WO2012007959A1 - Procédé pour la préparation de dronédarone - Google Patents

Procédé pour la préparation de dronédarone Download PDF

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Publication number
WO2012007959A1
WO2012007959A1 PCT/IN2011/000434 IN2011000434W WO2012007959A1 WO 2012007959 A1 WO2012007959 A1 WO 2012007959A1 IN 2011000434 W IN2011000434 W IN 2011000434W WO 2012007959 A1 WO2012007959 A1 WO 2012007959A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
dronedarone
particle size
acid
Prior art date
Application number
PCT/IN2011/000434
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English (en)
Inventor
Sachin Srivastava
Anthony Melvin Crasto
Milind Gharpure
Dinesh Bansilal Deore
Suresh Babu Narayanan
Original Assignee
Glenmark Generics Limited
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 Glenmark Generics Limited filed Critical Glenmark Generics Limited
Publication of WO2012007959A1 publication Critical patent/WO2012007959A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to a process for the preparation of dronedarone, its pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • the present invention relates to a novel amorphous form of dronedarone hydrochloride, and a process for its preparation.
  • Dronedarone also known as 2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, is represented by the structure of formula I.
  • Dronedarone hydrochloride compound of formula II, is an anti- arrhythmic agent used for the prevention and treatment of atrial fibrillation. Dronedarone hydrochloride is marketed under the brand name MULTAQTM in the United States (approved in July 2009) and in Europe (approved in November 2009).
  • United States Patent No. 5223510 discloses dronedarone and its hydrochloride salt.
  • the '510 patent discloses a process for the preparation of dronedarone hydrochloride as schematically represented by Scheme I.
  • U.S. Patent No. 6828448 discloses a process for the preparation of dronedarone hydrochloride as schematically represented by Scheme II.
  • 2-butyl-5-methylsulfonamidobenzofuran was prepared by the reaction of 5-amino-2-butylbenzofuran with methanesulfonyl chloride or methanesulfonic anhydride in the presence of an acid acceptor, such as triethylamine or ammonia.
  • 2-butyl-5-bismethylsulfonamidobenzofuran may be formed as an impurity which can be further carried in the preparation of dronedarone.
  • the present invention provides a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, comprising:
  • the present invention provides a process for the purification of dronedarone, compound of formula I
  • the present invention provides dronedarone having less than 0.05% of compound of formula V.
  • the present invention provides an amorphous form of dronedarone hydrochloride, compound of formula II
  • XRPD X-ray powder diffraction
  • the present invention provides a process for the preparation of dronedarone hydrochloride in amorphous form, comprising:
  • the present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 200 ⁇ and mean particle size less than 100 ⁇ .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 ⁇ and mean particle size less than 100 ⁇ and at least one pharmaceutically acceptable carrier.
  • Figure 1 is a characteristic XRPD of dronedarone hydrochloride in amorphous form as obtained in Example 9.
  • Figure 2 is a scanning electron microscope (SEM) picture (magnification
  • the present invention relates to dronedarone, its pharmaceutical salts and compositions thereof.
  • the present invention relates to amorphous form of dronedarone hydrochloride.
  • the present invention provides a process for the preparation dronedarone, compound of formula I
  • room temperature means a temperature of about 25 °C to about 30°C.
  • a suitable hydrogenation catalyst used in the process includes, but is not limited to platinum oxide, palladium oxide, palladium on carbon.
  • the hydrogenation catalyst selected is palladium on carbon.
  • reaction is carried out in the presence of a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like; esters such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate and the like.
  • the organic solvent selected is ethyl acetate.
  • the reaction may be carried out at a hydrogen pressure in the range of about 0.5 kg to 20 kg. Preferably the reaction is carried out at a hydrogen pressure of about 3 kg to about 5 kg. [0027] The reaction may be carried out at a temperature in the range of about 0°C to about 80°C. Preferably the reaction is carried out at a temperature of about 25°C to about 45°C.
  • the reaction is carried out for a period of about 2 hours to about 24 hours. Preferably the reaction is carried out for a period of about 8 hours to about 12 hours.
  • reaction completion may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the acid may be inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid; organic acid such as oxalic acid, fumaric acid, succinic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulphonic acid.
  • organic acid such as oxalic acid, fumaric acid, succinic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulphonic acid.
  • the acid is selected from organic acid and more preferably the acid is oxalic acid.
