Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals

Definitions

• the present invention belongs to the field of organic chemistry. More particularly, the present invention desc ibes an improved process for the preparation of montelukast acid and its pharmaceutically acceptable salts and esters. The process is cost effective, environmentally friendly, and easily scaled up to commercial level.
• the present invention provides a novel crystalline form of an intermediate that is useful in the process for the preparation of montelukast acid and its pharmaceutically acceptable salts and esters therof.
• the crystalline intermediate is preferably (R,E)-1 -(2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3- mercaptopropyl)phenyl)ethanone in crystalline form.
• Montelukast sodium has the chemical name sodium (R,E)-2-(1 -(((1 -(3-(2-(7- chloroquinoSin-2-yi)vinyl)phenyl)-3-(2-(2-hydroxypropan-2- yl)phenyl)propyl)thio)methyl)cyclopropyl)acetate, and it is represented by the formula:
• Montelukast sodium is marketed in the form of film coated tablets, chewing tablets and granules under the trade name SINGULAIR ® .
• EP 480 717 A1 The preparation process of EP 480 717 is as disclosed in the following Scheme :
• prior art processes lead to the formation of undesirable amounts of byproducts, and the desired monteiukast species cannot be obtained in the desired chemical and optical purity in large scale.
• prior-art applications mainly disclose purification of monteiukast acid by formation of amine salts. This is an additional step in production process of pure monteiukast acid or its salts that may lead to problems because of carrying over of amine impurities. Therefore, a process of purification via monteiukast acid with good yield and good efficiency would be advantageous.
• the present invention discloses an efficient preparation of monteiukast acid or its salts having high chemical and optical purity. Furthermore, the present invention provides a novel crystalline intermediate that is useful in this preparation and that leads to higher chemical and optical purity of the desired monteiukast species. Summary of the invention inventors of the present invention have developed an efficient industrial process for the preparation of pure monteiukast acid or its pharmaceutically acceptable salts and esters having high chemical and optica! purity, wherein monteiukast acid is efficiently purified by emulsion crystallization or by supercritical fluid chromatography or by silica gel chromatography or by ion exchange chromatography.
• One aspect of the present invention is thus an efficient process for the production of monteiukast acid and its pharmaceutically acceptable salts and esters, particularly sodium salt, comprising the steps of:
• An additional aspect of the present invention is to provide an efficient process for the purification of monteiukast acid that could be performed in one or more of the following ways:
• Another aspect of the present invention is the purification of monte!ukast acid by emulsion crystallization comprising the following steps:
• Another aspect of the present invention provides a compound of formula (IV) in crystalline form.
• R-j represents a C-j -Cg aikyl group, and preferably -CH3.
• the compound is preferably (R,E)-methyl 2-(3-(acetylthio)-3-(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)propyl)benzoate.
• the crystalline compound preferably has a chemical purity greater than 90%, more preferably greater than 95%, most preferably greater than 99% and an optical purity of preferably greater than 95%, more preferably greater than 99%, and most preferably greater than 99.9%.
• Still another aspect of the present invention is the process for preparing the crystalline compound of formula (IV) comprising the steps of:
• Another aspect of the present invention is the usage of lanthanide metal catalyst and minimizing the amount of water, especially in the reaction mixture, in order to minimize the amount of formed impurity in the preparation of a compound of formula (V) produced from a compound of formula (IV) (step (i)).
• the impurity in the compound with chemical name (R T E)-2-(2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3- mercaptopropyl)phenyl)propan-2-ol has the chemical name (R,E)-1 -(2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyt)-3- mercaptopropyl)phenyi)ethanone.
• the use of the lanthanide metal catalyst and preferably minimizing the amount of water in the reaction mixture allows limiting the amount of the above impurity to preferably less than 1 %, more preferably less than 0.
• the present invention provides a method for the preparation of monteiukast acid and pharmaceutically acceptable salts or esters thereof, which comprises the following step (i):
• organometailic reagent and in the presence of a lanthanide metal catalyst:
• represents a C-j -Cg alkyl group, and preferably -CH3, and wherein the reaction is conducted in such a manner that the amount of water in the reaction mixture is less than 0.05 w/w% before and/or at the time when the compound of formula (!V) is reacted with the organometaliic agent to form the compound of formula (V).
• a further aspect of the present invention is a method for the preparation of montelukast acid and pharmaceutically acceptable salts or esters thereof, which comprises the following step (ii):
• i3 ⁇ 4 is hydrogen, a C-j -Cs alkyl group or a substituted or
• the process of the present invention comprises the above step (i), and it may or may not comprise the above step (ii). in other words, the process comprises the step (i) and optionally the step (ii). in a preferred embodiment, the process of the present invention comprises both the step (i) and the step (ii).
• Still another aspect of the present invention is the pharmaceutical composition comprising montelukast acid or its pharmaceutically acceptable salts or esters prepared by the processes of the present invention.
• Figure 1 Two microscope pictures of montelukast acid crystals purified by the method disclosed in example 2.
• Figure 2 Particle size distribution of montelukast acid crystals purified by the method disclosed in example 2.
• Figure 3 XRPD pattern of (R,E)-methyl 2-(3-(acetyithio)-3-(3-(2-(7-chloroquinoiin- 2-yl)vinyl)phenyl)propy!benzoate prepared in Example 1 .
• the key step in an improved process for the preparation of montelukast acid and its pharmaceutically acceptable salts and esters according to the present invention is the hydrolysis of montelukast ester, optionally without isolation of intermediate products, and further purification of montelukast acid.
