EP2094664A2 - Neues verfahren zur herstellung von montelukast - Google Patents

Neues verfahren zur herstellung von montelukast

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Publication number
EP2094664A2
EP2094664A2 EP07821912A EP07821912A EP2094664A2 EP 2094664 A2 EP2094664 A2 EP 2094664A2 EP 07821912 A EP07821912 A EP 07821912A EP 07821912 A EP07821912 A EP 07821912A EP 2094664 A2 EP2094664 A2 EP 2094664A2
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EP
European Patent Office
Prior art keywords
formula
montelukast
group
acid
palladium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07821912A
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English (en)
French (fr)
Inventor
Davor Kidemet
Vesna Kroselj
Renata Osolnik
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KRKA dd
Original Assignee
KRKA Tovarna Zdravil dd
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Publication of EP2094664A2 publication Critical patent/EP2094664A2/de
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/53—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention describes a novel process for the preparation of montelukast acid, and its pharmaceutically acceptable salts and esters.
  • Montelukast sodium is a potent inhibitor of CysLTl , and it is used for chronic treatment and prevention of asthma in adult and pediatric patients.
  • Montelukast sodium is a hygroscopic, optically active, white to off-white powder.
  • Montelukast sodium is freely soluble in ethanol, methanol, and water, and practically insoluble in acetonitrile .
  • Montelukast sodium is a selective and orally active leucotriene receptor antagonist that inhibits the cysteinyl leucotriene CysL-Ti receptor.
  • Montelukast sodium is marketed in the form of film coated tablets, chewing tablets and granules under the trade name ⁇ INGULAIR ® .
  • the commercially available film coated SINGULAIR ® tablets contain microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate and coating which comprises hyproxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red and yellow ferric oxide and carnauba wax.
  • EP 480 717 Al It was first described in EP 480 717 Al.
  • the preparation process of EP 480 717 is as disclosed in the following scheme 1 :
  • WO 2006/05845 relates to a process for the preparation of montelukast wherein 2- [2- [3 (S) - [3- [ (IE) -2- (7-chloroquinoline- 2-yl) ethenyl] phenyl] -3-methylsulfonyloxypropyl] phenyl-2- propanol is reacted with 1- (mercaptomethyl) cyclopropaneacetic acid in the presence of a base, preferably an alkali hydroxide.
  • a base preferably an alkali hydroxide
  • WO 2006/008562 discloses a process for the preparation of montelukast by asymmetric transfer hydrogenation of the ketone intermediate by using chiral ruthenium or rhodium catalysts, in the presence of a hydrogen source.
  • the present invention relates to an efficient process for the preparation of montelukast comprising the steps of:
  • Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium;
  • R3 represents Ci-Cs alkyl
  • R' represents a negative charge, hydrogen, alkyl, trifluoromethyl, C3-C8 cycloalkyl or a Cs-Cio aryl group
  • L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group;
  • Met represents a metal residue selected from -MgCl, -MgBr,
  • Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate ;
  • R3 represents Ci-Ce alkyl, preferably methyl
  • R' represents a negative charge, hydrogen, alkyl, trifluoromethy1, C3 ⁇ Cs cycloalkyl or a CB-CIO aryl group;
  • L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group, preferably chlorine or a methylsulfonyloxy group ; is provided.
  • Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate;
  • R3 represents Ci-Cs alkyl, preferably methyl;
  • R' represents a negative charge, hydrogen, alkyl, trifluoromethyl , C3-Cs cycloalkyl or a C5-C10 aryl group; is provided.
  • Another embodiment of the present invention is montelukast arginine salt and the preparation thereof.
  • Figure 1 Powder X-ray diffraction pattern of amorphous montelukast arginine salt.
  • Figure 2 FTIR spectrum of amorphous montelukast arginine sale .
