INTRODUCTION

Aspects of the present application relate to process for the preparation of agomelatine also intermediates used in the process and its manufacturing process.

The drug compound having the adopted name “agomelatine” can be represented by structural formula I where each “Me” represents a methyl group and it has a new pharmacological mechanism of action which combines its melatonin MT1 and MT2 agonist properties with a serotonin 5-HT2C antagonist effect. The 5-HT2C receptor is considered a relevant target with regard to antidepressant therapy as several currently used antidepressant drugs have 5-HT2C receptor antagonist properties.

Agomelatine is a non-hygroscopic white or almost white powder practically insoluble in water and containing no asymmetric carbon atoms. A chemical name for agomelatine is N-[2-(7-methoxy-1-naphthylen-1-yl)ethyl]acetamide and it is the active ingredient in VALDOXAN® tablets sold for the treatment of major depressive episodes in adults.

U.S. Patent No. 5 225 442 discloses agomelatine a pharmaceutically acceptable salt thereof a pharmaceutical composition thereof and a method for the treatment of a living animal afflicted with treatable disorder of the melatoninergic system comprising the step of administering to the living animal an effective amount of the compound. A number of methods for the synthesis of agomelatine have been reported in US 5 225 442 WO 2005/77887 A1 WO 2010/15745 A1 WO 2010/15746 A1 WO 2010/12208 A1 and CN 101973897 A.

However there remains a need for an environmentally-friendly cost-effective and industrially applicable processes for the preparation of agomelatine which alleviates the problems associated with the prior art processes as discussed above.

SUMMARY

In an aspect the application provides a process for the preparation of compound of Formula V which comprises:

a) reacting 2-naphthol with an acetylating agent to provide a compound of Formula II;

Formula II

b) reacting the compound of Formula II with chloroacetyl chloride to obtain the compound of Formula III; Formula III

c) reducing the compound of Formula III to provide the compound of Formula IV; and Formula IV

d) reacting the compound Formula IV with dimethyl sulphate to provide the compound of Formula V: Formula V

In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises:

a) reacting the compound of Formula V: Formula V with potassium phthalimide in the presence of a solvent to provide the compound of Formula VI; and Formula VI

b) hydrolyzing the compound of Formula VI to provide 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII: Formula VII

In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises:

a) reacting the compound of Formula V with an alkali diformylamide salt to provide a compound of Formula VIII; and Formula V Formula VIII b) hydrolyzing the compound of Formula VIII to provide 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII: Formula VIII Formula VII.

In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises:

a) reacting the compound of Formula V with a nitrite salt in the presence of a solvent to provide the compound of Formula IX; and Formula V Formula IX.

b) reducing the compound of Formula IX to provide 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII: Formula IX Formula VII.

In another aspect the application provides a process for the preparation of agomelatine which further comprises reacting the 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII made by any of the processes describes above with an acetylating agent to provide agomelatine of Formula I: Formula VII Formula I.

In another aspect the application provides a process for the preparation of agomelatine which comprises: a) preparing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III from the 7-acetoxynaphthalene compound of Formula II; and Formula II Formula III.

b) converting the 1-chloroacetyl-7-acetoxynaphthalene of Formula III into aglomelatine of Formula I: Formula III Formula I In another aspect the application provides a process for the preparation of agomelatine which comprises:

a) preparing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III from the 7-acetoxynaphthalene compound of Formula II; Formula II Formula III.

b) reducing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III to produce the 1-(2-chloroethyl)-7-acetoxynaphthalene compound of Formula IV; and Formula III Formula IV.

c) converting the 1-(2-chloroethyl)-7-acetoxynaphthalene compound of Formula IV into aglomelatine of Formula I: Formula IV Formula I.

DETAILED DESCRIPTION

One aspect of the application provides a compound of Formula III. Formula III In another aspect the application provides a compound of Formula IIIA.

Formula IIIA wherein n=1-5 and X = halogen. In another aspect the application provides a compound of Formula IV. Formula IV In another aspect the application provides a compound of Formula VIII.

