EP2934502A1 - Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci - Google Patents

Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci

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Publication number
EP2934502A1
EP2934502A1 EP13821818.5A EP13821818A EP2934502A1 EP 2934502 A1 EP2934502 A1 EP 2934502A1 EP 13821818 A EP13821818 A EP 13821818A EP 2934502 A1 EP2934502 A1 EP 2934502A1
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EP
European Patent Office
Prior art keywords
agomelatine
acid
mol
solid form
compound
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Withdrawn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
EP13821818.5A
Other languages
German (de)
English (en)
Inventor
Pere Dalmases Barjoan
Juan Huguet Clotet
Noelia Calcerrada Muñoz
Jordi Ceron Bertran
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Laboratorios Lesvi SL
Original Assignee
Laboratorios Lesvi SL
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Priority to EP13821818.5A priority Critical patent/EP2934502A1/fr
Publication of EP2934502A1 publication Critical patent/EP2934502A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
    • C07C53/16—Halogenated acetic acids
    • C07C53/18—Halogenated acetic acids containing fluorine
    • 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

  • the present invention refers to solid forms of /V-(2-(7-methoxy-1 -naphthalenyl)ethyl) acetamide, a process for their preparation and pharmaceutical compositions containing them.
  • the present invention also refers to an efficient and environmentally friendly process for the preparation of /V-(2-(7-methoxy-1 -naphthalenyl)ethyl)acetamide and pharmaceutically acceptable salts thereof in high yield and purity, which are also suitable for industrial scale applications.
  • /V-(2-(7-methoxy-1 -naphthalenyl)ethyl)acetamide also known as agomelatine, is a melatonin agonist and 5-HT 2 c antagonist, developed by Servier for the treatment of depression.
  • Agomelatine depicted below as (1 ), is marketed under the tradename of ValdoxanO/Thymanax®, for the treatment of adult patients with major depressive episodes.
  • agomelatine In view of the pharmaceutical value of Agomeltine, it is important to obtain an efficient and safe process for the preparation of agomelatine and salts thereof that can be applied at an industrial scale with low energy and costs involve as well as in high yield and purity. In addition, as solubility of compound (1 ) in water is very poor, it is also important to obtain solid forms of agomelatine including polymorphs, solvates, co- crystals, complexes or acid addition salts with good purity and a good solubility. A number of methods of synthesis of agomelatine have been reported up to date, as disclosed below.
  • Agomelatine was first disclosed by the European patent EP447285 to Adir et Compagnie, wherein the preparation of agomelatine in eight steps, starting from 7- methoxy-1 -tetralone, was also described, as depicted below in scheme A.
  • the process described in the aforementioned patent involved the use of a large number of steps providing agomelatine in very low yields, which had to be purified by means of column chromatography, an unsuitable method for industrial scale applications.
  • the hydrogenation step of the cyano intermediate required particularly high pressures, as high as 300 atm, being very difficult to generate at industrial scale.
  • agomelatine is obtained by crystallization from isopropyl ether; however no description relating the polymorphic form obtained is included in this patent.
  • EP2418195 describes a hydrohalide complex of agomelatine, as depicted in formula (2) wherein X is defined as halogen, preferably CI or Br, their process of preparation and pharmaceutical compositions containing it.
  • hydrohalide complexes described in EP2418195 have improved solubility, stability and purity when compared to agomelatine, being appropriate for use in the manufacture of pharmaceutical compositions containing agomelatine.
  • patent application EP2418195 discloses that inorganic acids such as sulfuric acid, phosphoric acid or perchloric acid and organic acids such as acetic acid, oxalic acid, tartaric acid or fumaric acid are not suitable for preparing said hydrohalide complex of agomelatine.
  • a stable complex of agomelatine may be only prepared by reacting agomelatine with a hydrogen halide.
  • EP2418195 also disclosed that the attempt to prepare agomelatine complexes of sulfuric acid, glacial acetic acid or fumaric acid did fail.
  • WO201 1/1 13362 relates to an agomelatine hydrochloride hydrate having good solubility, stability and purity.
  • room temperature or below is preferred; the most preferred reaction temperature is 0-20°C.
  • the examples disclosed in this application describe yields of about 81 -88 % when the acid is added to the solution containing agomelatine at a temperature of 10°C. However, these yields are still low for industrial scale applications.
  • agomelatine having suitable properties for pharmaceutical use
  • European patent EP1564202 to Laboratories Servier described an improved synthetic route whereby agomelatine is provided in only four steps starting from 7-methoxy-1 -tetralone. Although the number of synthetic steps was reduced when compared to EP447285, the manufacturing process still required significantly high pressures, very difficult to generate at industrial scale, for the production of the cyano intermediate, in the hydrogenation step.
  • the second route involved the reduction of (7-methoxynaphthalen-1 -yl)acetamide using metallic hydrides such as H4UAI to directly obtain the compound (7-methoxynaphthalen-1 -yl)ethanamine.
  • metallic hydrides such as H4UAI
  • Chinese patent CN101709036 discloses the use of potassium or sodium borohydride in presence of a Lewis acid to prepare (7-methoxynaphthalen-1 -yl)ethanamine from (7- methoxynaphthalen-1 -yl)acetamide.
  • the process described in this patent reduced the number of synthetic steps with respect to the product patent EP0447285, however the used borohydrides, highly flammable compounds, is undesirable for industrial applications.
  • the ignition temperature of a borohydride is about 38-52 °C and can spontaneously ignite in contact with moist air.
  • yields disclosed in this patent CN 101709036 are always below 87 %.
  • agomelatine, pharmaceutical acceptable salts or co-crystal thereof having high HPLC purity, good solubility and polymorphic stability still remains highly desirable.
  • the prior-art provides hazardous, multi-step, complex and expensive methods for obtaining agomelatine in high yield and purity.
  • These facts increase the cost of the final agomelatine and the pharmaceutical compositions containing it, which has already resulted in expensive medications. Therefore, there is a need to develop an improved industrially feasible and more economical process for the preparation of agomelatine or pharmaceutical acceptable salts or co-crystal thereof that is more environmentally friendly, which can yield agomelatine in high purity and yield and that can be easily performed at industrial scale.
  • Figure 1 shows IR spectra of agomelatine sulfuric acid compound, polymorph I.
  • Figure 2 shows the TGA and DSC analysis of agomelatine sulfuric acid compound, polymorph I.
  • Figure 3 shows the XPRD analysis of agomelatine sulfuric acid compound, polymorph I.
  • Figure 4 shows the TGA and DSC analysis of agomelatine sulfuric acid compound, polymorph II.
  • Figure 5 shows the XPRD analysis of agomelatine sulfuric acid compound, polymorph II.
  • Figure 6 shows the XPRD analysis of agomelatine sulfuric acid compound, hydrated form.
  • Figure 7 shows IR spectra of agomelatine trifluoroacetic acid compound.
  • Figure 8 shows the DSC analysis of agomelatine trifluoroacetic acid compound.
  • Figure 9 shows XPRD analysis of agomelatine trifluoroacetic acid compound.
  • Figure 10 shows IR spectra of agomelatine phosphoric acid compound.
  • Figure 1 1 shows the TGA and DSC analysis of agomelatine phosphoric acid compound.
  • Figure 12 shows XPRD analysis of agomelatine phosphoric acid compound.
  • Figure 13 shows XPRD analysis of agomelatine.
  • a first aspect of the present invention relates to solid forms of agomelatine with the following formula (3),
  • HA is an acid.
  • These solid forms of agomelatine are characterized to have good solubility, stability and high purity and are suitable for the manufacture of pharmaceutical formulations containing them.
