SI22382A - New procedure for preparation of montelukast - Google Patents
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- SI22382A SI22382A SI200600255A SI200600255A SI22382A SI 22382 A SI22382 A SI 22382A SI 200600255 A SI200600255 A SI 200600255A SI 200600255 A SI200600255 A SI 200600255A SI 22382 A SI22382 A SI 22382A
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Abstract
Description
Nov postopek za pripravo montelukastaA new process for preparing montelukast
Področje izumaFIELD OF THE INVENTION
Predloženi izum opisuje nov postopek za pripravo montelukasta in njegovih farmacevtsko sprejemljivih soli in estrov.The present invention describes a novel process for the preparation of montelukast and its pharmaceutically acceptable salts and esters.
Ozadje izumaBACKGROUND OF THE INVENTION
Natrijev montelukast je močan inhibitor CysLTl in se uporablja za kronično zdravljenje in preprečevanje astme pri odraslih in pediatričnih pacientih.Montelukast sodium is a potent CysLT1 inhibitor and is used for the chronic treatment and prevention of asthma in adult and pediatric patients.
Njegovo kemijsko ime je mononatrijeva sol l-[[[[3-[(lE)-2-(7-klorokinolin-2il)etenil]fenil]-3-[2-(l-hidroksi-l-metiletil)fenil]-propil]tio]metil]ciklopropan ocetne kisline in je prikazan z naslednjo formulo:Its chemical name is the monosodium salt of l - [[[[3 - [(1E) -2- (7-chloroquinolin-2yl) ethenyl] phenyl] -3- [2- (1-hydroxy-1-methylethyl) phenyl] - propyl] thio] methyl] cyclopropane acetic acid and is represented by the following formula:
Empirična formula je C35H35ClNNaO3S in njegova molekulska masa je 608,18. Natrijev montelukast je higroskopičen, optično aktiven bel do sivobel prašek. Natrijev montelukast se zlahka topi v etanolu, metanolu in vodi in je praktično netopen v acetonitrilu. Natrijev montelukast je selektiven in oralno aktiven antagonist levkotrienskega receptorja, ki inhibira receptor cisteinil levkotriena CysLTi. Aktiven je kot protiastmatično, protialergijsko, protivnetno in krioprotektivno sredstvo in je zato uporaben pri zdravljenju angine, cerebralnega krča, gloinerulonefritisa. hepatitisa, endotoksemije, uveitisa in zavračanja presadkov.The empirical formula is C35H3 5 ClNNaO 3 S and its molecular weight is 608.18. Montelukast sodium is a hygroscopic, optically active white to off-white powder. Montelukast sodium is readily soluble in ethanol, methanol and water and is practically insoluble in acetonitrile. Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor CysLTi. It is active as an anti-asthmatic, anti-allergic, anti-inflammatory and cryoprotective agent and is therefore useful in the treatment of angina, cerebral spasm, gloinerulonephritis. hepatitis, endotoxemia, uveitis and graft rejection.
Natrijev montelukast prodajajo v obliki filmsko obloženih tablet, žvečljivih tablet in granul pod trgovskim imenom SINGULAIR®. Komercialno dosegljive filmsko obložene tablete SINGULAIR® vsebujejo mikrokristalinično celulozo, laktozni monohidrat, natrijevo kroskarmelozo, hidroksipropilcelulozo, magnezijev stearat in prevleko, ki obsega hidroksipropilmetilcelulozo, hidroksipropilcelulozo, titanov dioksid, rdeč in rumen železov oksid in vosek kamauba.Montelukast sodium is marketed in the form of film-coated tablets, chewable tablets and granules under the trade name SINGULAIR®. Commercially available SINGULAIR® film-coated tablets contain microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, magnesium stearate and a coating comprising hydroxypropylmethylcellulose, hydroxypropyl titulose dioxide, and redosulphoseliculose dioxide.
Prvič je bil opisan v EP 480 717 Al. Pripravljalni postopek iz EP 480 717 je prikazan na shemi 1. Mezilat reagira z metil l-(merkaptometil)ciklopropan acetatom, ki ga proizvedejo in situ iz metil 1 -(acetiltiometil)ciklopropan acetata s hidrazinom. Tvorjeni ester hidrolizirajo v prosto kislino (I):It was first described in EP 480 717 Al. The preparation process of EP 480 717 is shown in Scheme 1. The mesylate is reacted with methyl 1- (mercaptomethyl) cyclopropane acetate, which is produced in situ from methyl 1- (acetylthiomethyl) cyclopropane acetate with hydrazine. The formed ester is hydrolyzed to free acid (I):
kjer R pomeni 2-(2-hidroksi)propilno skupino, in prosto kislino pretvorijo v natrijev montelukast. Prikazan postopek je neprikladen za proizvodnjo v večjem merilu zaradi potrebe po kromatografskem čiščenju, ki ga ni mogoče uporabiti v industrijskem merilu. Poleg tega se pri uporabi oksazaborolidinskega kompleksa v začetnih reakcijskih stopnjah tvori delno prekomerno reduciran proizvod v količini do 10 %.where R is a 2- (2-hydroxy) propyl group, and the free acid is converted to montelukast sodium. The process shown is unsuitable for large scale production due to the need for chromatographic purification which cannot be used on an industrial scale. In addition, when using the oxazaborolidine complex, an over-reduced product of up to 10% is formed in the initial reaction steps.
Izboljšan postopek je opisan v EP 737 186, kjer dilitijeva sol 1(merkaptometil)ciklopropanacetata reagira z enakim mezilatom, kot je na shemi 1. Organsko raztopino montelukasta pretvorijo v dicikloheksilamonijevo sol montelukasta. Pomanjkljivost tega načina sinteze je uporaba n-butil litija, ki je zelo reaktiven in je težko ravnati z njim v industrijskem merilu.An improved process is described in EP 737 186, wherein the dilithium salt 1 (mercaptomethyl) of cyclopropanacetate is reacted with the same mesylate as in Scheme 1. The organic solution of montelukast is converted to the dicyclohexylammonium salt of montelukast. The disadvantage of this synthesis method is the use of n-butyl lithium, which is very reactive and difficult to handle on an industrial scale.