Formula VIII In another aspect the application provides a compound of Formula IX. Formula IX In an aspect the application provides a process for the preparation of compound of Formula V which comprises:

a) reacting 2-naphthol with an acetylating agent to provide a compound of Formula II; Formula II b) reacting the compound of Formula II with chloroacetyl chloride to obtain the compound of Formula III;

Formula III c) reducing the compound of Formula III to provide the compound of Formula IV; and Formula IV d) reacting the compound Formula IV with dimethyl sulphate to provide the compound of Formula V:

Formula V Step a) involves the acetylation of 2-Naphthol to provide 7-acetoxynaphtalene. In embodiments of step a) the acetylation of 2-Naphthol can be carried out in the presence of a base and a solvent. The acetylating agents which can be used include but are not limited to acetic anhydride and acetyl chloride or any acetylating agent which produces compound of Formula II.

In embodiments of step a) the acetylation can be carried out in the presence of a suitable inert solvent. Suitable inert solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include but are not limited to: ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane and dimethoxyethane; ketones such as acetone methyl ethyl ketone methyl isobutyl ketone and diethyl ketone; esters such as ethyl acetate propyl acetate isopropyl acetate and butyl acetate; alcohols such as methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol iso-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol and C1-C6 alcohols; nitriles such as acetonitrile and propionitrile; amides such as formamide N N-dimethylformamide N N-dimethylacetamide N-methyl-2-pyrrolidone and hexamethyl phosphoric triamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as toluene; any mixtures of two or more thereof.

In embodiments of step a) the acetylation can be carried out in the presence of a base. Bases that are useful in the reaction include but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates hydrogen carbonates hydroxides oxides carboxylates or alkoxides e.g. potassium carbonate potassium hydrogen carbonate potassium hydroxide potassium acetate potassium methoxide sodium carbonate sodium hydrogen carbonate sodium hydroxide sodium acetate sodium methoxide lithium carbonate lithium hydrogen carbonate lithium hydroxide lithium acetate lithium methoxide barium hydroxide calcium oxide or alkali metal hydrides e.g. lithium hydride sodium hydride potassium hydride or the like; or organic bases such as for example amines e.g. triethylamine N N-dimethylethanolamine N N-diethylethanolamine 4-ethylmorpholine 1 4-diazabicyclo[2.2.2]-octane N-methyl morpholine dimethylaminopyridine diisopropylamine diisopropylethylamine pyridine or the like.

In embodiments of step a) the reaction can be carried out at a temperature ranging from about -10°C to about 50°C. In one embodiment the reaction can be carried out from about -5°C to 25°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step a) the product of step a) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like. In embodiments of step a) the product of step-a) i.e. compound of Formula II is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step a) the product of step-a) i.e. compound of Formula II may be used in the next step without isolation.

Step-b) involves reaction of the compound of Formula II with chloroacetyl chloride in the presence of a lewis acid and a solvent to provide the compound of Formula III. In embodiments of step b) the reaction of Formula II with chloroacetyl chloride can be carried out in the presence of a lewis acid such as anhydrous aluminium chloride (AlCl3) anhydrous ferric chloride (FeCl3) boron trifluoride (BF3) titanium tetrachloride (TiCl4) zinc chloride (ZnCl2) stannic chloride (SnCl4) or the like. In embodiments of step b) the reaction of Formula II with chloroacetyl chloride can be carried out in the presence of a suitable inert solvent. The suitable inert solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane or dimethoxyethane; ketones such as acetone or methyl ethyl ketone methyl isobutyl ketone or diethyl ketone; esters such as ethyl acetate propyl acetate or butyl acetate; nitriles such as acetonitrile propionitrile; amides such as N N-dimethylformamide N N-dimethyl acetamide N-methyl-2-pyrrolidone or hexamethyl phosphoric triamide; sulfoxides such as dimethyl sulfoxide; aliphatic or halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride 1 2-dichloroethane chlorobenzene or dichlorobenzene; aliphatic hydrocarbons such as hexane cyclohexane heptane; carbon disulfide or their mixtures thereof.

In embodiments of step b) the reaction can be carried out at a temperature ranging from about -40°C to about 50°C. In one embodiment the reaction can be carried out from about -30°C to 30°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step b) the product of step b) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step b) the product of step-b) i.e. compound of Formula III is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step b) optionally the product of step-b) i.e. compound of Formula III may be used in the next step without isolation.

In embodiments of step b) the product of step-b) i.e. compound of Formula III is new and useful intermediate in the synthesis of agomelatine. Step-c) involves the reduction of the compound of Formula III to provide the compound of Formula IV.

