WO2008126075A1 - Procédé de préparation de montélukast et de ses sels utilisant du 2-(2-(3(s)-(3-(7-chloro-2-quinolinyl)éthényl)phényl)-3-hydroxypropyl)phényl-2-propanol optiquement impur - Google Patents

Procédé de préparation de montélukast et de ses sels utilisant du 2-(2-(3(s)-(3-(7-chloro-2-quinolinyl)éthényl)phényl)-3-hydroxypropyl)phényl-2-propanol optiquement impur Download PDF

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Publication number
WO2008126075A1
WO2008126075A1 PCT/IL2008/000484 IL2008000484W WO2008126075A1 WO 2008126075 A1 WO2008126075 A1 WO 2008126075A1 IL 2008000484 W IL2008000484 W IL 2008000484W WO 2008126075 A1 WO2008126075 A1 WO 2008126075A1
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WIPO (PCT)
Prior art keywords
compound
organic solvent
acid
acetate
organic
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PCT/IL2008/000484
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English (en)
Inventor
Michal Noiman
Ada Salman
Inna Levin
Oded Arad
Joseph Kaspi
Alex Weisman
Yael Gafni
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Chemagis Ltd.
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Publication of WO2008126075A1 publication Critical patent/WO2008126075A1/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 present invention relates to the field of organic chemistry and, more particularly, to a process for preparing montelukast and salts thereof using optically impure 2-(2-(3 (S)-(3 -(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3 -(hydroxypropyl)phenyl)-2 propanol (II) as starting material.
  • Montelukast sodium, (R)-(E)- 1-(((1 -(3 -(2-(7-chloro-2-quinolinyl)- ethenyl)phenyl)-3 -(2-(I -hydroxy- 1 -methylethyl)phenyl)propyl)thio)methyl)- cyclopropaneacetic acid sodium salt is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent.
  • Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis and is marketed in the United States and other countries by Merck & Co. Inc. under the trade name Singulair®.
  • Montelukast sodium is represented by the structural formula (I) below:
  • Montelukast sodium possesses one chiral carbon center, and a racemic form of montelukast sodium contains equal amounts of the two enantiomeric forms, i.e., the S and R optical isomers.
  • the biologically active form of montelukast sodium is the R stereoisomer. Since the biological activity of the two enantiomers can be different, it is imperative that the amount of the S stereoisomer in the commercial product be controlled to within acceptable limits, as required by the various national drug regulatory agencies (e.g., the FDA).
  • the ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • the relevant ICH guideline is "Impurities in New Drug Substances Q3 A (R2)," second revision, issued in October 2006.
  • this guideline states that any impurity present at a level of 0.05% or above must be reported.
  • the structure of any impurity present at a level of 0.10% or more must be determined.
  • a toxicological qualification to assess its risk to humans is required. Accordingly, the amount of the S optical isomer of montelukast should be lower than 0.15%.
  • Montelukast sodium was first disclosed in European Patent No. EP 480 717 (EP '717).
  • the synthesis of montelukast sodium is depicted in Scheme 1 below and involves reacting compound (II) with methanesulfonyl chloride (MsCl) to obtain the mesylate alcohol, compound (III).
  • Compound (III) then is coupled with methyl l-(mercapto- methyl)cyclopropane acetate, compound (IV), to afford the montelukast methyl ester, compound (V).
  • compound (V) is hydrolyzed to form montelukast free acid, compound (VI).
  • Treatment of compound (VI) with aqueous sodium hydroxide affords montelukast sodium salt, compound (I), which is isolated by freeze drying.
  • U.S. Patent No. 5,614,632 discloses a method of preparing crystalline montelukast sodium salt.
  • the dilithium dianion of l-(mercaptomethyl)cyclopropaneacetic acid, compound (VII) is prepared using n-butyl lithium, which reacts with compound (III) to afford a solution of montelukast acid in ethyl acetate.
  • Reaction of the montelukast acid with dicyclohexylamine affords solid montelukast dicyclohexylamine salt, compound (IX), which subsequently is converted into crystalline montelukast sodium.
  • optically impure compound (II) There are several options for purifying optically impure compound (II) which include separation of enantiomers via differential absorption, chiral recognition, biochemical processes, kinetic resolution, and/or deracemization, selective formation of a desired enantiomer over the undesired one, and the like. These procedures require extensive efforts and are time consuming.
  • the process comprises the steps of:
  • compound (e) optionally converting compound (IX) to montelukast sodium (I), wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, C 1-15 alkyl, and aryl, with the proviso that no more than two OfR 1 , R 2 , and R 3 can be hydrogen, and the resulting compound (I) or compound (IX) has an enantiomeric excess of at least 99.7%.
  • step (a) comprises: i) reacting optically impure compound (II), a base, and methanesulfonyl chloride in an organic solvent to form a suspension comprising compound (III); and ii) separating the suspension to obtain a filtrate comprising compound (III).