WO 2006/008562 opisuje postopek za pripravo montelukasta z asimetričnim transfernim hidrogeniranjem ketonskega intermediata z uporabo kiralnega rutenijevega ali rodijevega katalizatorja v prisotnosti -vira vodika. Pomanjkljivost te reakcije je, da ni selektivna - tvori se zmes prekomerno reduciranega proizvoda, želenega proizvoda in izhodne spojine.WO 2006/008562 describes a process for the preparation of montelukast by asymmetric transfer hydrogenation of a ketone intermediate using a chiral ruthenium or rhodium catalyst in the presence of a hydrogen source. The disadvantage of this reaction is that it is not selective - a mixture of the over-reduced product, the desired product and the starting compound is formed.
WO 2006/05845 se nanaša na postopek za pripravo montelukasta, kjer 2-[2-[3(S)-[3[(l£)-2-(7-klorokinolin-2-il)etenil]fenil]-3-metilsulfoniloksipropil]fenil-2-propanol reagira z l-(merkaptometil)ciklopropan ocetno kislino v prisotnosti baze, prednostno alkalijskega hidroksida. Pomanjkljivost tega postopka je, da je treba dobljeno kislino, ki se tvori z nakisanjem reakcijske zmesi, nadalje očistiti pred pretvorbo le-te v natrijevo sol montelukasta.WO 2006/05845 relates to a process for the preparation of montelukast, wherein 2- [2- [3 (S) - [3 [(1 S) -2- (7-chloroquinolin-2-yl) ethenyl] phenyl] -3- methylsulfonyloxypropyl] phenyl-2-propanol is reacted with 1- (mercaptomethyl) cyclopropane acetic acid in the presence of a base, preferably alkali hydroxide. The disadvantage of this process is that the resulting acid, which is formed by acidifying the reaction mixture, must be further purified before converting it to the montelukast sodium salt.
Tako še vedno obstaja potreba po učinkoviti sintezi natrijevega montelukasta, prikladni za proizvodnjo v velikem obsegu.Thus, there is still a need for efficient synthesis of montelukast sodium, suitable for large-scale production.
Glavna vsebina izumaThe main content of the invention
Presenetljivo smo ugotovili, da lahko dobimo proizvod (I) z dobrim dobitkom z reakcijo intermediata (II) z intermediatom (III) z reakcijo pripajanja po Hecku, kot je prikazano na shemi 2.It was surprisingly found that product (I) can be obtained in good yield by reaction of intermediate (II) with intermediate (III) by the Heck coupling reaction as shown in Scheme 2.
Glavne vidike predloženega izuma lahko povzamemo naslednje:The main aspects of the present invention can be summarized as follows:
i) reakcija spojine (II) s spojino (III) v bazičnih razmerah v prisotnosti katalizatorja, pri čemer Ri pomeni atom halogena, SO2R' ali diazonij; R2 pomeni COOR3- ali CORi-skupino ali 2-(2-hidroksi)propilni ali hidroksi zaščiten 2-(2-hidroksi)propilni del; in R3 ter R4 pomenita Ci-C6 alkil, prednostno metil, in R' pomeni negativni naboj, vodik, alkilno, cikloalkilno, cikloarilno ali arilno skupino;i) reacting compound (II) with compound (III) under basic conditions in the presence of a catalyst, wherein R 1 represents a halogen atom, SO 2 R 'or diazonium; R 2 represents a COOR 3 or COR 1 group or a 2- (2-hydroxy) propyl or hydroxy protected 2- (2-hydroxy) propyl moiety; and R 3 and R 4 are C 1 -C 6 alkyl, preferably methyl, and R 'represents a negative charge, hydrogen, alkyl, cycloalkyl, cycloaryl or aryl group;
ii) izolacija in po izbiri čiščenje tvoijenega proizvoda, po izbiri s pretvorbo v ustrezno sol;ii) isolation and optionally cleaning of your product, optionally by conversion to the corresponding salt;
iii) metilacija, če R2 pomeni COOR3- ali COR^-skupino, kjer sta R3 in R4, kot je definirano zgoraj, ali deprotekcija, če R2 pomeni hidroksi zaščiteno 2-(2hidroksi)propilno skupino;iii) methylation if R 2 represents a COOR 3 - or COR 4 -group wherein R 3 and R 4 are as defined above or deprotection if R 2 represents a hydroxy protected 2- (2 hydroxy) propyl group;
iv) naalkaljenje proizvoda iz stopnje iii) in izolacija montelukasta v obliki farmacevtsko sprejemljive soli.iv) calcining the product of step iii) and isolating montelukast in the form of a pharmaceutically acceptable salt.
V najbolj prednostnih izvedbah pustimo, daIn the most preferred embodiments, let us
a) spojina (llb) in 2-etenil-7-klorokinolin (III) alia) compound (11b) and 2-ethenyl-7-chloroquinoline (III), or
b) spojina (Ila) in 2-etenil-7-klorokinolin (III) reagirata v prisotnosti Pd(OAc)2, P(o-tolila)3 in Et3N v raztopini ali suspenziji DMF.b) compound (Ila) and 2-ethenyl-7-chloroquinoline (III) are reacted in the presence of Pd (OAc) 2 , P (o-tolyl) 3 and Et 3 N in DMF solution or suspension.
V primeru reakcije a) pridobljeni proizvod (Ib) nadalje metiliramo in naalkalimo, da dobimo farmacevtsko sprejemljivo sol montelukasta, kot je prikazano na shemi 3. V primeru b) pridobljeni proizvod le naalkalimo in izoliramo v obliki soli montelukasta.In case of reaction a) the obtained product (Ib) is further methylated and basified to give the pharmaceutically acceptable salt of montelukast as shown in Scheme 3. In example b) the obtained product is only basified and isolated in the form of a montelukast salt.