• the present invention thus enables to obtain montelukast acid with high chemical and optical purity in a cost effective, environmentally friendly, and easily scale up manner.
• a preferred variant of the process of the invention is schematically depicted in Scheme 1 , wherein L and U represent a leaving group, selected form the group consisting of chlorine, bromine or iodine, a Ct-C 8 a!kyl sulfonyloxy group or a substituted C5-C 1 0 aryl sulfonyloxy group; and
• R represents a CrC s alky! group or a substituted C 5 -C 10 aryl group.
• the step of converting a compound of formula (IV) to a compound of formula (V) is a preferred embodiment of the step (i).
• a process according to the scheme 1 above involves the step (i), and it may or may not involve also the step (ii).
• step (ii) serves to separate reaction by-products (impurities), which have a ketone function at the carbon atom carrying the tertiary hydroxy! group in montelukast acid, from the compound of formula (VI) or formula (VII).
• step (ii) may be performed before the compound of formula (VI) is converted to a compound of formula (VII), or before the compound of formula (Vf l) is converted to montelukast sodium of formula (!).
• the present invention provides an efficient process for the production of montelukast acid and its pharmaceutically acceptable salts and esters, particularly sodium salt, comprising the steps of: a) Synthesis of (R.E)-methyl 2-(3-(acetylthio)-3-(3-(2-(7-chloroquinolin-2- yl)vinyl)phenyl)propyl)benzoate
• the obtained crude compound of formula (VI) is optionally further purified by column chromatography, or by extractions or by filtration through silica. c) Hydrolysis of monteiukast ester to monteiukast acid
• monteiukast ester compound of formula (VI)
• monteiukast acid compound of formula VII
• the preferred bases to provide monteiukast acid of high quality and with lower costs are alkaline hydroxides, such as for example sodium hydroxide.
• d) Purification of monteiukast acid The obtained crude montelukast acid can be directly used in the next step of the synthesis or is supplementary purified:
• montelukast acid is transformed into its pharmaceutically acceptable salts and esters.
• montelukast is transformed into its sodium salt, particularly preferably with ethanolic sodium hydroxide.
• Precipitation of Montelukast sodium from n-heptane and toluene gives active substance as amorphous Montelukast sodium.
• the product is finally dried to obtain the final product.
• One aspect of the present invention is a process for preparing a compound of formuia (IV) by reaction of compound of formula (!!) to form a compound of formula (IIS), and subsequent reaction of the compound of formu!a (III) to form a compound of formula (IV).
• represents a C-j -Ce aikyl group, and preferably -CH3, and L is defined as in scheme 1.
• the (R,E)-methyl 2-(3- (acetylthio)-3-(3-(2-(7-chloroquinolin-2-yl)vinyi)phenyl)propyl)benzoate (a specific example of a compound of formula IV, wherein R-
• Activating group may be selected from, but not limited to, chlorine, bromine, iodine or a C 1 -C3 aikyl sulfonyloxy group or a substituted C 6 -Ci 0 aryl sulfonyloxy group, preferably methylsulfonyloxy group is used. Unsubstituted C 6 -Ci 0 aryl sulfonyloxy groups may also be used. The reaction can be performed with an aikyl or aryl sulfony!
• halide selected from the group consisting of but not limited to, methyl, ethyl, n-butyi, besyl, o-nosyl, p-nosyl or 0, p-nosyl sulfonyl halide in an inert solvent in the presence of a base such as for example any organic tertiary non-nucSeophiiic base such as for example tnethylamine, N-ethylditsopropyiamine, or similar bases.
• the suitable inert solvent may be selected from dichloromethane, tetrahydrofurane, 2- methyltetrahydrofurane, ⁇ , ⁇ -dimethylformamide and toluene or mixture thereof.
• the reaction may be performed in the presence of a catalyst such as for example 4-dimethylaminopyridine.
• a catalyst such as for example 4-dimethylaminopyridine.
• the reaction temperature is typically below the boiling temperature of the solvent used, preferably between about -78°C to boiling temperature of the solvent, more preferably between about -20°C to about 0°C.
• methanesulfonyi chloride in toluene is used.
• the reaction can be performed with a halogen acid or an inorganic acid haiide selected from the group consisting of but not limited to HCI, HBr, Hi, SOCS 2 , PCI 3l POCI 3 , PBr 3 in a suitable solvent.
• suitable solvents may be selected from dichloromethane, tetrahydrofurane, 2-methyltetrahydrofurane. toluene and N.N-dimethyiformamide.
• the reaction temperature is typically below the boiling temperature of the solvent used, preferably between about ⁇ 78°C to boiling temperature of the solvent, more preferably between about -1 Q°C to about 35°C.
• Intermediate activated alcohol of formula (l!S) is further transformed to compound of formula (IV) by nucleophilic substitution with potassium thioacetate in a suitable solvent.
• the solvent can be selected from the group of solvents, consisting of, but not limited to, benzene, toluene, tetrahydrofurane, 2-methyltetrahydrofurane, dioxane, acetonitri!e, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide or any combination of two abovementioned solvents.
• a 1 : 1 mixture of tetrahydrofurane and toluene or 2-methyltetrahydrofurane is used.
