EP2046750A2 - Procédé de préparation de montelukast - Google Patents

Procédé de préparation de montelukast

Info

Publication number
EP2046750A2
EP2046750A2 EP07766340A EP07766340A EP2046750A2 EP 2046750 A2 EP2046750 A2 EP 2046750A2 EP 07766340 A EP07766340 A EP 07766340A EP 07766340 A EP07766340 A EP 07766340A EP 2046750 A2 EP2046750 A2 EP 2046750A2
Authority
EP
European Patent Office
Prior art keywords
formula
montelukast
compound
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07766340A
Other languages
German (de)
English (en)
Inventor
Amir Avdagic
Juraj Jerkovic
Davorka Pavlicic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pliva Hrvatska doo
Original Assignee
Pliva Hrvatska doo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pliva Hrvatska doo filed Critical Pliva Hrvatska doo
Publication of EP2046750A2 publication Critical patent/EP2046750A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention is concerned with the preparation of montelukast, or a pharmaceutically acceptable salt thereof, in particular montelukast sodium.
  • Montelukast is the international non-proprietary name for l-[[[(lR)-l-[3-[(lE)-2-(7-Chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, having the following structural formula (I)
  • Montelukast is generally employed as its sodium salt and is a leukotriene antagonist. Montelukast, and its sodium salt, is thus useful as an anti-asthmatic, anti-allergic, antiinflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of allergic rhinitis and asthma.
  • EP 0737186B describes crystalline montelukast sodium and a process of preparing the same.
  • the process involves the preparation of the dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid as an intermediate, followed by condensation thereof with 2-(2-(3- (S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2- propanol, to yield montelukast acid, according to the following key reaction step
  • the resulting montelukast acid is converted, via a corresponding amine salt, to montelukast sodium.
  • the montelukast sodium is crystallized from a toluene/acetonitrile solution to obtain crystalline montelukast sodium.
  • EP 0737186B confirms that montelukast as disclosed in EP 0480717B is amorphous montelukast sodium.
  • WO 05/105751 discloses a process of preparing a pharmaceutically acceptable salt of montelukast, where 2-(2-(3(S)-(2-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-(( ⁇ - hydroxy)propyl)phenyl-2-propanol is activated with a benzylsulfonyl or mesyl group, the activated product is reacted with l-(mercaptomethyl)cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a co-solvent and a base, followed by hydrolysis.
  • a base selected from sodium hydroxide, sodium methoxide, sodium secondary butoxide, sodium tertiary butoxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium tertiary butoxide, or potassium carbonate, optionally in a solvent selected from a group consisting of methanol, ethanol, 1-pro ⁇ anol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, glycol; diethyl ether, diisopropyl ether, methyl isopropyl ether, tetrahydrofuran, diethylene glycol, 1,4-dioxan, methoxy ethanol; and toluene, cyclohexane, hexanes, n-heptane or mixtures of two or more miscible solvents.
  • a base selected from sodium hydroxide, sodium methoxide, sodium secondary butoxide, sodium tertiary butoxide, sodium carbonate, sodium bi
  • WO 05/105749 describes intermediates useful in the synthesis of montelukast, namely 2-(2- (3(S)- ⁇ 3-(2-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3(thio) ⁇ ropyl ⁇ phenyl ⁇ -2-propanol and 2-(2-(3(S)- ⁇ 3-(2-(7-chloro-2-quinolinyl)-ethenyl)-phenyl)-3(acetylthio) ⁇ ropyl ⁇ henyl ⁇ -2- propanol.
  • WO 05/105750 also describes intermediates useful in the synthesis of montelukast, namely methyl 2-((3R)-acetylsulfanyl)-3- ⁇ 3-[(E)-2-(7-chloro-2-quinolinyl)-ethenyl]- ⁇ henyl ⁇ -pro ⁇ yl)- benzoate and a cyclopropylacetate intermediate.
  • US 2005/0107612 discloses preparation of montelukast, or a salt thereof, by reacting a late intermediate compound which is 2-[l-[l-R-3-[2-(7-chloroquinolin-2-yl)vinyl [phenyl] -3- [2- methoxycarbonylphenyl]propylsulfonylmethyl]cyclopropyl]acetic acid or a salt thereof with methyl magnesium chloride or methyl magnesium bromide in an organic solvent.
  • a process for preparation of montelukast Na comprising: (i) providing a solution of starting montelukast free acid in a halogenated solvent, aromatic solvent, or mixtures thereof; (ii) treating said solution with an alcoholic base to convert said montelukast free acid into a sodium salt of montelukast; (iii) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said sodium salt of montelukast.
  • WO 06/021974 also discloses processes of preparing various intermediates useful in the preparation of montelukast sodium.
  • montelukast remains a difficult compound to prepare.
  • an unprotected mesylate intermediate as shown above with reference to EP 0737186B, WO 05/105751 and US 2005/0234241
