EP2867210A1 - A process for the preparation of solifenacin or a salt thereof - Google Patents

A process for the preparation of solifenacin or a salt thereof

Info

Publication number
EP2867210A1
EP2867210A1 EP12750992.5A EP12750992A EP2867210A1 EP 2867210 A1 EP2867210 A1 EP 2867210A1 EP 12750992 A EP12750992 A EP 12750992A EP 2867210 A1 EP2867210 A1 EP 2867210A1
Authority
EP
European Patent Office
Prior art keywords
formula
solifenacin
impurity
compound
phenyl
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Withdrawn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
EP12750992.5A
Other languages
German (de)
English (en)
French (fr)
Inventor
Theocharis V. KOFTIS
Rohit Ravikant Soni
Bharat Becharbhai Boda
Ravindra Charudatta Ghotikar
Vimal Sudhirbhai PATEL
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP2867210A1 publication Critical patent/EP2867210A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to an improved process for the preparation of Solifenacin or a salt thereof, more particularly the present invention relates to an economically viable and industrially advantageous process for the preparation of highly pure Solifenacin or a salt thereof.
  • Solifenacin salt of formula I acts as a muscarinic M3-receptor antagonist and is used for symptomatic treatment of urgent incontinence and/or increased frequency of urinating and urgency of urinating in patients with a hyperactive urinary bladder.
  • Solifenacin is chemically known as (lS,3 ' ?)-quinuclidin-3 '-yl-l -phenyl-l ,2,3,4-tetrahydro isoquinoline-2-carboxylate.
  • Commercially, Solifenacin succinate is available under the trade name Vesicare ® .
  • EP 0 801 067 discloses a process for the preparation of Solifenacin, a racemic mixture or biologically active pure isomer ( ⁇ S,3 'R) thereof.
  • the patent discloses the reaction of quinuclidinol and l-phenyl-l,2,3,4-tetrahydroisoquinoline carbamoyl derivative in the presence of sodium hydride. Further, the patent discloses the condensation of 1-phenyl-l , 2,3,4- tetrahydroisoquinoline and an activated quinuclidinol derivative, such as the chloroformate or the carbonate derivative in the presence of pyridine.
  • the obtained racemic compounds are resolved by chiral high-pressure liquid chromatography.
  • the main disadvantage of the process is the use of column chromatography for the purification of Solifenacin base and long reaction times, which render the process industrially unsuitable.
  • EP 1 879 867 discloses the preparation of Solifenacin by condensing (S)- 1-phenyl-l, 2,3, 4-tetra hydroisoquinoline and a haloalkyl haloformate in the presence of a first base to yield a haloalkyl- 1,2,3,4-tetrahydroisoquinoline carbamate, which is subsequently converted to Solifenacin.
  • (i?)-3-quinuclidinol is condensed with a haloalkyl haloformate in the presence of a base to obtain haloalkyl-quinuclidylcarbonate which is converted to Solifenacin.
  • the reaction procedure is tedious while its cost-efficiency is hampered by the need to use two different bases for the two stages of the condensation.
  • EP 1 757 604 discloses the reaction of (5)- 1-phenyl-l , 2, 3, 4-tetrahydroisoquinoline with leaving groups such as 1 H-imidazole-l-yl, 2,5-dioxopyrrolidin-l-yloxy , 3 -methyl- lH-imidazol-3 -ium-1- yl or chloro and further condensation with (J?)-3-quinuclidinol in the presence of sodium hydride as a base and a mixture of toluene and dimethylformamide or toluene alone as a reaction medium.
  • leaving groups such as 1 H-imidazole-l-yl, 2,5-dioxopyrrolidin-l-yloxy , 3 -methyl- lH-imidazol-3 -ium-1- yl or chloro and further condensation with (J?)-3-quinuclidinol in the presence of sodium hydride as a base and a mixture of toluen
  • WO 2010/103529 discloses a process for preparing Solifenacin by reacting (i?)-3-quinuclidinol with bis(aryl) carbonate to form aryl carbonate substituted (i?)-3-quinuclidinol, which was further condensed with (15)- 1 -phenyl- 1 , 2,3, 4-tetrahydroisoquinoline to provide Solifenacin.
  • the major disadvantage of this process is its low yield and the formation of undesired isomers which requires additional purification steps.
  • WO 2008/120080 discloses a process for the preparation of Solifenacin by reacting (i?)-3- quinuclidinol and l ,l -carbonyl-di-(l ,2,4-triazole) in an organic solvent, followed by condensation with (1 S)- 1 -phenyl- 1 , 2,3, 4-tetrahydroisoquinoline in the presence of triethylamine to provide Solifenacin.
