WO2016046833A2 - Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires - Google Patents

Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires Download PDF

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WO2016046833A2
WO2016046833A2 PCT/IN2014/000618 IN2014000618W WO2016046833A2 WO 2016046833 A2 WO2016046833 A2 WO 2016046833A2 IN 2014000618 W IN2014000618 W IN 2014000618W WO 2016046833 A2 WO2016046833 A2 WO 2016046833A2
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formula
ethyl
group
naphthalenyl
acetamide
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WO2016046833A3 (fr
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Dodda Mohan Rao
Vanga MALLA REDDY
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Symed Labs Ltd
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Symed Labs Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • 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

Definitions

  • the present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of Agomelatine, in high yield and purity, using novel intermediates.
  • U.S. Patent No. 5,225,442 discloses 1- alkoxy-2-(acylaminoethyl)naphthalene derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds possess valuable pharmacological properties with regard to the central nervous system, particularly anxiolytic, antipsychotic and analgesic properties, and with regard to ovulation, cerebral circulation and immunomodulation.
  • Agomelatine chemically named N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide, is an important antidepressant and useful for the treatment of major depressive episodes in adults.
  • Agomelatine has dual pharmacological effects, which is not only the agonist of melatonergic system receptor, but also the antagonist of 5HT 2 c receptor.
  • Agomelatine is represented by the following structural formula I:
  • Agomelatine is marketed by Servier (Ireland) Industries Ltd. in Europe under the brand names VALDOXAN ® and THYMANAX ® , and it is orally administered as tablets containing 25 mg of agomelatine.
  • the synthesis of agomelatine was first described in the US'442 patent and its corresponding European equivalent Patent No. EP 0447285 B l .
  • Various processes for the preparation of agomelatine, its intermediates, and related compounds are described in U.S. Patent Nos. US 5,420,158, US 7,476,751, US 7,544,839, US 7,999,129, US 8,212,077 and US 8, 143,449; EP Patent Application No. 2562151 Al, PCT Publication Nos.
  • N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide (Agomelatine) is prepared by a process as depicted in scheme 1 :
  • Agomelatine is prepared by reacting 7-methoxy- 1 -tetralone with ethyl bromoacetate in the presence of activated zinc fillings and benzene to produce ethyl (7-methoxy-l,2,3,4-tetrahydro-l- naphthalenylidene)acetate, which is then subjected to aromatization with sulfur at 215°C to produce ethyl (7-methoxy-l-naphthalenyl)acetate, followed by hydrolysis and subsequent reaction with thionyl chloride in chloroform to produce (7-methoxy-l-naphthalenyl)acetyl chloride.
  • This acid chloride on ammonification with aqueous ammonia yields (7-methoxy- l-naphthalenyl)acetamide.
  • This amide is subjected to dehydration with triflic anhydride in the presence of triethylamine to produce (7-methoxy-l-naphthalenyl)acetonitrile.
  • the reduction of the nitrile compound with Raney nickel under hydrogen pressure gives 2-(7- methoxy-l-naphthalenyl)ethyl amine, which is finally acetylated with acetyl chloride in pyridine to produce Agomelatine.
  • Agomelatine is prepared by reacting 7-methoxy-l-tetralone with cyanoacetic acid in the presence of heptanoic acid and benzylamine to produce (7-methoxy-3,4-dihydro-l- naphthalenyl)acetonitrile, followed by dehydrogenation with allyl methacrylate in the presence of Pd/C as a catalyst to produce (7-methoxy-l-naphthalenyl)acetonitrile, which is then subjected to reduction with Raney nickel under hydrogen pressure in the presence of ammonium hydroxide to produce 2-(7-methoxy-l-naphthalenyl)ethanamine hydrochloride, followed by acetylation to produce agomelatine.
  • the reported overall yield of the product is 72%.
  • Agomelatine is prepared by a process as depicte
  • the known methoxy intermediates are not stable and they decompose at higher temperatures due to their low melting points.