  • EP 0480717B does employ a protected form of the above referenced intermediate, but this process is also not suitable for industrial application, as it requires numerous purification steps and finishes with harsh reaction conditions employing highly flammable butyl lithium at extremely low temperatures.
  • the process of EP 0480717B is also undesirable in that it employs the commercially unavailable di-ester of 1- (mercaptornethyi)cyclopropaneacetic acid.
  • an improved process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof comprises reacting a protected intermediate of formula (II) with a cyclopropyl intermediate of formula (III)
  • P 1 represents a hydroxy protecting group
  • L represents a leaving group, such as arylsulfonyl, typically selected from benzenesulfonyl or toluene sulfonyl, or C 1-4 alkylsulfonyl;
  • X represents a monovalent cation, for example Na + or Li + ;
  • Y represents -CN or -CO 2 X, where X is as above;
  • L represents C 1-4 alkylsulfonyl, especially methanesulphonyl.
  • X represent Na + .
  • Ms represents methanesulphonyl (mesyl); and P 1 is a hydroxy protecting group as above;
  • a process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (UIb)
  • Ms represents methanesulphonyl (mesyl); and P 1 is a hydroxy protecting group as above;
  • a process for the preparation of montelukast of formula (I), or a pharmaceutically acceptable salt thereof comprises reacting a protected intermediate of formula (Ha) with a cyclopropyl intermediate of formula (HIc)
  • Ms represents methanesulphonyl (mesyl); and P 1 is a hydroxy protecting group as above;
  • a cyclopropyl intermediate of formula (III), and as such any of intermediates (Ilia), (HIb) and (IHc). is added to a reaction medium for intermediates (II) and (III), as a precursor compound of formula (IV)
  • the reaction medium also includes a source of the monovalent cation X as present in formula (III).
  • the source of the monovalent cation is a strong base, such as an alkali metal alkoxide, preferably an alkali metal C 1-4 alkoxide, such as sodium or lithium C 1-4 alkoxide, for example sodium or lithium methoxide.
  • L and P 1 are substantially as hereinbefore described, and R represents C 1-4 alkyl, preferably methyl, and converting a compound of formula (XII) to the free acid form of montelukast of formula (I)
  • P 1 in formula (II) can represent any suitable hydroxy protecting group, for example alkyl, such as methyl, methoxyniethyl or methoxyethoxymethyl; aralkyl, such as benzyl, diphenylmethyl, or triphenylmethyl; heterocyclic groups, such as tetrahydropyranyl or tetrahydrofuranyl; acyl, such as acetyl or benzoyl; and silyl groups, such as trialkylsilyl, for example tert-butyldimethylsilyl.
  • P 1 represents tetrahydropyranyl.
  • Preferably conversion of the reaction product to the free acid form of montelukast of formula (I) is subject to deprotection and where required conversion of moiety Y as present in the reaction product to the free acid.
  • deprotection can be by hydrolysis under basic or acidic conditions. Pyridinium p-toluensulfonate can be used in the deprotection and the reaction is often heated over several hours, typically in the presence of a C 1-4 alcohol and a suitable inert organic solvent, such as tetrahydrofuran.
  • inert organic solvent is meant an organic solvent, which under the reaction conditions employed, does not enter into any appreciable reaction with either the reactants or the products.
  • Conversion of a cyano moiety Y, namely -CN, to the free acid can typically be carried out by acid or base hydrolysis, for example hydrolysis in the presence of an alkali metal hydroxide, such as sodium hydroxide.
  • a pharmaceutically acceptable salt of montelukast of formula (I) such as montelukast sodium
  • montelukast free acid of formula (I) may initially be converted to an intermediate amine salt, such as the dicyclohexylamine or adamantylamine salt, prior to conversion to a pharmaceutically acceptable salt, such as the sodium salt.
  • This intermediate amine salt formation can be advantageous in offering a simple and efficient method for purification of montelukast.
  • the salt forming amine is added to a solution of the montelukast free acid of formula (I) in a suitable solvent, such as ethyl acetate, followed by crystallization.
  • crystallization can be by hexane addition to effect crystallization of the required amine salt.
  • an adamantylamine salt is employed, specifically 1 -adamantylamine.
  • a process of preparing a pharmaceutically acceptable salt of montelukast of formula (I), in particular the sodium salt comprises treating the l-adamantylarnine salt of montelukast of formula (I) with an acid, treating the product thus obtained with a source of the pharmaceutically acceptable salt forming species, typically a source of sodium ions, and crystallizing the resulting pharmaceutically acceptable salt of montelukast of formula (I), typically montelukast sodium.
  • a process of preparing montelukast sodium comprises treating the 1 -adamantylamine salt of montelukast of formula (I) with an acid, treating the product thus obtained with a source of sodium ions, and crystallizing the resulting montelukast sodium.
  • a compound of formula (II) is prepared from a corresponding hydroxy compound of formula (V)