  • step (b) comprises: i) reacting compound (VII) with a base in an organic solvent, which optionally comprises a co-solvent, to form a dianion of compound (VII); ii) reacting the dianion of compound (VII) with compound (III) to form a salt of compound (VI); iii) adding an organic solvent, water, and an acid; and iv) separating the organic layer comprising compound (VI).
  • step (c) comprises adding an organic amine to a solution of compound (VI) in an organic solvent to form compound (IX).
  • step (d) comprises isolating compound (IX).
  • compound (IX) is isolated by filtration.
  • step (d) comprises purifying compound (IX) by crystallizing from an organic solvent.
  • step (e) comprises: i) admixing compound (IX), an acid, an organic solvent, and water to form an aqueous layer and an organic layer, comprising compound (VI); ii) separating the organic layer from the aqueous layer; iii) washing the organic layer with water; iv) evaporating a portion of the organic solvent to form a concentrated mixture; v) adding a base and water to the concentrated mixture to form an aqueous layer, comprising compound (I), and an organic layer; vi) separating the aqueous layer, comprising compound (I); and vii) isolating compound (I).
  • an optically impure compound (II) can be used to prepare an optically pure (R)-montelukast acid or salt thereof, wherein the resulting (R)-montelukast acid or salt thereof contains less than 0.15% by weight of (S)- enantiomer of montelukast acid or a salt thereof.
  • the present invention provides a process for preparing montelukast acid or a salt thereof from optically impure compound (II), as shown in Scheme 3.
  • optical impure refers to a compound having from 84% to 99% enantiomeric excess.
  • optically pure refers to a compound having an enantiomeric excess equal or greater than 99%.
  • alkyl means straight chained and branched hydrocarbon groups containing from 1 to 20 carbon atoms, typically methyl, ethyl, propyl and straight chained and branched butyl groups.
  • alkyl also includes "bridged alkyl,” i.e., a C 6 -C 16 bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl.
  • Alkyl groups optionally can be substituted, for example, with hydroxy (OH), halo, aryl, heteroaryl, amino, and sulfonyl.
  • aryl means a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, C 1-6 alkyl, OCF 3 , NO 2 , CN, NC, CO 2 H, and OC 1-6 alkyl.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.
  • the process for preparing montelukast or a salt thereof preferably includes the steps of:
  • Step (a) comprises the steps of: i) reacting optically impure compound (II), a base, and methanesulfonyl chloride in an organic solvent to form a suspension comprising compound (III); and ii) separating the suspension to obtain a filtrate comprising compound (III).
  • the organic solvent of step (i) is selected from the group consisting of toluene, xylenes, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, and mixtures thereof.
  • the organic solvent is THF.
  • the base of step (i) typically is an organic amine.
  • suitable organic amines for use as a base in step (a) include triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylaniline, and mixtures thereof.
  • the base is DIPEA.
  • Step (b) comprises the steps of: i) reacting compound (VII) with a base in an organic solvent, which optionally comprises a co-solvent, to form a dianion of compound (VII); ii) reacting the dianion of compound (VII) with compound (III) to form a salt of compound (VI); iii) adding an organic solvent, water, and an acid; and iv) separating the organic layer comprising compound (VI).
  • the organic solvent of step (i) is selected from the group consisting of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), 2-methyl- tetrahydrofuran, acetonitrile, acetone or a mixture thereof.
  • the organic solvent is NMP.
  • the co-solvent of step (i) is water.
  • the co-solvent can be present in a volume/volume ratio of about 1 to about 10% v/v of the solvent.
  • the amount of co-solvent is from about 4% v/v to about 6% v/v, based on the total volume of the mixture.
  • the base of step (i) is selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • the base is sodium hydroxide.
  • the amount of base used in step (i) is at least about 1.1 moles per mole of compound (VII).
  • the amount of base can be about 1.3 to about 2.5 moles base per mole compound (VII), about 1.7 to about 2.2 moles base per mole compound (VII), or about 1.9 to about 2.1 moles base per mole compound (VII).
  • the organic solvent of step (iii) comprises methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene or a mixture thereof.
  • the organic solvent is toluene.
  • the acid used in step (iii) can be an inorganic acid or an organic acid.
  • the acid is an organic acid, such as acetic acid, propionic acid, oxalic acid, benzoic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, malic acid, citric acid or a mixture thereof.
  • the organic acid comprises tartaric acid.
  • Step (c) comprises adding an organic amine to a solution of compound (VI) in an organic solvent to form compound (IX).