  • sulfur which is a cheaper aromatizing agent
  • it requires high temperatures, 180-200°C to produce (7-methoxy-l-naphthalenyl)acetonitrile, which leads to the formation of unacceptable amounts of impurities, thereby decreasing the yield and purity of the product.
  • Agomelatine is prepared by reacting 7-methoxy-l-tetralone with acetonitrile in the presence of sodium hexamethyldisilazide in tetrahydrofuran to provide 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile, which is further purified by crystallization from cyclohexane to produce pure compound, which is then treated with hydrogen gas in the presence of Raney Ni, in aqueous methanol and ammonia at 45-60°C to provide 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine, followed by treatment with hydrochloric acid in ethyl acetate to produce its hydrochloride salt.
  • the salt is then acetylated with acetyl chloride in the presence of potassium carbonate in aqueous ethyl acetate to produce N-(2-(7-methoxy-3,4-dihydronaphthalen-l -yl)ethyl)acetamide isolated in solid form using cyclohexane. It is then aromatized with DDQ in dichloromethane to produce Agomelatine.
  • Agomelatine is prepared by a process as depicted in scheme 4:
  • the WO'706 publication discloses that the novel hydroxy intermediate compounds disclosed therein are characterized by having higher melting points when compared with that of the known methoxy intermediates.
  • the WO'706 publication further sets forth that the hydrochloride salt of 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine is characterized by having melting range at about 195-200°C, whereas the corresponding methoxy analogue, i.e., the hydrochloride salt of 2-(7-methoxy-3,4-dihydro-l- naphthalenyl)ethanamine is characterized by having melting point at about 151.12°C.
  • This high melting range of the hydroxy intermediate compounds is advantageous since this property makes these compounds stable even at higher temperature (e.g. 185-190°C), thereby facilitating the employment of the cheaper aromatization reagents such as sulfur for aromatizing the respective dihydro intermediates, at higher temperature, for example, at 160-190°C.
  • the corresponding methoxy intermediates decompose at such higher temperatures (due to their low melting points) while aromatizing with sulfur and thereby effecting purity and yield of the resulting products.
  • Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Agomelatine, in high purity and high yield.
  • aromatization of the dihydro intermediate to the corresponding aromatized product is a key and essential process step.
  • sulfur is a cheaper aromatizing agent over others.
  • the conventional methoxy intermediate compounds are not suitable for aromatization with sulfur as they decompose and get charred at higher temperatures due to their low melting points (this reaction requires heating the reactants at higher temperatures, i.e., between 160-200°C), thus leading to the formation of unacceptable amounts of impurities, thereby decreasing the yield and purity of the product.
  • an improved, commercially viable and industrially advantageous process for the preparation of Agomelatine of formula I in high purity and with high yield comprises acetylating 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine or an acid addition salt thereof with a suitable acetylating agent to produce a novel compound N-[2-(7-acetyloxy-3,4-dihydro-l-naphthalenyl)ethyl] acetamide, which is then subjected to aromatization with a suitable reagent, preferably sulfur, to produce N-[2-(7-acetyloxy- l-naphthalenyl)ethyl]acetamide, followed by treatment with a base to produce N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide, which is then reacted with a methylating agent to produce Agomelatine.
  • a suitable reagent preferably sulfur
  • ' ⁇ ' represents a hydroxy-protecting group selected from -C(0)R, -C(0)OR and -S(0) 2 R; and wherein R represents C].i 2 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
  • N-[2- :thanesulfonyloxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide of formula IVd:
  • the present invention also encompasses the use of the novel compounds of formulae IV disclosed herein for preparing Agomelatine and its intermediates.
  • R represents CM 2 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, to produce a protected compound of formula IV:
  • radical ' P' represents a hydroxy-protecting group selected from -C(0)R, -C(0)OR and -S(0) 2 R; wherein R is as defined above;
  • the term 'salt' as used herein may include acid addition salts and base addition salts.
  • the term 'acid addition salts' include the salts that are derived from organic and inorganic acids.