  • a compound of formula (II) is a mesyl protected intermediate
  • mesylation of a compound of formula (V) is carried out in an inert organic solvent, such as methylene chloride, suitably in the presence of a tertiary amine base, such as diisopropylethylamme, and at a temperature of ⁇ 0°C, preferably at a temperature in the range of about -15 to -5°C.
  • a compound of formula (V) can be prepared by selective deprotection of a protected derivative of formula (VI)
  • P 1 is a hydroxy protecting group substantially as hereinbefore described; and P 2 is a second hydroxy protecting group, which is different from P 1 ;
  • P 1 and P 2 are respectively such that P 2 can be selectively removed in preference to P 1 so as to yield a compound of formula (V).
  • P 1 represents a heterocycle, such as tetrahydropyranyl
  • P 2 represents a silyl group, such as trialkylsilyl, for example tert-butyldimethylsilyl, dimethylisopropylsilyl, tert-butyldiphenylsilyl or the like.
  • a suitable deprotecting agent can be a hydrated alkylammonium halide, such as tetra-n- butylammonium fluoride trihydrate which can be used in the selective removal of a silyl protecting group.
  • a compound of formula (VI) is typically prepared by the stepwise protection of the corresponding di-hydroxy compound of formula (VII)
  • P 1 and P 2 are respectively selcected and introduced so that P 2 can be preferentially removed to yield a compound of formula (V) as described above.
  • P 2 is first introduced as a protecting group for the secondary hydroxy group substituted on the propylene chain and P 1 is subsequently introduced as a protecting group for the tertiary hydroxy group substituted on the phenyl ring, although it is of course appreciated that the above protecting steps could be carried out in the reverse order with P 1 introduction followed by P 2 introduction.
  • a compound of formula (VII) is suitably prepared from a corresponding hydroxy ester of formula (VIII)
  • R 1 is a lower alkyl, namely C 1-4 alkyl, typically methyl or ethyl.
  • a solution of a compound of formula (VIII) is initially formed under reflux and the hydroxy ester of formula (VIII) is then converted to the di-hydroxy compound of formula (VII) under Grignard conditions.
  • a Grignard reagent such as methyl magnesium chloride in the presence of cerium chloride is employed.
  • the reaction can be carried out under anhydrous conditions, preferably using anhydrous cerium chloride, the hydroxy ester of formula (VIII) and solvents.
  • a suitable solvent is tetrahydrofuran.
  • a compound of formula (VIII) is suitably prepared from a compound of formula (IX)
  • the chiral ruthenium or rhodium catalyst is prepared in situ by reaction of a ruthenium or rhodium catalyst precursor and a chiral N-sulfamoyl-l,2-diamine type ligand.
  • the hydroxy ester of formula (VIII) is thus prepared in the form of a monohydrate.
  • montelukast free acid shown as molecule 10 of above Scheme 1
  • montelukast free acid may not necessarily be prepared in a process according to the present invention.
  • the sodium salt shown as molecule 11 of above Scheme 1 can be a direct product obtained from molecule 9.
  • the sodium salt shown as molecule 10 of above Scheme 2
  • the sodium salt shown as molecule 11 of above Scheme 3, can be a direct product obtained from molecule 9, in the case of basic hydrolysis, for example with NaOH.
  • T represents -CN, -CO 2 H or -CO 2 X 5 where X represents a monovalent cation, for example
  • Adamantylamine salts of montelukast of formula (I) substantially as hereinbefore described also represent novel compounds according to the present invention. Specifically, therefore, the present invention provides 1 -adamantylamine salt of montelukast of formula (I).
  • montelukast, or a pharmaceutically acceptable salt thereof, as prepared according to the present invention is generally useful for the preparation of pharmaceutical compositions, where montelukast, or a pharmaceutically acceptable salt thereof, is an active ingredient.
  • a pharmaceutical composition provided by the present invention includes montelukast, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a pharmaceutical composition which includes montelukast prepared by a process as described herein generally includes, in addition to the carrier or diluent, such components as antibacterial agents, antioxidant agents, binding agents, buffering agents, bulking agents, coloring agents, diluents, disintegrants, emulsifying agents, excipients, flavoring agents, glidants, lubricants, skin penetration enhancers, sweetening agents, viscosity modifying agents and any combination thereof, which provide the composition with desired characteristics.
  • the carrier or diluent such components as antibacterial agents, antioxidant agents, binding agents, buffering agents, bulking agents, coloring agents, diluents, disintegrants, emulsifying agents, excipients, flavoring agents, glidants, lubricants, skin penetration enhancers, sweetening agents, viscosity modifying agents and any combination thereof, which provide the composition with desired characteristics.