In embodiments of step-c) the reduction of compound of Formula III may be carried out in the presence of a solvent and a reducing agent to provide a compound of Formula IV.

In embodiments of step c) the reduction may be carried out by using a suitable reducing agent. The reducing agents which may be used but are not limited to triethylsilane in the presence of titanium tetrachloride zinc amalgam/concentrated hydrochloric acid hydrazine in the presence of a base etc.

In embodiments of step c) the reaction may be carried out in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents at least to some extent. Examples of such solvents include tetrahydrofuran methanol dichloromethane acetonitrile dimethylformamide or their mixture thereof.

In embodiments of step c) the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment the reaction can be carried out from about 0°C to room temperature. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step c) the product of step c) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step c) the product of step-c) i.e. compound of Formula IV is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step c) optionally the product of step-c) i.e. compound of Formula IV may be used in the next step without isolation. In embodiments of step c) the product of step-c) i.e. compound of Formula IV is new and useful intermediate in the synthesis of agomelatine.

Step-d) involves the preparation of the compound of Formula V by the reaction of compound of Formula IV with dimethyl sulphate. In embodiments of step d) the reaction can be carried out in the presence of a base and a solvent. In embodiments of step d) the reaction can be carried out by using dimethyl sulphate.

In embodiments of step d) the reaction can be carried by using dimethyl sulphate in the presence of a base and a solvent. Any of the solvent listed in embodiment of step-a) may be used in the reaction. Any of the bases listed in embodiment of step-a) may be used in the reaction. In embodiments of step d) the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment the reaction can be carried out from about 10°C to 70°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step d) the product of step d) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like. In embodiments of step d) the product of step-d) i.e. compound of Formula V is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step d) the product may be isolated as solid or resiudue and further purified by the techniques known in the art such as recrystallization slurry washing column chromatography crystallization etc. to enhance the chemical purity. In embodiments of step d) optionally the product of step-d) i.e. compound of Formula V may be used in the next step without isolation.

In another aspect the application provides process for the preparation of compound of Formula IIIA. In embodiments the compound of Formula IIIA can be prepared by the same procedure as described for the preparation of compound of Formula III herein using appropriate acid chloride.

In another aspect the application provides process for the preparation of compound of Formula VA. Formula VA Wherein X = halogen In embodiments the compound of Formula VA can be prepared by the same procedure as described for the preparation of compound of Formula V herein using appropriate methods.

In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises: a)reacting the compound of Formula V: Formula V with potassium phthalimide in the presence of a solvent to provide the compound of Formula VI; and

Formula VI b) hydrolyzing the compound of Formula VI to provide 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII: Formula VII.

In embodiments of step a) the reaction of compound of Formula V can be carried out with potassium phthalimide in the presence of a solvent to provide the compound of Formula VI. Suitable inert solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include but are not limited to: ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane and dimethoxyethane; ketones such as acetone methyl ethyl ketone methyl isobutyl ketone and diethyl ketone; esters such as ethyl acetate propyl acetate isopropyl acetate and butyl acetate; alcohols such as methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol iso-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol and C1-C6 alcohols; nitriles such as acetonitrile and propionitrile; amides such as formamide N N-dimethylformamide N N-dimethylacetamide N-methyl-2-pyrrolidone and hexamethyl phosphoric triamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as toluene; any mixtures of two or more thereof.

In embodiments of step a) the reaction can be carried out at a temperature ranging from about 10°C to about boiling temperature of the solvent. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step a) the product of step a) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step a) the product of step-a) i.e. compound of Formula VI is isolated by filteration of the precipitated product. Step-b) involves the hydrolysis of the compound of Formula VI to provide the compound of Formula VII.

In embodiments of step b) the hydrolysis of compound of Formula VI can be carried out in the presence of acid or base to provide the compound of Formula VII. In embodiments of step b) the bases which can be used for the hydrolysis is selected from alkali metal hydroxide such as lithium hydroxide sodium hydroxide potassium hydroxide; alkaline-earth metal hydroxide such as magnesium hydroxide calcium hydroxide or hydrazine hydrate. In embodiments of step b) the hydrolysis can be carried out in the presence of acid such as hydrochloric acid sulfuric acid etc.