  • the present invention relates to an efficient process for the preparation of montelukast acid comprising the steps of:
  • R represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium;
  • R.3 represents Ci-Ce alkyl
  • R' represents a negative charge, hydrogen, alkyl, trifluoromethyl , C3-Cs cycloalkyl or a C5-C10 aryl group;
  • L represents a leaving group such as chlorine, bromine, iodine, a Ci-Cs alkyl sulfonyloxy group or a C5-C10 aryl sulfonyloxy group;
  • Met represents a metal residue selected from -MgCl, -MgBr,
  • the secondary alcohol of formula (V ) is prepared hy asymmetric reduction of ketone of formula (VI) with a reducing agent, selected from sodium and lithium borohydride, in an inert solvent and a tartaric acid-derived boronate ester as a catalyst.
  • a reducing agent selected from sodium and lithium borohydride
  • the reaction is performed at a temperature between about -5O 0 C and about 100 0 C, preferably at a temperature between about 0 and about 3O 0 C, for approximately 2 to 4 hours .
  • the inert solvents for the reaction can be selected from a variety of known process solvents.
  • the tartaric acid-derived boronate ester is prepared by reacting the (D) -tartaric acid with an appropriately substituted arylboronic acid in refluxing THF, and in the presence of CaH2.
  • Substituted arylboronic acids are represented by the compound of formula (VII) :
  • the secondary alcohol of formula (V ) is prepared by metal- catalysed transfer hydrogenation of compounds of the general formula (VI) by using a hydrogen donor in the presence of a metal catalyst based on ruthenium complexes of optically active N-sulfamoyl-1 , 2-diamine ligands of the general formula (VIII) :
  • Rs and R7 independently represent a hydrogen atom, a linear or branched Ci-Cis alkyl group that is optionally substituted with a C5-C10 aryl group, or Re and R7 may be linked together to form with the nitrogen atom an optionally substituted 4 -
  • Rs and R9 independently represent a hydrogen atom, an optionally substituted Cs-Cio aryl group, or a C3-Ca cycloalkyl group, or Rs and Ra may be linked together to form a cyclohexane ring.
  • Rs and R7 are independently selected from the group consisting of methyl, isopropyl and cyclohexyl, or Rs and R7 are linked together to form a ring selected from the group consisting of pyrrolidyl, piperidyl, morpholyl and azepanyl .
  • optically active N-sulfamoyl-1 , 2-diamine ligands used in the process of the present invention have an enantiomeric excess of more than 95%, preferably more than 99%.
  • the metal catalyst is prepared from a ruthenium metal precursor and an optically active N-sulfamoyl-1 , 2-diamine ligand of the general formula (VIII)
  • the ruthenium metal catalyst used in the process of the present invention is prepared from a precursor of the formula [RuX2 ()j 6 -arene) ] 2 , wherein ⁇ 6 -arene represents an arene group, selected from the group consisting of benzene, p-cymene, mesitylene, 1 , 3 , 5-triethylbenzene, hexamethylbenzene and anisole, and X is halide selected from the group consisting of chloride, bromide and iodide.
  • the hydrogen donor used in the process of the present invention is based on HCO2H.
  • Examples for preferred hydrogen donors comprise HCO2H-Et3N, HCChH-iso-P ⁇ NEt , HCOsH-metal bicarbonates and HC02H-metal carbonates, wherein the metal is selected from ISJa, K, Cs, Mg and Ca.
  • the metal-catalysed transfer hydrogenation according to the present invention is conducted in a solvent selected from the group consisting of dichloroethane, acetonltrile, N, N- dimethyl formamide, N,N-dimethylacetamide, 1-methyl-2- pyrrolidinone (WMP), 1, 1 , 3 , 3-tetramethylurea, 1, 3-dimethyl-2- imidazolidinone, ISI, N' -dimethylpropyleneurea and mixtures thereof .
  • a solvent selected from the group consisting of dichloroethane, acetonltrile, N, N- dimethyl formamide, N,N-dimethylacetamide, 1-methyl-2- pyrrolidinone (WMP), 1, 1 , 3 , 3-tetramethylurea, 1, 3-dimethyl-2- imidazolidinone, ISI, N' -dimethylpropyleneurea and mixtures thereof .
  • Starting ketone of formula (VI) used in an asymetric reduction according to the present invention can be prepared by any process known by the prior art, as for example disclosed in R. D. Larsen et al, J. Org, Chem. 1996, 61, 3398- 3405.