  • Montelukast as prepared by a process as described herein is typically in amorphous form.
  • a pharmaceutical composition according to the present invention can include, in addition to montelukast, or a pharmaceutically acceptable salt thereof, as prepared by a process as described herein, an additional form of montelukast sodium, and / or an additional active ingredient other than montelukast.
  • a pharmaceutical composition of the present invention can be formulated in various forms. These include, without limitations, an aerosol, a bolus, a capsule, a cream, a delayed release capsule, a dispersion, a dissolvable powder, drops, a gel capsule, granules, an injection, an inhalable form, a liposome, an ointment, a patch, a pill, a powder, a suppository, a suspension, a syrup, a tablet, a tincture and a topical cream.
  • montelukast is administered orally and as such preferred pharmaceutical compositions include solid dosage forms for oral administration such as, but not limited to, tablets (including chewable tablets), capsules, powders and granules.
  • compositions including montelukast as prepared by a process as described herein, or a pharmaceutically acceptable salt thereof may in turn be manufactured by processes well known in the art, for example by means of conventional mixing, dissolving, granulating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions suitable for use in context of the present invention include compositions where the active ingredients are contained in a therapeutically effective amount so as to achieve a required therapeutic purpose.
  • a therapeutically effective amount means an amount of active ingredient effective to cure a condition, treat a condition, prevent a condition, treat symptoms of a condition, cure symptoms of a condition, ameliorate symptoms of a condition, treat effects of a condition, ameliorate effects of a condition, and prevent results of a condition.
  • the pharmaceutical compositions according to the present invention are particularly useful with regard to conditions in which treatment by montelukast sodium is known to be beneficial. Such conditions include, but are not limited to, allergic rhinitis, asthma, and any related conditions.
  • a pharmaceutical composition of the present invention is useful in implementing a method of treating a medical condition in which administration of a leukotriene antagonist is beneficial. Accordingly, the present invention provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of a leukotriene antagonist in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of montelukast, or a pharmaceutically acceptable salt thereof, prepared by a process as described herein. Preferably, the administering is effected orally. Further preferably, the pharmaceutical composition is formulated in a solid dosage form.
  • the present invention also provides use of montelukast, or a pharmaceutically acceptable salt thereof prepared by a process as described herein, in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a leukotriene antagonist.
  • disease states or conditions include, but are not limited to, allergic rhinitis, asthma, and any related conditions.
  • anhydrous CeCl 3 (3.4g, 0.014mol) was suspended in anhydrous THF (6OmL).
  • THF 6OmL
  • the grey suspension was degassed with nitrogen and heated at 45°C for 2 hours and the resulting white suspension was cooled to -5 to 0 0 C.
  • a solution of methyl magnesium chloride (3M in THF, 45mL, 0.135mol) was added dropwise over 30 minutes to the CeCl 3 suspension, whilst maintaining the temperature under 0°C.
  • the solution was aged at 0°C for 2 hours.
  • the solution of Intermediate 1 in toluene from step 1 was added dropwise over 2 hours whilst maintaining the temperature at 3 to 5°C.
  • reaction mixture was aged for 15 minutes after the addition was complete. The reaction was then quenched by cautious addition of the obtained reaction mixture to a mixture of ice water (30OmL), toluene (30OmL) and acetic acid (8OmL) whilst maintaining the temperature under 25 °C. The yellow solution was stirred for 15 minutes and the layers were separated. The organic layer was washed with water and 5% sodium carbonate solution, dried over sodium sulfate and concentrated in vacuum. The title compound was obtained as yellow oil (12.7g, 103%, 94.5 area% by HPLC).
  • DCHA dicyclohexylamine
  • the white solid of the DCHA salt of montelukast free acid (5.85g) was dissolved in methylene chloride (15OmL) and acidified with 10% acetic acid (15OmL). The organic layer was separated, washed with water, dried over Na 2 SO 4 and concentrated in vacuum. The title compound, montelukast free acid, was obtained as a yellow oil (5.7g, 86.1 area%).
  • the 1-adamantylamine salt of montelukast free acid was prepared for purposes of purifying montelukast. Specifically, montelukast free acid was placed in ethyl acetate (15OmL) and 1-adamantylamine (3.2g, 21.2mmol in 3OmL of ethyl acetate) was added. The mixture was stirred for 30 minutes at room temperature and hexane (20OmL) was added followed by seed crystals (lOmg).