  • a second aspect of the present invention relates to a process for the preparation of the solid forms of agomelatine of the first aspect, wherein agomelatine is reacted with the corresponding acid in an organic solvent to produce a solid form of agomelatine of the first aspect.
  • the process to produce these solid forms of agomelatine is easy reproducible, at an industrial scale, providing low energy and costs and high yields.
  • these solid forms of agomelatine are obtained in high purity.
  • the third aspect of the present invention provides an efficient and environmentally friendly process for manufacturing agomelatine or a pharmaceutically acceptable salt or co-crystal thereof, or the solid forms of the first aspect in high yields and applicable at industrial scale. This process also allows obtaining agomelatine without requiring laborious and unfeasible purification steps, yielding a high purity which complies with pharmaceutical standards.
  • the third aspect of the present invention provides a process for manufacturing agomelatine or a pharmaceutically acceptable salt or co-crystal thereof, wherein the process comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ) in the presence of an organic solvent to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine, compound III;
  • agomelatine into a salt or co-crystal thereof, and alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • a fourth aspect of the present invention relates to the use of the solid forms of agomelatine provided according to the first, second or third aspect as intermediates for the preparation of, polymorphically stable agomelatine and pharmaceutical acceptable salts thereof in high purity and high yields.
  • a fifth aspect of the present invention relates to the preparation process of stable agomelatine and pharmaceutical acceptable salts thereof in high polymorphic and HPLC purity and high yields from the solid forms of agomelatine provided according to the first, second or third aspect.
  • a sixth aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of agomelatine or a pharmaceutically acceptable salt or the solid forms thereof provided according to the first, second or third aspect of the present invention together with appropriate amount of pharmaceutically acceptable excipients or carriers.
  • a seventh aspect of the present invention relates to the use of the pharmaceutical composition of the sixth aspect of the present invention for use as a medicament.
  • An eight aspect of the present invention relates to the use of the pharmaceutical composition of aspect sixth for the treatment of major depressive episodes in adults.
  • a ninth aspect of the present invention relates to the pharmaceutical composition of the sixth aspect of the present invention for use as an antidepressant.
  • a tenth aspect of the present invention relates to the agomelatine or a pharmaceutically acceptable salt thereof or the solid forms provided according to the first, second or third aspect of the present invention for use as a medicament.
  • a eleventh aspect of the present invention relates to the agomelatine or a pharmaceutically acceptable salt thereof or the solid forms provided according to the first, second or third aspect of the present invention for use as an antidepressant.
  • bases refers to a substance that tends to accept a proton. Suitable bases include, metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate and potassium bicarbonate; metal acetates, such as sodium acetate and potassium acetate; ammonia derivatives such as triethylamine, dicyclohexylamine, ⁇ /,/V-diisopropylethylamine and methanolic ammonia and heterocyclic bases such as pyridine.
  • metal hydroxides such as sodium hydroxide and potassium hydroxide
  • metal carbonates such as sodium carbonate and potassium bicarbonate
  • metal acetates such as sodium acetate and potassium acetate
  • ammonia derivatives such as triethylamine, dicyclohexylamine, ⁇ /,/V-diisopropylethylamine and methanolic ammonia and heterocyclic bases such as pyridine.
  • antisolvent refers to a solvent in which the compound is not fully soluble. Suitable antisolvents for the purification process of agomelatine include alcohols, ketones, ethers, esters, hydrocarbons and any mixtures thereof.
  • the term “consisting essentially of” refers that the entity or process may comprise further features, but those features do not materially cause any surprising technical affect.
  • agomelatine derivates refers to salts or co-crystals of agomelatine.
  • solvate refers to a molecular complex comprising agomelatine or agomelatine derivate and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g. acetone).
  • solvent molecules e.g. acetone
  • hydrate refers to a molecular complex comprising agomelatine or agomelatine derivate and a stoichiometric or non-stoichiometric amount of water.
  • washing refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and/or through the solid mass, as to remove undesirable soluble matter.
  • the process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtering, decanting, or a combination thereof.
  • washing includes contacting solids with solvent or solvent mixture, vigorously stirring (e.g., for two hours), and filtering.
  • the solvent can be water, can be an aqueous solvent system, or can be an organic solvent system. Additionally, the washing can be carried out with the solvent having any suitable temperature. For example, the washing can be carried out with the solvent having a temperature between about 0°C and about 100°C.
  • inventions refers to the process wherein an isolated product can be obtained, which can be carried out on an industrial scale such as solvent extraction, filtration, distillation, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
  • solvent extraction refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.
  • filtration refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid.
  • filament refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size.
  • filter cake refers to residual solid material remaining on a feed side of a filtration element.
  • evaporation refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor.
  • Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.
  • slurrying refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.
  • phase separation refers to a solution or mixture having at least two physically distinct regions.
  • crystallization refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
  • purification refers to the process wherein a purified drug substance can be obtained.
  • industrial purification refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
  • the term “acid” refers to a substance that tends to release a proton.
  • the term “acid” contemplates all inorganic or organic acids. Suitable acids for the present invention are hypochloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid (also known as ortho phosphoric acid), fluoroboric acid, trifluoroacetic acid, succinic acid, formic acid, salicylic acid, acetyl salicylic acid, gluconic acid, lactic acid, succinic acid and their mixtures.
  • sulfuric acid, phosphoric acid and trifluoroacetic acid Preferably sulfuric acid, phosphoric acid and trifluoroacetic acid.
  • organic solvent refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute).
  • Organic solvents may be liquids at room temperature.
  • examples of organic solvents that may be used for the present invention include, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g.
  • polar solvent means a solvent that tends to interact with other compounds or itself through acid-base interactions, hydrogen bonding, dipole- dipole interactions, or by dipole-induced dipole interactions.
  • non-polar solvent as used herein means a solvent that is not a polar solvent.
  • Non-polar solvents interact with other compounds or themselves predominantly through dispersion forces.
  • Non-polar solvents interact with polar solvents mainly through dipole-induced dipole interactions or through dispersion forces.
  • Non-limiting examples of these solvents include toluene, xylene, n-heptane, octane, isooctane, cyclohexane, pentane and 1 ,4-dioxane.
  • aprotic solvent means any molecular solvent which cannot donate H + .
  • aprotic solvents that may be used for the present invention include, but are not limited to: tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetone, ethyl acetate, isopropyl acetate, toluene, methyl cyclohexane, acetonitrile, methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK).
  • THF tetrahydrofuran
  • 2-methyl tetrahydrofuran acetone
  • ethyl acetate isopropyl acetate
  • toluene methyl cyclohexane
  • MEK methyl ethyl ketone
  • MiBK methyl isobutyl ketone
  • a first aspect of the present invention relates to solid forms of agomelatine with the following formula (3),
  • HA is an acid.
  • Suitable acids are selected from hypochloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, fluoroboric acid, trifluoroacetic acid, succinic acid, formic acid, salicylic acid, acetyl salicylic acid, gluconic acid, lactic acid, succinic acid and their mixtures.
  • HA is sulfuric acid, phosphoric acid and trifluoroacetic acid. More preferably HA is sulfuric acid and phosphoric acid.
  • the solid forms of agomelatine may exist in crystalline form or non-crystalline form or as a mixture thereof.
  • solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as ethyl acetate, isopropyl acetate acetone, dichloromethane, tetrahydrofuran, acetonitrile, methylsulfoxide, dimethyl-formamide, toluene, ethanol or they may involve water.
  • Solvates wherein water is the solvate that is incorporated into the crystal lattice are typically referred as to hydrates.