• the compound of formula (IV) used in the above step (a) is preferably a compound of formula (IV) prepared by the above process of preparing a compound of formuia (IV) from a compound of formuia (ii) via the intermediate of formuia (ill). Accordingly, in a preferred aspect of the present invention, the process of preparing a compound of formula (IV) from a compound of formuia ( ⁇ ) via the intermediate of formuia (111) is a process for preparing a crystalline form of compound (IV) which further includes the above steps (a) to (d).
• a crude compound of formuia (IV) is dissolved at elevated temperature in organic solvent or any mixture thereof.
• at least one organic solvent is selected from the group consisting of ketones, esters, alcohols and halogenated solvents, preferably C3-C5 ketones, esters of C1 -C3 alcohols with C1 -C3 acids, C1 -C3 alcohols, and halogenated solvents with one or two carbon atoms. More preferably, methanol is used.
• the temperature can be between about 30°C and about reflux temperature of the solvent, preferably between about 40 and about 50°C.
• the obtained solution is cooled to temperature between about 35°C to about 40°C, preferably 37 to 39°C and optionally seeded with crystals of compound of formula (IV) obtained in previous run (or batch).
• the crystallization mixture is further cooled to temperature about 20°C to about 30°C, preferably 20 to 25°C and seeded for a period of time, such as for example during night, and further cooled to temperature about -20°C to about 0°C, preferably -15°C to -5°C. isolating step can be performed in any known manner.
• the obtained compound of formula (IV) in crystalline form has high chemical as well as optical purity, which is contrary to the teaching of prior art (such as for example disclosed in WO 2007/057227 or WO 2007/057228) that discloses the compound of formula IV as an oil that has to be transformed into various salts in view of subsequent purification step.
• the compound of formula (iV) in crystalline form preferably has a chemical purity greater than 90%, more preferably greater than 95%, even more preferably greater than 99%.
• the abovementioned compound is provided with optica! purity of preferably greater than 95%, preferably greater than 99% and more preferably greater than 99.9%.
• the crystalline compound of formula (!V) has characteristic X-ray powder diffraction peaks, designated by 2 ⁇ and expressed in degrees, at 7.3 ⁇ 0.2°; 8.5 ⁇ 0.2°, 1 1 .3 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.3 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.8 ⁇ 0.2°, 22.1 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.7 ⁇ 0.2°.
• R- is preferably -CH3.
• a compound of formula (IV) is then converted to compound of formula (V).
• the compound of formula (V) has the chemical name (R,E)-2-(2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-mercapto- propy()phenyl)propan-2-oI.
• the conversion to the compound of formula (V) can be accomplished by reaction with an organometallic reagent, usually in the presence of a lanthanide metal cataiyst in an inert solvent.
• this step of converting the compound of formula (IV) to the compound of formula (V) is the above step (i).
• 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 -40°C to about 25°C. Other preferred ranges of the reaction temperature are between about -30°C and about 10°C, and between about -20°C and about 0°C. Residual water in the reaction leads to the formation of undestred by-products.
• all processing equipment for this reaction step is preferably thoroughly dried, more preferably to less than 0.02 w/w% of water, prior to the conversion of compound (IV) to compound (V).
• This can for instance be accomplished by heating the inert solvent to its boiling point and refluxing for a period of time before commencing the reaction. This period of time is preferably several hours, e.g. up to 5 hours (e.g. 1 - 5 hours), up to 3 hours (e.g. 1 -3 hours), or up to 2 hours (e.g. 0.5 - 2 hours).
• the sequence is repeated until the level of water in the solvent, after passing through the equipment by refluxing, is less than 0.02 w/w%, starting from an anhydrous solvent.
• This maximum amount of water in the solvent after refluxing is indicative that the desired dryness of the processing equipment has been reached. That the required dryness of the processing equipment has been reached can be tested by refluxing the dry solvent for 1 hour and measuring the amount of water, which has then to be less than 0.02 w/w%.
• this level of dryness of the processing equipment can be achieved by heating the processing equipment, e.g. to 150 a C, and purging with dry inert gas, such as nitrogen or argon. After drying the equipment, the reactor is charged with compound of formula (IV) and inert solvent.
• dry inert gas such as nitrogen or argon
• the compound of formula (IV) is additionally azeotropicaliy dried by distillation of some amount of inert solvent to iess than 0.05 w/w% of water, preferably less than 0.02 w/w% of water, most preferably to less than 0.01 w/w% of water, before the organometaiiic reagent and the lanthanum meta! catalyst are added.
• the organometaiiic reagent can be selected from the group consisting of, but not limited to, methylmagnesium chloride, methylmagnesium bromide, methyl- magnesium iodide or methyllithium. Methylmagnesium iodide and methylmagnesium bromide is preferably used.
• the organometaiiic reagent is preferably added in amounts of 2 to 10 mole equivalents relative to the compound of formula (IV), more preferably 5 to 8 mole equivalents.
• a lanthanide metal catalyst is used.
• the lanthanide metal catalyst is selected form the group of lanthanide (111) halogenides.
• lanthanide (!il) halogenides can be selected from anhydrous lanthanum (III) chloride or cerium (III) chloride.
• the lanthanide metal catalyst is preferably added in amounts of 0.1 to 1.5 mole equivalents relative to the compound of formula (IV), most preferably 0.4 to 0.8 mole equivalents.
• the lanthanide metal catalyst can be added to the solution of the compound of formula (IV) before the organometailic reagent is added.
• the lanthanide metal catalyst is added to the solution of compound (IV) up to 12 hours, more preferably up 4 hours, most preferably 1 - 4 hours, before commencing the reaction by the addition of the organometailic reagent.