  • the molar equivalent of the acid employed is from about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula IV.
  • the molar equivalent of the acid employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula IV.
  • reaction is carried out in the presence of a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like; ethers such as diethyl ether, ethyl methyl ether, methyl tertiary-butyl ether and the like.
  • the organic solvent selected is ethanol.
  • the reaction may be carried out at a temperature in the range of about
  • the reaction is carried out for a period of about 0.5 hour to about 10 hours.
  • the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.
  • the compound of formula IV is reacted with oxalic acid to form a dioxalate salt form of formula IV.
  • the salt form of formula IV, obtained is purified and used in (c) of the above process.
  • the solvent used in the purification process includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like.
  • the organic solvent selected is methanol.
  • the reaction is carried out in the presence of water and a suitable water immiscible organic solvent.
  • suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; aromatic hydrocarbons such as toluene and the like.
  • the organic solvent is selected from dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dichloromethane.
  • the base includes, but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, aqueous ammonia.
  • the base selected is aqueous ammonia and the pH is adjusted in the range of about 8-10.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 30°C. Preferably the reaction is carried out at a temperature of about 15°C to about 25°C.
  • the reaction is carried out for a period of about 0.5 hour to about 10 hours, preferably for a period of about 1 hour to about 3 hours followed by the separation of the two layers.
  • the organic layer containing free form of formula IV may be optionally treated with NoritTM charcoal.
  • the solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Preferably, the solvent is removed by distillation under vacuum.
  • the dioxalate salt form of formula IV is neutralized with aqueous ammonia to a free form of formula IV.
  • the compound of formula IV obtained in (c) is reacted with methanesulfonyl chloride or methanesulfonic anhydride in the presence of a suitable acid acceptor to form dronedarone.
  • the suitable acid acceptor includes, but is not limited to potassium carbonate, sodium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine.
  • the acid acceptor selected is triethylamine.
  • reaction is carried out in the presence of a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to haloalkanes such as dichloromethane, dichloroethane, chloroform and the like.
  • haloalkanes such as dichloromethane, dichloroethane, chloroform and the like.
  • the organic solvent selected is dichloromethane.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 30°C.
  • the reaction is carried out for a period of about 0.5 hour to about 10 hours.
  • reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.
  • dronedarone obtained in (d) containing a compound of formula V, the presence of which is undesirable, and thus considered an impurity is treated with alcoholic alkali metal hydroxide in a suitable organic solvent.
  • the alcohol used includes, but is not limited to ethanol, methanol, propanol, butanol and the like.
  • the alcohol selected is ethanol.
  • the alkali metal hydroxide used includes, but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide.
  • the alkali metal hydroxide selected is sodium hydroxide.
  • reaction is carried out in the presence of a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like.
  • the organic solvent selected is ethanol.
  • the molar equivalent of the alkali metal hydroxide employed is from about an equimolar amount to about 10 times the equimolar amount with respect to the compound of formula IV.
  • the molar equivalent of the alkali metal hydroxide employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula IV.
  • the reaction may be carried out at a temperature in the range of about
  • the reaction is carried out for a period of about 0.5 hour to about 10 hours.
  • the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.
  • reaction completion may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; aromatic hydrocarbons such as toluene and the like.
  • the water immiscible organic solvent is ethyl acetate.
  • the organic layer containing dronedarone may be optionally treated with NoritTM charcoal.
  • the solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum. Any temperature and vacuum conditions, generally, may be used provided these do not influence the nature of the product.
  • the vacuum and the temperature used for the removal of the solvent depend on parameters like the boiling point range of the solvent, which are apparent to persons of ordinary skill in the art.
  • the organic layer containing dronedarone may be directly used in acid-addition salt formation of (f) in the process described.
  • the present invention provides dronedarone, which is obtained after alcoholic alkali metal hydroxide treatment of the process described above, having a content of compound of formula V below detection limit as measured by high performance liquid chromatography.
  • dronedarone obtained in (e) is optionally treated with nonpolar solvent and converted to its pharmaceutically acceptable salt.
  • the nonpolar solvent used includes, but is not limited to aliphatic hydrocarbons such as hexane, heptane, cyclohexane, pentane and the like; aromatic hydrocarbons such as toluene, xylene and the like.
  • the nonpolar solvent selected is hexane.