Nadaljnji vidik tega izuma se nanaša na izboljšan postopek za pripravo enantiomemo obogatenega alkohola s formulo (V) iz formule (VI). V skladu s predloženim izumom je zagotovljen izboljšan postopek za pripravo enantiomemo obogatenih alkoholov s formulo (V). Postopek vključuje asimetrično redukcijo ustreznega ketona (VI) z uporabo redukcijskega sredstva, prednostno natrijevega ali litijevega borohidrida in boronatnih estrov, izvedenih iz vinske kisline:A further aspect of the present invention relates to an improved process for the preparation of enantiome-enriched alcohols of formula (V) of formula (VI). According to the present invention there is provided an improved process for the preparation of enantiomerically enriched alcohols of formula (V). The process involves the asymmetric reduction of the corresponding ketone (VI) using a reducing agent, preferably sodium or lithium borohydride and boronic acid esters derived from tartaric acid:
OHOH
(V)(V)
OOh
OHOH
OOh
(V) kjer je Ri izbran iz skupine, ki obsega halogene, OR', SO2R' in (£)-2-(7-klorokinolin2-il)etenil; in R2 pomeni COOR3- ali CORt-skupino ali 2-(2-hidroksi)propilno ali hidroksi zaščiteno 2-(2-hidroksi)propilno skupino; in R3 ter R4 pomenita CrC6-alkil, prednostno metil, in R' pomeni negativni naboj, vodik, alkilno, cikloalkilno, cikloarilno ali arilno skupino.(V) wherein R 1 is selected from the group consisting of halogens, OR ', SO 2 R' and (S) -2- (7-chloroquinolin-2-yl) ethenyl; and R 2 represents a COOR 3 or CORt group or a 2- (2-hydroxy) propyl or hydroxy protected 2- (2-hydroxy) propyl group; and R 3 and R 4 denote C r C 6 -alkyl, preferably methyl, and R 'is a negative charge, hydrogen, alkyl, cycloalkyl, cikloarilno or an aryl group.
Opis izumaDescription of the invention
Po vidiku i) predloženega izuma pripravimo spojino (I) z reagiranjem spojine (II) s spojino (III) v inertnem topilu in v prisotnosti katalizatorja. Reakcijo izvedemo pri temperaturi med 60 °C in 200 °C, prednostno pri temperaturi med 80 °C in 110 °C v približno 7-15 h, kot je prikazano na shemi 2.According to aspect i) of the present invention, compound (I) is prepared by reacting compound (II) with compound (III) in an inert solvent and in the presence of a catalyst. The reaction is carried out at a temperature between 60 ° C and 200 ° C, preferably at a temperature between 80 ° C and 110 ° C, for about 7-15 h, as shown in Scheme 2.
Topila za reakcijo pripajanja lahko izberemo izmed različnih znanih procesnih topil. Primeri topil za pripajanje, ki jih lahko uporabimo ali same ali v kombinaciji, so: benzen, toluen, tetrahidrofuran, dioksan, acetonitril, dimetilformamid, dimetilacetamid, etanol, metanol, propanol, voda, 2-metiltetrahidrofuran ali dietoksimetan, N-metilpirolidinon, heksametilfosforamid, superkritični CO2 in/ali ionske tekočine.The coupling reaction solvents can be selected from various known process solvents. Examples of coupling solvents that can be used either alone or in combination are: benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, ethanol, methanol, propanol, water, 2-methyltetrahydrofuran or diethoxymethane, N-methylpyrrolidinone, hexamethylphosphamide, hexamethylfamide , supercritical CO 2 and / or ionic liquids.
Kovinski katalizator, uporabljen v reakciji pripajanja po Hecku s sheme 2, je kompleks niklja, paladija ali platine, prednostno paladijev kompleks, kot je tetrakis (tri(4-metil)fenilfosfin) paladij, tetrakis (trifenilfosfm) paladij, bis(dibenzilidenaceton)paladij, tris(dibenzilidenaceton)dipaladij, fosfmiran paladijev (II) kompleks, izbran iz skupine, ki jo sestavljajo bis(trifenilfosfin)paladijev klorid, bis(trifenilfosfm)paladijev bromid, bis(trifenilfosfm)paladijev acetat, bis(triizopropilfosfit)paladijev klorid, bis(triizopropilfosfit)paladijev bromid, bis(triizopropilfosfit)paladijev acetat, [l,2-bis(difenilfosfmo)etan]paladijev klorid, [l,2-bis(difenilfosfino)etan]paladijev bromid, (l,2-bis(difenilfosfino)etan]paladijev acetat, 3-bis(difenilfosfmo)propan]paladijev klorid, (1,3bis(difenilfosfmo)propan]paladijev bromid, (1,3-bis(difenilfosfino)propan]paladijev acetat, [l,4-bis(difenilfosfino)butan]paladijev klorid, [1,4bis(difenilfosfino)butan]paladijev bromid in [l,4-bis(difenilfosfino)butan]paladijev acetat.The metal catalyst used in the Heck coupling reaction of Scheme 2 is a nickel, palladium or platinum complex, preferably a palladium complex such as tetrakis (three (4-methyl) phenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium , tris (dibenzylideneacetone) dipaladium, phosphated palladium (II) complex selected from the group consisting of bis (triphenylphosphine) palladium chloride, bis (triphenylphosphine) palladium bromide, bis (triphenylphosphine) palladium acetate, bis (triisopropylphosphite) palladium) (triisopropylphosphite) palladium bromide, bis (triisopropylphosphite) palladium acetate, [1,2-bis (diphenylphosphino) ethane] palladium chloride, [1,2-bis (diphenylphosphino) ethane] palladium bromide, (1,2-bis (diphenylphosphino) ethane] palladium acetate, 3-bis (diphenylphosphino) propane] palladium chloride, (1,3bis (diphenylphosphino) propane] palladium bromide, (1,3-bis (diphenylphosphino) propane] palladium acetate, [1,4-bis (diphenylphosphino) ) butane] palladium chloride, [1,4bis (diphenylphosphino) butane] palladium bromide and [1,4-bis (diphenylpho) sphino) butane] palladium acetate.
Aktivni katalizator lahko pripravimo vnaprej ali proizvedemo v reakcijski zmesi. Na primer, z dodatkom tris(dibenzilidenaceton)dipaladija v reakcijsko zmes, ki vsebuje trifenilfosfm v topilu, ki tvori katalizator, proizvedemo aktivni trifenilfosfm paladijev kompleks.The active catalyst can be prepared in advance or produced in the reaction mixture. For example, by adding tris (dibenzylideneacetone) dipaladium to a reaction mixture containing triphenylphosphine in a catalyst-forming solvent, the active triphenylphosphine palladium complex is produced.