  • the reagents used, i.e. l , l -carbonyl-di-(l ,2,4-triazole) are costly. It is apparent that large volumes of solvents are required and reaction is carried out at reflux temperature.
  • reaction of aryl/heteroaryl substituted heteroaryl carbonate or chloroformate with ( IS)- 1 -phenyl- 1 ,2,3, 4- tetrahydroisoquinoline in the presence of a base is described which is further reacted with (i?)-3- quinuclidinol in the presence of a base to obtain Solifenacin base.
  • reaction of aryl/heteroaryl/substituted heteroaryl carbonate or chloroformate with (/?)-3- quinuclidinol in the presence of a base which is further reacted with (lS)-l -phenyl-l ,2,3,4- tetrahydroisoquinoline in the presence of a base to obtain Solifenacin base.
  • the disadvantage of these processes is that the key intermediates are obtained in low yield and purity which ultimately leads to a costly final product.
  • Another object of the present invention is to provide an improved method for the preparation of Solifenacin or a salt thereof by providing novel intermediate compounds and further selecting the appropriate reactants, catalysts, solvent systems and conditions used to afford the products in high yield and purity.
  • Yet another object of the present invention is to provide substantially pure Solifenacin or a salt thereof substantially free of unwanted isomers.
  • R represents one of the following
  • R and R' are as defined above, provided that R' is not and alkyl;
  • impurities are formed during the synthesis of Solifenacin or its salts, which are persistent impurities in the final stage and have not been previously disclosed. Hence these impurities need to be strictly controlled.
  • impurities X, Y and Z described impurities X and Y are novel and thus form part of the present invention.
  • An object of the present invention is to provide an isolated impurity, l-( ⁇ [(lS)-l-phenyl-3,4- dihydroisoquinolin-2(lH)-yl]carbonyl ⁇ oxy)pyrrolidine-2,5-dione (impurity X) having the following structural formula:
  • Yet another object of the present invention is to provide impurity X as an impurity of Solifenacin or salts thereof.
  • Yet another object of the present invention is to provide a process for synthesizing and isolating impurity X.
  • Yet another object of the present invention is to provide an isolated impurity bis[(lS)-l-phenyl- 1,2,3,4-tetrahydro isoquinolin-2-yl]methanone (impurity Y), having the following structural formula:
  • Still another object of the present invention is to provide impurity Y as an impurity of Solifenacin or salts thereof.
  • Yet another object of the present invention is to provide a process for the synthesizing and isolating impurity Y.
  • Isomeric impurity ( 1 ,3i?)-3-[[( 1 '-phenyl- 1 ',2 , ,3',4'-tetrahydro-2 ' -isoquinolyl)carbonyl]oxy] quinuclidine 1 -oxide (impurity Z ) has been disclosed in EP 0 801 067 and characterized.
  • Still another object of the present invention is to provide highly pure Solifenacin or salts thereof substantially free of impurity X, impurity Y and impurity Z.
  • Yet another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising Solifenacin or salt thereof substantially free of impurity X, impurity Y and impurity Z and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising Solifenacin or salt thereof prepared by the process disclosed herein and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention is to provide novel compound of general formula A which is a useful intermediate in the preparation of Solifenacin succinate.
  • R represents one of the following:
  • the present invention provides advantages such as high yield and purity, no use of hazardous base like sodium hydride or sodium ethoxide which have handling difficulties in industrial scale, all reactions are carried out at room temperature, it is an easily scalable process and no racemization occurs at any of the stereocenters.
  • FIG.1 Illustrates an XRPD pattern of Solifenacin succinate.
  • FIG.2 Illustrates a DSC thermogram of Solifenacin succinate.
  • ambient temperature means 20-40°C, preferably 20-35°C.
  • reflux temperature means boiling temperature of the solvent used.
  • the process for preparing Solifenacin or salts thereof comprises the following stages:
  • reaction of compound of formula II with compound of formula III, wherein R and R' are as defined above is carried out in a solvent selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably acetonitrile.
  • the reaction mixture is stirred at ambient temperature for about 3-6 hours, preferably about 3-4 hours, more preferably until completion of the reaction.
