WO2008087628A1 - Procédé de préparation de montélukast sodique contenant des taux contrôlés d'impuretés - Google Patents

Procédé de préparation de montélukast sodique contenant des taux contrôlés d'impuretés Download PDF

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Publication number
WO2008087628A1
WO2008087628A1 PCT/IL2008/000055 IL2008000055W WO2008087628A1 WO 2008087628 A1 WO2008087628 A1 WO 2008087628A1 IL 2008000055 W IL2008000055 W IL 2008000055W WO 2008087628 A1 WO2008087628 A1 WO 2008087628A1
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Prior art keywords
acid
compound
montelukast
base
organic solvent
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PCT/IL2008/000055
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English (en)
Inventor
Michael Brand
Alex Weisman
Yael Gafni
Lior Zelikovitch
Guy Davidi
Efrat Manoff
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Chemagis Ltd.
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Publication of WO2008087628A1 publication Critical patent/WO2008087628A1/fr

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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

Definitions

  • the invention relates to the chemistry of the drug montelukast sodium, and more particularly to an improved process for preparing montelukast sodium containing a low level of a dehydration impurity, which results from elimination of the tertiary alcohol group of montelukast to form a styrenyl moiety.
  • Montelukast sodium is a leukotriene antagonist, and is useful as an antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agent.
  • Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma.
  • Montelukast sodium formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), typically is given once daily to a patient for the treatment of asthma and seasonal allergic rhinitis.
  • Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name SINGULAIR®.
  • U.S. Patent No. 5,523,477 describes the formation of montelukast and its subsequent conversion into the dicyclohexyl ammonium salt, which is converted to montelukast sodium.
  • U.S. Patent No. 5,614,632 describes a method of preparing crystalline montelukast sodium, which involves the preparation of the dilithium dianion of 1- (mercaptomethyl)cyclopropaneacetic acid (compound (VII)), using butyl lithium, followed by condensation thereof with compound (III) to yield montelukast acid as a viscous oil, after workup. The resulting montelukast acid is converted, via the corresponding dicyclohexyl ammonium salt, into crystalline montelukast sodium.
  • compound (VII) 1- (mercaptomethyl)cyclopropaneacetic acid
  • III compound (III)
  • a drug manufacturer must submit data demonstrating that the product intended for marketing complies with the regulations with regard to the content of impurities.
  • the content of an unidentified impurity cannot exceed 0.1% by weight, while the amount of a known impurity cannot exceed 0.15%.
  • the drug manufacturer usually submits analytical data to the regulatory authority demonstrating that the content of each impurity is in accordance with the regulations.
  • the regulatory authority checks the submitted data in order to ensure that the drug is free of impurities and is suitable for marketing.
  • U.S. Patent Application Publication No. 2006/0194839 discloses a process for converting montelukast dicyclohexylamine salt into the acid form by treatment with dilute solution of a weak acid, indicating it is a "somewhat delicate” step because impurities, such as (R-(E))-l-(((l-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(2- ( 1 -methylethenyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid (compound (VI)), may be formed during the treatment with acid.
  • This impurity is derived from dehydration of the tertiary alcohol group and "is difficult to remove.”
  • an improved process for preparing montelukast acid or salts thereof, having low levels of compound (VI), comprising the steps of: (a) admixing compound (II) and methanesulfonyl chloride to obtain compound (III); (b) admixing compound (III) and compound (VII) to obtain montelukast or a salt thereof; and (c) admixing compound (III) and compound (VII), optionally in the presence of a base, to obtain montelukast or a salt thereof, and wherein the amount of compound (VI) produced is less than 0.15%, less than 0.12%, or less than 0.1% by weight.
  • the molar ratio of methanesulfonyl chloride to compound (II) is about 1.1:1 to about 1.5: 1. In some cases, the molar ratio of methanesulfonyl chloride to compound (II) is about 1.15:1 to about 1.45:1, about 1.2:1 to about 1.45:1, or about 1.35:1 to about 1.45:1. Molar ratios greater than about 1.5:1 typically produce greater amounts of impurities, such as compound (VI), while molar ratios less than about 1.1 : 1 do not produce a high enough yield of compound (III).
  • the process also comprises adding a base to compound (II) and cooling, prior to addition of the methanesulfonyl chloride.
  • the mixture of the base and compound (II) is typically cooled to below about 2O 0 C, but can be cooled to below about 10 0 C, below about 0°C, or at or below about -10 0 C.