• the inert solvent 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-methy!tetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether and toluene, preferably 2-methyitetrahydrofurane and toluene.
• the temperature of the reaction is preferably between about -40°C to about 25°C.
• Other preferred ranges of the reaction temperature are the range between about - 30°C to about 10°C, and the range between about -20 to about 0°C as well as the ranges defined by combinations of limiting values indicated above with respect to different ranges, such as the ranges between about -40°C and about 10°C, between about -30°C and about 0°C, and also ranges like between about -30°C and about -20°C.
• the amount of formed ketone impurity/by-product in the reaction product of formula (V) can be reduced to preferably iess than 1%, more preferably less than 0.5%, most preferably less than 0.3%.
• the ketone impurity which is reduced to these amounts has the chemical name (R,E)-1 -(2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyi)-3- mercaptopropyl)phenyi)ethanone.
• nucleophiiic substitution of the compound of formula (V) is performed by reaction the compound of formula (V) with compound of formula (XI) in scheme 1 in the presence of a base and in a solvent to obtain the compound of formula (VI) - montelukast ester.
• the reaction from the compound of formula (!V) to the compound of formula (V! can be performed without isolation of compound of formula (V).
• the nucleophiiic substitution of the compound of formula (V) is carried out without the presence of a base.
• the surplus of Grignard reagent is quenched with the addition of ketone, preferably acetone.
• the base can be selected from the group consisting of, but not limited to, an alkali hydroxide, an alkaline earth hydroxide, alkali carbonate, alkali aikoxide, alkali hydride, alkyl lithium or lithium hexamethyldisilazide, preferably sodium methoxide is used.
• the solvent can be selected from the group consisting of, but not limited to, benzene, toluene, tetrahydrofuran, dioxane, acetonitri!e, N,N-dimethylformamide, ⁇ , ⁇ -dimethyiacetamide, ethanol, methanol, propanol, 2-methyltetrahydrofuran, diethoxymethane, N-methylpyrrolidinone or mixture thereof.
• benzene toluene
• tetrahydrofuran dioxane
• acetonitri!e
• the hydrolysis of compound of formula (Vi) into montelukast acid is performed in the presence of base in a suitable solvent.
• the base can be selected from the group consisting of, but not limited to, an alkali hydroxide, an alkaline earth hydroxide, alkaline carbonate or alkaline alkoxide, preferably sodium hydroxide in water is used.
• the solvent can be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, acetonitriie, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone or any mixture of abovementioned solvents.
• tetrahydrofurane and methanol mixture is used.
• the temperature of the reaction is preferably between about 0 to about reflux temperature, more preferably between ambient temperature to about 60°C.
• the compound of formula (VI) or the compound of formula (VII) may contain ketone impurities.
• the compound of formula (VIII) is represented by the following formula (Villa) and (IX), wherein R2 is H or -CH3, respectively.
• step (ii) will be described for these two formulae. However, the skilled person understands that these descriptions of preferred embodiments for formulae (Villa) and (IX) are applicable to all embodiments of formula (Vill) above.
• Ketone impurity of formuia (Vllia) or of formula (IX) reacts with hydrazine derivatives to form hydrazone derivatives.
• These hydrazone derivatives significantly differ from the starting carbonyl compound(s) and can be efficientiy removed by precipitation from a dilute solution or by separation by aqueous workup.
• Ketone impurity of formula (Vllia) or of formula (IX) may react with 2,4- dinitrophenylhydrazine to form 2,4-dinitrophenylhydrazone of ketone impurity of formula (VII I) or of formula (IX) which precipitate from reaction mixture.
• Ketone impurity of formula (Vil la) or of formula (iX) may react with semicarbazide to form semicarbazone of ketone impurity of formuia (VIII) or of formula (IX).
• Another scheme of separation involves conversion of ketone impurity of formula (Villa) or of formula (IX) into water soluble derivative with the use of Girard's trimethyiaminoacetohydrazide chioride.
• Ketone impurity of formula (Vl!ia) or of formula (IX) react with p- toluensulfonylhydrazide or solid supported p-toiuensulfonylhydrazide to form p- toluensulfonyi hidrazides.
• Typical reaction procedure involves stirring of compound of formula (VI) or compound of formuia (VII) with ketone impurity of formula (VIII) (preferably of formula (Vil la) or of formuia (IX)) in suitable solvent with hydrazine in the presence of an acid.
• ketone impurity of formula (VIII) preferably of formula (Vil la) or of formuia (IX)
• the stirring is performed for at least 24 hrs.
• the solvent can be selected from the group consisting of, but not limited to, tetrahydrofuran, dioxane, acetonitrile, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone or any mixture of abovementioned solvents.
• N N tetrahydrofuran, dioxane, acetonitrile, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone or any mixture of abovementioned solvents.
• N , N-dimethylformamide is used.
• the acid can be selected from the group consisting of, but not limited to, acetic acid, hydrochloric acid, sulfuric acid, sodium acetate and phosphoric acid.
• acetic acid is used.
• the hydrazine derivative can be selected from 2,4-dinitrophenythydrazine, semicarbazide, trimethylaminoacetohydrazide chloride, p-toluensulfonyihydrazide or solid supported p-toluensulfony!hydrazide.
• the montelukast free acid prepared according to the process of the present invention i.e the process comprising the step (i) and optionally step (ii), can be directly used in the next step of the synthesis or can be supplementary purified.