  • the crystalline solid forms of agomelatine may also exist as an anhydride material. It is also understood by the skilled in the art that the term anhydrous when used in reference to solid forms of agomelatine describes solid forms of agomelatine which are substantially free of water.
  • the solid forms of agomelatine of the first aspect are characterized to have good solubility, good polymorphic and colour stability and high purity, as determined by HPLC, the level of total impurities is lower than 0.5 % suitable for use in the manufacture of pharmaceutical formulations containing it.
  • the obtained solid forms of agomelatine of the present invention have a particle size D 50 of less than about 400 ⁇ , preferably less than about 200 ⁇ , more preferably less than about 100 ⁇ , still more preferably less than about 50 ⁇ and most preferably less than 15 ⁇ .
  • Dx means that x % of the particles in a composition (based on volume) have a diameter below a specified D value.
  • a D 50 of 400 ⁇ means that 50 % of the particles, by volume, have a diameter below 400 ⁇ .
  • the inventors have found that these solid forms of agomelatine can be also used as intermediates for the preparation of stable agomelatine and agomelatine derivates in high yield and purity as it is disclosed in the fourth aspect of the present invention.
  • the inventors have found that the solid forms of agomelatine of the first aspect, remained colour stable, since showed no change in color over a long period of time, preferably over a month, when left under atmospheric conditions at room temperature.
  • the solid forms are stable under humidity conditions, as no water intake was produced at a temperature of 30 °C and 60 % RH (relative humidity). Thus, they do not have to be stored in special packaging containers or under expensive inert gas conditions to prevent or minimize their degradation or water intake.
  • the polymorphic stability of solid forms of agomelatine and agomelatine obtained from the solid forms of agomelatine was determined by X-ray powder diffraction on several samples that were stored at 25 °C under air conditions.
  • stable means that no changes in 2-theta values of the X-ray powder diffraction pattern were detected after a period of time with respect to the X-ray powder diffraction pattern at time 0 weeks. Thus no change in polymorphic form is observed.
  • the present invention provides a polymorph of crystalline agomelatine sulfuric acid compound, polymorph I, which is characterized by at least one of the following:
  • °C values can vary by 2 °C, preferably by 1 °C.
  • polymorph I of the agomelatine sulfuric acid compound is further characterized in that the pattern further X-ray powder diffraction further comprises the following peaks at approximately: 6.9, 14.2, 17.6, 17.7, 20.7 and 23.4 ⁇ 0.2 degrees two theta.
  • the invention provides a polymorph I of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an XRD pattern substantially in accordance to figure 3.
  • the invention provides a polymorph of crystalline agomelatine sulfuric acid compound, polymorph I, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values shown below:
  • the invention provides a polymorph of a crystalline agomelatine sulfuric acid compound, polymorph I, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity (in percentage) at approximately the values shown below:
  • the term "approximately” means in this context of XRD intensity measurements that there is an uncertainty in the measurements of the relative intensities. It is known to the person skilled in the art that the uncertainty of the relative intensities depends strongly on the measurement conditions.
  • the relative intensity values can e.g. vary by 30 %.
  • the invention provides a polymorph of a crystalline agomelatine sulfuric acid compound, polymorph I, characterized in that it provides a TGA substantially in accordance to figure 2.
  • the invention provides polymorph I of a crystalline agomelatine sulfuric acid compound, characterized in that it provides a DSC substantially in accordance to figure 2. In a further embodiment, the invention provides a polymorph I of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an IR substantially in accordance to figure 1 .
  • the invention relates especially to the polymorph I of agomelatine sulfuric acid wherein at least 70 % are a crystalline polymorph as defined above, particularly wherein at least 90 % are a crystalline polymorph as defined above, more particularly wherein at least 95 % are a crystalline polymorph as defined above and even more particularly wherein at least 99 % are a crystalline polymorph as defined above.
  • the invention encompasses the polymorph I of crystalline agomelatine sulfuric acid compound in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products.
  • the present invention also provides a polymorph of crystalline agomelatine sulfuric acid compound, polymorph II, which is characterized by at least one of the following: (i) a X-ray crystal structure (SCXR) having the following cell parameters:
  • PXRD powder X-ray diffraction
  • the agomelatine sulfuric acid compound, polymorph II is further characterized in that the pattern further X-ray powder diffraction further comprises the following values at approximately: 8.8, 13.3, 15.4 and 19.4 ⁇ 0.2 degrees two theta.
  • the invention provides a polymorph of a crystalline agomelatine sulfuric acid compound, polymorph I I , characterized in that it provides an XRD pattern substantially in accordance to figure 5.
  • the invention provides the polymorph II of crystalline agomelatine sulfuric acid compound, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance at approximately the values shown below:
  • the invention provides the polymorph II of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity (in percentage) at approximately the values shown below:
  • the invention provides a polymorph II of a crystalline agomelatine sulfuric acid compound, characterized in that it provides a TGA substantially in accordance to figure 4. In a further embodiment, the invention provides polymorph II of a crystalline agomelatine sulfuric acid compound, characterized in that it provides a DSC substantially in accordance to figure 4.
  • the invention relates especially to the polymorph II of agomelatine sulfuric acid wherein at least 70 % are a crystalline polymorph as defined above, particularly wherein at least 90 % are a crystalline polymorph as defined above, more particularly wherein at least 95 % are a crystalline polymorph as defined above and even more particularly wherein at least 99 % are a crystalline polymorph as defined above.
  • the present invention also provides a hydrate of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an XRD pattern substantially in accordance to figure 6. This hydrate is obtained when agomelatine sulfuric acid compound is exposed at relative humidity above 90 % for two hours.
  • a hydrate form of crystalline agomelatine sulfuric acid compound is characterized by a powder X-ray diffraction (PXRD) pattern having characteristics peaks at approximately 1 1 .5, 16.2, 19.5, 20.4, 23.4 and 29.1 ⁇ 0.2 degrees two theta (i.e. Bragg's angle).
  • PXRD powder X-ray diffraction
  • the hydrate form of the agomelatine sulfuric acid compound is further characterized in that the pattern further X-ray powder diffraction further comprises the following peaks at approximately: 22.8, 24.2, 20.7 and 27.7 ⁇ 0.2 degrees two theta.
  • the invention provides the hydrate form of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an XRD pattern substantially in accordance to figure 6.
  • the invention provides a hydrate of crystalline agomelatine sulfuric acid compound, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values shown below:
  • the invention provides a hydrated form of a crystalline agomelatine sulfuric acid compound, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity (in percentage) at approximately the values shown below:
  • the present invention also provides a polymorph of crystalline agomelatine trifluoroacetic acid compound, which is characterized by at least one of the following:
  • the agomelatine trifluoroacetic acid compound of a crystalline agomelatine is further characterized in that the pattern further X-ray powder diffraction further comprises the following values at approximately: 17.6, 18.2, 18.6 and 21 .0 ⁇ 0.2 degrees two theta.
  • the invention provides a polymorph of a crystalline agomelatine trifluoroacetic acid compound characterized in that it provides an XRD pattern substantially in accordance to figure 9.
  • the invention provides a polymorph of crystalline agomelatine trifluoroacetic acid compound characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance at approximately the values shown below:
  • the invention provides a polymorph of a crystalline agomelatine trifluoroacetic acid compound characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity at approximately the values (in percentage) shown below:
  • the invention provides a polymorph of a crystalline agomelatine trifluoroacetic acid compound characterized in that it provides a DSC substantially in accordance to figure 8.