  • the base is typically an organic base, and more specifically, an amine.
  • Amines contemplated for use in the process include, but are not limited to, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, N,N-diisopropylethylamine, N,N- dimethylaniline, and mixtures.
  • the base comprises N 3 N- diisopropylethylamine (DIEA).
  • the molar ratio of base to compound (II) is typically less than or equal to 2:1.
  • the molar ratio of base to compound (II) is about 1.2:1 to about 2:1, about 1.25:1 to about 1.8:1, about 1.3:1 to about 1.5:1, or about 1.35:1 to about 1.45:1.
  • Molar ratios of base to compound (II) above about 2:1 can lead to greater production of undesired impurities, such as compound (VI), while molar ratios of base to compound (II) below about 1.2:1 are less efficient for maximizing product yield.
  • the methansulfonyl chloride can be added to the cooled mixture of base and compound (II). The addition can be dropwise or at least two portions.
  • the methanesulfonyl chloride can be added in three portions, four portions, five portions, or six portions.
  • the admixture of compound (III) and compound (VII) further comprises mixing compound (VII) and an organic solvent; adding a base to the mixture; and then adding compound (III), where compound (III) can be added dropwise or in at least two portions.
  • the organic solvent can be N 5 N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2- pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, or mixtures thereof.
  • the organic solvent comprises N-methyl-2- pyrrolidone.
  • the base is typically an inorganic base.
  • Specific bases contemplated for use include, but are not limited to, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • the base comprises sodium hydroxide.
  • the molar ration of base to compound (III) is about 1.5:1 to about 2.5:1.
  • a cosolvent such as water
  • the amount of cosolvent is typically at least 1% by volume of the organic solvent, and can be about 3%, about 5%, or about 10%. In some embodiments, the cosolvent is about 5% by volume of the organic solvent.
  • the process further comprises admixing an organic acid and the reaction product of compound (III) and (VII) (i.e., step (c)) to obtain montelukast acid.
  • the organic acid of this step can be any acid compatible with the reaction conditions, but typically is selected from acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, and mixtures thereof.
  • the organic acid comprises tartaric acid.
  • the process further comprises admixing an amine and the reaction product of compound (III) and (VII) (i.e., step (c)) to obtain an ammonium salt of montelukast.
  • amines that can be used include cyclohexylamine, cyclopentylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, phenethylamine, and mixtures thereof.
  • the amine is cyclooctylamine.
  • this process can also include seeding the admixture with a crystal of the ammonium salt of montelukast, and/or purifying the ammonium salt of montelukast.
  • Purifying can be any means to remove impurities from the ammonium salt of montelukast, including, but not limited to, crystallizing the ammonium salt of montelukast, using chromatography or other separation techniques, extracting the ammonium salt of montelukast from impurities, filtering the ammonium salt of montelukast, or mixtures of any two or more of these techniques.
  • Crystallizing the ammonium salt of montelukast typically comprises adding an organic solvent to the ammonium salt of montelukast in order to promote crystallization.
  • organic solvents used include, but are not limited to, methanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, toluene, and mixtures thereof.
  • the organic solvent comprises toluene or toluene having up to 5% methanol.
  • the ammonium salt of montelukast is converted to the sodium salt of montelukast (i.e., montelukast sodium). Therefore, the process further comprises (1) admixing the ammonium salt, an acid, an organic solvent, and water; (2) separating the water; (3) optionally evaporating at least a portion of the organic solvent; (4) adding a base and water; (5) separating the organic solvent; and (6) drying the resulting aqueous mixture to obtain montelukast sodium. The drying can be via spray-drying.
  • the organic acid used can be any organic acid compatible with the process, but is typically acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, or mixtures thereof.
  • the organic acid is tartaric acid.
  • Two steps in the process that are particularly susceptible to forming impurities are the reaction of compound (II) and methanesulfonyl chloride to form compound (III) and the reaction of compound (III) with compound (IV) or compound (VII).
  • API active pharmaceutical ingredient
  • One of the main impurities of montelukast or its salts is compound (VI), a dehydration impurity which is difficult to remove once it has been formed. Therefore, the disclosed processes are directed to minimizing the amount of impurities formed.