• the montelukast free acid prepared according by the method of the present invention is purified by one or more of the following methods:
• the purification of montelukast acid is performed at least by emulsion crystallization (a) and comprises the following steps:
• the purification of montelukast acid is performed at least by (c) silicagel chromatography and comprises the following steps:
• the process of the present application comprising the step (i) and optionally the step (ii) described above preferably comprises one or more of the purification methods (a) to (d) above, and more preferably it comprises one of the methods (a) and (c). Further preferably, the process comprises a purification by emulsion crystallization comprising the above steps (a-i) to (a-v) or a purification by silicagel chromatography comprising the steps (c-i) to (c-iii).
• the emulsion crystallization can be performed in one or more repeated crystallization cycles.
• Starting montelukast acid can be prepared by the process according to the present invention or by any process known from the prior art.
• an emulsion of montelukast acid refers to two phase system, comprising a droplet phase and a continuous phase and optionally any other known emulsion phase like micellar structures, W/O/W type emulsion and similar, and being characterized by Free Gibbs energy of droplet formation ( ⁇ ) more than 0.
• Montelukast acid can be dissolved in the droplet or in the continuous phase, depending on which basic type of emulsion is present (W/O or Q/W). However, the montelukast acid is completely dissolved and there are no montelukast acid particles present at this point.
• the droplet phase comprises droplets with an average size between around 0.05 to around 100 ⁇ .
• the droplet phase is composed of an organic solvent which is water insoluble and capable of forming an emulsion with water.
• organic solvent aromatic hydrocarbons such as toluene, benzene, halogenated benzene and similar, higher ketones ⁇ C 4 -C 8 ) such as diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone and similar, esters such C 3 -C 8 esters and similar, higher alcohols (C 4 -C 10 ) such as butanol, hexanol, decanol, tert- butanol and similar and any mixtures thereof can be used.
• the continuous phase is composed of water, which acts as the anti-solvent phase.
• the continuous phase is composed of an organic solvent which is water insoluble and capable of forming an emulsion with water.
• organic solvent aromatic hydrocarbons such as toluene, benzene, halogenated benzene and similar, higher ketones (C 4 -C 8 ) such as diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone and similar, esters such C3- C 8 esters and similar, higher alcohols (C -Ci 0 ) such as butanol, hexanol, decanol, tert-butanoi and similar and any mixtures thereof can be used.
• the droplet phase is composed of water, which acts as the anti-solvent phase.
• organic solvent volume ratio (vol/vol) of organic solvent and water phase can be between 0.18 - 20, preferably 0.5 : 10, most preferably 0.7 - 2.0.
• the emulsion of montelukast acid according to the present invention can comprise one or more additives such as surfactants and dispersants.
• the additives can be cationic, anionic and non-ionic by their nature, preferably sodium dioctyl suifosuccinate can be used, also the sodium benzoate as a co-surfactant can be added; the use of a combination of these two substances is particularly preferred.
• the main purpose of added additives is to stabilize emulsion and to increase selectivity during the emulsion crystallization process towards highly pure montelukast acid.
• the additives can be present in an emulsion as a mass fraction (w/w%) of 0.01 - 40 %, preferably 0.05 - 10 %, most preferably 0.5- 4%.
• the emulsion of moloisukast acid according to the present invention is prepared by combining the crude montelukast acid prepared by the process defined above with an organic solvent, such as for example aromatic hydrocarbons such as toluene, benzene, halogenated benzene and similar, higher ketones (C 4 -C 8 ) such as diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone and similar, esters such C 3 -C 8 and similar, higher alcohols (C4-C10) such as butanoi, hexanoi, decanol, tert-butanol and similar and any mixtures thereof, preferably an acetate ester solvent can be used, most preferably e
• suspo-emulsion of montelukast acid refers to a three phase system that is composed of the emulsion according to the present invention and solid particles of montelukast acid dispersed in said emulsion.
• the suspo-emulsion of montelukast acid according to the present invention is prepared by seeding the prepared emuision of montelukast acid with seed crystals of pure montelukast acid (secondary nucleation process) and/or by particles, which are formed during the primary nucleation process of montelukast acid from the supersaturated emulsion of montelukast acid.
• the temperature of forming the suspo-emulsion can be between 5 and 70 °C be!ow the temperature, at which all montelukast acid is dissolved in the emulsion of montelukast acid.
• Seed crystals of pure monteiukast acid can be prepared by any known process disclosed in the prior art, such as for example from CN 1420113, CN 1428335, WO03066598, WO 2005/040123, WO2005073194, WO 2005/074935, !n addition to seeding or primary nucleation any other method of "forced" nuc!eation can be used, such as for example ultrasound and similar methods, to efficiently obtain suspo-emulsion from the supersaturated emulsion of montelukast acid.
• the obtained product, montelukast acid is isolated by any suitable known method from the art and washed with water.
• the purification of montelukast acid by emulsion crystallization provides particles of montelukast acid with an average size of the particles above ⁇ , preferably above 100 ⁇ , most preferably above 200 ⁇ . Moreover, the montelukast acid is obtained with high yield (>80%, preferably >85%, most preferably >90%), with a high purity (HPLC purity >98%, preferably >99%, most preferably >99.5%).
• the particle size was determined by laser light diffraction method using a Malvern Mastersizer MS 2000 with vegetable oil as the dispersion medium.
• crude montelukast acid refers to montelukast acid with mass fraction of montelukast acid (w/w% assay) at least 30%, preferably >50%, most preferably >70 % w/w assay, which can be determined by any appropriate anaiyticai method like for example HPLC, NMR, LC-MS, IR according to commonly used procedures.