  • the invention provides a polymorph of a crystalline agomelatine trifluoroacetic acid compound characterized in that it provides an IR substantially in accordance to figure 7.
  • the invention encompasses the polymorph of a crystalline agomelatine trifluoroacetic acid compound in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products.
  • the present invention also provides a polymorph of crystalline agomelatine phosphoric acid compound which is characterized by at least one of the following:
  • the agomelatine phosphoric acid compound is further characterized in that the pattern further X-ray powder diffraction further comprises the following values at approximately: 13.0, 13.5, 20.3, 22.3, 23.3 and 31 .0 ⁇ 0.2 degrees two theta.
  • the invention provides a polymorph of a crystalline agomelatine phosphoric acid compound characterized in that it provides an XRD pattern substantially in accordance to figure 12.
  • the invention provides a polymorph of crystalline agomelatine phosphoric acid compound characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values shown below:
  • the invention provides a polymorph of a crystalline agomelatine phosphoric acid compound characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity in percentage shown below:
  • the invention provides a polymorph of a crystalline agomelatine phosphoric acid compound characterized in that it provides a TGA substantially in accordance to figure 1 1 .
  • the invention provides a polymorph of a crystalline agomelatine phosphoric acid compound characterized in that it provides a DSC substantially in accordance to figure 1 1 .
  • the invention provides a polymorph of a crystalline agomelatine phosphoric acid compound characterized in that it provides an IR substantially in accordance to figure 10.
  • the invention encompasses the polymorph of a crystalline agomelatine phosphoric acid compound in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products.
  • the invention relates especially to the polymorph of agomelatine phosphoric acid wherein at least 70 % are a crystalline polymorph as defined above, particularly wherein at least 90 % are a crystalline polymorph as defined above, more particularly wherein at least 95 % are a crystalline polymorph as defined above and even more particularly wherein at least 99 % are a crystalline polymorph as defined above.
  • a second aspect of the present invention relates to a process for the preparation of the- solid forms of agomelatine of the first aspect of the present invention, wherein agomelatine is reacted with an acid at temperature between -10 °C and 100 °C to produce the solid forms of agomelatine.
  • the temperature is between 0 °C and 100 °C.
  • the process for obtaining these solid forms of agomelatine provides agomelatine compounds in excellent yields and purity, even if the reaction is carried out at room temperature.
  • the obtained mixture can also be stirred to easy the formation of the solid forms of agomelatine, as a precipitate.
  • the obtained solid form is isolated by means of conventional isolation techniques. Preferably, the solid form is isolated by filtration.
  • the solid form of agomelatine obtained is purified or dried or both.
  • Suitable acids are selected from hypochloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, fluoroboric acid, trifluoroacetic acid, succinic acid, formic acid, salicylic acid, acetyl salicylic acid, gluconic acid, lactic acid, succinic acid and their mixtures.
  • sulfuric acid, phosphoric acid and trifluoroacetic acid More preferably sulfuric acid and phosphoric acid.
  • the ratio of the acid to agomelatine may be from 1 :3 (mol/mol) to 5:1 (mol/mol), 1 mol of acid per 3 mols of agomelatine to 5 mol of acid per mol of agomelatine, more preferably from 1 :3 (mol/mol) to 2:1 (mol/mol). Most preferably, the ratio is about 1 .5:1 (mol/mol).
  • the reaction can be carried out in the presence of an organic solvent as a reaction media.
  • the organic solvent is a polar aprotic solvent and it is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, isopropyl acetate, methyl cyclohexane, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone. Most preferably acetone, methyl ethyl ketone, ethyl acetate or isopropyl acetate.
  • the use of an organic solvent, as a reaction media allows dissipating the energy when the preparation of the solid forms of agomelatine is an exothermic reaction.
  • the use of acetone improves the purity of the solid forms of agomelatine.
  • the ratio of organic solvent to agomelatine may be from 100:1 (v/w) to 1 :1 (v/w), 100 volumes of solvent per gram of agomelatine to 1 volumes of solvent per gram of agomelatine.
  • the ratio is from 20:1 (v/w) to 5:1 (v/w).
  • the process for the preparation of the solid forms of agomelatine comprises reacting agomelatine with an acid a temperature between -10 °C and 100 °C in the presence of an organic solvent, optionally stirring the mixture and followed by collection of the precipitated obtained.
  • the temperature is between 0 °C and 100 °C, more preferably between 0 °C and 75 °C. Most preferably between 15 °C and 40 °C.
  • the preferred organic solvent is a polar aprotic solvent, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, isopropyl acetate methyl cyclohexane, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone. Most preferably acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate or isopropyl acetate.
  • the obtained mixture can also be stirred to ease the formation of the solid forms of agomelatine as a precipitate. Afterwards, the obtained solid form is isolated by means of conventional isolation techniques. Preferably the solid form is isolated by filtration. Optionally the solid form of agomelatine obtained may be purified or dried or both.
  • the process for the preparation of the solid forms of agomelatine comprises reacting agomelatine with an acid at temperature between 0 °C and 75 °C, more preferably between 15 °C and 40 °C in the presence of an organic solvent, optionally stirring the mixture and followed by collection of the precipitated obtained.
  • the preferred ratio of the acid to agomelatine is about 1 .5:1 (mol/mol).
  • the preferred organic solvent is acetone, methyl ethyl ketone, ethyl acetate or isopropyl acetate.
  • the preferred ratio of organic solvent to agomelatine is from 20:1 (v/w) to 5:1 (v/w).
  • the obtained mixture can also be stirred to ease the formation of the solid forms of agomelatine as a precipitate.
  • the obtained solid form is isolated by means of conventional isolation techniques.
  • the solid form is isolated by filtration.
  • the solid form of agomelatine obtained purified or dried or both.
  • the invention provides a process for the preparation of agomelatine sulfuric acid polymorph II , wherein agomelatine sulfuric acid polymorph I is dissolved or suspended with stirring at temperature between 15-100 °C in an organic solvent.
  • the preferred organic solvent is a polar aprotic solvent, preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, methyl cyclohexane, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone.
  • the polar aprotic solvent is acetone, acetonitrile, isopropyl acetate or ethyl acetate.
  • the resulting solution or suspension is cooled to room temperature.
  • the crystals obtained are isolated by means of conventional isolation techniques, preferably by filtration.
  • the obtained solid form of agomelatine, polymorph II may be further purified or dried or both.
  • room temperature in the context of the preparation of agomelatine sulfuric acid polymorph I I means that the temperature is between 15-30 °C.
  • the process is easy reproducible at an industrial scale with low energy and costs.
  • the product is obtained in high yields and high polymorphic and HPLC purity.
  • Solid forms of agomelatine are obtained in good yield and high HPLC and polymorphic purity.
  • the HPLC purity is as high as 99 %.
  • the solid forms of 4 N-(2-(7- methoxy-1 -naphthalenyl)ethyl)acetamide are polymorphically and colour stable in atmospheric conditions (25 °C, 60 % RH) for at least 3 weeks and also very soluble.
  • the third aspect of the present invention refers to an environmentally friendly process for the preparation of agomelatine and pharmaceutically salts or co-crystals thereof, in high purity and yield, which can be easily performed at industrial scale and, wherein the process comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II , with alane (AIH 3 ) in the presence of an organic solvent to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine, compound I I I ;
  • the 2-(7-methoxynaphthalen-1 -yl)acetamide (compound II) is added to a mixture of the alane (AIH 3 ) in an organic solvent and further heated to reflux temperature to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine (compound III).
  • the compound II is slowly added to the mixture to allow a good control of the reaction.
  • the mixture can also be stirred to ease the formation of the compound II I.