  • the secondary alcohol of formula (V) obtained by asymmetric reduction of ketone of formula (VI) can be used in the next step of the process according to the present invention or it can be optionally further converted to secondary alcohol of formula (V) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent.
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about -78 0 C to boiling temperature of the solvent, more preferably between about -10 0 C to about 35°C.
  • the organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium.
  • Methylmagnesium iodide is preferably used.
  • the inert solvents can be selected from a variety of known process solvents . Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2- methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene .
  • the compound of formula (IV) or (IV) is prepared by the conversion of the OH-group in secondary alcohol of formula (V) or (V ⁇ to a leaving group L such as for example chlorine, bromine, iodine or a Ci-Cs alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group, preferably a chlorine atom and a methylsulfonyloxy group .
  • a leaving group L such as for example chlorine, bromine, iodine or a Ci-Cs alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group, preferably a chlorine atom and a methylsulfonyloxy group .
  • the reaction can be performed with an alkyl or aryl sulfonyl halide selected from the group consisting of methyl, ethyl, n-butyl, besyl or tosyl sulfonyl halide in an inert solvent
  • a base such as any organic tertiary non- nucleophilic base such as for example triethylamine, N- ethyldiisopropylamine, or similar.
  • the suitable solvent may be selected from dichloromethane, tetrahydrofurane, 2- methyltetrahydrofurane, and N, N-dimethyIformamide .
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about -78°C to boiling temperature of the solvent, more preferably between about - 10 0 C to about 35 0 C.
  • methanesulfonyl chloride in dichlorometane is used.
  • the reaction can be performed with a halogen acid or inorganic acid halide selected from the group consisting of HCl, HBr, HI, SOCI2, PCI3, POCIa, PBn in a suitable solvent.
  • suitable solvents may be selected from dichloromethane, tetrahydrofurane, 2-methyltetrahydrofurane, and N,N-dimethyIformamide.
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about TM78°C to boiling temperature of the solvent, more preferably between about -10 0 C to about 35 0 C.
  • SOCI2 is used in dichloromethane as the solvent.
  • the compound of formula (IV ) obtained by the conversion of the secondary alcohol of formula (V ) can be used in the next step of the process according to the present invention or it can be optionally further converted to compound of formula (IV) by the reaction with organornetalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent.
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about -78 0 C to boiling temperature of the solvent, more preferably between about -10 0 C to about 35 0 C.
  • the organometalic reagent can be selected from the group consisting of methyimagnesium chloride, metylmagnesium bromide, methyimagnesium iodide or methyllithium. Methyimagnesium iodide is preferably used.
  • the inert solvents can be selected from a variety of known process solvents.
  • the nucleophilic substitution of the compound of formula (IV) or (IV) is performed by reacting the compound of formula (IV) or (IV) with 2- (1-mercaptomethyl) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into carboxylic acid, in the presence of a base and in a solvent to obtain the compound of formula (II) or (II' ⁇ -
  • the base can be selected from the group consisting of an alkali hydroxide, an alkaline earth hydroxide, alkali carbonate, alkali alkoxide, alkali hydride, alkyllithium or lithium hexamethydisilazide, preferrably sodium t-butoxyde, n-butyllithium, or caesium carbonate is used.
  • the solvent can be selected from the group consisting of benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, N, N-dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran, diethoxymethane, or N-methylpyrrolidinone.
  • the compounds of formula (II) or (II') may be isolated as organic base salts by dissolving the residue in ethyl acetate or toluene after distilling the solvent, treating with organic amine such as diisopropylamine, dipropylamine, tributylamine, dibenzylamine, dicyclohexylamine, alpha-methylamine or L-arginine, at temperature about 1O 0 C to about 5O 0 C, adding hexane, heptane or acetonitrileto yield the organic base salt of the compound of formula (II) or (II').
  • organic amine such as diisopropylamine, dipropylamine, tributylamine, dibenzylamine, dicyclohexylamine, alpha-methylamine or L-arginine
  • Compound 2- ( 1-mercaptomethyl) cyclopropyl) acetic acid or an intermediate thereof that can be transformed into carboxylic acid used in nucleophilic substitution of the present invention can be prepared by any process known by the prior art, as for example disclosed in EP 0480717, US 6320052.