  • one embodiment provides an improved process for preparing montelukast acid or salt thereof, having low levels of compound (VI), comprising the steps of: (a) admixing compound (II) and methanesulfonyl chloride to obtain compound (III); and (b) admixing compound (III) and compound (VII), optionally in the presence of a base, to obtain montelukast or a salt thereof, wherein the amount of compound (VI) produced is less than 0.15%, less than 0.12%, or less than 0.1% by weight.
  • the molar ratio of methanesulfonyl chloride to compound (II) is about 1.1:1 to about 1.5: 1. In some cases, the molar ratio of methanesulfonyl chloride to compound (II) is about 1.15:1 to about 1.45:1, about 1.2:1 to about 1.45:1, or about 1.35:1 to about 1.45:1. Molar ratios greater than about 1.5:1 typically produce greater amounts of impurities, such as compound (VI), while molar ratios less than about 1.1 :1 do not produce a high enough yield of compound (III). [0033] The process also comprises adding a base to compound (II) and cooling, prior to addition of the rnethanesulfonyl chloride.
  • the mixture of the base and compound (II) is typically cooled to below about 20°C, but can be cooled to below about 10 0 C, below about 0°C, or at or below about -10 0 C.
  • the base is typically an organic base, and in specific embodiments, is an amine.
  • Amines contemplated for use in the process include, but are not limited to, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, N,N-diisopropylethylamine, N,N- dimethylaniline, and mixtures thereof.
  • the base comprises N,N-diisopropylethylamine (DIEA).
  • the molar ratio of base to compound (II) is typically less than or equal to 2: 1. hi various embodiments, the molar ratio of base to compound (II) is about 1.2: 1 to about 2:1, about 1.25:1 to about 1.8:1, about 1.3:1 to about 1.5:1, or about 1.35:1 to about 1.45:1. Molar ratios of base to compound (II) above about 2:1 can lead to greater production of undesired impurities, such as compound (VI), while molar ratios of base to compound (II) below about 1.2:1 are less efficient for maximizing product yield.
  • the methansulfonyl chloride can be added to the cooled mixture of base and compound (II). The addition can be dropwise or at least two portions.
  • the methanesulfonyl chloride can be added in three portions, four portions, five portions, or six portions.
  • the admixture of compound (III) and compound (VII) further comprises mixing compound (VII) and an organic solvent; adding a base to the mixture; and then adding compound (III), where compound (III) can be added dropwise or in at least two portions.
  • the organic solvent can be N 5 N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2- pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, or mixtures thereof.
  • the organic solvent comprises N-methyl-2- pyrrolidone.
  • Compound (VII) can be mixed with a base prior to reaction with compound (III).
  • the base is an inorganic base.
  • bases include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • the ratio of base to compound (VII) is typically at least about 1.1:1, but can be about 1.5:1 to about 2.5:1, or about 1.8:1 to about 2.1:1.
  • Compound (VII) and the base typically are mixed in a polar organic solvent.
  • Non-limiting examples of organic solvents suitable for this step include N,N-dimethylformamide (DMF), N 5 N- dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, acetone, and mixtures thereof.
  • the polar organic solvent is NMP.
  • the organic solvent can be mixed with a cosolvent, such as water.
  • the amount of cosolvent is at least 1% by volume, and can be about 3% to about 10%, or about 4% to about 6% by volume.
  • a polar solvent e.g., NMP with optional addition of about 5% water, efficiently dissolves the dianion of compound (VII) (e.g., a disodium dianion) and allows for better reaction between compound (VII) and compound (III).
  • Montelukast acid can be isolated from the reaction of compound (VII) and compound (III) by adding an acid to the mixture.
  • the acid can be either an inorganic acid or an organic acid.
  • the acid is an organic acid selected from the group consisting of acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, and combinations thereof, and preferably comprises tartaric acid.
  • a process for producing an ammonium salt of montelukast comprising admixing an amine and the reaction product of compound (VII) and compound (III) to obtain an ammonium salt of montelukast, and optionally purifying the ammonium salt of montelukast.
  • an amine include cyclohexylamine, cyclopentylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, and phenethylamine.
  • An organic solvent can be added to the reaction mixture prior to purifying the ammonium salt of montelukast.
  • the organic solvent can be methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene or mixtures thereof.
  • the organic solvent comprises toluene.
  • Purifying can be any means to remove impurities from the ammonium salt of montelukast, including, but not limited to, crystallizing the ammonium salt of montelukast, using chromatography or other separation techniques, extracting the ammonium salt of montelukast from impurities, filtering the ammonium salt of montelukast, or mixtures of any two or more of these techniques.