• the obtained particles of montelukast acid possess excellent filterabiiity properties and are substantially free of agglomerates that are advantageous for large-scale manufacturing process.
• Montelukast acid particles obtained according to the present invention have excellent properties of bulk material like low triboelectric chargeability, low bulk volume, low hygroscopicity and improved stability that are all properties advantageous for storing monteiukast acid as an intermediate in the preparation of pharmaceutically acceptable salts or esters thereof or when montelukast acid is directly used in the preparation of the pharmaceutical composition.
• the purification of monteiukast acid by silicagel chromatography comprises the foilowing steps:
• silicagel stationary phases For the purification of the montelukast acid by chromatography different silicagel stationary phases can be used with particles between 5-300 pm, preferably 10- 150 pm and most preferably 10-63 pm.
• the monte!ukast acid prepared and isolated according to the process by the present invention can be used in the pharmaceuticai composition as the active substance together with other pharmaceutically acceptabie excipients or it can be further converted without isolation into any known pharmaceutical acceptabie salt as for example disclosed in EP 480717 B1 , WO 0006585, WO 2006008751 , WO 2006043846, WO 2006064269, WO 2007096875, WO 2007107297.
• 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 B1 , WO 03066598, WO 2004091618, WO 2004108679, WO 2005075427, WO 2005074893, WO 2007005965, WO 2007012075, WO 2007059325, WO 20071 16240.
• the sodium salt of montelukast is prepared from montelukast acid prepared by the process of the present invention by reacting the pure monteiukast acid in a polar protic solvent with a source of sodium ion followed by evaporation of the solvent and triturating of the residue with non-poiar solvent to obtain the sodium salt of monteiukast.
• 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.
• to!uene 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, cyclopenty! methyl ether, diisopropyi ether.
• n-heptane is used.
• the compound methyl 2-(1 - ⁇ bromomethyl)cyclopropyi)acetate used in the step of synthesis of montelukast methyl ester can be prepared by any method known from the prior art, preferably by the method as presented in Scheme 2.
• R is as defined above in scheme 1 .
• reaction mixture is cooled to -10 0°C and 3 M solution of methylmagnesium iodide in diethyl ether (204 mL, 0.612 mol) is added dropwise during 1 -2 hr while maintaining the temperature below -10°C. Temperature is gradually raised to 10 to 25°C and maintained for several hours. Reaction is poured into cold sat. NH 4 Ci (600 mL), and randalite (100 g) is added. Suspension is filtered off, layers separated and aqueous layer extracted with toluene. Combined organic layers are washed with saturated NaHC0 3 (400 mL), and solvent evaporated (temperature beiow 40°C).
• 3 M solution of methylmagnesium iodide in diethyl ether 204 mL, 0.612 mol
• Temperature is gradually raised to 10 to 25°C and maintained for several hours.
• Reaction is poured into cold sat. NH 4 Ci (600 mL), and ran
• Residue is dissolved in dimethylformamide (400 mL), cooled to -10°C, and solution of NaOMe (5.97 g, 0.1 10 mol) in methanol (50 mL) is added dropwise during 1 hr, than solution of methyl 2-[1 -(bromomethyl)cyclopropyl]acetate (26.4 g, 0.127 mol) in dimethylformamide (50 mL), and mixture stirred at room temperature for 5 to 24 hrs. Reaction is poured into saturated NaCI (500 mL), and extracted twice with ethyl acetate (400 mL).
• Reactor is charged with toluene (20 L) heated to 120°C and toluene destiled off (5L), and than heated at 1 10°C for 3 hrs. The solvent is cooled to room temperature and drained. The reactor is than charged with toluene (35 L) and (R.E)- ethyl 2-(3-(acetylthio)-3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)propyl) benzoate (2 kg), degassed, and toluene disstiled off (5 L) at normal pressure and temperature 120°C.
• the reactor is cooled down to room temperature and 15% solution of lanthanum chloride and lithium chloride in tetrahydrofuran (3.13 L) is added, and the suspension is stirred at room temperature for 1 hr. Thereafter, the reaction mixture is cooled to -30 0°C and 3.2 M solution of methylmagnesium bromide in 2-methyltetrahydrofurane (6.67 kg) is added dropwise during 1 -2 hr while maintaining the temperature below -10°C. Temperature is gradually raised to 10 °C and maintained until complete conversion. Reaction is poured into cold 10% aqueous solution of acetic acid (25 L), Layers are separated and aqueous layer extracted with toluene (8 L).
• Procedure C Reactor is charged with toluene (1 L) heated to 120°C and toluene destiied off (300 mL), and than heated at 1 10°C for 3 hrs. The solvent is cooled to room temperature and drained. The reactor is than charged with toluene ⁇ 1 .23 L) and (R.E)-Methyl 2-(3-(acetylthio)-3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)propyl) benzoate (60.6 g), degassed, and toluene dssstiled off (300 mL) at norma! pressure and temperature 120°C.
• the reactor is cooled down to room temperature and 15% solution of lanthanum chloride and lithium chloride in tetrahydrofuran (94 mL) is added, and the suspension is stirred at room temperature for 1 hr. Thereafter, the reaction mixture is cooled to -30 0°C and 3.2 M solution of methyimagnesium bromide in 2-methyltetrahydrofurane (182 mL) is added dropwise during 1 -2 hr while maintaining the temperature be!ow -30°C. Temperature is gradually raised to 0 °C and maintained until complete conversion. After complete conversion of reactant to product, acetone (8.6 mL) was added dropwise at 0°C.