  • the compound of formula (II') obtained by the nucleophilic substitution can be used in the next step of the process according to the present invention or it can be optionally further converted to compound of formula (II) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent.
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about -78 0 C to boiling temperature of the solvent, more preferably between about -10 0 C to about 35 0 C.
  • the organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium.
  • Methylmagnesium iodide is preferably used.
  • the inert solvents can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2TM methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene .
  • the compound of formula (I) or (I') is prepared by reacting the acetic acid derivative of formula (II) or (II') with the vinylquinoline of formula (III) in the presence of a catalyst and a base in an inert solvent under conditions known per se as Heck coupling reaction.
  • the reaction is performed at a temperature between about 60 and about 200 0 C, preferably at a temperature between about 80 and about HO 0 C for approximately 7 to 15 hours at normal or elevated pressure and in an inert atmosphere, as for example under argon or nitrogen.
  • the catalyst used in the Heck coupling reaction can be selected from the group consisting of Pd source, such as palladium ⁇ II) acetate, palladium (II) chloride, palladium dibenzylideneacetone, dichlorobis (acetonitrile) palladium (II) , dichlorobis (benzonitrile) palladium (II) , dichlorodiamine palladium ( II ), palladium ⁇ II) acetylacetonate, palladium (II) bromide, palladium (II) cyanide, palladium (II) iodide, palladium oxide, palladium ⁇ l) nitrate hydrate, palladium(II) sulfate dihydrate, palladium (II) trifluoroacetate, tetraamine palladium (II) tetrachloropalladate and tetrakis (acetonitrile) palladium (II) tetrafluo
  • Organic or inorganic bases may be used in the Heck coupling reaction.
  • organic bases primary, secondary or tertiary amines may be used, such as for example triethylamine or diisopropylethylamine .
  • Inorganic bases may be carbonates, hydrogencarbonates, hydroxides and alkali metal alkoxides such as for example potassium carbonate, sodium carbonate, sodium hydrogencarbonate, caesium carbonate, thallium carbonate, potassium hydroxide, sodium hydroxide, thallium hydroxide, or the alkoxides of these alkali metals.
  • Organic solvent soluble bases such as tetra-n- butylammonium carbonate or tetra-n-butylammonium hydroxide, benzyltrimethylammonium carbonate, benzyltrimethylammonium methyl carbonate, benzyltrimethylammonium methoxide or benzyltrimethylammonium hydroxide, or other basic tetraalkylammonium compounds may be useful in certain cases.
  • triethylamine is used.
  • the inert solvents used in the Heck coupling reaction may be selected from a variety of known process solvents.
  • Illustrative of the coupling solvents that can be utilized either singly or in combinations are benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, N, N- dimethylformamide, N, N ⁇ dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran or diethoxymethane, N-methylpyrrolidinone, hexarnethylphosphoramide, supercritical CO2, and/or ionic liquids.
  • the acetic acid derivative of formula (II) or (II' ⁇ wherein Ri is Br and RJ is methyl reacts ⁇ with 2-ethenyl-7-chloroquinoline (compound of formula III) in the presence of Pd(OAc) 2, P(o-tolyl)- and Et--N, in a DMF solution or suspension.
  • the compound of formula ⁇ !') obtained by the Heck coupling reaction is further converted to compound of montelukast acid of formula (I) by the reaction with organometalic reagent and optionally cerium catalyst selected from the group consisting of cerium (III) chloride in an inert solvent.
  • the reaction temperature is below the boiling temperature of the solvent used, preferably between about -78 0 C to boiling temperature of the solvent, more preferably between about -10 0 C to about 35°C.
  • the organometalic reagent can be selected from the group consisting of methylmagnesium chloride, metylmagnesium bromide, methylmagnesium iodide or methyllithium. Methylmagnesium iodide is preferably used.
