EP2705023A1 - Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide - Google Patents

Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide

Info

Publication number
EP2705023A1
EP2705023A1 EP11854945.0A EP11854945A EP2705023A1 EP 2705023 A1 EP2705023 A1 EP 2705023A1 EP 11854945 A EP11854945 A EP 11854945A EP 2705023 A1 EP2705023 A1 EP 2705023A1
Authority
EP
European Patent Office
Prior art keywords
compound
agomelatine
formula
methoxy
ethyl
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Withdrawn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
EP11854945.0A
Other languages
German (de)
English (en)
Other versions
EP2705023A4 (fr
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
Ambati Anna Reddy
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.)
Symed Labs Ltd
Original Assignee
Symed Labs Ltd
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 Symed Labs Ltd filed Critical Symed Labs Ltd
Publication of EP2705023A1 publication Critical patent/EP2705023A1/fr
Publication of EP2705023A4 publication Critical patent/EP2705023A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Agomelatine is on one hand, an agonist of melatoninergic system receptors and, on the other hand, an antagonist of the 5-HT2C receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, and pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity.
  • Agomelatine is under regulatory review in US and is being approved in EU. It is available in the EU market under the brand name Valdoxan in the form of tablets in dosage strength 25 mg.
  • Agomelatine is chemically described as N-[2-(7-methoxy-l -naphthyl)ethyl]acetamide (herein after referred by generic name agomelatine) and is represented by the structural formula I
  • U.S.Patent No. 5,225,442 describes agomelatine, a pharmaceutical composition, a method of treatment, and a process for the preparation thereof.
  • Aforementioned processes uses expensive reagents and involve prolong reaction time periods thus rendering the processes expensive and not viable on commercial scale thus posing a need for an improved process for the preparation of agomelatine and its intermediates, which avoids the use of hazardous and expensive chemicals thus reducing the formation of process related impurities.
  • the processes of present invention are simple, eco-friendly, inexpensive, reproducible, and robust and feasible on an industrial scale.
  • the present invention relates to processes for the preparation of N-[2-(7-methoxy-l - naphthyl) ethyl] acetamide (I).
  • the present invention provides a process for the preparation of N-[2-(7- methoxy-1 -naphthyl) ethyl] acetamide of formula I
  • the present invention provides a process for the preparation of
  • the present invention provides novel compound of formula III or a salt thereof
  • the present invention provides compound of formula II
  • the present invention provides an alternate process for the preparation of N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide of formula I
  • HX is an organic or inorganic acids such as HC1, HBr, maleic acid, oxalic acid, tartaric acid, and the like,
  • the present invention provides a process for the synthesized product.
  • the present invention provides a process for the synthesis of (7-methoxy-l-naphthyl) acetonitrile of formula (IVa)
  • the present invention provides a process for purifying agomelatine comprising: a) providing a solution or suspension of agomelatine in a solvent or a mixture of solvents or their aqueous mixtures and b) precipitating the solid from the solution, and c) recovering the agomelatine in pure form.
  • the present invention provides an amorphous form of agomelatine alone or in combination with a pharmaceutically acceptable carrier characterized by X- ray powder diffraction pattern, which is substantially in accordance with Figure 2.
  • the present invention provides a process for the preparation of amorphous agomelatine comprising:
  • the present invention provides agomelatine having purity greater than about 98.0 area % to about 99.0 area% as measured by HPLC, preferably greater than about 99.0area% to about 99.5area%, more preferably greater about 99.5area% to about 99.9area%.
  • the present invention provides agomelatine having individual impurities lower than about 0.15 area %, and total impurities lower than about 0.5 area % by HPLC.
  • the present invention provides Agomelatine (I) having the compound bis-(7-methoxy-3,4-dihydro-l-na hthyl)ethylamine of structure
  • the present invention provides Agomelatine (I) having the compound bis-(7-methoxy-l-naphthyl)ethylamine of structure
  • the present invention provides Agomelatine (I) having the compound bis-[(7-methoxy-3,4-dihydr -l-naphthyl)ethyl] acetamide of structure
  • the present invention provides Agomelatine (I) having the compound represented by the structure
  • the present invention provides Agomelatine (I) having the compound represented by the structur
  • the present invention provides Agomelatine (I) having the following compounds represented by the structures
  • desacetamide-agomelatine- carboxylic acid each in an amount less than or equal to 0.10 area percent, as measured by HPLC.
  • agomelatine (I) obtained by the processes described herein has 50 volume-percent of the particles (D 5 o) having a size of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 100 microns, still more specifically less than or equal to about 60 microns, and most specifically less than or equal to about 15 microns.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising agomelatine of formula I and atleast a pharmaceutically acceptable carrier.
  • Fig. 1 is a schematic representation of the processes of the present invention.
  • Fig. 2 is an X-ray powder diffraction pattern of amorphous agomelatine.
