stirred and heated to 55⁰C. N-hexane (12OmL) was added dropwise over a period of 2 hours. The solution was cooled slowly to 20⁰C and at a temperature of about 35°C pure crystalline title compound started to precipitate. The crystallization was aged at 1O⁰C for 3 hours and filtered. Crystalline title compound was dried in a vacuum over 5 hours to yield a pale beige solid (24.6g, 99.4 area%). Intermediate 4 - Preparation of l-Cl-G-CSVCS-l-Cy-chloro-quinolinylVethenvπphenylVS- (dimethyl-(2-metliyl-2-propyl^')silyloxy)propyl)phenyl-2-propoxy)-tetrahvdropyran (Compound 5, Scheme 2)

In a 50OmL flask, with a mechanical stirrer, reflux condenser and nitrogen inlet, crystalline Intermediate 3 (16.Og, 0.028mol) was dissolved in methylene chloride (16OmL). The resulting solution was stirred and 2,4-dihydropyran (25.5mL, 0.280mol) and triphenylphosphonium bromide (0.96g, 0.0028mol) were added and the mixture was heated at 40°C. After approximately 24 hours of reaction time, the reaction mixture was cooled to room temperature. The methylene chloride solution was washed with water and 5% NaHCO₃, dried over Na₂SO₄ and concentrated under vacuum. The title compound was obtained as light brown oil (20.5g, 93.0 area% by HPLC).

Intermediate 5 - Preparation of l-(S)-(3-2-('7-chloro-quinolinyl^')-ethenyl)-phenylV3-f2-(2- ((^"tetrahydropyran-2-yDoxy)-2-propyl)-phenyl-l -propanoic (Compound 6, Scheme 2)

In a 500 niL flask, with a mechanical stirrer, reflux condenser and nitrogen inlet, light brown oil Intermediate 4 (18.0g, 0.027mol) was dissolved in a mixture of tetrahydrofuran (30OmL) and methylene chloride (3OmL). To a stirred solution tetra-n-butylammonium fluoride trihydrate (23.6g, 0.075mol) was added and the mixture was heated at 40°C. After 24 hours of reaction time, the reaction mixture was cooled down to a room temperature. The methylene chloride was added to the reaction mixture and the resulting solution was washed with water, 1% acetic acid and 5% NaHCO₃, dried over Na₂SO₄ and concentrated under vacuum. The title compound was obtained as light brown oil (16.95g, 89.0 area% by HPLC).

Intermediate 6 - Preparation of 2-(2-(2-3-(SV(3-(2-(7-chloro-2-quinolinyl)-ethenyl)ρhenyl)-3- (methanesulfonyloxy)-propyDphenyl-2-propoxy)-tetrahydropyran (Compound 7, Scheme 2)

In a 10OmL flask, with a mechanical stirrer and nitrogen inlet, light brown oil Intermediate 5 (6.3g, 0.012mol) was dissolved in methylene chloride (7OmL). The solution was cooled down to about -15°C and diisopropylethylamine (3.5g, 0.027mol) was added. To a cold stirred solution methanesulfonyl chloride (2.8g, 0.024mol) was added dropwise whilst maintaining the temperature under — 10°C. After 1 hour of reaction time, the reaction mixture was washed with 10% NaHCO₃ and dried over MgSO₄ and concentrated under vacuum. The title compound was obtained as yellow oil (6.7g) and was used for subsequent reaction without further purification.

Intermediate 7 - Preparation of (TD-l-ri-π-ri-ry-cnloro^-quinolinylVethenvD-phenvD-S-rα- (2-(2-tetrahvdropyranyloxy)-2-propylVphenyl)-propyl^')-thio] -cyclopropane acetic acid (Compound 8, Scheme T)

In a 25OmL flask, with a mechanical stirrer and nitrogen inlet, sodium methoxide powder (2.Ig) was dissolved in dry methanol (3OmL). The solution was stirred at room temperature for 15 minutes and l-(thiomethyl)-cyclopropan acetic acid (2.63g, 0.018mol) was added. After 3 hours, an N,N-dimethylformamide solution of Intermediate 6 (6.7g) was added dropwise to the reaction mixture, over a time period of 30 minutes. After 3 hours of reaction time, the reaction mixture was dissolved in a mixture of 10OmL ethyl acetate and 10OmL of a 10% solution of sodium chloride. The organic layer was washed with a 0.5M solution of tartaric acid and water, dried over magnesium sulfate and concentrated in vacuum. The title compound was obtained as a yellow oil (7.6g, 76.2 area%).