  • the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maieic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
  • Exemplary acid addition salts of the compound of formula V include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
  • a most specific acid addition salt is hydrochloride salt.
  • Base addition salts may be derived from an organic or an inorganic base.
  • the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium; ammonium salt, organic amines such as ethylamine, tert-butylamine, diethylamine, diisopropylamine, and the like.
  • alkyl denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain.
  • the alkyl may be substituted with one or more "cycloalkyl groups". Exemplary alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n- butyl, iso-butyl, t-butyl, and n-pentyl.
  • cycloalkyl denotes a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to 10 carbon atoms.
  • exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • aralkyl denotes an aryl-alkyl group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.
  • aryl denotes an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms.
  • the aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • exemplary aryl groups include phenyl, tolyl, nitrophenyl or naphthyl.
  • the group 'R' in the compounds of formulae III, IV, VII(a), VII(b), VII(c), VII(d), VII(e) and Vll(f) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, fluoromethyl, trifluoromethyl, phenyl, p-tolyl, benzyl, 4-nitrophenyl, 4-chlorophenyl, 3-nitrophenyl, 4-chlorobenzyl, p- methoxybenzyl and the like; and most specifically, R is methyl, ethyl, tert-butyl or p-tolyl.
  • Exemplary hydroxy-protecting groups ' ⁇ ' include, but are not limited to, acetyl, propanoyl, butanoyi, benzoyl, ethoxycarbonyl, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl, trichloroethxoycarbonyl (Troc), allyloxycarbonyl, methanesulfonyl, p-toluenesulfonyl, t-butoxycarbonyl (BOC), pivaloyl and the like.
  • a most preferred hydroxy-protecting group 'P' is acetyl.
  • novel intermediate compounds of formula IV specifically N-[2-(7- acetyloxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide of formula IVa, as a key intermediate in the preparation of Agomelatine of formula I and its intermediates as disclosed herein allows the products to be easily isolated in high purity and high overall yield.
  • the compounds of formula IV disclosed herein are novel and constitute another aspect of the present invention.
  • the use of the novel intermediate compounds of formula IV in the preparation of Agomelatine of formula I is novel and forms further aspect of the present invention.
  • Exemplary activating agents used in step-(a) include, but are not limited to, acetyl chloride, acetyl bromide, propionyl chloride, butanoyi chloride, pivaloyl chloride, benzoyl chloride; carbonates such as di-tert-butyldicarbonate; alkyl chloroformates such methyl chloroformate, ethyl chloroformate; aryl chloroformates such as benzyl chloroformate; alkyl sulfonyl halides such as methanesulfonyl chloride and ethanesulfonyl chloride; aryl sulfonyl halides such as p-toluenesulfonyl chloride, acid anhydrides such as acetic anhydride; and the like, or a combination thereof.
  • the reaction in step-(a) is optionally carried out in the presence of a base.
  • the base is an organic or inorganic base, and most specifically an organic base.
  • Exemplary bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals; ammonia, sodium acetate, collidine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N- methylmorpholine, 4-(N,N-dimethylamino)pyridine, 1 -alkylimidazole and the like.
  • Specific bases are triethylamine, aqueous ammonia, sodium acetate, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and a most specific base is triethylamine.
  • reaction in step-(a) is carried out in the presence of a suitable solvent.
  • Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, an aromatic hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
  • the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, acetone, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • a most specific solvent is dichloromethane.
  • the activating agent in step-(a) is used in a ratio of about 1 to 3 equivalents, specifically about 1.2 to 1.6 equivalents, with respect to the N-[2-(7- hydroxy-3,4-dihydro-l -naphthalenyl)ethyl]acetamide of formula VI in order to ensure a proper course of the reaction.
  • the reaction in step-(a) is carried out at a temperature of about -5°C to the reflux temperature of the solvent used, specifically at a temperature of about 0°C to about 35°C, and most specifically at a temperature of about 0°C to about 25°C.