  • Fig. 3 is an X-ray powder diffraction pattern of intermediate compound of formula II.
  • Fig. 4 is a Differential Scanning Calometry endotherm curve of intermediate compound of formula II.
  • Fig. 5 is an X-ray powder diffraction pattern of intermediate compound of formula Ilia.
  • Fig. 6 is a Differential Scanning Calometry endotherm curve of intermediate
  • the present invention is directed to processes for the preparation of N-[2-(7-methoxy- 1 -naphthyl) ethyl] acetamide of formula I.
  • the suitable reagent includes but not limited to sulphur, hydrogenation catalysts such as palladium on carbon in various percentages, platinum oxide, Raney Nickel, palladium oxide and the like; Preferably sulphur in any form is being used.
  • the molar ratio of sulphur to the compound of formula (II) can be from about 5: 1 to about 1 :1, preferably 1 :1.
  • the optionally used solvents include but are not limited to water, halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), N- methyl pyrrolidine (NMP) and the like; or mixtures thereof in various proportions without limitation.
  • the reaction is being carried in the absence of solvent or neat.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 35°C to about 200°C, preferably at a temperature of from about 175°C to about 190 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
  • the process of present invention provides the compound of formula I from intermediate compound of formula II by using sulphur resulting in higher yields and purities which would results in higher yields and purities of final product. And moreover the present process is very cost effective, reproducible and more viable on commercial scale.
  • the compound of formula I may be obtained in crystalline or amorphous form. .
  • the compound of formula I is optionally converted into a pharmaceutically acceptable salt for purification purposes based on the requirement.
  • the compound of formula I is optionally purified by recrystallisation, using a solvent or mixture of solvents; such as aqueous methanol, ethanol, isopropyl alcohol, n-hexane, aqueous ⁇ , ⁇ -dimethyl formamide, cyclohexane, acetone, acetonitrile and mixtures thereof.
  • a solvent or mixture of solvents such as aqueous methanol, ethanol, isopropyl alcohol, n-hexane, aqueous ⁇ , ⁇ -dimethyl formamide, cyclohexane, acetone, acetonitrile and mixtures thereof.
  • cyano reagents used in step a) can be CNCH 2 COOR where R is Na, , Ca, NH4 + , H, C r C 8 alkyl straight chain or branched or aryl alkyl.
  • R is Na, , Ca, NH4 + , H, C r C 8 alkyl straight chain or branched or aryl alkyl.
  • cyano acetic acid methyl cyano acetate, ethyl cyano acetate and the like; or mixtures thereof.
  • cyano acetic acid is being used.
  • the molar ratio of cyano acetic acid to the compound of formula V can be from about
  • the suitable ammonium derivatives in step a) that can be used include but are not limited to ammonium acetate, ammonium hydroxide, ammonia gas, ammonium carbonate and the like or mixtures thereof.
  • ammonium acetate Preferably ammonium acetate.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 35°C to about 200°C, preferably at a temperature of from about 95°C to about 120 °C. More preferably at boiling temperatures of the solvents used.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 40 hours, preferably from about 30 hour to 40 hours.
  • the suitable reducing agents that can be used in step b) can include but are not limited to hydrogenation catalysts such as palladium carbon in various percentages, platinum oxide, Raney Nickel, palladium oxide and the like; other reducing agent such as sodium borohydride, lithium aluminum hydride, n-butyl lithium, Vitride and the like.
  • hydrogenation catalyst Raney Nickel is being used.
  • the solvents that can be used in step b) include but are not limited to water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; or mixtures thereof in various proportions without limitation.
  • ethanol is being used.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 30°C to about 100°C, preferably at a temperature of from about 35°C to about 40 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 to 5 hours.
  • the conversion of intermediate compound of formula IV to the compound of formula III can also be performed using sodium borohydride and nickel chloride.
  • acetylating agents that can be used in step c) can include but are not limited to acetic anhydride, acetyl halide like acetyl chloride, acetyl bromide, acetyl iodide and the like.
  • acetic anhydride is being used.
  • the organic solvents that can be used in step c) include but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; or mixtures thereof in various proportions without limitation.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like
  • esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like
  • hydrocarbon solvents such as n-heptane,
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 15 minutes to about 5 hours, preferably from about 30 minutes to about 1 hour.
  • the reaction step c) is being carried out by employing a base.
  • the bases that can be used is selected from the group consisting of organic bases such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; inorganic bases such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide.
  • triethylamine is an equimolar amount to 5 times the equimolar amount of the starting material of formula III. When an excess of an organic amine is employed as the base, this may optionally serve as the solvent.
  • step a) the compound of formula III is converted into acid addition salt such as hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt and the like.
  • acid addition salt such as hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt and the like.