Intermediate 8 - Preparation of rR)-l-fl-(3-(2-(7-chloro-2-qumolmyl)-ethenyl)-phenyl)-3-r(2-

(2-(2-tetrahydropyranyloxyV2-propylVphenylVpropylVthio]methvn cyclopropane acetonitrile (Compound 8, Scheme 1)

In a 25OmL flask, with mechanical stirrer and nitrogen inlet, sodium methoxide powder (0.97g, lδ.lmmol, 2.0eq.) was dissolved in dry methanol (25mL). The suspension was stirred at room temperature for 15 minutes and l-(thiomethyl)-cyclopropane acetonitrile (1.46g, 11.5mmol, 1.5eq.) in 25mL DMF was added. After 1 hour, a solution of intermediate 6 (5.6g) in 3OmL DMF was added dropwise to the reaction mixture over 30 minutes. After 5 hours, the reaction mixture was dissolved in a mixture of 5OmL ethyl acetate and 5OmL 10% solution of sodium chloride. The organic layer was washed with 0.5M solution of tartaric acid and water, dried over magnesium sulfate and concentrated in vacuum. The title compound was obtained as light brown oil (5.9g, 79.6 area%). Intermediate 9 - Preparation of (RVl-ri-G-ri-rT-chloro-l-quinolmylVethenylVphenylVS-fQ- fl-hvdroxy-l-methylethylVphenylVpropyD-thioimethyli-cvclopropane acetonitrile

(Compound 9, Scheme 1)

In a 25OmL flask, with mechanical stirrer, reflux condenser and nitrogen inlet, light brown oil of Intermediate 8 (5.9g, 79.6 area%) was dissolved in a mixture of tetrahydrofuran (15mL) and methanol (5OmLj. To a stirred solution, pyridiniurn p-toluensulfonate (0.42g, 0.3eq.) was added and the mixture was heated at 40°C. After 7 hours of reaction time, the reaction mixture was cooled down to room temperature. Ethyl acetate was added and the solution was washed twice with water. The organic layer was separated, dried over Na₂SO₄ and concentrated in vacuum. The title compound was obtained as yellow oil (4.5g, 83.1 area%).

Intermediate 10 - Alternative Preparation of (RVl-|^"l-(3-(2-(7-chloro-2-quinolmyl)-ethenyl^')- phenylV3-(r2-(2-r2-tetrahydropyranyloxy^')-2-propylVphenyl)-propyl)-thiol-cvclopropane acetic acid (Compound 9, Scheme 3)

In a 25OmL flask, with mechanical stirrer and nitrogen inlet, sodium methoxide powder (1.25g, 23.0mmol, 2.5eq.) was dissolved in dry methanol (25mL). The solution was stirred at room temperature for 15 minutes and methyl- l-(thiomethyl)-cyclopropane acetate (2.2g, 13.9mmol, 1.5eq.) was added. After 2 hours, a solution of Intermediate 6 in N₅N- dimethylformamide (3OmL) was added dropwise to the reaction mixture (theor.: 5.7g, 9.2mmol) over a time period of 30 minutes. The mixture was stirred further at about 4O⁰C with monitoring by HPLC. Upon completion of the reaction (approx. 5-7 hours), 10 mL of methanol and 5 mL of 40% sodium hydroxide were added to a reaction mixture containing compound 8 of Scheme 3. The mixture was heated at reflux for about 5 hours. After cooling to room temperature, the reaction mixture was acidified with 10% hydrochloric acid to pH 4.5 and extracted with dichloromethane. The dichloromethane solution was washed with 3 x 10OmL 5% NaCl, dried over sodium sulfate and concentrated in vacuum. The title compound was obtained as a yellow oil (5.4 g, ~70 area%). Example 1 - Preparation of rRVl-fl-O-α-CT-chloro^-αuinolinylVethenylVphenylVS-rα-ri- hydroxy-l-methylethyl)-phenyD-propyl)-thio1 -cyclopropane acetic acid, Montelukast Free Acid (Compound 9, Scheme 2)