  • the compound II I is isolated by means of conventional isolation techniques.
  • the solvent is removed by distillation.
  • the compound III obtained is purified by means of conventional purification techniques.
  • Suitable organic solvents are selected from methyltetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1 ,4- dioxane and their mixtures with hydrocarbons such as n-pentane, n-hexane, n- heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, which also includes aromatic hydrocarbon solvents, benzene, toluene, o-xylene, m-xylene, and p-xylene, halogenated hydrocarbon solvents, 1 ,2-dichloroethane, dichloromethane and chloroform.
  • the organic solvent is tetrahydrofuran, methyltetrahydrofuran and their mixtures with toluene. More preferably the organic solvent is
  • the ratio of the alane (AIH 3 ) to compound II may be from 10:1 (mol/mol) to 2:1 (mol/mol), 10 mols of alane (AIH 3 ) per 1 mol of compound II to 2 mols of alane (AIH 3 ) per 1 mol of compound II.
  • the ratio is from 5:1 (mol/mol) to 2:1 (mol/mol).
  • the ratio is about 3.3:1 (mol/mol).
  • obtaining an acid addition salt of compound III wherein the acid used to form the acid addition salt is an inorganic or organic acid;
  • 2-(7-methoxynaphtalen-1 -yl)ethanamine (compound III) obtained in step a) may be converted into an acid addition salt.
  • the acid used to obtain the acid addition salt of compound III may be, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, fumaric acid, acetic acid, trifluoroacetic, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, succinic acid, malic acid.
  • Preferred acid is hydrochloric acid.
  • the reaction may be carried out by mixing the compound III, with an organic solvent and an acid.
  • the suspension obtained can be stirred to ease the formation of the 2-(7-methoxynaphtalen-1 -yl)ethanamine acid addition salt (acid addition salt of compound III) as a precipitate.
  • the obtained precipitate is isolated by means of conventional isolation techniques.
  • the acid addition salt of compound III obtained is isolated by filtration.
  • the acid addition salt of compound III obtained may be further purified by conventional methods.
  • the acid addition salt of compound II I obtained is purified by washings with an organic solvent such as ethyl acetate, isopropyl acetate, methylene chloride, toluene, tetrahydrofuran, acetone or dimethylformamide.
  • the acid addition salt of compound III obtained may be further dried.
  • the preferred acid addition salt of compound III is the hydrochloride of compound III.
  • Compound III and salts thereof are obtained in very high purity and yields. Yields are of at least 97 %, and the purity is not less than 99 %.
  • Suitable acetylation agents are selected from methyl acetyl phosphate, zinc acetate, acetyl chloride, acetyl bromide and acetic anhydride.
  • the acetylation agent is acetic anhydride or acetyl chloride.
  • Suitable bases include non-limiting examples, metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate and potassium bicarbonate; metal acetates, such as sodium acetate and potassium acetate; ammonia derivatives; such as triethylamine, dicyclohexylamine, ⁇ /,/V-diisopropyl-ethylamine and methanolic ammonia, and heterocyclic bases such as pyridine or mixtures thereof. Among them triethylamine and metal carbonates are preferred. More preferably, triethylamine and sodium carbonate.
  • step c) 2-(7-methoxynaphtalen-1 -yl)ethanamine (Compound III) or acid addition salts of 2-(7-methoxynaphtalen-1 -yl)ethanamine (acid addition salts of compound III) is mixed with a base.
  • the mixture obtained may be stirred.
  • the acetylation reaction is carried out by adding an acetylation agent to the mixture.
  • the reaction mass can also be stirred to easy the formation of agomelatine (compound I).
  • the acetylation reaction is carried out over a range of temperatures from 0 °C to 100 °C.
  • the reaction temperature range was from 10 °C to 60 °C.
  • the preferred acid addition salt of compound III is the hydrochloride of compound III.
  • the ratio of the base to compound III or an acid addition salt of compound III may be from 10:1 (mol/mol) to 1 :1 (mol/mol), 10 mols of base per 1 mol of compound III or compound III hydrochloride to 1 mol of base per 1 mol of compound III or compound III hydrochloride.
  • the ratio is from 5:1 (mol/mol) to 1 :1 (mol/mol).
  • the ratio is from 3: 1 (mol/mol) to 1 :1 (mol/mol).
  • the preferred acid addition salt of compound III is the hydrochloride of compound III.
  • the acetylation agent of step c) may also act as a reaction media.
  • the reaction can also be carried out in the presence of an organic solvent.
  • Suitable organic solvent include hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, which also includes aromatic hydrocarbon solvents, such as benzene, toluene, o-xylene, m-xylene, and p-xylene; halogenated hydrocarbon solvents, such as 1 ,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, isopropyl acetate, ethyl acetate, ethyl malonate; ketone solvents, acetone,
  • the ratio of organic solvent to compound III or an acid addition salt of compound III may be from 100:1 (v/w) to 1 :1 (v/w), 100 volumes of solvent per gram of solid to 1 volume of solvent per gram of solid. Preferably, the ratio is from 10:1 (v/w) to 5:1 (v/w).
  • the preferred acid addition salt of compound III is the hydrochloride of compound III.
  • the acetylation reaction takes place by providing a mixture of compound III or an acid addition salt of compound I II with a base in the presence of an organic solvent.
  • organic solvents include isopropyl acetate, ethyl acetate, toluene, acetone, methyl ethyl ketone, acetonitrile, /V,/V-dimethylformamide, N,N- dimethylacetamide, dichloromethane, acetic anhydride.
  • the mixture may be stirred.
  • the acetylation reaction is carried out by adding an acetylation agent to the mixture.
  • the reaction mass can also be stirred to ease the formation of the compound I.
  • the acetylation reaction is carried out over a range of temperatures from 0 °C to 100 °C.
  • the reaction temperature range was from 10 °C to 60 °C. Most preferably, between 15 °C and 40 °C.
  • the preferred acid addition salt of compound III is the hydrochloride of compound III.
  • Salts or co-crystals of agomelatine also referred as solid forms of agomelatine, as depicted below, can be prepared by reacting agomelatine with an acid at temperature between -10 °C and 100 °C.
  • the temperature is between 0 °C and 100 °C. More preferably, between 0 °C and 75 °C. Most preferably, between 15 °C and 40 °C.
  • the obtained mixture can also be stirred to easy the formation of the solid forms of agomelatine, as a precipitate. Afterwards, the obtained solid form is isolated by means of conventional isolation techniques. Preferably, the solid form is isolated by filtration. Optionally, the solid form of agomelatine obtained is purified.
  • this process provides salts and co-crystals of agomelatine in excellent yields and purity, even if the reaction is carried out at room temperature.
  • Suitable acids (HA) for the preparation of the solid form of agomelatine are selected from hypochloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, fluoroboric acid, trifluoroacetic acid, succinic acid, formic acid, salicylic acid, acetyl salicylic acid, gluconic acid, lactic acid, succinic acid and their mixtures.
  • this process provides the solid forms of agomelatine of the first and second aspect of the present invention.
  • sulfuric acid, phosphoric acid and trifluoroacetic acid More preferably sulfuric acid and phosphoric acid (also known as orthophosphoric acid).
  • the solid form of agomelatine is alternatively converted to agomelatine by mixing and stirring the solid form of agomelatine in water at room temperature.
  • room temperature in the context of the preparation of agomelatine solid form means that the temperature is between 10 °C and 40 °C.
  • agomelatine described in the unpublished European Patent Application EP12199081 .6 and as described in examples 1 to 1 1 may be used herein when the step d) is carried out. Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques. Preferably, agomelatine is purified by washings with an organic solvent, such as ethyl acetate or toluene, or water.