  • the reaction time may vary between about 20 minutes to about 3 hours, and specifically about 30 minutes to about 1 hour.
  • the reaction mass containing the compound of formula IV obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof.
  • the reaction mass may be used directly in the next reaction step to produce the compound of formula III or the compound of formula IV may be isolated and then used in the next reaction step.
  • the compound of formula IV is isolated in the form of a solid or a residue and then used in the next reaction step.
  • the compound of formula IV is isolated and/or re- crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used for isolating and/or recrystallizing the pure compound of formula IV is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon solvent, a halogenated hydrocarbon, and mixtures thereof.
  • the solvent used for isolation is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • Exemplary reagents suitable for facilitating the aromatization reaction in step-(b) include, but are not limited to, sulfur or its derivatives, selenium metal, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, and the like; quinone derivatives such as 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l ,4-dione (p- Chloranil), p-bromanil, p-floranil, 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ), 2,3- dibromo-5,6-dicyano benzoquinone, and the like.
  • quinone derivatives such as 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l ,4-dione
  • p- Chloranil 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l ,4
  • step-(b) is advantageously carried out by using sulfur.
  • the aromatization reaction in step-(b) is carried out in the presence or absence of a solvent.
  • the aromatization in step-(b) is carried out as a neat reaction.
  • the aromatization in step-(b) is carried out in the presence of a suitable solvent.
  • solvent also includes mixture of solvents.
  • Exemplary solvents suitable for facilitating the aromatization in step-(b) include, but are not limited to, paraffin liquid, a halogenated hydrocarbon solvent, a hydrocarbon solvent, an ether, a polar aprotic solvent, and mixtures thereof.
  • the solvent used for facilitating the aromatization in step-(b) is selected from the group consisting of paraffin liquid, dichloromethane, dichloroethane, chloroform, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diisopropyl ether, methyl tert-butyl ether, monoglynie, diglyme, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, and mixtures thereof.
  • the aromatization with sulfur in step-(b) is carried out either in the presence of paraffin liquid or as a neat reaction.
  • the aromatization reaction with sulfur is advantageously carried out in the presence of paraffin liquid.
  • reaction temperature and time period will ordinarily depend on the starting compounds, reagents and/or solvents employed in the reaction.
  • the aromatization with sulfur is carried out by heating the contents at a temperature of about 160°C to about 190°C, and most specifically at a temperature of about 165°C to about 175°C.
  • the reaction time may vary between about 30 minutes to about 10 hours, and most specifically about 1 hour to about 3 hours.
  • the sulfur is used in a molar ratio of about 1 to 3 equivalents, specifically about 1.5 to 2.5 equivalents, with respect to the compound of formula IV in order to ensure a proper course of the reaction.
  • the aromatization with other aromatizing agents like noble metal catalysts and quinone derivatives is generally carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 50°C to the reflux temperature of the solvent used, and more specifically at about 60°C to about 120°C.
  • reaction mass containing the compound of formula III obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass obtained in step-(b) may be used directly in the next step to produce the N-[2-(7-hydroxy- l -naphthalenyl)ethyl]acetamide of formula II or the compound of formula III may be isolated and/or recrystallized and then used in the next step.
  • the compound of formula III obtained in step-(b) is isolated in the form of a solid or as a residue.
  • the compound of formula HI is isolated and/or re- crystallized from a suitable solvent by the methods as described hereinabove.
  • the solvent used for isolating and/or recrystallizing the compound of formula III is selected from the group as described hereinabove. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • the deprotecting agent used in step-(c) is an acid or a base.
  • the deprotecting agent used in step-(c) is an organic or inorganic base selected from the group as described herein above.
  • Specific bases are triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and a most specific base is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
  • the deprotecting agent used in step-(c) is an organic or inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, and mixtures thereof.
  • the deprotection in step-(c) is carried out in the presence of a reaction inert solvent.
  • solvent also includes mixture of solvents.