  • hydrochloric acid salt is being prepared.
  • the conversion takes place by reaction of the compound of formula III with a suitable acid like hydrochloric acid by any means can be gaseous form or dissolved in a solvent form or aqueous form in any percentage (%v/v).
  • a suitable acid like hydrochloric acid by any means can be gaseous form or dissolved in a solvent form or aqueous form in any percentage (%v/v).
  • solvent saturated with hydrochloric acid gas More preferably isopropyl alcohol saturated with a hydrochloric acid gas.
  • the reaction time and the temperature in step a) In general; it is convenient to carry out the reaction at a temperature of from about -10°C to about 100°C, preferably at a temperature of from about 0°C to about 5°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 15 minutes to about 5 hours, preferably from about 30 minutes to 1 hour is sufficient.
  • the suitable reagent include sulphur or its derivatives, hydrogenation catalysts such as palladium carbon in various percentages, platinum oxide, Raney Nickel, palladium oxide and the like can be used; Preferably sulphur in any form is being used.
  • the molar ratio of sulphur to the compound of formula (Ilia) can be from about 5:1 to about 1 :1, preferably 1 : 1.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 35°C to about 200°C, preferably at a temperature of from about 170°C to about 190 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
  • acetylating agents that can be used in step c) can include but are not limited to acetic anhydride, acetyl halide like acetyl chloride, acetyl bromide, acetyl iodide and the like.
  • acetic anhydride is being used.
  • the solvents that can be used in step c) include but are not limited to water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; or mixtures thereof in various proportions without limitation.
  • ethanol is being used.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 15 minutes to about 5 hours, preferably from about 30 minutes to 1 hour.
  • the bases that can be used is selected from the group consisting of organic bases such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; inorganic bases alkali metal carbonates, such as sodium carbonate or potassium carbonate and the like; other base such as sodium acetate, ammonium acetate, potassium acetate and the like; Preferably, triethylamine is being used.
  • the amount of base employed is an equimolar amount to 5 times the equimolar amount of the starting material of formula Illb. When an excess of an organic amine is employed as the base, this may optionally serve as the solvent.
  • the intermediates compounds of formulae III and II are converted to an acid addition salt by reacting with a suitable acid preferably mineral acid to make it into stable form.
  • intermediate compounds of formulae III and II are being isolated in solid form by recrystallization using polar aprotic solvents such as acetone, acetonitrile and the like.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • the working-up of reaction mixtures, especially in order to isolate desired compounds follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the processes of present invention described herein produces the intermediates and the final product in high yields and purities than the processes reported in the literature that too using simple and cost effective industrially applicable processes.
  • agomelatine (I) wherein the compound of formula III in the form of HCl salt is characterized by XRPD and DSC which are substantially in accordance with the fig. 5 and 6.
  • agomelatine (I) wherein the compound of formula II is characterized by XRPD and DSC which are substantially in accordance with the fig. 3 and 4.
  • the compounds of formula (III) and (II) obtained according to the processes of the invention are novel and useful as intermediates in the synthesis of active naphthalene derivatives like agomelatine (I), which were identified, characterized and confirmed by the characterization data like C 13 NMR, 1H 1 NMR, MASS, IR.
  • the compounds of formula (III) and (II) obtained can be crystalline or amorphous.
  • the present invention provides a process for the synthesis of (7-methoxy-l-riaphthyl) acetonitrile of formula (IVa)
  • the suitable reagent used include but not limited to sulphur and the like; Preferably sulphur in any form is being used.
  • the molar ratio of sulphur to the compound of formula (II) can be from about 5: 1 to about 1 : 1, preferably 1 : 1.
  • the optionally used solvents that can include but are not limited to water, halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), N- methyl pyrrlolidine (NMP) and the like; or mixtures thereof in various proportions without limitation.
  • the reaction is being carried in the absence of solvent or neat.
  • the reaction time and the temperature should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 35°C to about 200°C, preferably at a temperature of from about 185°C to about 190 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours is sufficient.
  • the present invention provides a process for the synthesis of (7-methoxy-l-naphthyl) acetonitrile of formula (IVa)
  • the hydrogenation catalysts used include but not limited to palladium carbon in various percentages, platinum oxide, Raney Nickel, palladium oxide and the like; Preferably
  • the organic solvents that can be used include but are not limited to water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; or mixtures thereof in various proportions without limitation.
  • o-xylene is being used.
  • reaction time and the temperature should be suitable to bring the reaction to completion . at a minimum time, without the production of unwanted side products.
  • temperature Preferably at temperature from about 75°C to about