In embodiments of step b) the reaction can be carried out at a temperature ranging from about 10°C to about boiling temperature of the solvent. In one embodiment the reaction can be carried out from about 20°C to 90°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step b) the product of step b) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step b) the product of step-b) i.e. compound of Formula VII is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step b) the product of step-b) i.e. compound of Formula VII obtained from the above process is used for the preparation of agomelatine.

In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises: a)reacting the compound of Formula V with an alkali diformylamide salt to provide a compound of Formula VIII; and Formula V Formula VIII b) hydrolyzing the compound of Formula VIII to provide 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII: Formula VIII Formula VII Step-a) involves the preparation of compound of Formula VIII by the reaction of compound of Formula V with sodium diformyl amide. In embodiments of step a) sodium diformyl amide used in the reaction can be prepared by reacting formamide with sodium methoxide.

In embodiments of step a) the reaction can be carried out in the presence or absence of a suitable solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents at least to some extent. Examples of such solvents include but are not limited to: ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane and dimethoxyethane; ketones such as acetone methyl ethyl ketone methyl isobutyl ketone and diethyl ketone; esters such as ethyl acetate propyl acetate isopropyl acetate and butyl acetate; alcohols such as methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol iso-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol and C1-C6 alcohols; nitriles such as acetonitrile and propionitrile; amides such as formamide N N-dimethylformamide N N-dimethylacetamide N-methyl-2-pyrrolidone and hexamethyl phosphoric triamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as toluene; any mixtures of two or more thereof.

In embodiments of step a) the reaction can be carried out at a temperature ranging from about 10°C to about boiling temperature of the solvent. In one embodiment the reaction can be carried out from about 20°C to 110°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step a) the product of step a) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step a) the product of step-a) i.e. compound of Formula VIII is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step a) the product of step-a) i.e. compound of Formula VIII is new and useful intermediate in the synthesis of agomelatine. Step b) involves the hydrolysis the compound of Formula VIII to provide 1-(2-aminoethyl)-7-methoxynaphthalene.

In embodiments of step b) the hydrolysis can be carried out in the presence of acid in a solvent. The acid can be used in the reaction selected from hydrochloric acid sulfuric acid or the like. Any of the solvent listed in step-a) can be used in the reaction. In embodiments of step b) the hydrolysis can also be carried out in the presence of base in a solvent. Any of the base and solvent described herein can be used in the reaction.

In embodiments of step b) the reaction can be carried out at a temperature ranging from about 10°C to about boiling temperature of the solvent. In one embodiment the reaction can be carried out at a temperature from about 20°C to 90°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step b) the product of step b) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like.

In embodiments of step b) the product of step-b) i.e. compound of Formula VII is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In another aspect the application provides a process for the preparation of 1-(2-aminoethyl)-7-methoxynaphthalene compound of Formula VII which comprises:

a) reacting the compound of Formula V with a nitrite salt in the presence of a solvent to provide the compound of Formula IX; and Formula V Formula IX b) reducing the compound of Formula IX to provide 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII: Formula IX Formula VII Step-a) involves the preparation of compound of Formula IX by the reaction of compound of Formula V with a nitrite salt in the presence of a solvent. Suitable agents for displacement of halogen by nitrite used in step a) include but are not limited to metallic nitrites such as sodium nitrite potassium nitrite lithium nitrite silver nitrite or like. In embodiments of step a) the compound of Formula IX can be prepared by the reaction of compound of Formula V sodium nitrite. In embodiments of step a) the reaction can be carried out in the presence of a polar solvent. In embodiments of step a) the reaction can be carried out in the presence of solvents such as dimethylformamide dimethylacetamide dimethylsulfoxide acetonitrile or the like.

In embodiments of step a) the reaction can be carried out at a temperature ranging from about 10°C to about boiling temperature of the solvent. In one embodiment the reaction can be carried out from about 20°C to 110°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step a) the product of step a) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like. In embodiments of step a) the product of step-a) i.e. compound of Formula IX is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step a) the product of step-a) i.e. compound of Formula IX is new and useful intermediate in the synthesis of agomelatine. Step-b) involves the preparation of compound of Formula VII by the reduction of compound of Formula IX. In embodiments of step b) the reduction may be carried out in the presence of a suitable reducing agent and a solvent. In embodiments of step b) the reducing agents that may be used but are not limited to palladium on carbon raney nickel or the like.