  • crystallizing is used, the mixture can optionally be seeded with a crystal of the ammonium salt of montelukast.
  • Crystallizing the ammonium salt of montelukast typically comprises adding an organic solvent to the ammonium salt of montelukast in order to promote crystallization.
  • organic solvents used include, but are not limited to, methanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, toluene, and mixtures thereof.
  • the organic solvent comprises toluene or toluene having up to 5% methanol.
  • a process for preparing the sodium salt of montelukast from an ammonium salt further comprises (1) admixing the ammonium salt, an acid, an organic solvent, and water; (2) separating the water; (3) optionally evaporating at least a portion of the organic solvent; (4) adding a base and water; (5) separating the organic solvent; and (6) drying the resulting aqueous mixture to obtain montelukast sodium.
  • the drying can be via spray-drying.
  • the organic acid used can be any organic acid compatible with the process, but is typically acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, or mixtures thereof.
  • the organic acid is tartaric acid.
  • Non-limiting examples of the organic solvent include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene and mixtures thereof.
  • the organic solvent comprises ethyl acetate.
  • step (b) heating the admixture of step (a) to afford a solution
  • step (e) optionally seeding the mixture of step (d) with a crystal of compound (VI); (f) crystallizing compound (VI) from the mixture of step (d) or step (c);
  • (h) optionally re-crystallizing the compound (VI) crystals from an organic solvent.
  • organic solvent include toluene, xylenes, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, isopropyl alcohol, and mixtures thereof.
  • Toluene is a preferred organic solvent.
  • the acid used in the process for preparing compound (VI) can be either an inorganic or organic acid.
  • the acid is an organic acid.
  • Non-limiting examples of organic acids include acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid, and combinations thereof.
  • the organic acid comprises maleic acid.
  • Compound VI prepared using the disclosed processes is produced in at least about 70% yield.
  • the purity is at least 98.5%, and can be more than 99%, or greater than 99.5% (as determined by HPLC).
  • DIPEA N,N-diisopropylethylamine
  • the crude montelukast acid cyclooctyl ammonium salt was crystallized from toluene to obtain a product having 97% purity and containing 1.4% of the methylene impurity.
  • Ethyl acetate 25 mL was added followed by addition of 17 mL of 0.5M tartaric acid solution. The mixture was stirred at room temperature for half an hour to afford a two phase system. The layers were separated and the upper ethyl acetate layer (containing the montelukast acid) was washed with 10 mL water. A solution of 0.15 g of solid sodium hydroxide in 25 mL of water was added in portions to the organic phase, and the layers were separated.
  • the aqueous layer (containing the desired end product) was transferred into a three-necked flask equipped with nitrogen inlet, a stirrer, and a distillation head, and the solution was concentrated under vacuum at about 40°C. Acetonitrile was added and the mixture was allowed to cool to ambient temperature and seeded with crystalline montelukast sodium. The crystalline product was obtained by filtration and washed with acetonitrile.
  • Toluene (130 mL) and 130 mL of a saturated sodium chloride solution (brine) were added to the reaction mixture and mixing was maintained for 20 minutes. The layers were separated and the organic layer was washed with 130 mL of brine, and the layers were separated. Tartaric acid (84 mL of 0.5 M solution) was added to the upper layer and the layers were separated. The upper layer was washed with 40 mL of water and again separated. The organic layer was distilled to dryness to afford an oily residue. Toluene (90 mL) was added to the residue and the mixture was distilled to dryness to afford 11 g of an oily residue. Toluene (90 mL) was added to the residue under stirring to obtain a solution.
  • a saturated sodium chloride solution brine
  • the crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol to obtain a product having 99% purity and containing 0.1% compound (VI).
  • Ethyl acetate 100 mL was added followed by addition of 17 mL of 0.5M tartaric acid solution. The mixture was stirred at room temperature for half an hour to afford a two-phase system. The layers were separated and the ethyl acetate layer (containing the montelukast acid) was washed with 3 x 70 mL of water and concentrated by distillation to about half of its volume.
  • the cake was washed with toluene (550 mL) and dried to afford montelukast cycloocyl ammonium salt (1.13 g, 70% yield).