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 5 to 8 hours.
  • agomelatine can contain extraneous compounds or impurities that can come from many sources. These extraneous materials can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in agomelatine or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
  • agomelatine At certain stages during processing of the API, agomelatine, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
  • the API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
  • the present invention provides a process for purifying agomelatine (I) comprising: a) providing a solution or suspension of agomelatine (I) in a solvent or a mixture of solvents or their aqueous mixtures and b) precipitating the solid from the solution, and c) recovering the agomelatine (I) in pure form.
  • the solvents include but are limited to water, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl methyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, n-hexane, n-heptane, cyclohexane and the like; aprotic polar solvents such as N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and the like; ethers such as dimethyl ether, diethyl ether, isopropyl ether, methyl tertiary butyl ether (MTBE), tetrahydrofuran, 1,4-dioxane and the like; esters such as ethyl acetate, isopropyl
  • the present invention provides agomelatine (I) having purity greater than about 98.0 area% to about 99.0 area % as measured by HPLC, preferably greater than about 99.0 area % to about 99.5 area %, more preferably greater about 99.5 area % to about 99.9 area %.
  • the present invention provides agomelatine (I) having individual impurities lower than about 0.15 area %, preferably lower than about 0.1 area % and total impurities lower than about 0.5 area% by HPLC.
  • the present invention provides Agomelatine (I) having an impurity bis-(7-methoxy-3,4-dihydro-l-naphthyl)ethylamine of structure
  • the present invention provides Agomelatine (I) having an impurity bis-(7-methoxy-l-naphth l)ethylamine represented by the structure
  • the present invention provides Agomelatine (I) having the compound bis-[(7-methoxy- -dihydro-l-naphthyl)ethyl] acetamide of structure
  • the present invention provides Agomelatine (I) having the compound bis-[(7-methoxy-l-naphthyl)ethyl]acetamide of structure
  • the present invention provides Agomelatine (I) having impurities represented by the structures
  • the content of impurities in the final product agomelatine (I) and the purity of the final product Agomelatine or a pharmaceutically acceptable salt thereof was measured by high performance liquid chromatography by using chromatographic system under the following conditions: Column : Merck, HiBar, Purospherstar RP-18e, 250x4.6mm; 5 ⁇ or equivalent.
  • Diluent Methanol Buffer preparation: Prepare 0.01 M of monobasic sodium phosphate anhydrous and adjust the pH to 2.5 with dilute phosphoric acid (50%v/v).
  • Mobile phase preparation Prepare a mixture of Buffer, acetonitrile and methanol in the ratio of 450: 350: 200 and mix and pass through membrane filter (0.45 ⁇ ) and degas.
  • agomelatine (I) obtained by the processes described here in above has a D 50 particle size of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 100 microns, still more specifically less than or equal to about 60 microns, and most specifically less than or equal to about 15 microns.
  • the particle sizes of the agomelatine (I) obtained by the processes of present invention may be reduced by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
  • amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the present invention provides an amorphous form of agomelatine alone or in combination with a pharmaceutically acceptable carrier characterized by X- ray powder diffraction pattern, which is substantially in accordance with Figure 2.
  • the present invention provides a process for the preparation of amorphous agomelatine comprising:
  • agomelatine As used herein, a solvent is any liquid substance capable of dissolving agomelatine.
  • antisolvent means a liquid in which a compound is poorly soluble.
  • a mixture of solvents refers to a composition comprising more than one solvent.
  • the process provides a solution of agomelatine in a solvent or mixture of solvents or aqueous mixtures thereof;
  • the solution of agomelatine can be obtained by dissolving agomelatine in a solvent or mixture of solvents or their aqueous mixtures thereof.
  • the solvents that can be used include, but are not limited to water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2- butanone and the like; halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like; nitrile solvents such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions without limitation.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like
  • the temperature for obtaining a clear and homogenous solution can range from about 25°C to about 75°C or the boiling point of the solvent/s used, preferably from about 25°C to about 40°C.
  • the solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.
  • the pharmaceutically acceptable carriers that can be used for the preparation of amorphous agomelatine include, but are not limited to, pharmaceutical hydrophilic carriers such as polyvinylpyrrolidone (homopolymers, also called “povidone,” or copolymers of N- vinylpyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols.
  • pharmaceutical hydrophilic carriers such as polyvinylpyrrolidone (homopolymers, also called “povidone,” or copolymers of N- vinylpyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols.
  • pharmaceutical hydrophilic carriers such as polyvinyl
  • Evaporation or removal of solvent(s) is accomplished by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere.