Aktivni katalizator lahko pripravimo iz Pd(II)-soli, kot je paladijev klorid, paladijev bromid ali paladijev acetat, s triarilfosfinom, značilno trifenilfosfinom ali tri(4metil)fenilfosfinom, z delovanjem redukcijskih sredstev, kot je dialkilcink, alkilcinkov halogenid, dialkilmagnezij, alkilmagnezijev halogenid, trialkilaluminij, dialkilaluminijev hidrid, natrijev borohidrid, hidrazin ali arilboronska kislina, v prisotnosti topila, ki tvori katalizator. Prednostno redukcijsko sredstvo je dietilcink.The active catalyst can be prepared from Pd (II) salts, such as palladium chloride, palladium bromide or palladium acetate, with triarylphosphine, typically triphenylphosphine or three (4methyl) phenylphosphine, by the action of reducing agents such as dialkyl zinc, alkyl zinc halide, dialkyl halide, halide, trialkylaluminum, dialkylaluminum hydride, sodium borohydride, hydrazine or arylboronic acid, in the presence of a catalyst-forming solvent. The preferred reducing agent is diethyl zinc.
V reakcijah v smislu predloženega izuma lahko uporabimo organske in anorganske baze. Kot organske baze lahko uporabimo npr. primarne, sekundarne ali terciarneOrganic and inorganic bases can be used in the reactions of the present invention. As organic bases, for example, primary, secondary or tertiary
Ί amine, kot je trietilamin ali diizopropiletilamin. Kot anorganske baze lahko uporabimo npr. karbonate, hidrogenkarbonate, hidrokside in alkokside alkalijskih kovin, npr. kalijev karbonat, natrijev karbonat, natrijev hidrogenkarbonat, cezijev karbonat, talijev karbonat, kalijev hidroksid, natrijev hidroksid, talijev hidroksid ali alkokside teh alkalijskih kovin.Ine amines such as triethylamine or diisopropylethylamine. As inorganic bases, for example, carbonates, hydrogen carbonates, hydroxides and alkali metal alkoxides, e.g. potassium carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, thallium carbonate, potassium hydroxide, sodium hydroxide, thallium hydroxide or alkoxides of these alkali metals.
Če uporabimo anorgansko bazo, ki je netopna v organskem topilu, je potrebno raztapljanje v vodi; uporaba katalizatorja za fazni transfer, kot je tetra-n-butilamonijev bromid ali krona eter, lahko pospeši reakcijo. V nekaterih primerih so posebno uporabne baze, topne v organskem topilu, kot je tetra-n-butilamonijev karbonat ali tetra-n-butilamonijev hidroksid, benziltrimetilamonijev karbonat, benziltrimetilamonijev metil karbonat, benziltrimetilamonijev metoksid ali benziltrimetilamonijev hidroksid, ali druge bazične tetraalkilamonijeve spojine. Prednostno uporabimo trietilamin.If an inorganic base is insoluble in an organic solvent, dissolution in water is required; the use of a phase transfer catalyst such as tetra-n-butylammonium bromide or ether crown can accelerate the reaction. In some cases, solvents soluble in an organic solvent, such as tetra-n-butylammonium carbonate or tetra-n-butylammonium hydroxide, benzyltrimethylammonium carbonate, benzyltrimethylammonium methyl carbonate, benzyltrimethylammonium methoxide or benzyltrimethylammonium hydroxide, or other basylammonium tetrahydroalkyl, or other bases are particularly useful. Preferably triethylamine is used.
V najbolj prednostnih izvedbah pustimo, daIn the most preferred embodiments, let us
a) spojina (Ilb) in 2-etenil-7-klorokinolin (III) alia) compound (Ilb) and 2-ethenyl-7-chloroquinoline (III), or
b) spojina (Ha) in 2-etenil-7-klorokinolin (III) reagirata v prisotnosti Pd(OAc)2, P(o-tolila)3 in Et3N v raztopini ali suspenziji DMF.b) Compound (Ha) and 2-ethenyl-7-chloroquinoline (III) are reacted in the presence of Pd (OAc) 2 , P (o-tolyl) 3 and Et 3 N in DMF solution or suspension.
V primeru reakcije a) pridobljeni proizvod (Ib) nadalje metiliramo in naalkalimo, da dobimo farmacevtsko sprejemljivo sol montelukasta, kot je prikazano na shemi 3. V primeru b) pridobljeni proizvod le naalkalimo in izoliramo v obliki soli montelukasta.In case of reaction a) the obtained product (Ib) is further methylated and basified to give the pharmaceutically acceptable salt of montelukast as shown in Scheme 3. In example b) the obtained product is only basified and isolated in the form of a montelukast salt.
Prednostno je, da pripravimo spojine (II) z reagiranjem intermediata (IV), kjer Rj pomeni atom halogena, SO2R' ali diazonij; R2 pomeni COOR3- ali COR4-skupino ali 2-(2-hidroksi)propilni ali hidroksi zaščiten 2-(2-hidroksi)propilni del; in R3 ter R4 pomenita Ci-C6-alkil, prednostno metil, in R' pomeni negativni naboj, vodik, alkilno, cikloalkilno, cikloarilno ali arilno skupino, z 2-(l-merkaptometil)ciklopropil ocetno kislino ali njenim derivatom v prisotnosti močne baze, kot je t-BuONa, v prikladnem topilu, kot je DMF.It is preferred that the compounds (II) by reacting the intermediate (IV), wherein R represents a halogen atom, SO 2 R ', or diazonium; R 2 represents a COOR 3 or COR 4 group or a 2- (2-hydroxy) propyl or hydroxy protected 2- (2-hydroxy) propyl moiety; and R 3 and R 4 are C 1 -C 6 -alkyl, preferably methyl, and R 'represents a negative charge, hydrogen, alkyl, cycloalkyl, cycloaryl or aryl group, with 2- (1-mercaptomethyl) cyclopropyl acetic acid or a derivative thereof in the presence strong bases such as t-BuONa in a suitable solvent such as DMF.
V prednostni izvedbi je R2 2-(2-hidroksi)propil (spojina (IVa)) ali COOMe (spojina (IVb)) in Rj je brom. Ta postopek je shematsko prikazan na shemi 4.In a preferred embodiment, R 2 is 2- (2-hydroxy) propyl (compound (IVa)) or COOMe (compound (IVb)) and R 1 is bromine. This process is shown schematically in Scheme 4.