In embodiments of step b) the reaction can be carried out in the presence of a suitable solvent. The suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents at least to some extent. Examples of such solvents include but are not limited to: ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane and dimethoxyethane; ketones such as acetone methyl ethyl ketone methyl isobutyl ketone and diethyl ketone; esters such as ethyl acetate propyl acetate isopropyl acetate and butyl acetate; alcohols such as methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol iso-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol and C1-C6 alcohols; nitriles such as acetonitrile and propionitrile; amides such as formamide N N-dimethylformamide N N-dimethylacetamide N-methyl-2-pyrrolidone and hexamethyl phosphoric triamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as toluene; any mixtures of two or more thereof.

In embodiments of step b) the reaction can be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. In one embodiment the reaction can be carried out from about 10°C to 70°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of step b) the product of step b) may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like. In embodiments of step b) the product of step-b) i.e. compound of Formula VII is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In an embodiment 1-(2-aminoethyl)-7-methoxynaphthalene obtained in any of the processes described above can be used as such or can be isolated directly from the reaction as a pharmaceutically acceptable salt or can be converted into a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of 1-(2-aminoethyl)-7-methoxynaphthalene can be converted 1-(2-aminoethyl)-7-methoxy naphthalene by treatment with a base whenever required or before or during the next step. The bases that are described in the present application can be used for this conversion step. The acids which can be used for the salt preparation are mineral acids such as hydrochloric acid hydrobromic acid sulfuric acid etc.

In another aspect the application provides a process for the preparation of agomelatine which further comprises reacting the 1-(2-aminoethyl)-7-methoxynaphthalene of Formula VII made by any of the processes describes above with an acetylating agent to provide agomelatine of Formula I: Formula VII Formula I The process involves the preparation of agomelatine by acetylating 1-(2-aminoethyl)-7-methoxynaphthalene with a suitable acetylating agent. In embodiments of the process the acetylation of 1-(2-aminoethyl)-7-methoxynaphthalene can be carried out in the presence of a base and a solvent.

The acetylating agents which can be used include but are not limited to acetic anhydride and acetyl chloride or any acetylating agent which produces agomelatine. In embodiments of the process the acetylation can be carried out in the presence of a suitable inert solvent. Suitable inert solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include but are not limited to: ethers such as diethyl ether diisopropyl ether tetrahydrofuran dioxane and dimethoxyethane; ketones such as acetone methyl ethyl ketone methyl isobutyl ketone and diethyl ketone; esters such as ethyl acetate propyl acetate isopropyl acetate and butyl acetate; alcohols such as methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol iso-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol and C1-C6 alcohols; nitriles such as acetonitrile and propionitrile; amides such as formamide N N-dimethylformamide N N-dimethylacetamide N-methyl-2-pyrrolidone and hexamethyl phosphoric triamide; sulfoxides such as dimethylsulfoxide; halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as toluene; any mixtures of two or more thereof.

In embodiments of the process the acetylation can be carried out in the presence of a base. Bases that are useful in the reaction include but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates hydrogen carbonates hydroxides oxides carboxylates or alkoxides e.g. potassium carbonate potassium hydrogen carbonate potassium hydroxide potassium acetate potassium methoxide sodium carbonate sodium hydrogen carbonate sodium hydroxide sodium acetate sodium methoxide lithium carbonate lithium hydrogen carbonate lithium hydroxide lithium acetate lithium methoxide barium hydroxide calcium oxide or alkali metal hydrides e.g. lithium hydride sodium hydride potassium hydride or the like; or organic bases such as for example amines e.g. triethylamine N N-dimethylethanolamine N N-diethylethanolamine 4-ethylmorpholine 1 4-diazabicyclo[2.2.2]-octane N-methyl morpholine dimethylaminopyridine diisopropylamine diisopropylethylamine pyridine or the like.

In embodiments of the process the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment the reaction can be carried out from about 10°C to 80°C. The time required for the reaction may also vary widely depending on many factors notably the reaction temperature and the nature of the reagents and solvent employed. However provided that the reaction is effected under the conditions outlined above for a period of about 1 to about 24 hours or longer.