  • the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique.
  • the solution may also be completely evaporated in, for example, a pilot plant rota vapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer (ATFD), or evaporated by spray drying to obtain a dry amorphous powder.
  • the methods for drying are spray drying or vertical agitated thin-film drying (or evaporation).
  • a solution of agomelatine in (b) is sprayed into the spray drier at the flow rate ranging from about 10 ml/hr to about 300 ml/hr, preferably at flow rate of about 40 ml/hr to about 200ml/hr.
  • the air inlet temperature to the spray drier used may range from about 25°C to about 150°C, preferably from about 60°C to about 1 10°C and the outlet air temperature used may range from about 30°C to about 90°C preferably from about 35°C to about 50°C.
  • Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition.
  • vertical agitated thin-film drying (or evaporation) ATFD-V
  • the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket.
  • the rotor rotation agitates the downside-flowing solution while the heating jacket heats it.
  • the amorphous agomelatine can also be precipitated by sudden cooling of the solution comprising agomelatine to below about -5°C.
  • agomelatine (I) can be achieved by any conventional methods known in the art, for example filtration.
  • the agomelatine (I) substantially in an amorphous form obtained by the above process may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents.
  • the preferred instrument is a vacuum tray dryer.
  • amorphous agomelatine and the crystalline forms of intermediate compounds of formula II and Ilia were done using Bruker axs D8 advance X-ray powder diffractometer having Copper- ⁇ radiation. Approximately 1 g of sample was gently flattened on a sample holder and scanned from 2 to 50° two theta, at 0.03° two theta per step and a step time of 1 second (or 0.5 seconds). The sample was simply placed on the sample holder. The sample was rotated at 30rpm at a voltage 40 KV and current 35 mA.
  • Optionally seeding of the corresponding polymorph is used to obtain the desired polymorph by adding to the solution of agomelatine to afford the desired polymorph of agomelatine.
  • agomelatine (I) obtained by the processes of present invention has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 500ppm of dichloromethane, less than l OOOppm of methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, less than about 100 ppm of acetonitrile and 50 ppm of toluene.
  • the different physicochemical properties of the active ingredient and those of its excipients are to be considered, as these properties affect the process and formulation properties of the compound.
  • Various important physicochemical properties include but are not limited to particle sizes, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc.
  • Particle sizes of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle size and size distribution. This will be even more critical for low-dose drugs and satisfactory dosage units of low doses cannot be manufactured from a drug that does not meet certain particle size and size distribution specifications.
  • CU content uniformity
  • particle sizes play an important role in dissolution of active ingredient form the final dosage form for certain drugs like agomelatine because of their poor solubility.
  • these physicochemical properties not only affect the processes of the preparing the pharmaceutical formulations but also affect the performance of the pharmaceutical product both in vitro and in vivo.
  • D10, D50, and D90 values are useful ways for indicating a particle size distribution.
  • D90 is a size value where at least 90 percent of the particles have a size smaller than the stated value.
  • D10 refers to 10 percent of the particles having a size smaller than the stated value.
  • D50 refers to at least 50 percent of the particles having a size smaller than the stated value and
  • D [4,3] value refers to a mean particle size.
  • particle size plays a pivotal role in the solubility properties of an API, like agomelatine.
  • Particle size reduction techniques are employed to increase a compound's solubility. Particle size reduction increases the surface area of the solid phase that is in contact with the liquid medium.
  • particle size reduction cannot alter the solubility of the compound in a solvent, which is a thermodynamic quantity.
  • the rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption by the body, it is recognized that the bioavailability of such drugs may be enhanced when administration occurs in a finely divided state.
  • particle size can also affect how free crystals or a powdered form of a drug will flow past each other, which in turn, has consequences in the production process of pharmaceutical products containing the drug.
  • solubility and bioavailability of an active pharmaceutical ingredient may be affected by various factors. It is recognized that there is an inverse relationship between solubility and bioavailability and particle size; whereupon, the available surface area for drug dissolution correlates to the rate of dissolution and solubility. A smaller particle size enhances both the solubility and the rate of dissolution of a drug, which in turn, may improve its bioavailability and potentially its toxicity profiles.
  • solubility may affect the bioavailability of a poorly water soluble active ingredient like for eg. Agomelatine.
  • active pharmaceutical ingredients such as agomelatine
  • Agomelatine of defined particle size may be produced by precipitation from appropriate solvents. Particle size may be adjusted by customary methods such as cooling, pH adjustment, pouring a concentrated solution into an anti-solvent and/or by co-precipitation so as to obtain a precipitate with the appropriate particle size distribution.