  • the organic amine can be any amine of formula NR 1 R 2 R 3 , wherein R 1 , R 2 , and R 3 are as defined above, and include primary, secondary and tertiary amines, e.g., amines where no more than two OfR 1 , R 2 , and R 3 are hydrogen.
  • the organic amine is selected from the group consisting of cyclohexyl amine, cyclopentylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, and phenethylamine. In a preferred embodiment, the organic amine is cyclooctylamine.
  • the organic solvent can be any organic solvent compatible with the reaction, and is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene, and mixtures thereof.
  • the organic solvent is toluene.
  • Step (d) comprises isolating compound (IX).
  • compound (IX) is isolated by filtration.
  • compound (IX) is optionally purified by crystallizing compound (IX) from an organic solvent.
  • the organic solvent typically is methanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, toluene, xylenes, and mixtures thereof.
  • the organic solvent for crystallization comprises toluene.
  • the organic solvent further comprises up to about 5% methanol.
  • the organic solvent comprises 0.5% methanol.
  • Step (e) optionally comprises the steps of: i) admixing compound (IX), an acid, and an organic solvent to form compound (VI) in a biphasic system of a first organic layer and a first aqueous layer; ii) separating the first organic layer, comprising compound (VI), from the first aqueous layer; iii) washing the first organic layer with water; iv) evaporating a portion of the organic solvent to form a concentrated mixture; v) adding a base and water to the concentrated mixture of step (iv) to form a second aqueous layer, comprising compound (I), and a second organic layer; vi) separating the second aqueous layer from the second organic layer; and vii) isolating compound (I) from the second aqueous layer.
  • the organic solvent of step (i) can be any organic solvent compatible with the conditions of step (i) of step (e).
  • the organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, chloroform, dichloromethane, toluene, and mixtures thereof.
  • the organic solvent is ethyl acetate.
  • the acid used of step (i) typically is an organic acid.
  • Suitable organic acids include 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 is tartaric acid.
  • the base of step (v) comprises sodium hydroxide.
  • Isolating compound (I) in the aqueous layer of step (vii) can be via precipitation, crystallization, spray-drying, filtration, evaporation, chromatography, and the like.
  • compound (I) is isolated from the aqueous layer by spray-drying.
  • the enantiomeric excess of compound (I) obtained via the present process herein typically is greater than 99.7%, greater than 99.8% or greater than 99.9%.
  • the present process results in pure compound (I) comprising total impurities (e.g., any compound that is different from the chemical entity defined as the new drug substance and represented by structural formula (I)) in amounts less than about 0.5% by weight. In preferred embodiments, the amount of impurities is less than about 0.2% by weight.
  • total impurities e.g., any compound that is different from the chemical entity defined as the new drug substance and represented by structural formula (I)
  • Step 1 Preparation of compound (III): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged at room temperature with (S)-compound (II) having 8.0% by weight of R-compound (II) as an impurity (9.34 g, 0.0205 moles) and anhydrous THF (50 mL). The mixture was stirred and cooled to about - 20°C. DIPEA (5.04 mL, 0.0291 moles) was added in portions, followed by the addition of methanesulfonyl chloride (1.93 mL, 0.0249 moles), also in portions.
  • DIPEA 5.04 mL, 0.0291 moles
  • Step 2 Preparation of compound (IX): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged at room temperature with compound (VII) (6.41 g, 0.0408 moles) and NMP (50 mL). The mixture was stirred under a nitrogen atmosphere to obtain a solution. 50% NaOH (w/w) solution (4.73 ml, 0.0902 moles) were added in portions at room temperature. The reaction mixture was stirred for 1 hour at room temperature to afford a suspension. A solution of compound (III), prepared in Step 1, in THF (about 50 mL), was maintained at about -20°C and added in portions to the dianion mixture of compound (VII) at room temperature.
  • the HPLC purity of (R)-montelukast cyclooctylammonium salt was 99.3%.
  • the crude montelukast cyclooctylammonium salt was crystallized twice from toluene containing about 0.5% by volume methanol to afford 5.9 g of dry crystalline (R)-montelukast cyclooctylammonium salt in 78% yield with 99.7% HPLC purity and less than 0.1% by weight of the (S) isomer.
  • Step 3 Preparation of montelukast sodium (I): A three-necked flask equipped with a thermometer, a nitrogen inlet, and a magnetic stirrer was charged with crystalline montelukast cyclooctylammonium salt (5.9 g) and ethyl acetate (90 mL). The mixture was stirred, then tartaric acid solution (15 mL of a 0.5M solution) was added. After stirring at room temperature for 30 minutes, a two-phase system was formed. The layers were separated, and the organic layer (containing compound (I)) was washed three times with water (65 mL), then concentrated by evaporation to about half of its volume.