In a 100 mL flask, with a mechanical stirrer, reflux condenser and nitrogen inlet, yellow oil Intermediate 7 (7.6g, 76.2 area%) was dissolved in a mixture of tetrahydrofuran (15mL) and methanol (5OmL). The resulting solution was stirred and pyridmium p-toluensulfonate (0.65g, 0.3eq.) was added and the mixture was heated at 40°C. After 5 hours of reaction time, the reaction mixture was cooled down to a room temperature. To the reaction mixture ethyl acetate was added and the solution was washed with 0.5M tartaric acid and water. The organic layer was separated and dried over Na₂SO₄.

To the ethyl acetate solution of montelukast free acid, dicyclohexylamine (DCHA) (2.OmL) was added. The mixture was stirred for half an hour at room temperature and n-hexane was added dropwise. The clear solution of DCHA salt of montelukast acid was cooled down very slowly (1°C/15 min.) from 25°C to 17°C and white solid started to precipitate. The mixture was stirred for one hour at 17⁰C and two hours at 15⁰C. The white solid was then filtered off, washed with n-hexane and dried under vacuum. The white solid of the DCHA salt of montelukast free acid (5.85g) was dissolved in methylene chloride (15OmL) and acidified with 10% acetic acid (15OmL). The organic layer was separated, washed with water, dried over Na₂SO₄ and concentrated in vacuum. The title compound, montelukast free acid, was obtained as a yellow oil (5.7g, 86.1 area%).

Alternatively, the 1-adamantylamine salt of montelukast free acid was prepared for purposes of purifying montelukast. Specifically, montelukast free acid was placed in ethyl acetate (15OmL) and 1-adamantylamine (3.2g, 21.2mmol in 3OmL of ethyl acetate) was added. The mixture was stirred for 30 minutes at room temperature and hexane (20OmL) was added followed by seed crystals (lOmg). The white suspension was stirred over night and filtered, the product was washed with hexane (3OmL) and dried under reduced pressure to give 8.9Og of the 1-adamantylamine salt of montelukast (53.9%, ee>99.5 %).

¹H NMR (MeOH) δ/ppm: 0.36-0.51 (m, 4 H), 1.54 (d, 6 H), 1.67-1.80 (m, 6H), 1.88 (s, 6H),

2.16 (s, 3 H), 2.10-2.20 (m, 2 H)₅ 2.33 (d, 1 H)₅ 2.41 (d, 1 H), 2.48 (d, 1 H), 2.56 (d, 1 H), 2.83-2.86 (m, 1 H), 3.10-3.14 (m, 1 H), 3.95 (dd, 1 H), 7.03-7.13 (m, 3 H), 7.24-7.32 (m, 4 H), 7.36-7.63 (m, 4

H)₅ 7.99 (d, 2 H).

¹³C NMR (MeOH) δ/ppm: 11.89, 12.17, 16.31, 28.69, 31.33, 31.77, 34.75, 38.47, 39.42,

39.74, 40.19, 49.88, 50.55, 73.32, 118.67, 124.92, 125.13, 125.15, 126.61, 126.63, 126.99, 127.02, 128.17, 128.52, 130.98, 135.94, 136.01, 139.66, 143.15, 144.78, 156.42, 175.70.

The above prepared 1-adamantylamine salt of montelukast was then converted to montelukast using procedures as described above for the DCHA salt of montelukast.

Example 2 - Preparation of (RVl-ri-(3-(^'2-(7-chloro-2-quinolinylVethenyl)-phenylV3-fr2-ri- hvdroxy-l-methylethvD-phenvD-propylVthioi-cyclopropaneacetic acid sodium salt, Montelukast Sodium (Compound 10, Scheme 2)

To a stirred solution of the title compound of Example 1, montelukast free acid, (5.7 g), in dry toluene (4OmL), sodium methoxide (0.55g) in methanol was added. The resulting mixture was stirred for 30 minutes and diisopropyl ether (25OmL) was added dropwise over a period of 60 minutes. White solid started to precipitate. The white solid was then filtered off, washed with diisopropyl ether and dried under vacuum. The title compound, montelukast sodium, was obtained as an amorphous white solid (5.2g, 98.2 area%).