  • the dronedarone acid-addition salts may be prepared by reacting dronedarone with a pharmaceutically acceptable acid, where the acid may be an aqueous acid or a solvent containing an acid or in gaseous form.
  • the acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the acid is hydrochloric acid.
  • a solvent containing an acid can be used.
  • the suitable solvent containing an acid includes esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like.
  • the solvent selected is acetone.
  • the dissolution of dronedarone is carried out by using suitable organic solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like.
  • the solvent selected is acetone.
  • the dronedarone acid-addition salt formation may be carried out at a temperature in the range of about 0°C to about 30°C for a period of about 1 hour to about 10 hours.
  • the reaction is carried out at a temperature of about 0°C to about 15°C for a period of about 1 hour to about 5 hours.
  • the dronedarone acid-addition salts may be purified by addition of solvent which includes, but is not limited to, esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; water and mixtures thereof.
  • the solvent is acetone, methanol, water and mixtures thereof.
  • Suitable temperatures for dissolution of dronedarone acid-addition salts in a solvent may range from about 10°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer.
  • the solution may be optionally treated with NoritTM charcoal and filtered to get a particle-free solution.
  • the product is isolated by conventional methods known in the art, preferably, filtration.
  • Drying may be carried out for any desired time until the required product quality is achieved.
  • the drying time may vary from about 1 hour to about 20 hours, or longer.
  • the present invention provides a process for the purification of dronedarone
  • the alcohol that may be used includes, but is not limited to ethanol, methanol, propanol, butanol and the like and the alkali metal hydroxide includes, but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide.
  • the alcohol is ethanol and the alkali metal hydroxide is sodium hydroxide.
  • reaction is carried out in the presence of a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to alcohols such as ethanol, methanol, propanol, butanol and the like.
  • the organic solvent is ethanol.
  • the molar equivalent of the alkali metal hydroxide employed is from about an equimolar amount to about 10 times the equimolar amount with respect to the compound of formula I.
  • the molar equivalent of the alkali metal hydroxide employed is about an equimolar amount to about 2.5 times the equimolar amount of the compound of formula I.
  • the reaction may be carried out at a temperature in the range of about
  • the reaction is carried out for a period of about 0.5 hour to about 10 hours.
  • the reaction is carried out at a temperature of about 20°C to about 30°C for a period of about 1 hour to about 4 hours.
  • reaction completion may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, the reaction mass is cooled to about 10°C to about 20°C and treated with water immiscible organic solvent and water.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the suitable water immiscible organic solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like; aromatic hydrocarbons such as toluene and the like.
  • the water immiscible organic solvent is ethyl acetate.
  • the organic layer containing dronedarone may be optionally treated with
  • the solvent may be removed using any suitable method, known in the art, such as evaporation, atmospheric distillation, or distillation under vacuum.
  • the organic layer containing dronedarone may be directly used in acid- addition salt formation.
  • the present invention provides dronedarone having less than 0.1 % of compound of formula V as measured by high performance liquid chromatography.
  • the present invention provides dronedarone having less than 0.05% of compound of formula V as measured by high performance liquid chromatography.
  • the present invention provides dronedarone having compound of formula
  • the present invention provides dronedarone, obtained by the above process, having chemical purity, as described, analyzed by using high performance liquid chromatography (HPLC) with the conditions described below:
  • Diluent Water: Acetonitrile (1 : 1 , v/v); Flow Rate: 1.OmL/minute; Detection: UV 290nm; Injection Volume: 20 ⁇ .
  • the present invention provides amorphous form of dronedarone hydrochloride having an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.
  • XRPD X-ray powder diffraction
  • the present invention provides a process for the preparation of dronedarone hydrochloride in amorphous form, comprising the steps of:
  • the alcohol used includes, but is not limited to ethanol, methanol, propanol, butanol and the like.
  • the alcohol selected is methanol.
  • dronedarone hydrochloride is dissolved in methanol at room temperature to form a solution.
  • Removal of alcohol may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by spray drying to obtain a dry amorphous powder.
  • alcohol was removed under vacuum to give amorphous dronedarone hydrochloride.
  • the present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 400 ⁇ .
  • the present invention provides dronedarone hydrochloride having 90% of particles with particle size less than 200 ⁇ and mean particle size less than 100 ⁇ .
  • 90% of particles have particle size less than 100 ⁇ , more preferably less than 50 ⁇ .