  • organic solvent such as ethyl acetate or toluene, or water.
  • Agomelatine is obtained in very high purity and yields. Yields of the acetylation reaction are of at least 90 %, and the purity is not less than 99 %.
  • the process of the present invention reduces the number of synthetic steps to obtain agomelatine and salts thereof and is easily reproducible at an industrial scale with low energy and costs.
  • this process provides agomelatine and salts thereof in high yields and high HPLC purity.
  • the alane of step a) can be obtained by either:
  • Suitable tetrahydride alanate compounds are potassium aluminum hydride (KAIH 4 ), sodium aluminum hydride (NaAIH 4 ), beryllium tetrahydroaluminate (Be(AIH 4 ) 2 ), calcium tetrahydroaluminate (Ca(AIH 4 ) 2 ), manganese tetrahydroaluminate (Mn(AIH 4 ) 2 ), magnesium tetrahydroaluminate (Mg(AIH 4 ) 2 ) or lithium aluminum hydride (LiAIH 4 ).
  • the tetrahydride alanate is lithium aluminum hydride (LiAIH 4 ).
  • Suitable hydride compounds are lithium hydride, sodium hydride, potassium hydride, cesium hydride, beryllium hydride, magnesium hydride, calcium hydride, strontium hydride or barium hydride.
  • the hydride is lithium hydride.
  • the term "acid” as used herein refers to a non-aqueous compound which can act as a proton donor or as electron-pair acceptor. Suitable acids are selected from sulfuric acid, hydrogen chloride, methanesulfonic acid, p-toluenesulfonic acid, aluminum chloride, aluminum bromide, magnesium chloride, calcium chloride, strontium chloride, tin chloride, silicon dichloride, ferric bromide, ferric chloride, beryllium chloride, zinc chloride and mixtures thereof.
  • the acid is sulfuric acid, aluminum chloride and zinc chloride. More preferably, the acid is sulfuric acid.
  • the alane is prepared by two different pathways; i) either by providing a mixture of the tetrahydride alanate in an organic solvent followed by slow addition of an acid. Since the formation of the alane is an exothermic reaction, the mixture should be maintained at temperature between -20 °C and 10 °C, thus preventing any polymerization of the alane taking place. Preferably the temperature is maintained between -10° C and 0 °C; or ii) by providing a mixture of the hydride compound in an organic solvent followed by slow addition of aluminum chloride. Since the formation of the alane is an exothermic reaction, the mixture should be maintained at temperature between -20 °C and 10 °C, thus preventing any polymerization of the alane taking place. Preferably the temperature is maintained between -10 °C and 0 °C.
  • 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II can be obtained by reacting 2-(7-methoxynaphtalen-1 -yl)acetic acid, compound IV, with oxalyl chloride in an organic solvent obtaining a non-isolated product, that is treated with an ammonia derivative.
  • Suitable organic solvent include hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, which also includes aromatic hydrocarbon solvents; such as benzene, toluene, o-xylene, m-xylene, and p-xylene; halogenated hydrocarbon solvents, such as 1 ,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, ethyl malonate; ketone solvents, such as acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone; ether solvents, such as diethyl ether, dipropyl ether, diphenyl
  • the organic solvent may be formed by the combination of two or more organic solvents.
  • organic solvents such as mixtures of an aromatic hydrocarbon solvent such as toluene or xylene with N,N- dimethylformamide are preferred, still more preferably mixtures of toluene and N,N- dimethylformamide.
  • Suitable ammonia derivative include non-limiting examples, such as aqueous ammonia, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium hydroxide, ammonium sulfate, ammonium aluminum sulfate, ammonium benzoate, ammonium acetate and other compounds containing NH 3 and mixtures thereof. More preferably, the ammonia derivative is aqueous ammonia.
  • the 2-(7-methoxynaphtalen-1 -yl)acetic acid (compound IV) is mixed in an organic solvent and oxalyl chloride is added dropwise to the obtained suspension. Afterwards the mixture is stirred until a clear solution is obtained. The solution is treated with an ammonia derivative and the obtained suspension is stirred to obtain 2-(7- methoxynaphtalen-1 -yl)acetamide, compound II, as a precipitate.
  • the obtained precipitate is isolated by means of conventional isolation techniques.
  • the compound II is isolated by filtration.
  • the compound II obtained may be further purified by conventional methods.
  • compound II is purified by washings with water and an organic solvent such as toluene.
  • the compound II obtained may be further dried.
  • the reaction is carried out in toluene and N,N- dimethylformamide.
  • the reaction temperature range is from 0 °C to 100 °C.
  • the reaction temperature range was from 15 °C to 40 °C.
  • the molar ratio of 2-(7- methoxynaphtalen-1 -yl)acetic acid (Compound IV) to oxalyl chloride may be from 1 :1 (mol/mol) to 1 :2(mol/mol).
  • the molar ratio is from 1 :1 .1 (mol/mol) to 1 :1 .5 (mol/mol).
  • the molar ratio is from 1 :1.3 (mol/mol).
  • Compound II is obtained in very high purity and yields. Yields are of at least 97 %, and the purity is not less than 97 %.
  • agomelatine into a salt or co-crystal thereof, and alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • agomelatine into a salt or co-crystal thereof, and alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • the preparation of agomelatine and pharmaceutical acceptable salts or co-crystals thereof comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ) in the presence of an organic solvent to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine, compound III; wherein the alane (AIH 3 ) is obtained by either: i) the reaction of a tetrahydride alanate with an acid, or
  • agomelatine into a salt or co-crystal thereof, alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • the preparation of agomelatine and pharmaceutical acceptable salts or co-crystals thereof comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ), in a ratio of alane to 2-(7-methoxynaphtalen-1 -yl)acetamide from 10:1 (mol/mol) to 1 :2 (mol/mol), in the presence of an organic solvent selected from tetrahydrofuran, methyltetrahydrofuran and/or their mixtures with toluene to yield 2-(7-methoxynaphtalen-1 -yl)ethanamine, compound III;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • the preparation of agomelatine and pharmaceutical acceptable salts or co-crystals thereof comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ), in a ratio of alane to 2-(7-methoxynaphtalen-1 -yl)acetamide from 10:1 (mol/mol) to 1 :2 (mol/mol), in the presence of an organic solvent selected from tetrahydrofuran, methyltetrahydrofuran and/or their mixtures with toluene to yield 2-(7-methoxynaphtalen-1 -yl)ethanamine, compound III; wherein the alane (AIH 3 ) is obtained by either:
  • agomelatine into a salt or co-crystal thereof, and alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine.
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • the preparation of agomelatine and pharmaceutical acceptable salts or co-crystals thereof comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ) in the presence of an organic solvent to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine, compound III;
  • agomelatine into a salt or co-crystal thereof, alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • the preparation of agomelatine and pharmaceutical acceptable salts or co-crystals thereof comprises at least the following steps: a) Reacting 2-(7-methoxynaphtalen-1 -yl)acetamide, compound II, with alane (AIH 3 ) in the presence of an organic solvent to yield 2-(7-methoxynaphtalen-1 - yl)ethanamine, compound III;
  • step e) Isolating the agomelatine obtained in step d) and optionally purifying by means of conventional purification techniques; f) Optionally, converting the agomelatine obtained in step e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • agomelatine into a salt or co-crystal thereof, and alternatively, followed by hydrolysis of the salt or co-crystal of agomelatine, to obtain agomelatine;
  • step e) Isolating the agomelatine obtained in step c) or d) and optionally purifying by means of conventional purification techniques;
  • step c) converting the agomelatine obtained in step c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
  • a fourth aspect of the present invention relates to the use of the solid forms of agomelatine provided according to the first, second or third aspect as intermediates for the preparation of polymorphically stable agomelatine and pharmaceutical acceptable salts thereof in high purity and high yields.