In embodiments of the process the obtained agomelatine may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as quenching with a suitable reagent extraction or the like. In embodiments of the process the obtained agomelatine may be recrystallized to obtain pure agomelatine.

In another aspect the application provides a process for the preparation of agomelatine which comprises: a) preparing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III from the 7-acetoxynaphthalene compound of Formula II; and Formula II Formula III b) converting the 1-chloroacetyl-7-acetoxynaphthalene of Formula III into aglomelatine of Formula I: Formula III Formula I.

The compounds of Formula II Formula III and Formula I from Formula III can be prepared according to any of the processes described herein. In another aspect the application provides a process for the preparation of agomelatine which comprises: a) preparing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III from the 7-acetoxynaphthalene compound of Formula II; Formula II Formula III b) reducing the 1-chloroacetyl-7-acetoxynaphthalene compound of Formula III to produce the 1-(2-chloroethyl)-7-acetoxynaphthalene compound of Formula IV; and

Formula III Formula IV c) converting the 1-(2-chloroethyl)-7-acetoxynaphthalene compound of Formula IV into aglomelatine of Formula I: Formula IV Formula I The compounds of Formula II Formula III Formula IV and Formula I from Formula IV can be prepared according to any of the processes described herein.

In embodiments agomelatine or any of the intermediate described herein obtained from any of the processes described herein can be purified by any method known in the art such as recrystallization involving single solvent mixture of solvents or solvent-anti solvent technique; reprecipitation; slurring in a solvent; or chromatography to improve its chemical purity. Any of the solvents described in the present application can be used for the purification.

Agomelatine obtained according to processes of the present application can be milled or micronized by any process known in the art such as ball milling jet milling wet milling etc. to produce desired particle sizes and particle size distributions.

An aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of agomelatine together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising agomelatine of the invention together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as but not limited to: powders granules pellets tablets and capsules; liquid oral dosage forms such as but not limited to syrups suspensions dispersions and emulsions; and injectable preparations such as but not limited to solutions dispersions and freeze-dried compositions. Formulations may be in the form of immediate release delayed release or modified release. Further immediate release compositions may be conventional dispersible chewable mouth dissolving or flash melt preparations and modified release compositions may comprise hydrophilic or hydrophobic or combinations of hydrophilic and hydrophobic release rate-controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending dry granulation wet granulation and extrusion and spheronization. Compositions may be presented as uncoated film coated sugar coated powder coated enteric coated or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present application include but are not limited to any one or more of: diluents such as starches pregelatinized starches powdered cellulose microcrystalline cellulose dicalcium phosphate tricalcium phosphate mannitol sorbitol sugar and the like; binders such as acacia guar gum tragacanth gelatin polyvinylpyrrolidones hydroxypropyl celluloses hydroxypropyl methylcelluloses pregelatinized starches and the like; disintegrants such as starches sodium starch glycolate pregelatinized starches crospovidones croscarmellose sodium colloidal silicon dioxide and the like; lubricants such as stearic acid magnesium stearate zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic cationic and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses hydroxymethyl celluloses hydroxypropyl methylcelluloses ethylcelluloses methylcelluloses various grades of methyl methacrylates waxes and the like. Other pharmaceutically acceptable excipients that are useful include but are not limited to film-formers plasticizers colorants flavoring agents sweeteners viscosity enhancers preservatives antioxidants and the like.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application unless the context indicates otherwise. In general the number of carbon atoms present in a given group or compound is designated “Cx-Cy” where x and y are the lower and upper limits respectively. For example a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching but does not include carbon atoms of the substituents such as alkoxy substitutions and the like.

The term "reacting" is intended to represent bringing the chemical reactants together under conditions that cause the chemical reaction indicated to take place. Raney® nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney® is a registered trademark of W. R. Grace and Company. "Halo" or “halogen” refers to -F -Cl -Br or -I. The following abbreviations and acronyms are used herein and have the indicated definitions: An “acetylating agent” is an activated form of acetic acid which is capable of transferring an acetyl group (CH3C(O)-) to a substrate. Examples of an “acetylating agent” include but are not limited to acetic acid/mineral acid; acetic acid/coupling agent such as DEAD/CAT; acetyl halides such as acetyl fluoride acetyl chloride or acetyl bromide; acetic anhydride; mixed anhydrides of acetic acid such as acetic (isobutyl carbonic) anhydride; activated acetic acid an ester solvent like isopropenyl acetate vinyl acetate acetic acid N-hydroxysuccinimide ester or pentafluorophenyl acetate; ketene; or acetyl azide.