Example 3 - Preparation of (R)-l-ri-(^'3-f2-(^'7-chloro-2-quinolinvD-ethenylVphenylV3-(^'r2-Cl- hvdroxy-l-methylethylVphenylVpropylVthio]methyl] cyclopropaneacetic acid. Montelukast Free Acid (Compound 10, Scheme 1)

To a stirred solution of Intermediate 9 (4.Og) in ethanol (4OmL), 40% sodium hydroxide (0.55g) was added. The reaction mixture was heated at reflux. Upon completion of the 25 hours reaction time, the reaction mixture was cooled down to room temperature. To the reaction mixture, toluene (5OmL) and 10 % sodium chloride (5OmL) was added and after 20 minutes of stirring the organic layer was separated. To the toluene solution, water was added and the pH was adjusted to 5-5.5 with acetic acid and the mixture was stirred further for 30 minutes. The toluene layer was washed with water and 10% sodium bicarbonate, dried over Na₂SO₄ and concentrated under vacuum. The title compound was obtained as a yellow oil (3.8g, 65 area%* of title compound). (* according to the applied HPLC method retention time of title compound matching retention time of pure montelukast acid)

Claims

1. A process of preparing montelukast of formula (I)₅ or a pharmaceutically acceptable salt thereof,

(D

which process comprises reacting a protected intermediate of formula (II) with a cyclopropyl intermediate of formula (III)

where:

P₁ represents a hydroxy protecting group;

L represents a leaving group;

X represents a monovalent cation;

Y represents -CN or -CO₂X₅ where X is a monovalent cation as defined above;

and converting the reaction product to the free acid form of montelukast of formula (I), or a pharmaceutically acceptable salt thereof.

2. A process according to claim 1, wherein said reaction product is converted to montelukast sodium.

3. A process according to claim 1 or 2, wherein L is arylsulfonyl.

4. A process according to claim 3, wherein arylsulfonyl as denoted by L is either benzenesulfonyl or toluene sulfonyl.

5. A process according to claim 1 or 2, wherein L is C_1-4 alkylsulfonyl.

6. A process according to claim 5, wherein C_1-4 alkylsulfonyl as denoted by L is methanesulphonyl.

7. A process according to any of claims 1 to 6, wherein said monovalent cation as denoted by X is either Na⁺ or Li⁺.

8. A process according to claim 7, wherein X is Na⁺.

9. A process of preparing montelukast of formula (T), or a pharmaceutically acceptable salt thereof,

(I)

which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (Ilia)

wherein Ms represents methanesulphonyl; and P₁ is a hydroxy protecting group;

10. A process of preparing montelukast of formula (I), or a pharmaceutically acceptable salt thereof,

(D

which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (HIb)

wherein Ms represents methanesulphonyl; and P₁ is a hydroxy protecting group;

11. A process of preparing montelukast of formula (I), or a pharmaceutically acceptable salt thereof,

(I)

which process comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (IHc)

wherein Ms represents methanesulphonyl; and P₁ is a hydroxy protecting group;

12. A process according to any of claims 1 to 11, wherein said cyclopropyl intermediate of formula (III) is added to a reaction medium as a precursor compound of formula (IV)

(IV)

where Y' represents -CN or -CO₂H and wherein the reaction medium also includes a source of the monovalent cation X.

13. A process according to claim 12, wherein said source of the monovalent cation is an alkali metal alkoxide.

14. A process according to claim 13, wherein said alkali metal alkoxide is either sodium or lithium C_1-4 alkoxide.

15. A process according to any of claims 1 to 14, wherein conversion of said reaction product to the free acid form of montelukast of formula (I), or a pharmaceutically acceptable salt thereof, comprises deprotection and where required conversion of moiety Y as present in the reaction product to the free acid.

16. A process of preparing montelukast of formula (I), or a pharmaceutically acceptable salt thereof,

(I)

which process comprises the following reaction steps

P₁ represents a hydroxy protecting group;

L represents a leaving group;

R represents C_1-4 alkyl; and converting a compound of formula (XII) to the free acid form of montelukast of formula

(I), or a pharmaceutically acceptable salt thereof.