  • Exemplary solvents suitable for facilitating the deprotection in step-(c) include, but are not limited to, water, an alcohol, a ketone, an ether, a polar aprotic solvent, and mixtures thereof.
  • the solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isopropyl ketone, and mixtures thereof.
  • the deprotection in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 5°C to about 50°C, and most specifically at about 10°C to about 30°C.
  • reaction mass containing the N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide of formula II obtained in step-(c) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass obtained in step-(c) may be used directly in the next step to produce the Agomeltaine of formula I or the compound of formula II may be isolated and/or recrystallized and then used in the next step.
  • N-[2-(7-hydroxy-l-naphthaleny!)ethyl]acetamide of formula II obtained in step-(c) is isolated in the form of a solid or as a residue.
  • N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide of formula II is isolated and/or re-crystallized from a suitable solvent by the methods as described hereinabove.
  • the solvent used for isolating and/or recrystallizing the pure N-[2-(7-hydroxy- 1 - naphthalenyl)ethyl]acetamide of formula II is selected from the group as described hereinabove. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl- tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • methylating agents used in step-(d) include, but are not limited to, dimethyl sulfate, dimethyl carbonate, methyl iodide, and the like.
  • a most specific methylating agent is dimethyl sulfate.
  • the reaction in step-(d) is optionally carried out in the presence of a base.
  • the base is an organic or inorganic base, and most specifically an inorganic base, selected from the group as described hereinabove.
  • step-(d) Specific bases used in step-(d) are aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium carbonate.
  • the methylation in step-(d) is carried out in the presence of a suitable solvent.
  • Exemplary solvents used in step-(d) include, but are not limited to, water, a hydrocarbon solvent, a ketone, an ether, a nitriie, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
  • the solvent used in step-(d) is selected from the group consisting of water, acetone, methyl ethyl ketone, methyl isopropyl ketone, toluene, xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific solvents are water, acetone, and mixtures thereof.
  • the methylating agent in step-(d) is used in a ratio of about 1 to 3 equivalents, specifically about 1 to 1.5 equivalents, with respect to the N-[2-(7-hydroxy- l-naphthalenyl)ethyl]acetamide of formula II in order to ensure a proper course of the reaction.
  • the reaction in step-(d) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.
  • the reaction time may vary between about 30 minutes to about 6 hours, and specifically about 3 hours to about 5 hours.
  • the reaction mass containing the Agomelatine of formula I obtained may be subjected to usual work up such as a washing, an extraction, an evaporation, a pH adjustment etc., followed by isolation and/or recrystallization from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
  • the solvent used for isolating/recrystallizing the pure Agomelatine of formula I is selected from the group as described herein above. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
  • the isolation of Agomelatine is carried out by cooling the reaction mass at a temperature of below about 35°C, followed by the addition of water at a temperature of about 10°C to about 35°C, and more specifically at a temperature of about 20°C to about 30°C. After completion of addition process, the resulting mass is optionally stirred at a temperature of about 10°C to about 35°C for at least 10 minutes, and most specifically at a temperature of about 20°C to about 30°C for about 15 minutes to about 2 hours.
  • radical ' ⁇ ' represents a hydroxy-protecting group selected from -C(0)R, -C(0)OR and -S(0) 2 R; wherein R represents Ci.
  • radical P and the group R are as defined above;
  • the preparation of the compound of formula III from the compound of formula VI as described in the above process steps-(a) and (b) can be carried out by using the suitable reagents, methods and conditions as described hereinabove.
  • acetylating agents used in step-(a) include, but are not limited to, acetic anhydride, acetyl chloride, acetyl bromide, and the like, or a combination thereof.
  • a most specific acetylating agent is acetyl chloride.
  • reaction in step-(a) is carried out in the presence of a base selected from the group as described hereinabove for preparing the compound of formula IV.
  • a most specific base is triethylamine.
  • the acetylation in step-(a) is carried out in the presence of a suitable solvent wherein the solvent is selected from the group as described hereinabove for preparing the compound of formula IV.
  • a suitable solvent is dichloromethane.