  • the inert solvents can be selected from a variety of known process solvents. Illustrative of the solvents that can be utilized either singly or in combinations are tetrahydrofurane, 2- methyltetrahydrofurane, diglyme, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl eter, cyclopenthyl methyl ether and toluene, preferably tetrahydrofurane and toluene.
  • montelukast acid of formula (I) is prepared by reacting the compound of general formula (I' ⁇ with methylmagnesium bromide activated by cerium(III) chloride in tetrahydrofuran .
  • montelukast acid of formula (I) is isolated in the process according to the present invention.
  • the purification and isolation of all intermediates and final product by methods known in the art should be considered as included in the scope of the invention.
  • One of the standard purification method is the preparation of intermediates and final product in its solid state, by conventional crystallisation and recrystallisation techniques using solvents that a person skilled in the art considers to be the most suitable.
  • the process of the present invention represents a simple and economically viable way of the preparation of rnontelukast and its pharmaceutically acceptable salts and esters while the vinylquinoline building part of the molecule is introduced in the last step of the preparation of montelukast acid and the starting compound can be easily produced.
  • Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate;
  • R3 represents Ci-C ⁇ alkyl, preferably methyl
  • R' represents a negative charge, hydrogen, alkyl, trifluoromethyl, C3-C8 cycloalkyl or a Cs-Cio aryl group
  • L represents a leaving group such as chlorine, bromine, iodine, a Ci-Ca alkyl sulfonyloxy group or a Cs-Cio aryl sulfonyloxy group, preferably chlorine or a methylsulfonyloxy group ; is provided.
  • the compound of formula (Ii; or (II') is provided.
  • Ri represents a halogen atom, selected from chlorine, bromine or iodine, OSO2R' or diazonium, preferably bromine or trifluoromethanesulfonate ;
  • ⁇ b represents Ci-Ce alkyl, preferably methyl;
  • R' represents a negative charge, hydrogen, alkyl, trifiuoromethyi, C3-C8 cycloalkyi or a C5-C10 aryl group; is provided.
  • r ⁇ ontelukast acid prepared and isolated according to the process by the present invention can be used in the pharmaceutical composition as the active substance together with other pharmaceutically acceptable excipients or it can be further converted without isolation into any known pharmaceutical acceptable salt as for example disclosed in EP 480717 Bl, WO 0006585, WO 2006008751, WO 2006043846, WO 2006064269, WO 2007096875, WO 2007107297.
  • the pharmaceutical acceptable salt is sodium salt prepared by any method known in the art and being in amorphous or crystalline form as disclosed in for example EP 737186 Bl, WO 03066598, WO 2004091618, WO 2004108679, WO 2005075427, WO 2005074893, WO 2007005965, WO 2007012075, WO 2007059325, WO 2007116240.
  • the sodium salt of montelukast is prepared from montelukast acid prepared by the process of the present invention by reacting the pure montelukast acid in a polar protic solvent with a source of sodium ions followed by evaporation of the solvent and triturating of the residue with a non-polar solvent to obtain the sodium salt of montelukast .
  • the polar protic solvent may be selected form the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, methanol, acetonitrile, toluene, and the any mixture thereof.
  • toluene is used.
  • the source of sodium ion may be selected from the group consisting of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, preferably sodium hydroxide.
  • the non-polar solvent may be selected from n-hexane, n- heptane, cyclohexane, methyl tert-butyl ether, cyclopentyl methyl ether, diisopropyl ether.
  • n-heptane is used.
  • the present inventors surprisingly found a new salt of montelukast, montelukast arginine, obtained in high yield and characterized by the improved properties .
  • the main advantages of this salt are that it is prepared from natural occurring amino acid, that it has an active role in metabolism of mammals and that it is easily metabolized in mammals.
  • Another aspect of the present invention is the conversion of montelukast acid into montelukast arginine salt and optionally its further conversion into sodium salt comprising the steps of: a ⁇ obtaining the arginine salt of montelukast by adding L- arginine to the crude montelukast acid, b) optional purifying and converting the arginine salt of montelukast to montelukast acid and reacting the pure montelukast acid in a polar protic solvent with a source of sodium ions, followed by evaporation of solvent and crystallizing the pure sodium montelukast.