  • the HPLC purity of the montelukast cycloocyl ammonium salt was 97.7%, and contained 0.25% compound (VI) and 0.46% compound (VIII).
  • the montelukast cycloocyl ammonium salt then was crystallized from toluene having about 2% methanol to obtain montelukast cycloocyl ammonium salt in 85% yield having 99.5% purity and having 0.17% compound (VI) and 0.03% compound (VIII).
  • the product was re-crystallized to obtain 99.7% purity and 0.17% compound (VI) and no detectable compound (VIII).
  • the re-crystallized montelukast cycloocyl ammonium salt (690 g) was placed in a clean, dry reactor with dichloromethane (5.8 L) and stirred for 15 minutes at room temperature. A 5M citric acid solution (3.45 L) was added and the mixture stirred for 30 minutes at room temperature to afford a two-phase system. The layers were separated and the organic layer (containing the montelukast acid) was washed three times each with 3 liters of water. Water (4.7 liters) then was added to the organic phase and a solution IM NaOH (785 mL) was added drop-wise. The organic solvent was distilled off. The pH of the resulting aqueous layer was measured at 8.65.
  • Example 5 Preparation of Montelukast Cycloheptylamine Salt
  • N,N-diisopropylethylamine (2.6 mL; 0.015 moles) was added in portions followed by addition of 1 mL (0.013 moles) of methanesulfonyl chloride in portions, and stirring was maintained at about -20°C for about 2 hours.
  • the cold suspension containing the compound (III) was filtered at -20 0 C and the cake was washed with cold anhydrous THF.
  • a reaction vessel was charged with 2 g (0.0034 moles) of montelukast acid in 30 mL of toluene under stirring and the suspension was heated to reflux to afford a solution. Maleic acid (0.92 g; 0.0079 moles) was added, and reflux was maintained for about 4 hours. A sample was withdrawn and checked by HPLC to ensure that no more than 1% of the starting material was present.
  • the reaction mixture was cooled to about 25°C and seeded with compound (VI). Then, stirring was maintained for about 1 hour at about 25 0 C, and for about 1 hour at about 5°C. The mixture was filtered, washed with cold toluene and dried in vacuum to afford 1.4 g of the desired product in 70% yield, having a purity of 99.5% (by HPLC).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Quinoline Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé de préparation de Montélukast ou d'un sel de celui-ci, présentant des quantités minimales d'impuretés, telles qu'une impureté de déshydratation (composé (VI)) ou une impureté éther cyclique (composé (VIII)).
PCT/IL2008/000055 2007-01-15 2008-01-13 Procédé de préparation de montélukast sodique contenant des taux contrôlés d'impuretés WO2008087628A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011121091A1 (fr) 2010-03-31 2011-10-06 Krka, D.D., Novo Mesto Synthèse efficace pour la préparation de montélukast et nouvelle forme cristalline d'intermédiaires dans celle-ci
CN102164897B (zh) * 2008-09-26 2013-04-17 株式会社Lg生命科学 制备孟鲁司特钠盐的方法
DE102007061630B4 (de) * 2007-12-20 2013-07-04 Formosa Laboratories, Inc. Neue Verbindungen und Herstellung von Montelukast-Natrium
CN105646344A (zh) * 2016-02-29 2016-06-08 山东新时代药业有限公司 一种孟鲁司特的纯化方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006058545A1 (fr) * 2004-11-30 2006-06-08 Medichem, S.A. Nouveau procede de preparation d'un antagoniste de leucotriene

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006058545A1 (fr) * 2004-11-30 2006-06-08 Medichem, S.A. Nouveau procede de preparation d'un antagoniste de leucotriene

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007061630B4 (de) * 2007-12-20 2013-07-04 Formosa Laboratories, Inc. Neue Verbindungen und Herstellung von Montelukast-Natrium
CN102164897B (zh) * 2008-09-26 2013-04-17 株式会社Lg生命科学 制备孟鲁司特钠盐的方法
WO2011121091A1 (fr) 2010-03-31 2011-10-06 Krka, D.D., Novo Mesto Synthèse efficace pour la préparation de montélukast et nouvelle forme cristalline d'intermédiaires dans celle-ci
CN105646344A (zh) * 2016-02-29 2016-06-08 山东新时代药业有限公司 一种孟鲁司特的纯化方法
CN105646344B (zh) * 2016-02-29 2018-08-14 山东新时代药业有限公司 一种孟鲁司特的纯化方法

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