  • the acetylating agent in step-(a) is used in a ratio of about 1.5 to 3 equivalents, specifically about 1.8 to 2.4 equivalents, with respect to the 2-(7-hydroxy- 3,4-dihydro-l-naphthalenyl)ethanamine of formula V or an acid addition salt thereof in order to ensure a proper course of the reaction.
  • the acetylating agent in step-(a) is used in a ratio of about 1 to 2 equivalents, specifically about 1.2 to 1.6 equivalents, with respect to the N-[2-(7- hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide of formula VI in order to ensure a proper course of the reaction.
  • reaction in step-(a) is carried out at a temperature as described hereinabove for preparing the compound of formula IV.
  • reaction mass containing the N-[2-(7-acetyloxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide of formula IVa obtained in step-(a) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass may be used directly in the next reaction step to produce the N-[2-(7-acetyloxy-l-naphthalenyl)ethyl]acetamide of formula Ilia or the compound of formula IVa may be isolated and then used in the next reaction step.
  • the N-[2-(7-acetyloxy-3,4-dihydro-l-naphthalenyl)ethyl] acetamide of formula IVa is isolated in the form of a solid or as a residue and then used in the next reaction step.
  • the N-[2-(7-acetyloxy-3,4-dihydro-l-naphthalenyl)ethyl] acetamide of formula IVa is isolated and/or re-crystallized from a suitable solvent by the methods as described hereinabove.
  • the reagent suitable for facilitating the aromatization reaction in step-(b) is selected from the group as described hereinabove.
  • step-(b) is advantageously carried out by using sulfur as an aromatizing agent as per the methods and conditions described hereinabove.
  • the aromatization reaction in step-(b) is carried out in the presence or absence of a solvent. In another embodiment, the aromatization in step-(b) is carried out as a neat reaction.
  • the aromatization in step-(b) is carried out in the presence of paraffin liquid.
  • the sulfur is used in a molar ratio of about 1.5 to 2.5 equivalents, with respect to the N-[2-(7-acetyIoxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide of formula IVa in order to ensure a proper course of the reaction.
  • reaction mass containing the N-[2-(7-acetyloxy-l- naphthalenyl)ethyl]acetamide of formula Ilia obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass obtained in step-(b) may be used directly in the next step to produce the N-[2-(7-hydroxy-l- naphthalenyl)ethyl]acetamide of formula II or the compound of formula Ilia may be isolated and/or recrystallized and then used in the next step.
  • N-[2-(7-acetyloxy- l-naphthalenyl)ethyl]acetamide of formula Ilia obtained in step-(b) is isolated in the form of a solid or as a residue.
  • N-[2-(7-acetyloxy-l -naphthalenyl)ethyl]acetamide of formula Ilia is isolated and/or re-crystallized from a suitable solvent by the methods as described hereinabove.
  • the deprotecting agent used in step-(c) is a base selected from the group consisting of triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
  • the deprotecting agent used in step-(c) is selected from the group sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
  • step-(c) is carried out as per the methods and conditions as described hereinabove for preparing the compound of formula II.
  • reaction mass containing the N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide of formula II obtained in step-(c) may be subjected to usual work up methods as described hereinabove.
  • the reaction mass obtained in step-(c) may be used directly in the next step to produce the Agomeltaine of formula I or the compound of formula II may be isolated and/or recrystallized and then used in the next step.
  • N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide of formula II obtained in step-(c) is isolated in the form of a solid or as a residue.
  • N-[2-(7-hydroxy-l-naphthalenyl)ethyl]acetamide of formula II is isolated and/or re-crystallized from a suitable solvent selected from the group as described hereinabove.
  • methylating agents used in step-(d) include, but are not limited to, dimethyl sulfate, dimethyl carbonate, methyl iodide, and the like.
  • a most specific methylating agent is dimethyl sulfate.
  • reaction in step-(d) is optionally carried out in the presence of a base as per the methods and conditions described hereinabove for preparing the Agomelatine of formula I.