  • the completion of the reaction is monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) or gas chromatography.
  • a compound of formula A or compound of formula B may be optionally isolated by conventional techniques such as acid-base treatment, extraction with solvent, column chromatography and crystallization or used directly in the next step.
  • polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate
  • non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably acetonitrile
  • a solvent is added to the obtained residue selected from polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably toluene.
  • An acid is added to the solution, selected from hydrochloric acid, sulphuric acid and hydrobromic acid, preferably hydrochloric acid. The mixture is stirred for about 0.5 -3 hours, followed by phase separation.
  • the aqueous layer is basified using an inorganic base such as such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide or an organic base such as liquor ammonia, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5- ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), triethyl amine (TEA), or diisoproyl amine.
  • DBU dihydroxybenzyl amine
  • Preferred base is potassium carbonate.
  • the basified aqueous layer is extracted with a suitable solvent such as polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably ethyl acetate.
  • polar aprotic solvents such as dichloromethane, acetonitrile, dimethylformamide, tetrahydrofuran, ethyl acetate and non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably ethyl acetate.
  • non polar solvents such as toluene, cyclohexane or mixtures thereof, preferably ethyl acetate.
  • Solifenacin free base can be optionally isolated from the residue according to conventional methods to provide pure Solifenacin free base having chromatographic purity more than 90% and chiral purity more than 95%, preferably more than 98%, most preferably more than 99%.
  • the acid used in this stage for the salt formation of Solifenacin free base may be an inorganic acid or an organic acid.
  • Said inorganic acids include hydrochloric acid and hydrobromic acid and organic acids include succinic acid, oxalic acid and tartaric acid, preferably succinic acid.
  • the solvents used in this stage include polar protic solvents water, methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvent such as ethylacetate, acetone or mixtures thereof; preferably a mixture of ethylacetate and ethanol is used.
  • the solvent or mixture of solvents and the acid used are added to the residue of Solifenacin free base.
  • reaction mixture is heated to the reflux temperature of the solvent for about 0.5 to 1 hour.
  • the compound of formula I is isolated by conventional techniques such as acid-base treatment, extraction with solvent, column chromatography and crystallization.
  • the solution is cooled to room temperature, about 20-35°C.
  • the crystals are collected by filtration, washed with an organic solvent and dried in a hot air oven to obtain pure Solifenacin salt, preferably Solifenacin succinate of formula I.
  • an isolated impurity is provided, 1-( ⁇ [(1S)- l-phenyl-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl ⁇ oxy) pyrrolidine-2,5-dione (impurity X).
  • Impurity X has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy, ⁇ NMR spectroscopy and 13 C NMR spectroscopy consistent with the assigned structure.
  • impurity X is formed during the synthesis of Solifenacin or salts thereof.
  • impurity X can be prepared by reacting N,N- disuccinimidyl carbonate in a solvent with (15)- 1 -phenyl- 1, 2,3, 4-tetrahydroisoquinoline at suitable temperature with stirring.
  • the solvent of reaction mixture is distilled under reduced pressure; the residue is extracted in a suitable solvent or mixture of solvents and washed with water at ambient temperature.
  • Impurity X is isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.
  • impurity Y isolated impurity bis[(15)-l-phenyl-l,2,3,4-tetrahydro isoquinolin-2-yl]methanone is provided (impurity Y).
  • Impurity Y has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy, ⁇ NMR spectroscopy and 13 C NMR spectroscopy consistent with the assigned structure. According to the present invention, impurity Y is formed during the synthesis of Solifenacin or salts thereof.
  • impurity Y can be prepared by treating (1S)-1 -phenyl - 1,2,3, 4-tetrahydroisoquinoline with triphosgene in the presence of a base and in a suitable solvent. Impurity Y is isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.