17. A process of preparing montelukast of formula (I), or a pharmaceutically acceptable salt thereof,

(I)

which process comprises the following reaction steps

wherein Ms represents methanesulphonyl; and P₁ is a hydroxy protecting group; and converting a compound of formula (XII) to the free acid form of montelukast of formula (I)₅ or a pharmaceutically acceptable salt thereof.

18. A process according to any of claims 1 to 17, wherein P₁ represents tetrahydropyranyl.

19. A process according to any of claims 1 to 18, wherein said free acid of montelukast of formula (I) is initially converted to an intermediate amine salt prior to conversion to a pharmaceutically acceptable salt.

20. A process according to any of claims 1 to 19, wherein a compound of formula (II) or (Ha) is prepared from a corresponding hydroxy compound of formula (V)

by reacting said compound of formula (V) with a C_1-4 alkyl or aryl sulfonyl halide.

21. A process according to claim 20, wherein a compound of formula (V) is prepared by selective deprotection of a protected derivative of formula (VI)

where P₁ is a hydroxy protecting; and

P₂ is a second hydroxy protecting group, which is different from P₁; wherein P₁ and P₂ are respectively such that P₂ can be selectively removed in preference to P₁ so as to yield a compound of formula (V).

22. A process according to claim 21, wherein P₁ represents a heterocycle and P₂ represents a silyl group.

23. A process according to claim 22, wherein P₁ is tetrahydropyranyl and P₂ is tert- butyldimethylsilyl.

24. A process according to any of claims 21 to 23, wherein a compound of formula (VI) is prepared by the stepwise protection of a corresponding di-hydroxy compound of formula (VII)

25. A process according to claim 24, wherein P₂ is first introduced as a protecting group for the secondary hydroxy group substituted on the propylene chain and P₁ is subsequently introduced as a protecting group for the tertiary hydroxy group substituted on the phenyl ring, so as to provide protected intermediate of formula (VI).

26. A process according to claim 24 or 25, wherein a compound of formula (VII) is prepared from a corresponding hydroxy ester of formula (VIII)

wherein R₁ is C_1-4 alkyl.

27. A process according to claim 26, wherein a compound of formula (VIII) is prepared from a compound of formula (IX)

by asymmetric transfer hydrogenation employing a chiral ruthenium or rhodium catalyst, in the presence of a hydrogen source.

8.

wherein conversion of intermediate 7 to intermediate 8 is by way of reaction of intermediate 7 with the following compound

29.

30.

31. An intermediate compound useful in the preparation of montelukast, or a pharmaceutically acceptable salt thereof, said intermediate compound being of formula (X)

where P₁ is a hydroxy protecting group; and

T represents -CN, -CO₂H or -CO₂X, where X represents a monovalent cation.

32. Use of an intermediate compound of formula (X)

where P₁ is a hydroxy protecting group; and

T represents -CN, -CO₂H or -CO₂X, where X represents a monovalent cation, in the preparation of montelukast, or a pharmaceutically acceptable salt thereof.

33. A process of preparing montelukast, or a pharmaceutically acceptable salt thereof, which process employs an intermediate of formula (X)

where P₁ is a hydroxy protecting group; and

T represents -CN, -CO₂H or -CO₂X, where X represents a monovalent cation.

34. A compound, use or process as respectively defined in claims 31, 32 or 33, wherein said monovalent cation as denoted by X is Na⁺ or Li⁺.

35. A compound, use or process as defined in claim 34, wherein said monovalent cation is

Na⁺.

36. Adamantylamine salts of montelukast of formula (I)

(I)

37. 1 -adamantylamine salt of montelukast of formula (I)

(I)

38. A process of preparing a pharmaceutically acceptable salt of montelukast of formula (I)

(I)

which process comprises treating the 1-adamantylamine salt of montelukast of formula (I) with an acid, treating the product thus obtained with a source of the pharmaceutically acceptable salt forming species, and crystallizing the resulting pharmaceutically acceptable salt of montelukast of formula (I).

39. A process of preparing montelukast sodium, which process comprises treating the 1- adamantylamine salt of montelukast of formula (I)

(I)

with an acid, treating the product thus obtained with a source of sodium ions, and crystallizing the resulting montelukast sodium.