  • the process for preparing the crystalline solid comprising montelukast arginine salt according to the present invention comprises the following steps: a) providing a mixture of montelukast acid in an organic solvent while stirring and optionally heating to elevated temperature; b ⁇ adding L- arginine dissolved in water and distilling the water-solvent azeotrope; c) adding an anti-solvent upon cooling; d) stirring for sufficient time to allow crystallization; e ⁇ obtaining the crystals by filtering and washing; and f) optionally drying the obtained crystals .
  • the organic solvent can be selected from the group consisting of toluene, diisopropyl ether, tetrahydrofuran (THF) , ethyl acetate, acetone, methyl ethyl ketone ⁇ MEK ⁇ , methanol, isopropanol, acetonitrile, m-xylene, 2-methoxyethyl ether, isobutyl acetate, t-butyl alcohol, n-amyl alcohol and mixtures thereof.
  • THF tetrahydrofuran
  • MEK ⁇ methyl ethyl ketone
  • the anti-solvent can be selected from the group consisting of n-hexane, cyclohexane, n-heptane, methyl t-butyl ether (MTBE) , diisopropyl ether, ethoxymethyl ether, ethyl acetate, acetonitrile and mixtures thereof.
  • MTBE methyl t-butyl ether
  • the obtained montelukast arginine salt is in amorphous form and further characterized in Figures 1 and 2.
  • Average particle size of particles prepared and used in our work is 5 to 200 ⁇ m, preferably below 100 ⁇ m. If unstirred, crystallization from organic solvents, or their mixtures with water might also yield bigger particles, e.g. with an average diameter of above 200 ⁇ m which need to be milled or processed in any other way which reduces particle size, prior to their application in pharmaceutical formulations. When milling, particles of less then 3 ⁇ m average diameter may be produced. For this purpose air jet mills, ball mills or hammer mills are commonly used as milling equipment. However, it is not enough to control only the average size of particles, but also particle size distribution. Average particle size and particle size distribution is important to assure that the technological process is nanoble, i.e. does not cause segregation of ingredients of tabletting mixture if it is not tabletted/compressed just after preparation of tabletting mixture.
  • a pharmaceutical composition according to the present invention includes at least one of the substances montelukast acid or montelukast arginine or montelukast sodium as an active ingredient and optionally an additional active substance.
  • the pharmaceutical composition according to the present invention can be in any conventional form, preferably an oral dosage form such as a capsule, tablet, pill, liquid, emulsion, granule, suppositories, powder, sachet, suspension, solution, injection preparation and the like.
  • the formulations/compositions can be prepared using conventional pharmaceutically acceptable excipients.
  • Such pharmaceutically acceptable excipients and additives include fillers/diluents, binders, disintegrants, glidants, lubricants, wetting agents, preservatives, stabilizers, antioxidants, flavouring agents, coloring agents, emulsifier.
  • a pharmaceutical composition according to the present invention may include ingredients as disclosed in WO 2007/077135 and may be prepared by a process comprising the steps of preparing montelukast acid, montelukast arginine salt and/or montelukast sodium salt according to the process of the present invention and mixing a therapeutically effective amount thereof with one or more pharmaceutically acceptable excipients and optionally with one or more further active substances.
  • the pharmaceutical composition according to the present invention can be used to treat respiratory diseases such as asthma and allergic rhinitis in a mammal by administering a therapeutically effective amount of the active substance to a mammal in need.
  • the present invention is illustrated by the following Examples without being limited thereto.
  • the Ru-complex was prepared from [RuCl2 (mesitylene) ] 2 (2.1 mg, 7.2 ⁇ mol Ru at.) and ⁇ IS, 2S) -N-piperidylsulfamoyl-1 , 2- diphenylethylenediamine (3.2 mg, 8.9 ⁇ mol) by heating in (CHsCDa (0.5 ml) at 80 0 C for 30 min.
  • the mixture was stirred at room temperature for 48 hrs, and than quenched by pouring into water (200 mL) and ethyl acetate (50 mL) .
  • the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL) .