Shema 5 prikazuje eno od možnih pripravljalnih poti in vključuje tudi nižje intermediate.Scheme 5 shows one of the possible preparatory routes and also includes lower intermediates.
Intermediat (III) prednostno sintetiziramo iz 7-klorokinaldina z oksidacijo z SeO2 in kasnejšo Wittigovo reakcijo aldehida z metiltrifenilfosfonijevim bromidom, kot je prikazano na shemi 6.Intermediate (III) is preferably synthesized from 7-chloroquinaldine by oxidation with SeO 2 and subsequent Wittig reaction of the aldehyde with methylphenylphosphonium bromide, as shown in Scheme 6.
Po drugem vidiku predloženega izuma pripravimo spojino (IV) z asimetrično redukcijo spojine (V) z redukcijskim sredstvom, prednostno natrijevim ali litijevim borohidridom, v inertnem topilu in z boronatnim estrom, izvedenim iz vinske kisline, kot katalizatorjem. Reakcijo izvedemo pri temperaturi med -50 °C in 100 °C, prednostno pri temperaturi med 0 °C in 30 °C v približno 4-12 h.According to another aspect of the present invention, compound (IV) is prepared by asymmetric reduction of compound (V) with a reducing agent, preferably sodium or lithium borohydride, in an inert solvent and with a tartaric acid boronate ester as a catalyst. The reaction is carried out at a temperature between -50 ° C and 100 ° C, preferably at a temperature between 0 ° C and 30 ° C for about 4-12 hours.
Ta postopek je shematsko prikazan na shemi 7, kjer je Ri izbran iz skupine, ki obsega halogene, OR', SO2R' in (£)-2-(7-klorokinolin-2-il)etenil; in R2 pomeni COOR3- ali CORi-skupino ali 2-(2-hidroksi)propilno ali hidroksi zaščiteno 2-(2-hidroksi)propilno skupino; in R3 ter R4 pomenita Ci-C6-alkil, prednostno metil, in R' pomeni negativni naboj, vodik, alkilno, cikloalkilno, cikloarilno ali arilno skupino.This process is shown schematically in Scheme 7, wherein R 1 is selected from the group consisting of halogens, OR ', SO 2 R' and (S) -2- (7-chloroquinolin-2-yl) ethenyl; and R 2 represents a COOR 3 or COR 1 group or a 2- (2-hydroxy) propyl or hydroxy protected 2- (2-hydroxy) propyl group; and R 3 and R 4 represent C 1 -C 6 alkyl, preferably methyl, and R 'represents a negative charge, hydrogen, alkyl, cycloalkyl, cycloaryl or aryl group.
Prednostno je R2 2-(2-hidroksi)propil ali COOMe in Ri je brom.Preferably R 2 is 2- (2-hydroxy) propyl or COOMe and R 1 is bromine.
Topila za reakcijo lahko izberemo izmed različnih znanih procesnih topil. Primeri za topila, ki jih lahko uporabimo bodisi sama ali v kombinaciji, so: benzen, toluen, tetrahidrofuran, dioksan, dialkileter, acetonitril, 2-metiltetrahidrofiiran in/ali dietoksimetan.The reaction solvents can be selected from various known process solvents. Examples of solvents that can be used either alone or in combination are: benzene, toluene, tetrahydrofuran, dioxane, dialkyl ether, acetonitrile, 2-methyltetrahydrofiated and / or diethoxymethane.
V smislu predloženega izuma pripravimo boronatni ester, izveden iz vinske kisline, z reagiranjem (D)- ali (L)-vinske kisline z ustrezno substituirano arilboronsko kislino v refluktirajočem THF in v prisotnosti CaH2. Substituirane arilboronske kisline so prikazane s splošno formulo (VII):According to the present invention, a tartaric acid boronate ester is prepared by reacting (D) - or (L) -tartaric acid with the appropriately substituted arylboronic acid in refluxing THF and in the presence of CaH 2 . Substituted arylboronic acids are represented by the general formula (VII):
(VII) kjer R pomeni vodik, halogen, trifluorometil, ciano ali nitro substituent.(VII) wherein R is hydrogen, halogen, trifluoromethyl, cyano or nitro substituent.
Pomembno je, da kontroliramo velikost delcev natrijevega montelukasta med njegovo pripravo. Povprečna velikost delcev, pripravljenih in uporabljenih v smislu izuma, jeIt is important to control the particle size of sodium montelukast during its preparation. The average particle size prepared and used according to the invention is
5-200 pm, prednostno manjša od 100 pm. Če pri prekristalizaciji iz organskih topil ali njihovih zmesi z vodo ne izvajamo mešanja, lahko dobimo tudi večje delce, npr. s povprečnim premerom, večjim od 200 pm, in jih je potrebno zmleti ali obdelati na drug način za zmanjšanje velikosti delcev pred njihovo uporabo v farmacevtskih formulacijah. Pri mletju lahko proizvedemo delce, ki imajo povprečni premer manjši od 3 pm. Za ta namen kot naprave za mletje uporabimo mline na zračni curek, krogelne mline ali mline na kladiva. Vendar pa ni dovolj, da kontroliramo le povprečno velikost delcev, ampak tudi porazdelitev velikosti delcev.5-200 pm, preferably less than 100 pm. If recrystallization from organic solvents or mixtures thereof with water does not mix, larger particles can be obtained, e.g. having an average diameter greater than 200 µm and needing to be ground or otherwise treated to reduce particle size before being used in pharmaceutical formulations. When grinding, particles having an average diameter of less than 3 pm can be produced. For this purpose, we use air jet mills, ball mills or hammer mills as grinding machines. However, it is not enough to control only the average particle size, but also the particle size distribution.
Povprečna velikost delcev in porazdelitev velikosti delcev je pomembna, da zagotovimo, da je tehnološki postopek industrijsko uporaben, to je, da ne pride do segregacije sestavin zmesi za tabletiranje, če le-to ne tabletiramo/stisnemo takoj po njeni pripravi.The average particle size and particle size distribution is important to ensure that the process process is industrially applicable, that is, that no segregation of the constituents of the tabletting compound occurs unless it is tableted / compressed immediately after its preparation.
Predloženi izum je ponazorjen z naslednjimi Primeri, ki pa ga ne omejujejo.The present invention is illustrated by the following Examples, but which are not intended to be limiting.