  • the mean particle size is less than 50 ⁇ , more preferably less than 30 ⁇ and greater than 15 ⁇ .
  • Particle size distribution means the cumulative volume size distribution of equivalent spherical diameters.
  • Mean particle size refers to the mean of said particle size distribution.
  • D 90 refers to at least 90% of the particles have a size smaller than the stated value.
  • Dispersant Silicon oil Backgroud: With Dispersant
  • Sample Preparation About 150mg of sample in beaker. Add 3-4 drops of silicon oil. Make a paste. Add 25 mL of silicon oil and stir to mix well. Sonicate for 60 seconds. Obscuration: Between 10-20%
  • the present invention provides dronedarone hydrochloride wherein the particles are needle-shaped, which is substantially in accordance with Figure 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 ⁇ and mean particle size less than 100 ⁇ and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may comprise diluents, adjuvants, disintegrating agents, binders, excipients, lubricants, solubility enhancing agents and the like.
  • the pharmaceutically acceptable carrier comprises a solubility enhancing agent.
  • solubility enhancing agent may be used: co-solvents such as polyethylene glycol (PEG) 300, propylene glycol, ionic surfactants, such as sodium lauryl sulfate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Span®), esters of polyoxyethylenesorbitan and fatty acids (such as Tween®), polyoxyethylated hydrogenated castor oil (such as Cremophor®), polyoxyethylene stearates (such as Brij®), dimethylpolysiloxane, or any combination of the above mentioned surfactants.
  • the surface active agent is selected from co-solvents, fatty acids and esters, oil, ionic surfactants.
  • the organic layer was further treated with NoritTM charcoal, stirred for about 30min at about 25°C to about 30°C and filtered over hyflo bed.
  • the hyflo bed was washed with 250mL of dichloromethane. The combined filtrate and washings were collected together and concentrated under vacuum to give 75g of pale brown thick oil.
  • Impurity compound of formula V 0.04%
  • dronedarone hydrochloride tablet formulation comprising dronedarone hydrochloride having 90% of particles with particle size less than 200 ⁇ :
  • dronedarone hydrochloride microcrystalline cellulose, lactose and HPMC; granulating said blend with solution of sodium lauryl sulfate in water; mixing the resulting granules with anhydrous colloidal silica and stearic acid; compressing the final mixture into tablets.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé pour la préparation de dronédarone et de sels pharmaceutiquement acceptables de celle-ci. La présente invention porte en outre sur une nouvelle forme amorphe de chlorhydrate de dronédarone et sur un procédé pour sa préparation.
PCT/IN2011/000434 2010-07-16 2011-06-29 Procédé pour la préparation de dronédarone WO2012007959A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2048/MUM/2010 2010-07-16
IN2048MU2010 2010-07-16
IN2598/MUM/2010 2010-09-17
IN2598MU2010 2010-09-17

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Publication Number Publication Date
WO2012007959A1 true WO2012007959A1 (fr) 2012-01-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044369A (zh) * 2012-12-21 2013-04-17 北京华禧联合科技发展有限公司 一种盐酸决奈达隆的精制方法
CN104892553A (zh) * 2015-04-27 2015-09-09 惠州信立泰药业有限公司 一种盐酸决奈达隆的晶体及其制备方法和含有该晶体的药物组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223510A (en) * 1990-08-06 1993-06-29 Sanofi Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
US20040010032A1 (en) * 2000-12-11 2004-01-15 Michel Biard 2-butyl-3-(4-[3(dibutylamino)propoxy]benzoyl)-5-nitro-benzofuran hydrochloride and preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223510A (en) * 1990-08-06 1993-06-29 Sanofi Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them
US20040010032A1 (en) * 2000-12-11 2004-01-15 Michel Biard 2-butyl-3-(4-[3(dibutylamino)propoxy]benzoyl)-5-nitro-benzofuran hydrochloride and preparation thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044369A (zh) * 2012-12-21 2013-04-17 北京华禧联合科技发展有限公司 一种盐酸决奈达隆的精制方法
CN104892553A (zh) * 2015-04-27 2015-09-09 惠州信立泰药业有限公司 一种盐酸决奈达隆的晶体及其制备方法和含有该晶体的药物组合物
CN104892553B (zh) * 2015-04-27 2017-06-20 惠州信立泰药业有限公司 一种盐酸决奈达隆的晶体及其制备方法和含有该晶体的药物组合物

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