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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 du montélukast, ou d'un sel pharmaceutiquement acceptable de celui-ci, lequel procédé comprend la réaction d'un intermédiaire protégé représenté par la formule (II) telle que définie dans la description avec un intermédiaire cyclopropylé.
EP07766340A 2006-07-21 2007-07-23 Procédé de préparation de montelukast Withdrawn EP2046750A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0614485.1A GB0614485D0 (en) 2006-07-21 2006-07-21 Process
PCT/GB2007/002790 WO2008009970A2 (fr) 2006-07-21 2007-07-23 Procédé

Publications (1)

Publication Number Publication Date
EP2046750A2 true EP2046750A2 (fr) 2009-04-15

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EP07766340A Withdrawn EP2046750A2 (fr) 2006-07-21 2007-07-23 Procédé de préparation de montelukast

Country Status (5)

Country Link
EP (1) EP2046750A2 (fr)
CA (1) CA2658473A1 (fr)
GB (1) GB0614485D0 (fr)
IL (1) IL196602A0 (fr)
WO (1) WO2008009970A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1904448B1 (fr) 2005-07-05 2011-02-02 Teva Pharmaceutical Industries, Ltd. Purification du montélukast
EP1886998A1 (fr) 2006-08-09 2008-02-13 Esteve Quimica, S.A. Procédés de purification du montelukast et ses sels d'amine
EP2552892A1 (fr) 2010-03-31 2013-02-06 KRKA, D.D., Novo Mesto Synthèse efficace pour la préparation de montélukast et nouvelle forme cristalline d'intermédiaires dans celle-ci
HUP1000425A2 (en) 2010-08-11 2012-03-28 Richter Gedeon Nyrt Process for the production of montelukast sodium
WO2014081616A1 (fr) * 2012-11-21 2014-05-30 Merck Sharp & Dohme Corp. Préparation de précurseurs d'antagonistes de leucotriène
CN105541711B (zh) * 2016-02-22 2018-06-19 齐鲁天和惠世制药有限公司 一种孟鲁司特的制备方法
CN105541710B (zh) * 2016-02-22 2018-06-19 齐鲁天和惠世制药有限公司 一种孟鲁司特的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU222344B1 (hu) * 1990-10-12 2003-06-28 Merck Frosst Canada & Co. Eljárás telítetlen hidroxi-alkil-kinolinsavak, és ezeket tartalmazó gyógyszerkészítmények előállítására
TW448160B (en) * 1993-12-28 2001-08-01 Merck & Co Inc Novel dicyclohexylamine salt and process for the preparation of leukotriene antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008009970A3 *

Also Published As

Publication number Publication date
WO2008009970A2 (fr) 2008-01-24
WO2008009970A3 (fr) 2008-04-10
CA2658473A1 (fr) 2008-01-24
IL196602A0 (en) 2009-11-18
GB0614485D0 (en) 2006-09-27

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