• Reaction mixture is stirred at 0°C for 30 min and than added dropwise to the cold solution of 2-[1 -(bromomethyi)cyclopropyl]acetate (30.8 g) in N ; N-dimethylformamide (400 mL). The reaction mixture is stirred at room temperature until complete conversion. Reaction is poured into 10% aqueous acetic acid (1.55 L), and layers separated. Aqueous layer was extracted once more with toluene (500 mL).
• Monteiukast methyl ester more than 98.0% and ali individual impurities beiow 0.20%.
• Reaction is poured into mixture of saturated NaCI solution (22 kg) and ethyl- acetate (23 kg). Layers are separated and organic layer is washed with 0.5 M aqueous solution of tartaric acid (23 kg) and several times with water (18 kg). The solvent is concentrated in vacuo, and residue is dissolved in ethyl acetate fol!owed by slow addition of hexane at room temperature. Thereafter, crystal product is filtered off, washed, and dried under reduced pressure at 40°C to afford monteiukast acid,
• Procedure B (R,E)-methyl 2-(1 - ⁇ (1 -(3- ⁇ 2- ⁇ 7-chjoroquinoiin-2-yf)vinyl)phenyl)-3- ⁇ 2-(2- hydroxypropan-2-y!phenyl)propyithio)methyl)cyciopropyl)aceiate (70 g) is charged into reactor, dissolved in tetrahydrofuran (165 mL), methanol (220 mL) and 2 M aqueous solution of NaOH (300 mL). The solution is stirred at 50°C for 3 hours. Reaction is cooled and poured into mixture of saturated NaCi solution (500 mL) and ethyl-acetate (500 mL).
• Montelukast methyl ester (4.5 g, 1 .5% of ketone impurity) is dissolved in N,N- dimethylformamide and acetic acid (1 mL) and semicarbazide HCI (900 mg) was added. The suspension is stirred at room temperature for 24 hrs. Reaction mixture was filtered off, and poured into mixture of sat. NaC! solution (100 mL) and ethyl acetate (100 mL). Separated organic layer is washed twice with saturated NaCi solution (100 mL) and solvent evaporated to afford montelukast methyl ester (3.42 g, 0.07% of ketone impurity).
• the emulsion was cooled to 45 °C (RT) with cooiing ramp 0.5 K/min and after that the emulsion was slowly cooled with the cooling ramp 0.10 K/min to 15 °C (TRCT).
• ⁇ ⁇ se eds of pure monteiukast acid were added at 30 °C (RT), during the slow cooling.
• Formed suspo-emuision was homogenized at this temperature for the next 3 hours for monteiukast acid to fuily crystallize.
• the formed product is isolated with filtration and washed with water.
• the microscope pictures of formed product are presented in Figure 1 and particle size distribution in fig 2.
• Example 3 Purification of monteiukast acid by emulsion crystallization via primary nucleation of monteiukast acid
• Example 4 Purification of monteiukast acid by supercritical fluid chromatography
• the sample with chromatographic purity of about 80% was purified in one step to about 99.7% chromatographic purity, all individual impurities were below 0.10%.
• Injection volume 100 ⁇ (concentration: 320 mg/m!)
• Example 5 Purification of montelukast acid by silicagel chromatography
• Example 5.1 Purification of montelukast acid by silicagel chromatography
• Chromatographic column with dimensions 250x21 ,2 mm and with stationary phase silica 60 (40-63 ⁇ particles) was used.
• the following mobile phases were used: dicloromethane/methanol, toluene/acetone and dichloromethane/methanol (with 10% addition of 25% solution of ammonia in water).
• Chromatographic column with dimensions 1200 x 100 mm and with stationary phase Silicagel 60 (40-63 prn particle size) was used.
• the following mobile phases were used: dicloromethane/methanol, toluene/acetone and dichloromethane/methanol ⁇ with 10% addition of 25% solution of ammonia in water).
• the reactor is charged with toluene (8.8 kg) and monteiukast acid (0.6 kg, 1.024 mol) and the reactor is coo!ed to 0-5°C.
• the ethanolic solution of sodium hydroxide 47 g of NaOH in 2.2 L of ethanol
• the reaction mixture is stirred at 20-30°C for 2 hrs, than activated carbon is added and solution stirred at the same temperature for 2 hr.
• the reaction mixture is filtrated and activated charcoal is washed with the mixture of ethanol and toluene. Filtrate is concentrated to about 1 ⁇ 4 of the volume.
• the final product is amorphous montelukast sodium.
• a "substituted” group has 1 to 4, preferably 1 to 2 substituents, which are preferably selected from a C-t -Cs alkyi group, C-
• NR a Rb (wherein R a and are independently selected from H and C-j .g alkyl), silyl groups of formula -S1R3, wherein each R is independently selected from C-j - CQ alkyl, C-
• Process for preparing monielukast free acid or pharmaceutically acceptable salts thereof comprising the following step (i), and optionally the following step (ii): a step of converting a compound of the following formula (IV) to a compound of the following formula (V) in an inert solvent using an organometailic reagent and in the presence of a !anthanide metal catalyst:
• represents a C- -CQ alkyl group, and preferably -CH3, and wherein the reaction is conducted in such a manner that the amount of water in the reaction mixture is less than 0.05 wt-% before and/or at the time when the compound of formula (IV) is reacted with the organometallic agent to form the compound of formula (V); a step of removing an impurity represented by formula (VIII) by reacting the compound of formula (VIII) with a compound capable of reacting with the ketone function at the position marked with * in formula (VII!)