  • the agomelatine obtained from the solid forms of agomelatine has a HPLC purity not less than 98 % and a high polymorphic purity.
  • the agomelatine obtained from the solid forms of agomelatine is polymorphically stable in atmospheric conditions (at 25 and 40 °C, 60 % RH) for at least 3 weeks and also good solubility.
  • the agomelatine obtained from the solid forms of agomelatine of the present invention may have a particle size D 50 of less than about 400 ⁇ , preferably less than about 200 ⁇ , more preferably less than about 100 ⁇ , still more preferably less than about 50 ⁇ and most preferably less than 15 ⁇ .
  • a fifth aspect of the present invention relates to the preparation process of stable agomelatine and pharmaceutical acceptable salts thereof in high polymorphic and HPLC purity and high yields from the solid forms of agomelatine provided according to the first, second or third aspect.
  • the preparation of Agomelatine is carried out from the agomelatine sulfuric acid compound by mixing and stirring the solid form of agomelatine sulfuric acid in water at room temperature.
  • room temperature in the context of the preparation of agomelatine sulfuric acid polymorph II means that the temperature is between 10-40 °C.
  • the obtained precipitate of agomelatine is isolated by means of conventional isolation techniques.
  • the solid form is isolated by filtration.
  • the solid form of agomelatine obtained may be purified or dried or both.
  • An sixth aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of agomelatine or a pharmaceutically acceptable salt or the solid forms thereof provided according to the first, second or third aspect of the present invention together with appropriate amount of pharmaceutically acceptable excipients or carriers.
  • a seventh aspect of the present invention relates to the use of the pharmaceutical composition of the sixth aspect of the present invention for use as a medicament.
  • An eight aspect of the present invention relates to the use of the pharmaceutical composition of aspect sixth for the treatment of major depressive episodes in adults
  • a ninth aspect of the present invention relates to the pharmaceutical composition of the sixth aspect of the present invention for use as an antidepressant.
  • a tenth aspect of the present invention relates to the agomelatine or a pharmaceutically acceptable salt thereof or the solid forms provided according to the first, second or third aspect of the present invention for use as a medicament.
  • a eleventh aspect of the present invention relates to the agomelatine or a pharmaceutically acceptable salt thereof or the solid forms provided according to the first, second or third aspect of the present invention for use as an antidepressant.
  • the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.
  • agomelatine including agomelatine sulfuric acid, agomelatine phosphoric acid and agomelatine trifluoroacetic acid as well as agomelatine were characterized by common analytical techniques such as Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Thermogravimety (TGA) using the following methods:
  • PXRD Powder X-Ray Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimety
  • Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using CuKcd -radiation (1.54056 A) in transmission geometry.
  • the system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.
  • approximately 15 mg of the non- manipulated samples were prepared in standard sample holders using two foils of polyacetate.
  • Crystal structure solution was achieved using direct methods as implemented in SHELXTL4 and visualized using the program XP. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL. All non-hydrogen atoms were refined including anisotropic displacement parameters.
  • the solid forms of agomelatine trifluoroacetic acid compound were characterized by common analytical techniques such as Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC) using the following methods:
  • DSC Differential Scanning Calorimetry
  • Example 1 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide sulfuric acid compound.
  • agomelatine 1 .0 g was mixed with 10 mL of acetone at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.22 mL of 98 % sulfuric acid were added to the solution and the mixture was stirred until a precipitate was formed. The mixture was filtered and washed with acetone. The product obtained was dried in an oven at 45°C yielding 1 .4 g of the titled compound.
  • DSC Endothermic peak at 157 °C with an onset at 155 °C.
  • agomelatine 1 .0 g was mixed with 20 mL of ethyl acetate at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.22 mL of 98 % sulfuric acid were added to the solution and the mixture was stirred until a precipitate was formed. The mixture was filtered and washed with ethyl acetate. The product obtained was dried in an oven at 45 °C yielding 1 .4 g of the titled compound.
  • DSC Endothermic peak at 156 °C with an onset at 154 °C.
  • DSC Endothermic peak at 156 °C with an onset at 153 °C. Reported in figure 2.
  • TGA No weight loss observed below the decomposition temperature. Weight loss due to decomposition over 150 °C was observed.
  • agomelatine sulfuric acid compound, polymorph I 50 mg was slurried for 4 days in 1 mL of ethyl acetate at room temperature. The solid was filtered and dried in vacuum at 40 °C for 2 hours.
  • DSC Endothermic peak at 166 °C with an onset at 163°C. Reported in figure 4.
  • TGA No weight loss observed below the decomposition temperature. Weight loss due to decomposition at temperatures over 155 °C was observed. Reported in figure 4.
  • PXRD Reported in figure 5.
  • agomelatine sulfuric acid compound, polymorph I 25 mg was dissolved in 1 .5 mL of acetone at reflux temperature. The resulting solution was slowly cooled to room temperature and kept overnight. The resulting crystals were filtered in vacuum at 40 °C for 2 hours.
  • DSC Endothermic peak at 166 °C with an onset at 163 °C.
  • TGA No weight loss observed below the decomposition temperature. Weight loss due to decomposition at temperatures over 155 °C was observed.
  • DSC Endothermic peak at 166 °C with an onset at 163 °C.
  • TGA No weight loss observed below the decomposition temperature. Weight loss due to decomposition at temperatures over 155 °C was observed.
  • agomelatine 1 .0 g was mixed with 10 mL of ethyl acetate at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.31 mL of trifluoroacetic acid were added to the solution. The solvent was then evaporated to dryness giving rise to a residue. The product was washed with ethyl acetate and dried in an oven at 45 °C yielding 0.7 g of the titled compound.
  • Example 8 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide phosphoric acid compound.
  • agomelatine 1 .0 g was mixed with 10 mL of acetone at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.28 mL of phosphoric acid were added to the solution. The mixture was left to stand and a precipitated appeared. The product was washed with acetone and dried in an oven at
  • DSC Endothermic peak at 44 °C with an onset at 40 °C.
  • Example 9 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide phosphoric acid compound.
  • agomelatine 1 .0 g was mixed with 20 mL of ethyl acetate at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.28 mL of phosphoric acid were added to the solution. The mixture was left to stand and a precipitated appeared. The product was filtered and washed with ethyl acetate and dried in an oven at 45 °C yielding 0.7 g of the titled compound.
  • TGA No weight loss observed below the decomposition temperature. Weight loss due to decomposition over 160 °C. Reported in figure 1 1 .
  • DSC Endothermic peak at 47 °C with an onset at 42 °C, endothermic peak at 1 18 °C with an onset at 1 17 °C. Reported in figure 1 1.
  • agomelatine 1 .0 g was mixed with 10 mL of MEK at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.28 mL of phosphoric acid were added to the solution. The mixture was left to stand and a precipitated appeared. The product obtained was washed with MEK and dried in an oven at 45 °C yielding 1 .3 g of the titled compound.
  • DSC Endothermic peak at 43 °C with an onset at 39 °C, endothermic peak at 1 18 °C with an onset at 1 16 °C.
  • agomelatine sulfuric acid compound, polymorph I was stirred in water for 2 hours at room temperature. After this time, the solid was filtered off and dried in vacuum for 3 hours at 45 °C yielding 0.35 g of the titled compound.