  • agomelatine of defined particle size may be produced by known methods of particle size reduction starting with crystals, powder aggregates and course powder of either crystalline or amorphous agomelatine.
  • the principal operations of conventional size reduction are milling of a feedstock material and sorting of the milled material by size.
  • a fluid energy mill, or micronizer is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution.
  • the present invention provides crystal particles of agomelatine (I) obtained by the processes herein described, has 50 volume-percent of the particles (D 5 o) having a size of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 100 microns, still more specifically less than or equal to about 60 microns, and most specifically less than or equal to about 15 microns.
  • ⁇ refers to "micrometer” which is l xl 0 ⁇ 6 meter.
  • crystalline particles means any combination of single crystals, aggregates and agglomerates.
  • P.S.D. particle Size Distribution
  • Mean particle size distribution i.e., d (0.5)
  • d (0.5) means the median of said particle size distribution.
  • micronization means a process or method by which the size of a population of particles is reduced.
  • micron or “ ⁇ ” both refer to
  • micrometer which is 1x10 6 meter.
  • P.S.D particle Size Distribution
  • compositions comprising at least a therapeutically effective amount of highly pure agomelatine (I) and atleast a pharmaceutically acceptable excepient.
  • Such pharmaceutical compositions may be administered to a mammalian patient for the treatment or prevention of major depressive episodes in adults in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc.
  • dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • the highly pure agomelatine or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
  • the dosage forms may contain highly pure agomelatine substantially free of process related impurities as part of a composition.
  • the pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.
  • Tablets and powders may also be coated with an enteric coating.
  • the enteric-coated powder forms may have coatings containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents.
  • a coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
  • compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • the compositions described herein may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art.
  • Suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
  • binders such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes
  • disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others
  • lubricants like magnesium and calcium stearate and sodium stearyl fumarate
  • flavorings sweeteners
  • preservatives pharmaceutically acceptable dyes and
  • agomelatine of the present invention are simple, eco-friendly, robust, reproducible, cost effective and amenable on commercial scale.
  • Example -6 20gr. of (7-methoxy-3,4-dihydro-l-naphthyl)ethylamine was dissolved in 100ml. of dichloromethane. The resulting solution was cooled to 0-5°C.Then added acetic anhydride solution drop-wise below 10°C. Stirred for 30 min. at 0-5°C.Seperated the layers,washed the dichloromethane layer with 3x50 ml. of dimineralised water
  • Example -7 20gr. of (7-methoxy-3,4-dihydro-l-naphthyl)ethylamine was dissolved in 100ml. of toluene. The resulting solution was cooled to 0-5°C.Then added acetic anhydride solution drop-wise below 10°C. Stirred for 30min. at 0-5°C.Seperated the layers, washed the toluene layer with 3x50ml. of dimeralised water. The toluene layer was distilled under vacuum to give 23 gr. of the title compound.
  • Example -8 20gr. of (7-methoxy-3,4-dihydro-l-naphthyl)ethylamine was dissolved in 100ml. of ethyl acetate. The resulting solution was cooled to 0-5°C.Then added acetic anhydride solution drop-wise below 10°C. Stirred for 30min. at 0-5°C. Separated the layers, washed the ethyl acetate layer with 3x50ml. of dimeralised water. The ethyl acetate layer was distilled under vacuum to give 23gr. of the title compound.
  • IV IVa Taken 30gr. of 7-methoxy-3,4-dihydro-l-naphthyl acetonitrile (IV) and 4gr. of 5% palladium on carbon in 150ml. of o-xylene. The resultant solution was heated to reflux temperature and maintained for 7hrs. The solvent was distilled under vacuum to gave the crude residue and recrystallised form 120ml. of 20%aq.ethanol solution to give l Ogr. of the title compound.
  • Example 4 Purification of Agomelatine using a mixture of Ethyl acetate and n-hexane
  • Example 8 Purification of Agomelatine using chloroform: n-hexane (2:1)
  • Example 9 Purification of Agomelatine using water and ethanol (6.5: 3.5)
  • agomelatine (I) (5g) in dichloromethane (100 ml) was subjected to spray drying at 65° and obtained solid was dried at about 40°C for 1 hr. under reduced pressure to give 4.5 g of the title compound as white powder.
  • agomelatine (1) (5g) in dichloromethane (100 ml) was subjected to freeze drying at -25° and the solid obtained was dried at about 40°C for 1 hr. under reduced pressure to give 4.5 g of the title compound as white powder.
  • Example 7 Preparation of amorphous agomelatine (I) by sudden cooling.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur des procédés pour la synthèse de N-[2-(7-méthoxy-1-naphtyléthyl]acétamide, sur la forme amorphe du N-[2-(7-méthoxy-1-naphtyléthyl]acétamide et sur des compositions pharmaceutiques associés.
EP11854945.0A 2011-01-04 2011-01-04 Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide Withdrawn EP2705023A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000003 WO2012093402A1 (fr) 2011-01-04 2011-01-04 Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide

Publications (2)

Publication Number Publication Date
EP2705023A1 true EP2705023A1 (fr) 2014-03-12
EP2705023A4 EP2705023A4 (fr) 2014-11-19

Family

ID=46457287

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11854945.0A Withdrawn EP2705023A4 (fr) 2011-01-04 2011-01-04 Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide

Country Status (3)

Country Link
EP (1) EP2705023A4 (fr)
AR (1) AR083840A1 (fr)
WO (1) WO2012093402A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669494A (zh) * 2016-03-11 2016-06-15 上海韬鸿化工科技有限公司 一种2-(7-甲氧基-1-萘基)乙氰的制备方法

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276492B (zh) * 2010-06-08 2013-04-10 上海医药工业研究院 阿戈美拉汀中间体及其制备方法
WO2014040228A1 (fr) * 2012-09-11 2014-03-20 Les Laboratoires Servier Forme amorphe stabilisée de l'agomélatine, son procédé de préparation et compositions pharmaceutiques la contenant
FR2995896B1 (fr) * 2012-09-26 2014-11-21 Servier Lab Forme amorphe stabilisee de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent.
JO3339B1 (ar) * 2012-09-11 2019-03-13 Shanghai Inst Pharmaceutical Ind شكل مستقر غير متبلور من الأغوميلاتين وعملية تحضيره والتركيبات الدوائية التي تحتوي عليه
EP2909166A4 (fr) * 2012-10-22 2016-10-26 Symed Labs Ltd Procédé pour la préparation d'agomélatine à l'aide de nouveaux intermédiaires
CN102993040B (zh) * 2012-11-30 2015-09-30 中国药科大学 一种合成阿戈美拉汀的新方法
CN103073441A (zh) * 2012-12-27 2013-05-01 上海右手医药科技开发有限公司 合成（7-甲氧基-1-萘基）乙胺的新方法及其在合成阿戈美拉汀中的应用
CN103113243A (zh) * 2013-03-08 2013-05-22 山东方明药业集团股份有限公司 一种2-（7-甲氧基-1-萘基）乙胺盐酸盐的合成方法
CN104130154A (zh) * 2013-05-03 2014-11-05 郭炳华 一种制备高纯度阿戈美拉汀的方法
CZ2013621A3 (cs) * 2013-08-13 2015-02-25 Zentiva, K.S. Termodynamicky stabilní tuhý roztok agomelatinu pro použití ve farmaceutické formulaci
WO2015124496A1 (fr) 2014-02-19 2015-08-27 Synthon B.V. Composition pharmaceutique comprenant de l'agomélatine amorphe
WO2015189778A1 (fr) * 2014-06-10 2015-12-17 Laboratorio Chimico Internazionale S.P.A. Adsorbats et compositions d'agomélatine en solution
CN104262197A (zh) * 2014-08-28 2015-01-07 太仓运通生物化工有限公司 一种1-环己烯基乙腈的合成方法
WO2016046833A2 (fr) * 2014-09-24 2016-03-31 Symed Labs Limited Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires
EP3075724B1 (fr) 2015-03-31 2023-07-12 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Forme solide de l'agomélatine
CN105601537B (zh) * 2016-01-25 2018-11-06 江西同和药业股份有限公司 一种2-(7-甲氧基-1-萘基)乙腈的制备方法
CN107151221A (zh) * 2017-06-19 2017-09-12 太仓卡斯特姆新材料有限公司 一种制备阿戈美拉汀重要中间体7‑甲氧基萘乙腈的方法
CN109251151A (zh) * 2017-07-12 2019-01-22 北京广为医药科技有限公司 N-(2-(取代-萘-1-基)乙基)取代酰胺类化合物、其制备及其用途
CN107353229B (zh) * 2017-08-08 2019-04-30 许昌恒生制药有限公司 一种阿戈美拉汀中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137461A1 (fr) 2007-05-01 2008-11-13 Concert Pharmaceuticals Inc. Naphtyl(éthyl)acétamides