  • reaction mass containing the Agomelatine of formula I obtained may be subjected to usual work up, followed by isolation and/or recrystallization from a suitable solvent by methods as described hereinabove.
  • the preparation of the compound of formula IVa from the compound of formula V is carried out by using the suitable reagents, methods and conditions as described hereinabove.
  • the acetylating agent used in the above reaction is acetyl chloride.
  • the preparation of the compound of formula IVa from the compound of formula VI is carried out by using the suitable reagents, methods and conditions as described hereinabove.
  • the acetylating agent used in the above reaction is acetyl chloride.
  • the solids obtained in any of the above process steps described hereinabove may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
  • novel hydroxy-protected compounds of formula IV employed for the preparation of Agomelatine disclosed herein allows the product to be easily isolated and purified, thereby producing the product in high purity and high overall yield.
  • the highly pure Agomelatine obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 50°C to about 85°C.
  • the drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, spin flash dryer, flash dryer, and the like.
  • the highly pure Agomelatine or a salt thereof obtained by the processes disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.
  • the purity of the Agomelatine or a salt thereof can be about 99% to about 99.95%, or about 99.5% to about 99.99%.
  • 'P' represents a hydroxy-protecting group selected from -C(0)R, -C(0)OR and -S(0) 2 R; and wherein R represents C M 2 straight or branched chain alkyl, cycloalkyi, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
  • the present invention also encompasses the use of the novel compounds of formulae IV, specifically the N-[2-(7-acetyloxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide of formula IVa, disclosed herein for preparing Agomelatine and its intermediates.
  • Triethylamine (47 g, 0.46 mol) and 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine (35 g, 0.18 mol) were taken in dichloromethane (350 ml) at room temperature (25-30°C) and the resulting mass was cooled to 0-5°C, followed by the addition of acetyl chloride (32 g, 0.40 mol) at the same temperature. The reaction mass was stirred for 30 minutes at 0- 5°C and the temperature of the resulting mass was raised to 25°C, followed by the addition of water (70 ml) and then stirring the mass for 10 minutes at 25°C.
  • Triethylamine (27 g, 0.27 moles) and N-[2-(7-hydroxy-3,4-dihydro-l -naphthalenyl)ethyl] acetamide (30 g, 0.13 moles) were taken in dichloromethane (300 ml) at room temperature (25-30°C) and the resulting mass was cooled to 0-5°C, followed by the addition of acetyl chloride (15 g, 0.19 moles) at the same temperature. The reaction mass was stirred for 30 minutes at 0-5°C and the temperature of the mass was raised to 25°C, followed by the addition of water (60 ml) and then stirring the mass for 10 minutes at 25°C.
  • N-[2-(7-acetyloxy-l-naphthalenyl)ethyl]acetamide (43 g) and sodium bicarbonate (15 g) were taken in methanol (215 ml) and the resulting mixture was stirred for 1 hour at 25- 30°C.
  • the reaction mass was distilled under vacuum at 50°C to produce the titled compound as a residue.
  • the residue was added to water (130 ml) and then cooled the mass to 5-10°C.
  • the resulting mass was acidified with 15% aqueous hydrochloric acid solution at 5-10°C and then stirred for 30 minutes at the same temperature.
  • Triethylamine (20 g, 0.2 mol) and N-[2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl] acetamide (30 g, 0.13 mol) were taken in dichloromethane (300 ml) at 25-30°C and the resulting mixture was cooled to 0-5°C, followed by drop-wise addition of benzoyl chloride (20 g, 0.14 mol) at the same temperature. The reaction mass was stirred for 30 minutes at 0-5°C and then raised the temperature of the reaction mass to 25°C, followed by stirring the reaction mass for 10 minutes at the same temperature. Water (50 ml) was added to the reaction mass and stirred for 5 minutes at 25-30°C.