PRIMERIEXAMPLES
Primer 1:Example 1:
3-(2-(3-bromofenil)-2-oksoetil)izobenzofuran-I-(3LQ-on3- (2- (3-bromophenyl) -2-oxoethyl) isobenzofuran-1 - (3LQ-one
V raztopino 20 g 3-bromoacetofenona in 16,6 g 2-karboksibenzaldehida v 400 mL EtOH, ohlajeno na 0 °C, dodamo 24 mL 5 M raztopine NaOH. Reakcijsko zmes mešamo pri temperaturi <5 °C 10 h in jo nato pustimo, da se počasi segreje na 20 °C v nadaljnjih 10 h. Dodamo 30 mL koncentrirane H2SO4, medtem ko temperaturo zmesi vzdržujemo pri <40 °C. Zmes segrevamo na 60 °C 1 h do končane laktonizacije. Proizvod mešamo 1 h pri 0 °C, nato pa ga filtriramo, speremo s hladnimTo a solution of 20 g of 3-bromoacetophenone and 16.6 g of 2-carboxybenzaldehyde in 400 mL of EtOH cooled to 0 ° C was added 24 mL of 5 M NaOH solution. The reaction mixture was stirred at <5 ° C for 10 h and then allowed to slowly warm to 20 ° C for a further 10 h. 30 mL of concentrated H 2 SO 4 was added while maintaining the temperature of the mixture at <40 ° C. The mixture was heated to 60 ° C for 1 h until complete lactonization. The product was stirred for 1 h at 0 ° C, then filtered, washed with cold
EtOH/H2O (1 : 1) in posušimo, da dobimo 29,1 g proizvoda.EtOH / H 2 O (1: 1) and dried to give 29.1 g of product.
rH NMR (CDC13) b7ppm: 8,09 (t, IH), 7,94-7,84 (m, 2H), 7,74-7,64 (m, 2H), 7,577,52 (m, 2H), 7,36 (t, IH), 6,16 (t, IH), 3,73 (dd, IH), 3,37 (dd, IH). r H NMR (CDCl 3 ) b 7 ppm: 8.09 (t, 1H), 7.94-7.84 (m, 2H), 7.74-7.64 (m, 2H), 7.577.52 (m. 2H), 7.36 (t, 1H), 6.16 (t, 1H), 3.73 (dd, 1H), 3.37 (dd, 1H).
Primer 2:Example 2:
Natrijev 2-(3-(3-bromofenil)-3-oksopropil)benzoatSodium 2- (3- (3-bromophenyl) -3-oxopropyl) benzoate
8,7 g ketolaktona iz Primera 1 suspendiramo v 200 mL etanola in po kapljicah dodamo 5 mL 5 M NaOH (1,96 mL, 1,96 mmol), nato pa trdno snov raztopimo, da dobimo rumeno raztopino enona. Raztopino obdelujemo z vodikom pri 2,76 χ 105 Pa pri sobni temperaturi in v prisotnosti 300 mg Wilkinsonovega katalizatorja 24 h. EtOH odstranimo v vakuumu in surovi proizvod uporabimo v naslednji stopnji brez nadaljnjega čiščenja.8.7 g of the ketolactone of Example 1 were suspended in 200 mL of ethanol and 5 mL of 5 M NaOH (1.96 mL, 1.96 mmol) was added dropwise, then the solid was dissolved to give a yellow enone solution. The solution was treated with hydrogen at 2.76 χ 10 5 Pa at room temperature and in the presence of 300 mg Wilkinson catalyst for 24 h. The EtOH was removed in vacuo and the crude product was used in the next step without further purification.
Primer 3:Example 3:
Metil 2-(3-(3-bromofenil)-3-oksopropil)benzoat (Vib)Methyl 2- (3- (3-bromophenyl) -3-oxopropyl) benzoate (Vib)
Raztopino proizvoda, pridobljenega v Primeru 2, v 150 mL MeOH in 3 mL H2SO4 segrevamo ob refluksu 24 h. Hlapne snovi odstranimo v vakuumu pri temperaturi <40 °C in delno kristaliziran ostanek počasi razredčimo s 50 mL vode in ekstrahiramo s 3 χ 50 mL EtOAc. Združene EtOAc-plasti speremo s 100 mL nasičene raztopine NaHCO3, posušimo nad Na2SO4 in uparimo do suhega. Z bliskovno kromatografijo (SiO2, heksan/EtOAc od 9 : 1 do 5 : 1) dobimo 4,71 g želenega proizvoda.A solution of the product obtained in Example 2 in 150 mL MeOH and 3 mL H 2 SO 4 was heated at reflux for 24 h. The volatiles were removed in vacuo at <40 ° C and the partially crystallized residue was slowly diluted with 50 mL water and extracted with 3 χ 50 mL EtOAc. The combined EtOAc layers were washed with 100 mL of saturated NaHCO 3 solution, dried over Na 2 SO 4 and evaporated to dryness. Flash chromatography (SiO 2 , hexane / EtOAc from 9: 1 to 5: 1) gave 4.71 g of the desired product.
Primer 4:Example 4:
Metil 2-i3-(3-bromofenil)-3-hidroksipropil)benzoat (Vb)Methyl 2- (3- (3-bromophenyl) -3-hydroxypropyl) benzoate (Vb)
V 6,3 g metil 2-(3-(3-bromofenil)-3-oksopropila) v 30 mL THF in 30 mL EtOH po deležih dodamo 0,514 g NaBH4 v periodi 15 min pri temperaturi -10 °C. Reakcijsko zmes mešamo 2,5 h pri -10 °C, nato pa jo pogasimo s počasnim dodajanjem 20 mL 0,1 M HCI. Po mešanju 30 min zmes zlijemo na 20 mL slanice in ekstrahiramo s 3 χ 20 mL EtOAc. Združene organske plasti speremo s 50 mL slanice in sušimo nad Na2SO4. Topilo uparimo v vakuumu, da dobimo 6,4 g surovega proizvoda.To 6.3 g of methyl 2- (3- (3-bromophenyl) -3-oxopropyl) in 30 mL of THF and 30 mL of EtOH, 0.514 g of NaBH 4 was added portionwise over a period of 15 min at -10 ° C. The reaction mixture was stirred for 2.5 h at -10 ° C and then quenched by the slow addition of 20 mL of 0.1 M HCl. After stirring for 30 min, the mixture was poured onto 20 mL brine and extracted with 3 × 20 mL EtOAc. The combined organic layers were washed with 50 mL brine and dried over Na 2 SO 4 . The solvent was evaporated in vacuo to give 6.4 g of crude product.