• halogenides preferably lanthanum (III) halogenides and cerium (Hi) halogenides, more preferably anhydrous lanthanum (III) chloride or cerium (III) chloride.
• step (i) Process for preparing monteiukast free acid or pharmaceutically acceptable salts thereof according to any of items 1 , 2, 3, and 4, wherein the reaction equipment used for step (i) is dried before perfoming step (i) such that, upon refluxing the inert solvent in the reaction equipment for 1 hour, the inert solvent has a water content of 0.02 wt-% or less prior to the addition of the compound of formula (IV), the lanthanide metal catalyst and the organometailic reagent and process for preparing monteiukast free acid or pharmaceutically acceptable salts thereof according to any of items 1 , 2, 3, and 4, wherein the compound of formula (IV) is additionally azeotropicaily dried by distillation of some amount of inert solvent to less than 0.05 w/w% of water, preferably less than 0.02 w/w% of water, most preferably to less than 0.01 w/w% of water, before the organometailic reagent and the lanthanum metal catalyst are added.
• step (i) Process for preparing monteiukast free acid or pharmaceutically acceptable salts thereof according to any of item 1 , 2, 3, 4 and 5, wherein the amount of organometailic reagent used in step (i) is 2 - 10, preferably 5 - 8 moie equivalents, based on the amount of the compound of formula (IV).
• step (i) Process for preparing monteiukast free acid or pharmaceutically acceptable salts thereof according to any of item 1 , 2, 3, 4, 5 and 6, wherein in step (i) the amount of lanthanide metal catalyst is 0.1 - 1 .5 mole equivalent, preferably 0.4 - 0.8 equivalent, relative to the amount of the compound of formula (IV).
• step (ii) the step of separating the reaction product, which is formed by a reaction of a compound of formula (VIII) with a compound capable of reacting with the ketone function at the position marked with * , from a solution of a compound of formula (VI- VI! involves the removal of a precipitate of the reaction product from the solution or an aqueous work-up.
• the compound capable of reacting with the ketone function at the position marked with * used in step (ii) is selected from the group consisting of hydrazine, hydrazine derivatives and semicarbazides.
• step (i) the step of converting the compound of formula (IV) to the compound of formula (V) is step (i) according to any of items 1 to 12,
• L and U represent a leaving group, selected form the group consisting of chlorine, bromine or iodine, a CrC 8 alkyi sulfonyloxy group or a substituted C5-C 1 0 aryl sulfonyloxy group; and R represents a C-i-Ce alkyl group or a substituted or unsubstituted C5-C1 aryl group,
• represents a C-j -Cg alkyl group, and preferably -CH3.
• step (d) isolating the crystalline compound of formula (IV).
• Process for preparing montelukast free acid or pharmaceutically acceptable salts thereof according to any of items 1 to 12, wherein the crystalline compound of formula (IV) according to item 13 or 14 is used in step (i). Process for preparing montelukast free acid or pharmaceutically acceptable salts thereof according to any of items 1 to 12 and 16, wherein the process comprises the step of providing montelukast free acid, subjecting said montelukast free acid to purification treatment by means of one or more of the following methods:
• step (c-iii') isolation of montelukast acid wherein the emulsion of step (a-i) comprises ethyl acetate and water such that ethyl acetate and water are used in a volume ratio (vol/vol) of between 0.18 - 20, preferably 0.5 : 10, most preferably 0.7 - 2.0.
• step (a-i) comprises ethyl acetate and water such that ethyl acetate and water are used in a volume ratio (vol/vol) of between 0.18 - 20, preferably 0.5 : 10, most preferably 0.7 - 2.0.
• the purification treatment is repeated one or more cycles until the resulting montelukast free acid has a purity of at least 97%, preferably at least 99%, more preferably at least 99.5%.
• R represents a CrCs alkyl group or a substituted C 5 ⁇ Ci o aryl group
• the hydrolysis is preferably effected using an agent selected from alkali hydroxide, an alkaline earth hydroxide, alkaline carbonate and alkaline alkoxide.
• R represents a CrC 8 alkyl group or a substituted C5-C10 aryl group and wherein !_' represents a leaving group, selected form the group consisting of chlorine, bromine or iodine, a Ci -C 8 alkyl suifonyloxy group or a substituted C5-C10 aryl suifonyloxy group.
• !V represents a leaving group, selected form the group consisting of chlorine, bromine or iodine, a Ci -C 8 alkyl suifonyloxy group or a substituted C5-C10 aryl suifonyloxy group.
• L represents a leaving group, selected form the group consisting of chlorine, bromine or iodine, a CrC 8 alkyi sulfonyloxy group or a substituted C5-C 10 aryl sulfonyloxy group
• R-j is defined as in formula (IV) in item 1 and is preferably -CH3
• L represents a leaving group, selected form the group consisting of chlorine, bromine or iodine, a Ci-C 8 aikyl sulfonyloxy group or a substituted C5-C 1 Q aryl sulfonyloxy group, and R-j is defined as in formula (IV) and is preferably -CH3.
• Montelukast free acid or a pharmaceutically acceptable salt or ester thereof which is obtained according to a process as specified in one or more of items 1 to 12 and 16 to 26.
• Pharmaceutical composition comprising montelukast free acid or a pharmaceutically acceptable salt or ester thereof according to item 27.

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