  • N-[2-(7-hydroxy-3,4-dihydro-l-naphthyl)ethyl]acetamide (10 g, 0.04 mol), potassium carbonate (7 g, 0.05 mol) and benzyl chloride (8.5 g, 0.07 mol) were taken in dimethylformamide (50 ml) at 25-30°C.
  • the reaction mixture was heated to 75°C and maintained for 12-14 hours at the same temperature.
  • the reaction mass was cooled to 25- 30°C.
  • the reaction mixture was poured into 100 ml of ice water and then stirred for 30 minutes at 5-10°C.
  • Agomelatine (10 g, obtained in Example 16) was added to water (65 ml) at 25-30°C, followed by heating the mixture for 1 hour at 60-65°C.
  • Ethanol (35 ml) was added drop wise to the resulting suspension while maintaining the temperature at 60-65°C to form a clear solution.
  • the resulting solution was stirred for 10 minutes at the same temperature and the hot solution was suddenly cooled to 0-5°C, followed by stirring the mass for 30 minutes at 0-5°C.
  • the resulting crystals were filtered, washed the material with water (25 ml) and then dried at 50-55°C to produce 9.5 gm of pure Agomelatine crystalline Form 1 (Yield: 95%; Purity by HPLC: 99.95%).
  • the resulting Agomelatine crystalline Form I is characterized by an X-ray powder diffraction pattern (copper- ⁇ radiation) having peaks expressed as 2-theta angle positions at about 9.3, 10.9, 1 1.2, 1 1.9, 15.0, 15.4, 17.6, 18.4, 18.6 19.6, 19.8, 20.6, 21.1, 21.3, 21.8, 22.6, 23.1, 24.0, 24.7, 25.5, 26.2, 26.4, 27.1, 27.7, 30.2, 31.4 and 32.0 ⁇ 0.2 degrees. All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)

Abstract

L'invention concerne des procédés améliorés, commercialement viables et industriellement avantageux, de préparation de l'agomélatine dans un rendement élevé et avec une grande pureté, en ayant recours à de nouveaux intermédiaires.
PCT/IN2014/000618 2014-09-24 2014-09-24 Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires Ceased WO2016046833A2 (fr)

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Publication number Priority date Publication date Assignee Title
CN106565526A (zh) * 2016-11-02 2017-04-19 万全万特制药江苏有限公司 一种阿戈美拉汀杂质的制备方法
CN115253339A (zh) * 2022-07-21 2022-11-01 西安彩晶光电科技股份有限公司 一种1-丙基磷酸环酐的生产装置及工艺
CN116924931A (zh) * 2023-07-19 2023-10-24 常州瑞明药业有限公司 一种阿戈美拉汀的制备方法

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FR2689124A1 (fr) * 1992-03-27 1993-10-01 Adir Nouvelles naphtylalkylamines, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.
WO1997005098A1 (fr) * 1995-07-26 1997-02-13 Takeda Chemical Industries, Ltd. Composes de benzocycloalcene ayant une affinite de liaison au recepteur de melatonine, production et utilisation de ces composes
FR2866334B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese du (7-methoxy-1-naphtyl) acetonitrile et application a la synthese de l'agomelatine
EP2705023A4 (fr) * 2011-01-04 2014-11-19 Symed Labs Ltd Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
EP2909166A4 (fr) * 2012-10-22 2016-10-26 Symed Labs Ltd Procédé pour la préparation d'agomélatine à l'aide de nouveaux intermédiaires

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106565526A (zh) * 2016-11-02 2017-04-19 万全万特制药江苏有限公司 一种阿戈美拉汀杂质的制备方法
CN115253339A (zh) * 2022-07-21 2022-11-01 西安彩晶光电科技股份有限公司 一种1-丙基磷酸环酐的生产装置及工艺
CN115253339B (zh) * 2022-07-21 2024-04-12 西安彩晶光电科技股份有限公司 一种1-丙基磷酸环酐的生产装置及工艺
CN116924931A (zh) * 2023-07-19 2023-10-24 常州瑞明药业有限公司 一种阿戈美拉汀的制备方法

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