  • agomelatine sulfuric acid compound polymorph II
  • DSC Endothermic peak at 102 °C with an onset at 98 °C.
  • the reaction mass was then heated to reflux for another hour, cooled down to 20-25 °C and a mixture of water (5.8 mL) and THF (10 mL) was added dropwise while maintaining temperature at 20-25 °C. Next, a 15 % aqueous solution of sodium hydroxyde (5.8 mL) was added dropwise while maintaining temperature at 20-25 °C. Next, water (17.5 mL) was added dropwise while maintaining temperature at 20-25 °C. The obtained precipitated compounds were filtered and washed with THF (20 mL) and subsequently triturated with TH F (2x 60 mL), filtered and washed with THF. The obtained filtrates were combined and concentrated under reduced pressure to obtain an oily residue.
  • 2-(7-methoxynaphthalen-1 -yl)ethanamine hydrochloride (55.0 g, 231 .35 mmol) was charged into a reaction vessel. Isopropyl acetate (275 mL) was added and stirred and a suspension was obtained. Triethylamine (Et 3 N) (81 .3 mL, 578.48 mmol) was added to the previous suspension while stirring and maintaining the temperature at 20-25 °C. Next, acetic anhydride (32.8 mL, 346.9 mmol) was added dropwise maintaining the temperature at 20-25 °C. After the addition, the reaction mass was maintained at a temperature of 20-25 °C for one hour.
  • Example 17 Preparation of N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide.
  • 2-(7-methoxynaphthalen-1 -yl)ethanamine hydrochloride (10.0 g, 42.06 mmol) was charged into a reaction vessel.
  • Isopropyl acetate (50 mL) was added and stirred and a suspension was obtained.
  • a solution of sodium carbonate (Na 2 C0 3 ) (6.7 g, 63.21 mmol) in water (20 mL) was added to the previous suspension while stirring and maintaining the temperature at 20-25 °C.
  • acetic anhydride (4.8 mL, 50.78 mmol) was added dropwise maintaining the temperature at 20-25 °C. After the addition, the reaction mass was maintained at a temperature of 20-25 °C for one hour. The phases are separated and the organic phase was washed with water (20 mL). The organic solvents are concentrated under vacuum until an oily residue was obtained. Toluene (15 mL) was added to the oily residue and the obtained suspension was heated to a temperature of 65-70 °C to obtain a clear solution. The solution was then cooled down until a precipitate appears. The suspension was further cooled down to 0 °C and kept at this temperature for 1 hour.
  • Example 18 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide sulfuric acid compound.
  • 2-(7-methoxynaphthalen-1 -yl)ethanamine hydrochloride (10.0 g, 42.06 mmol) was charged into a reaction vessel. Isopropyl acetate (70 mL) was added and stirred and a suspension was obtained. A solution of Na 2 C0 3 (6.7 g, 63.21 mmol) in water (20 mL) was added to the previous suspension while stirring and maintaining the temperature at 20-25 °C. Next, acetic anhydride (4.8 mL, 50.78 mmol) was added dropwise maintaining the temperature at 20-25 °C. After the addition, the reaction mass was maintained at a temperature of 20-25 °C for one hour.
  • Example 19 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide sulfuric acid compound.
  • 2-(7-methoxynaphthalen-1 -yl)ethanamine hydrochloride (10.0 g, 42.06 mmol) was charged into a reaction vessel. Isopropyl acetate (50 mL) was added and stirred and a suspension was obtained. A solution of Na 2 C0 3 (6.7 g, 63.21 mmol) in water (20 mL) was added to the previous suspension while stirring and maintaining the temperature at 20-25 °C. Next, acetic anhydride (4.8 mL, 50.78 mmol) was added dropwise maintaining the temperature at 20-25 °C. After the addition of the acetic anhydride, the reaction mass was maintained at a temperature of 20-25 °C for one hour.
  • agomelatine 1 .0 g was mixed with 10 mL of acetone at room temperature. The mixture was stirred until a clear solution was obtained. Afterwards, 0.22 mL of 98 % sulfuric acid were added to the solution and the mixture was stirred until a precipitate was formed. The mixture was filtered and washed with acetone. The product obtained was dried in an oven at 45 °C yielding 1 .4 g of the titled compound.
  • 2-(7-methoxynaphthalen-1 -yl)ethanamine hydrochloride (10.0 g, 42.06 mmol) was charged into a reaction vessel. Isopropyl acetate (70 mL) was added and stirred and a suspension was obtained. A solution of Na 2 C0 3 (4.9 g, 46.23 mmol) in water (40 mL) was added to the previous suspension while stirring and maintaining the temperature at 20-25 °C. Next, acetic anhydride (4.18 mL, 44.22 mmol) was added dropwise maintaining the temperature at 20-25 °C. After the addition of the acetic anhydride, the reaction mass was maintained at a temperature of 20-25 °C for one hour.
  • the phases were separated and the aqueous phase was extracted with isopropyl acetate (20 mL). The combined organic phases were washed with water (2 x 20 mL). The organic solvents were concentrated under vacuum until an oily residue was obtained. Acetone (100 mL) was added to the oily residue to obtain a clear solution. Sulfuric acid (2.3 mL) diluted in acetone (10ml_) was then added dropwise to the solution. A precipitate appeared and the suspension was heated to reflux and maintained at this temperature for two hours. The suspension was then cooled down to 0 °C and maintained for one hour.
  • Example 22 Preparation of N-(2-(7-methoxy-1-naphthalenyl)ethyl)acetamide. 0.5 g of agomelatine sulfuric acid compound was stirred in water for 2 hours at room temperature. After this time, the solid was filtered off and dried in vacuum for 3 hours at 45 °C yielding 0.35 g of the titled compound.

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Abstract

La présente invention concerne des formes solides d'agomélatine, un procédé pour les préparer et des compositions pharmaceutiques les contenant. La présente invention concerne également un procédé de fabrication de N-[2-(7-méthoxy-1-naphtalényl)éthyl]acétamide (agomélatine) avec des rendements et une pureté améliorés et en réduisant les étapes du procédé global.
EP13821818.5A 2012-12-21 2013-12-20 Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci Withdrawn EP2934502A1 (fr)

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PCT/EP2013/077725 WO2014096373A1 (fr) 2012-12-21 2013-12-20 Procédé de préparation de n-(2-(7-méthoxy-1-naphtalényl)éthyl)acétamide et de formes solides de celui-ci

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EP2851363B1 (fr) * 2012-05-14 2018-01-03 Shanghai Righthand Pharmtech. Co., Ltd. Composite à base de radical acide d'agomélatine et procédé de préparation et application associés
CN105859573B (zh) * 2015-01-21 2018-02-09 上海右手医药科技开发有限公司 一种阿戈美拉汀硫酸复合物多晶型b及其制备方法和应用

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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
FR2889523B1 (fr) 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889522B1 (fr) 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889521B1 (fr) 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2923482B1 (fr) 2007-11-09 2010-01-29 Servier Lab Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
CN101481321B (zh) 2009-02-27 2012-04-18 上海医药工业研究院 阿戈美拉汀卤化氢复合物及其制备方法
CN101709036B (zh) 2009-12-17 2012-07-04 天津药物研究院 阿戈美拉汀中间体2-(7-甲氧基-1-萘基)乙胺的制备
CN102190594A (zh) 2010-03-17 2011-09-21 上海医药工业研究院 阿戈美拉汀氯化氢水合物及其制备方法
CN102702008B (zh) * 2012-06-03 2014-05-28 上海右手医药科技开发有限公司 阿戈美拉汀硫酸复合物及其制备方法

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