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

Abstract

L'invention concerne un procédé de préparation de montélukast et de ses sels utilisant du 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)éthényl)phényl)-3-hydroxypropyl)phényl-2-propanol optiquement impur en tant que matière première, ladite matière première contenant l'impureté énantiomère R en une quantité comprise entre plus de 0,5 % et environ 8,0 % en poids. Le procédé décrit dans le présent document utilisant un matériau optiquement impur permet d'obtenir le produit final, le montélukast de sodium, en une pureté optique supérieure à 99,7 % d'excès énantiomérique.
PCT/IL2008/000484 2007-04-12 2008-04-09 Procédé de préparation de montélukast et de ses sels utilisant du 2-(2-(3(s)-(3-(7-chloro-2-quinolinyl)éthényl)phényl)-3-hydroxypropyl)phényl-2-propanol optiquement impur WO2008126075A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7812168B2 (en) 2005-07-05 2010-10-12 Teva Pharmaceutical Industries Ltd. Purification of montelukast
WO2010148209A2 (fr) * 2009-06-19 2010-12-23 Dr. Reddy's Laboratories Ltd. Préparation de montelukast
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
JP2015055479A (ja) * 2013-09-10 2015-03-23 株式会社トクヤマ モンテルカストナトリウム中間体の分析方法
CN110045049A (zh) * 2018-01-17 2019-07-23 天津药物研究院有限公司 一种同时测定孟鲁司特钠及其制剂多种有关物质的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614632A (en) * 1993-12-28 1997-03-25 Merck & Co., Inc. Process for the preparation of leukotriene anatgonists
US20050107612A1 (en) * 2002-12-30 2005-05-19 Dr. Reddy's Laboratories Limited Process for preparation of montelukast and its salts
WO2006043846A1 (fr) * 2004-10-22 2006-04-27 Instytut Farmaceutyczny Sel de montelukast associe au tert-butylamine
WO2008001213A1 (fr) * 2006-06-26 2008-01-03 Aurobindo Pharma Limited Procédé amélioré de préparation de l'antagoniste récepteur d'un leucotriène (montélukast de sodium)
WO2008023044A1 (fr) * 2006-08-23 2008-02-28 Sandoz Ag Procédé de préparation de l'acide libre montélukast et ses sels aminés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614632A (en) * 1993-12-28 1997-03-25 Merck & Co., Inc. Process for the preparation of leukotriene anatgonists
US20050107612A1 (en) * 2002-12-30 2005-05-19 Dr. Reddy's Laboratories Limited Process for preparation of montelukast and its salts
WO2006043846A1 (fr) * 2004-10-22 2006-04-27 Instytut Farmaceutyczny Sel de montelukast associe au tert-butylamine
WO2008001213A1 (fr) * 2006-06-26 2008-01-03 Aurobindo Pharma Limited Procédé amélioré de préparation de l'antagoniste récepteur d'un leucotriène (montélukast de sodium)
WO2008023044A1 (fr) * 2006-08-23 2008-02-28 Sandoz Ag Procédé de préparation de l'acide libre montélukast et ses sels aminés

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7812168B2 (en) 2005-07-05 2010-10-12 Teva Pharmaceutical Industries Ltd. Purification of montelukast
WO2010148209A2 (fr) * 2009-06-19 2010-12-23 Dr. Reddy's Laboratories Ltd. Préparation de montelukast
WO2010148209A3 (fr) * 2009-06-19 2011-08-04 Dr. Reddy's Laboratories Ltd. Préparation de montelukast
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
JP2015055479A (ja) * 2013-09-10 2015-03-23 株式会社トクヤマ モンテルカストナトリウム中間体の分析方法
CN110045049A (zh) * 2018-01-17 2019-07-23 天津药物研究院有限公司 一种同时测定孟鲁司特钠及其制剂多种有关物质的方法
CN110045049B (zh) * 2018-01-17 2021-07-09 天津药物研究院有限公司 一种同时测定孟鲁司特钠及其制剂多种有关物质的方法

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