  • Impurity Z has been synthesized, isolated and identified by IR spectroscopy, mass spectroscopy and 1H NMR spectroscopy consistent with the assigned structure.
  • Impurity Z is formed as an impurity during the synthesis of Solifenacin or salts thereof of the present invention.
  • impurity Z can be prepared by treating Solifenacin with an oxidizing agent such as m-chloroperbenzoic acid in the presence of a base and in a suitable solvent.
  • Impurity Z may be isolated by conventional techniques such as evaporation, acid-base treatment, column chromatography and/or crystallization.
  • highly pure solifenacin or salts thereof prepared by the process of the present invention comprises one or more of impurity X, impurity Y and impurity Z, in an amount of about 0.01 area-% to about 0.1 area-% each, specifically in an amount of about 0.01 area-% to about 0.05 area-% each, as measured by HPLC.
  • highly pure Solifenacin or salts thereof substantially free of impurity X, impurity Y and impurity Z refers to Solifenacin or salts thereof comprising impurity X, impurity Y and impurity Z, in an amount of less than about 0.1 area-% each as measured by HPLC.
  • highly pure Solifenacin or salt thereof disclosed herein has a total purity of greater than about 99.5%, preferably greater than about 99.8%, more preferably greater than about 99.9%, and most preferably greater than about 99.95% as measured by HPLC.
  • Solifenacin or salt thereof substantially free of impurity X, impurity Y and impurity Z for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
  • Said specific pharmaceutical composition is selected from a solid dosage form and/or an oral suspension.
  • a pharmaceutical composition comprising Solifenacin or salt thereof prepared by the process disclosed herein is provided with one or more pharmaceutically acceptable excipients; pharmaceutical composition is preferably selected from a solid dosage form and/or an oral suspension.
  • Solifenacin free base Chromatographic purity: 91.03%, Chiral purity: 99.03%) ethyl acetate (20 ml), ethanol (3.5 ml) and succinic acid (1.09 g) were added, the reaction mixture was heated to reflux followed by cooling at room temperature, and formed crystals were collected by filtration, which were then washed with ethyl acetate (3 ml) twice and dried in a hot air oven to obtain 3.9 g of Solifenacin succinate. Yield: 1.95 w/w, % yield: 85%, Chromatographic purity: 99.46%, Chiral purity: 99.93%.
  • Solifenacin free base Chromatographic purity: 97.99%
  • ethyl acetate (200 ml), ethanol (35 ml) and succinic acid (10.9 g) were added, the reaction mixture was heated to reflux followed by cooling at 5°C, and the formed crystals were collected by filtration, which were then washed with ethyl acetate (30 ml) twice and dried in hot air oven to obtain 40.8 g of Solifenacin succinate. Yield: 2.04 w/w, % yield: 89%, Chromatographic purity: 99.89%, Chiral purity: 99.9%.
  • X-ray powder diffraction pattern of Solifenacin succinate gives characteristic peaks having significant reflections expressed as 20 ⁇ 0.2 values and % intensity as given in the table below.
  • Acetonitrile (45 ml) and ⁇ , ⁇ -disuucinimidyl carbonate (9.18 g) were charged into a round bottom flask and cooled to 20°C, followed by addition of (5)- 1 -phenyl- 1,2,3, 4- tetrahydroisoquinoline (5.0 g) at below 30°C.
  • the solution was stirred for 120 minutes followed by distillation under reduced pressure below 55°C.
  • the residue was extracted in ethyl acetate (50 ml) and water (50 ml).
  • the aqueous layer was separated and re-extracted with ethyl acetate (30 ml). Ethyl acetate layer was washed twice with water (20 ml x 2) at ambient temperature.
  • reaction mass was quenched with water (250 ml).
  • organic layer was separated and washed with a solution of sodium thiosulphate (25.0 g) in water (250 ml) followed by fresh water (75 ml).
  • the solvent was distilled off and degassed for 30 minutes under reduced pressure below 55°C to obtained crude (l£,3 'i?)-l '-oxido quinuclidin-3 '-yl 1 -phenyl- l ,2,3,4-tetrahydroisoquinoline-2-carboxylate (19.85 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP12750992.5A 2012-07-02 2012-07-02 A process for the preparation of solifenacin or a salt thereof Withdrawn EP2867210A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2012/002769 WO2014005601A1 (en) 2012-07-02 2012-07-02 A process for the preparation of solifenacin or a salt thereof