  • the product is filtered under nitrogen and washed with hexane (50 mL) , and dried under vacuum at 40 0 C for 12 hrs to yield amorphous form of montelukast arginine (6.89 g) .
  • the X-ray powder diffraction pattern was obtained by Philips PW3040/60 X' Pert powder diffTactometer, X'celerator detector at CuKa radiation, 1.54178 A, 3 2 ⁇ 2# ⁇ 30 a .
  • FT-IR spectra of KBr discs were recorded over the wave number range of 4000-400 cm l on Perkin Elmer FT-IR spectrometer Spectrum GX at a resolution 4 cm '1 .
  • Fig 1 Powder X-ray diffraction pattern of amorphous montelukast arginine salt
  • Fig 2 FTIR spectrum of amorphous montelukast arginine salt
  • Example 16 Montelukast sodr ⁇ m
  • Montelukast arginine salt (4.14 g) was dissolved in toluene (100 mL) . Acetic acid (1 mL) in water ⁇ 100 mL) was added. The mixture was stirred at rt for 30 min, and layers separated. To organic layer, solution of sodium hydroxide (218 mg) in methanol (12 mL) was added, and stirred at rt for 1 hr . The solvent is completely disstiled off under vacuum at below 50 0 C to afford the residue. The residue is dissolved in toluene (40 mL ⁇ and charcoal was added and stirred at 40 0 C for 2 hrs . The reaction mixture was filtered, and concentrated under vacuum to -20 mL.
  • the mixture was dropwise added to hexane (60 mL) and stirred under nitrogen 18 hrs.
  • the product is filtered under nitrogen and washed with hexane (20 mL) , and dried under vacuum at 4O 0 C for 12 hrs to yield amorphous form of montelukast sodium (2.07 g) .
  • a 1 kg batch was prepared. Manitol, aspartame, iron oxide red, microcrystalline cellulose, and croscarmellose sodium were mixed in a granulator and granulated with a solution of Klucel EF. The obtained granulate was dried and then, montelukast sodium, croscarmellose sodium, mictocrystalline cellulose, aroma cherry black, and magnesium stearate were admixed, and the obtained mixture was pressed into tablets using round, slightly biconvex punches to a target hardness of approx. 20 - 90 N. The same compression mixture was used for the preparation of 4 mg tablets with target weight 240 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
EP07821912A 2006-10-26 2007-10-26 Neues verfahren zur herstellung von montelukast Withdrawn EP2094664A2 (de)

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SI200600255A SI22382A (sl) 2006-10-26 2006-10-26 Nov postopek za pripravo montelukasta
PCT/EP2007/061552 WO2008049922A2 (en) 2006-10-26 2007-10-26 A new process for the preparation of montelukast

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US9717684B2 (en) 2014-04-25 2017-08-01 R.P. Scherer Technologies, Llc Stable montelukast solution

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EP1904448B1 (de) 2005-07-05 2011-02-02 Teva Pharmaceutical Industries, Ltd. Reinigung von montelukast
EP2287154A1 (de) * 2009-07-14 2011-02-23 KRKA, D.D., Novo Mesto Effiziente Synthese zur Herstellung von Montelukast
EP2552892A1 (de) 2010-03-31 2013-02-06 KRKA, D.D., Novo Mesto Effiziente synthese zur herstellung von montelukast und neue kristalline form von zwischenprodukten darin
WO2014081616A1 (en) * 2012-11-21 2014-05-30 Merck Sharp & Dohme Corp. Preparation of precursors for leukotriene antagonists
CN104109123B (zh) * 2013-04-16 2016-12-07 浙江奥翔药业股份有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN105330540B (zh) * 2015-12-01 2018-01-23 中山奕安泰医药科技有限公司 孟鲁斯特纳中间体的制备方法

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US7553853B2 (en) * 2003-10-10 2009-06-30 Synthon Bv Solid-state montelukast
US20090143590A1 (en) * 2004-07-19 2009-06-04 Matrix Laboratories Ltd. Process for the Preparation of Montelukast and its Salts

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US9717684B2 (en) 2014-04-25 2017-08-01 R.P. Scherer Technologies, Llc Stable montelukast solution

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