Primer 5:Example 5:
Metil 2-(3-(3-bromofenil)-3-kloropropil)benzoat (IVb)Methyl 2- (3- (3-bromophenyl) -3-chloropropyl) benzoate (IVb)
5,83 g metil 2-(3-(3-bromofenil)-3-hidroksipropil)benzoata raztopimo v 50 mL diklorometana in 2 mL Α,Α-dimetilformamida in ohladimo na -10 °C. V reakcijsko zmes po kapljicah v 1 h dodamo 2 mL SOC12 v 20 mL diklorometana. Reakcijsko zmes mešamo nadaljnjih 10 h pri -10 °C in nato 10 h pri sobni temperaturi. Zmes zlijemo v 20 mL nasičene raztopine NaHCO3 in ekstrahiramo s 3 χ 20 mL EtOAc. Organsko plast speremo s 50 mL nasičene raztopine NaHCO3, 50 mL slanice in sušimo nad Na2SO4. Topilo uparimo v vakuumu, da dobimo 5,63 g surovega proizvoda.5.83 g of methyl 2- (3- (3-bromophenyl) -3-hydroxypropyl) benzoate were dissolved in 50 mL of dichloromethane and 2 mL of α, α-dimethylformamide and cooled to -10 ° C. To the reaction mixture, 2 mL of SOCl 2 in 20 mL of dichloromethane was added dropwise over 1 h. The reaction mixture was stirred for a further 10 h at -10 ° C and then at room temperature for 10 h. The mixture was poured into 20 mL of saturated NaHCO 3 solution and extracted with 3 χ 20 mL of EtOAc. The organic layer was washed with 50 mL of saturated NaHCO 3 solution, 50 mL of brine and dried over Na 2 SO 4 . The solvent was evaporated in vacuo to give 5.63 g of crude product.
Primer 6:Example 6:
2-(l-((l-(3-bromofenil)-3-(2-(metoksikarbonil)fenil)propiltio)metil)ciklopropil)ocetna kislina (Ilb) mL DMF damo v 50 mL trigrlno bučko. Dodamo 1,364 g natrijevega t-butoksida pri kontinuimem mešanju. V to raztopino dodamo 1,080 g l-(merkaptometil)ciklopropan ocetne kisline z močnim mešanjem pri sobni temperaturi v 30 min. V reakcijsko zmes po kapljicah v 30 min dodamo raztopino 2,77 g metil 2-(3-(3bromofenil)-3-kloropropil)benzoata v 10 mL DMF. Zmes mešamo pri sobni temperaturi 48 h in jo nato pogasimo z vlivanjem v 20 mL vode in 20 mL etil acetata. Zmesi naravnamo pH na 7 z dodatkom 20-odstotne vinske kisline. Plasti ločimo in vodno plast ekstrahiramo z 2 χ 20 mL etil acetata. Združene organske plasti speremo z 20 mL 5-odstotne raztopine vinske kisline, 2 χ 20 mL vode in nato posušimo nad Na2SO4 in topilo uparimo. Z bliskovno kromatografijo (SiO2, heksan/EtOAc od 8 : 1 do 1 : 1) dobimo 1,48 g želenega proizvoda.2- (1 - ((1- (3-bromophenyl) -3- (2- (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (Ilb) mL of DMF was placed in a 50 mL triple flask. 1.364 g of sodium t-butoxide are added under continuous stirring. To this solution was added 1,080 g of l- (mercaptomethyl) cyclopropane acetic acid with vigorous stirring at room temperature for 30 min. A solution of 2.77 g of methyl 2- (3- (3bromophenyl) -3-chloropropyl) benzoate in 10 mL of DMF was added dropwise over 30 min. The mixture was stirred at room temperature for 48 h and then quenched by pouring into 20 mL water and 20 mL ethyl acetate. The mixture was adjusted to pH 7 with the addition of 20% tartaric acid. The layers were separated and the aqueous layer was extracted with 2 × 20 mL of ethyl acetate. The combined organic layers were washed with 20 mL of 5% tartaric acid solution, 2 χ 20 mL of water and then dried over Na 2 SO 4 and the solvent was evaporated. Flash chromatography (SiO 2 , hexane / EtOAc from 8: 1 to 1: 1) gave 1.48 g of the desired product.
Primer 7:Example 7:
(E)-2-(l-((l-(3-(2-(7-klorokinolin-2-il)vinil)fenil)-3-(2-(metoksikarbonil)fenil)propiltio)metil)ciklopropil)ocetna kislina (Ib)(E) -2- (1 - ((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (methoxycarbonyl) phenyl) propylthio) methyl) cyclopropyl) acetic acid (Ib)
V 265 mg spojine (Ilb) dodamo 7 mg Pd(OAc)2, 28 mg P(o-tolila)3, 100 mg 2-etenil7-klorokinolina (III) in 3 mL DMF. Temno zmes razplinjujemo 3-krat z uporabo tehnike zamrzovanja-črpanja-tajanja in nato dodamo 0,2 mL Et3N. Reakcijsko zmes segrevamo na 100 °C 4 h in jo nato ohladimo na 23 °C. Zmes zlijemo v 10 mL vode in ekstrahiramo s 3 χ 10 mL EtOAc. Združene organske plasti speremo z 20 mL slanice in posušimo nad Na2SO4. Topilo uparimo v vakuumu. Surovo zmes kromatografiramo na koloni silicijevega dioksida z uporabo EtOAc : n-heksan =1:2 + 1 % AcOH kot eluenta, pri čemer dobimo 191 mg proizvoda.To 265 mg of compound (Ilb) was added 7 mg Pd (OAc) 2 , 28 mg P (o-tolyl) 3, 100 mg 2-ethenyl7-chloroquinoline (III) and 3 mL DMF. The dark mixture was degassed 3 times using the freeze-pumping-thawing technique and then 0.2 mL of Et 3 N was added. The reaction mixture was heated to 100 ° C for 4 h and then cooled to 23 ° C. The mixture was poured into 10 mL of water and extracted with 3 χ 10 mL of EtOAc. The combined organic layers were washed with 20 mL brine and dried over Na 2 SO 4 . Evaporate the solvent in vacuo. The crude mixture was chromatographed on a silica column using EtOAc: n-hexane = 1: 2 + 1% AcOH as eluent to give 191 mg of product.