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2658818B1 (fr) * 1990-02-27 1993-12-31 Adir Cie Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
FR2934856B1 (fr) * 2008-08-05 2010-08-13 Servier Lab Nouveau procede d'obtention de la forme cristalline v de l'agomelatine
CN101585779B (zh) * 2009-03-10 2014-04-02 上海医药工业研究院 阿戈美拉汀的晶型vi及其制备方法和应用
WO2012130837A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Agomélatine solide sous une forme non cristalline
CN102716493B (zh) * 2011-03-31 2014-05-28 天津药物研究院 含无定型态阿戈美拉汀的共聚物、其制备方法、其药物组合物及用途
JO3339B1 (ar) * 2012-09-11 2019-03-13 Shanghai Inst Pharmaceutical Ind شكل مستقر غير متبلور من الأغوميلاتين وعملية تحضيره والتركيبات الدوائية التي تحتوي عليه
WO2014040228A1 (fr) * 2012-09-11 2014-03-20 Les Laboratoires Servier Forme amorphe stabilisée de l'agomélatine, son procédé de préparation et compositions pharmaceutiques la contenant
MX2015008171A (es) * 2012-12-20 2015-09-16 Synthon Bv Formulacion que comprende agomelatina amorfa.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137461A1 (fr) 2007-05-01 2008-11-13 Concert Pharmaceuticals Inc. Naphtyl(éthyl)acétamides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2012093402A1

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669494A (zh) * 2016-03-11 2016-06-15 上海韬鸿化工科技有限公司 一种2-(7-甲氧基-1-萘基)乙氰的制备方法

Also Published As

Publication number Publication date
AR083840A1 (es) 2013-03-27
WO2012093402A1 (fr) 2012-07-12
EP2705023A4 (fr) 2014-11-19

Similar Documents

Publication Publication Date Title
WO2012093402A1 (fr) Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
US10266492B2 (en) Processes and intermediates in the preparation of C5aR antagonists
US20090298947A1 (en) Polymorphic and amorphous forms of lacosamide and amorphous compositions
US20200369612A1 (en) Method for Safely Preparing Pimavanserin and Tartrate Thereof by Using Triphosgene
WO2014056434A1 (fr) Forme cristalline et forme amorphe de l'apixaban et leur préparation
WO2013065063A1 (fr) Forme anhydre du dasatinib, son procédé de préparation et son utilisation
US20170267633A1 (en) Novel crystalline arylalkylamine compound and process for producing the same
TWI376365B (en) New process for the synthesis of agomelatine
WO2015011659A1 (fr) Formes polymorphes cristallines du régorafénib et méthodes de préparation de la forme polymorphe i du régorafénib
WO2011158249A1 (fr) Méthode de préparation d'un intermédiaire de milnacipran et son utilisation dans la préparation de milnacipran pur
WO2015111085A2 (fr) Procédés de préparation d'eltrombopag et sels pharmaceutiquement acceptables, solvates et intermédiaires de celui-ci
JP2007524569A (ja) ナテグリニドの結晶形
WO2012090221A1 (fr) Nouveaux sels d'imatinib
US11434226B2 (en) Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof
CN108586450B (zh) 一种胆碱m受体抗结剂的重结晶纯化方法
KR20090044694A (ko) 모사프리드의 신규한 동질이상체 및 유사동질이상체
WO2016046833A2 (fr) Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires
EP1467964A1 (fr) Formes polymorphes de nateglinide
WO2013018100A1 (fr) Procédé de préparation de la forme cristalline 1 du n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide
KR100228328B1 (ko) (2r)-메틸-4,4,4-트리플루오로부틸아민 또는 이것의 산부가염을 제조하는 방법
US20240294479A1 (en) Polymorphs of 2-(3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid
US20110060145A1 (en) Process for production of compound having antagonistic activity on npyy5 receptor, and useful crystal
US20120059034A1 (en) Novel crystalline hydrate, amorphous and polymorphic forms of dihydro-benzoxazole-6-yl-acetamide derivative and processes for their preparation
CA3213234A1 (fr) Procede de preparation de composes derives de quinoleine
WO2021117057A1 (fr) Polymorphe de chlorhydrate de n-éthyl-1-(3- (trifluorométhyl) phényl) propan-2-amine et son procédé de préparation

Legal Events

Date Code Title Description
TPAC Observations by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20131120

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

A4 Supplementary search report drawn up and despatched

Effective date: 20141017

RIC1 Information provided on ipc code assigned before grant

Ipc: C07C 253/30 20060101ALI20141013BHEP

Ipc: C07C 213/02 20060101AFI20141013BHEP

Ipc: C07C 231/12 20060101ALI20141013BHEP

Ipc: C07C 233/18 20060101ALI20141013BHEP

Ipc: A61P 25/24 20060101ALI20141013BHEP

Ipc: C07C 231/02 20060101ALI20141013BHEP

Ipc: A61K 31/165 20060101ALI20141013BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20150514