Publications (1)

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EP2867210A1 true EP2867210A1 (en) 2015-05-06

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EP (1) EP2867210A1 (enExample)
JP (1) JP2015521635A (enExample)
CN (1) CN104411687A (enExample)
WO (1) WO2014005601A1 (enExample)

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CN104133011A (zh) * 2014-07-01 2014-11-05 北京万全德众医药生物技术有限公司 液相色谱法分离分析琥珀酸索利那新中间体及其有关物质
CN105348278B (zh) * 2014-11-14 2017-11-17 天津市医药集团技术发展有限公司 一种琥珀酸索利那新杂质的制备方法
CN105566315B (zh) * 2016-01-20 2017-07-18 成都华宇制药有限公司 一种索利那新的后处理及制备琥珀酸索利那新的方法

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NO2005012I1 (no) * 1994-12-28 2005-06-06 Debio Rech Pharma Sa Triptorelin og farmasoytisk akseptable salter derav
AUPP405098A0 (en) * 1998-06-12 1998-07-02 Access Pharmaceuticals Australia Pty Limited Novel methods of preparation of vitamin b12 derivatives suitable for conjugation to pharmaceuticals
ME01059B (me) * 2003-12-23 2012-10-20 Janssen Sciences Ireland Uc Proces za pripremanje (3r,3as,6ar)-heksahidrofuro [2,3-b] furan-3-il (1s,2r)-3-[[(4-aminofenil) sulfonil] (izobutil) amino]-1-benzil-2- hidroksipropilkarbamata
JPWO2005087231A1 (ja) 2004-03-16 2008-01-24 アステラス製薬株式会社 ソリフェナシン含有組成物
CN1934109B (zh) * 2004-03-25 2010-06-23 安斯泰来制药株式会社 用于固体制剂的索非那新或其盐的组合物
EP1879867A2 (en) 2005-12-21 2008-01-23 Teva Pharmaceutical Industries Ltd Intermediates for preparing solifenacin
CZ300699B6 (cs) * 2006-06-21 2009-07-22 Zentiva, A. S. Zpusob prípravy solifenacinu
CN101711248A (zh) 2007-03-30 2010-05-19 医药化学公司 一种改进的素非那新合成工艺
ITMI20080195A1 (it) * 2008-02-08 2009-08-09 Dipharma Francis Srl Procedimento per la preparazione di solifenacin
US8283470B2 (en) 2009-03-09 2012-10-09 Megafine Pharma(P) Ltd. Method for the preparation of solifenacin and intermediate thereof

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JP2015521635A (ja) 2015-07-30
CN104411687A (zh) 2015-03-11
WO2014005601A1 (en) 2014-01-09

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