vv
Primer 8: Žvečljive tablete 5 mgExample 8: Chewable Tablets 5 mg
* ustreza 5,00 mg proste kisline montelukasta* corresponds to 5.00 mg of montelukast free acid
Pripravimo šaržo 1 kg. Manitol, aspartam, Želov oksid rdeče, mikrokristalinično celulozo in natrijevo kroskarmelozo zmešamo v granulatorju in granuliramo z raztopino Klucel EF. Dobljeni granulat posušimo in nato primešamo natrijev montelukast, natrijevo kroskarmelozo, mikrokristalinično celulozo, aromo cherry black in magnezijev stearat ter dobljeno zmes stisnemo v tablete z uporabo okroglih rahlo bikonveksnih žigov do ciljne trdote približno 20-90 N. Isto kompresijsko zmes uporabimo za pripravo tablet 4 mg s ciljno maso 240 mg.Prepare a batch of 1 kg. Mannitol, aspartame, Gel oxide red, microcrystalline cellulose and croscarmellose sodium are mixed in a granulator and granulated with Klucel EF solution. The obtained granulate was dried and then mixed with montelukast sodium, croscarmellose sodium, microcrystalline cellulose, cherry black aroma and magnesium stearate, and the resulting mixture was compressed into tablets using round slightly biconvex stamps to a target hardness of about 20-90 N. The same compression mixture was used. mg with a target mass of 240 mg.
Shema 1:Scheme 1:
Shema 2:Scheme 2:
Ila: R1 = Br, R2 = 2-(2-hidroksijpropil, llb: R1 = Br, R2 = COOMe la: R1 = Br, R2 = 2-(2-hidroksijpropil, Ib: R1 = Br, R2 = COOMeSludge: R1 = Br, R2 = 2- (2-hydroxypropyl, 11b: R1 = Br, R2 = COOMe la: R1 = Br, R2 = 2- (2-hydroxypropyl, Ib: R1 = Br, R2 = COOMe
Shema 3:Scheme 3:
O) (I)O) (I)
Ib: R1 = Br, R2 = COOMe la: R1 = Br, R2 = 2-(2-hidroksi)propilIb: R1 = Br, R2 = COOMe la: R1 = Br, R2 = 2- (2-hydroxy) propyl
Shema 4:Scheme 4:
IVa: R1 = Br, R2 = 2-(2-hidroksi)propil, IVb: R1 = Br, R2 = COOMe lla: R1 = Br, R2= 2-(2-hidroksi)propil, llb: R1 = Br, R2= COOMeIVa: R1 = Br, R2 = 2- (2-hydroxy) propyl, IVb: R1 = Br, R2 = COOMe lla: R1 = Br, R2 = 2- (2-hydroxy) propyl, 11b: R1 = Br, R2 = COOMe
Shema 5:Scheme 5:
BrO o>BrO o >
metil 2-(3-(3-bromofenil) -3-oksopropl)benzoatemethyl 2- (3- (3-bromophenyl) -3-oxopropyl) benzoate
(Vb) (S>metil 2-(3-(3-bromofenlj •3-hidroksipropil)benzoat(Vb) (S> methyl 2- (3- (3-bromophenyl • 3-hydroxypropyl) benzoate
3-(2-{3-bromofenil)-2-oksoetil) izobenzofiran-1 (3H)-one3- (2- {3-bromophenyl) -2-oxoethyl) isobenzofuran-1 (3H) -one
MeMgOMeMgO
(S)-2-(2-(3-{3-bromofenil)-3-kloropropl) feril)propan-2-ol t-BuCNa, DMF(S) -2- (2- (3- {3-bromophenyl) -3-chloropropyl) feryl) propan-2-ol t-BuCNa, DMF
COOHCOOH
HSt-BuONa, DMFHSt-BuONa, DMF
-COOH-COOH
Shema 6:Scheme 6:
cici
SeO2 dioxaneSeO2 dioxane
Ph3PCH^r t-BuONa, FtiMe THFPh3PCH ^ r t-BuONa, FtiMe THF
7-kloro-2-metilkinolr7-chloro-2-methylquinolr
Shema 7:Scheme 7:
7-kbrokinoiin-2-karbaldehid7-kbrokinoin-2-carbaldehyde
Claims (5)
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SI200600255A SI22382A (en) | 2006-10-26 | 2006-10-26 | New procedure for preparation of montelukast |
EP07821912A EP2094664A2 (en) | 2006-10-26 | 2007-10-26 | A new process for the preparation of montelukast |
PCT/EP2007/061552 WO2008049922A2 (en) | 2006-10-26 | 2007-10-26 | A new process for the preparation of montelukast |
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ATE497492T1 (en) | 2005-07-05 | 2011-02-15 | Teva Pharma | CLEANING MONTELUKAST |
EP2287154A1 (en) * | 2009-07-14 | 2011-02-23 | KRKA, D.D., Novo Mesto | Efficient synthesis for the preparation of montelukast |
EP2552892A1 (en) | 2010-03-31 | 2013-02-06 | KRKA, D.D., Novo Mesto | Efficient synthesis for the preparation of montelukast and novel crystalline form of intermediates therein |
WO2014081616A1 (en) * | 2012-11-21 | 2014-05-30 | Merck Sharp & Dohme Corp. | Preparation of precursors for leukotriene antagonists |
CN104109123B (en) * | 2013-04-16 | 2016-12-07 | 浙江奥翔药业股份有限公司 | For midbody compound synthesizing montelukast and preparation method thereof |
US9717684B2 (en) | 2014-04-25 | 2017-08-01 | R.P. Scherer Technologies, Llc | Stable montelukast solution |
CN105330540B (en) * | 2015-12-01 | 2018-01-23 | 中山奕安泰医药科技有限公司 | Montelukast receives the preparation method of intermediate |
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ATE500225T1 (en) * | 2004-07-19 | 2011-03-15 | Matrix Lab Ltd | METHOD FOR PRODUCING MONTELUKAST AND SALTS THEREOF |
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