An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include but are not limited to methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol i-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol phenol glycerol and the like.

An “aliphatic hydrocarbon” is a liquid hydrocarbon compound which may be linear branched or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include but are not limited to n-pentane isopentane neopentane n-hexane isohexane 3-methylpentane 2 3-dimethylbutane neohexane n-heptane isoheptane 3-methylhexane neoheptane 2 3-dimethylpentane 2 4-dimethylpentane 3 3-dimethylpentane 3-ethylpentane 2 2 3-trimethylbutane n-octane isooctane 3-methylheptane neooctane cyclohexane methylcyclohexane cycloheptane petroleum ethers benzene toluene ethylbenzene m-xylene o-xylene p-xylene trimethylbenzene chlorobenzene fluorobenzene trifluorotoluene anisole and any mixtures thereof.

An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include but are not limited to ethyl acetate n-propyl acetate n-butyl acetate isobutyl acetate t-butyl acetate ethyl formate methyl acetate methyl propanoate ethyl propanoate methyl butanoate ethyl butanoate and the like.

An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include but are not limited to diethyl ether diisopropyl ether methyl t-butyl ether glyme diglyme tetrahydrofuran 2-methyltetrahydrofuran 1 4-dioxane dibutyl ether dimethylfuran 2-methoxyethanol 2-ethoxyethanol anisole and or the like.

A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include but are not limited to dichloromethane 1 2-dichloroethane trichloroethylene perchloroethylene 1 1 1-trichloroethane 1 1 2-trichloroethane chloroform carbon tetrachloride and the like.

A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include but are not limited to acetone ethyl methyl ketone diethyl ketone methyl isobutyl ketone ketones and the like.

A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 nitriles” include but are not limited to acetonitrile propionitrile butanenitrile and the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures as will be apparent to those skilled in the art are intended to be within the scope of the present application.

EXAMPLES

Example 1: Preparation of 7-acetoxynaphtalene (compound of Formula II): 2-naphthol (5 g) triethylamine (4.8 mL) and dichloromethane (25 mL) are charged into a round bottom flask at 28°C. The mixture is stirred for 10 minutes at 28°C to obtain a clear solution. The reaction mass is cooled to 5°C. Dimethylaminopyridine (0.01 g) is added to the reaction mass. Acetic anhydride (3.2 mL) is added dropwise to the reaction mass at 5°C in 10 minutes. The reaction mass is stirred for 40 minutes at 5°C. The temperature of the reaction mass is raised to 25°C and stirred for 45 minutes at the same temperature. Again acetic anhydride (0.5 equivalents) is added to the reaction mass to complete the reaction. Water (50 mL) is added to the reaction mass and stirred for 15 minutes at 25°C. The layers are separated and organic layer is washed with water (50 mL). The organic layer is evaporated under vacuum to get the title compound as residue.

Example 2: Preparation of 1-chloroacetyl-7-acetoxynaphthalene (compound of Formula III): 7-acetoxynaphthalene (25 g) and dichloromethane (500 mL) are charged into a round bottom flask at 26°C and stirred for 15 minutes at the same temperature. The reaction mass is cooled to 5°C. Aluminium chloride (80.4 g) is charged to the reaction mass at 5°C. The reaction mass is further cooled to -20°C. Chloroacetyl chloride (16 mL) is added dropwise to the reaction mass in 1 hour at -20°C. The reaction mass is maintained for 4 hours at -20°C. A 2 N hydrochloric acid solution is added dropwise to the reaction mass in 30 minutes at -20°C. Dichloromethane (200 mL) is added to the reaction mass and stirred for 20 minutes. The layers are separated and the organic layer is washed with saturated solution of sodium bicarbonate (400 mL). The organic layer is evaporated completely to obtain a residue. Ethyl acetate (25 mL) is added to the residue and stirred to get clear solution. The obtained solution is cooled to 5°C hexane (500 mL) is added and stirred for 2 hours at 5°C. The solvent is decanted ethyl acetate (25 mL) is added to the residue and stirred at 40°C until the residue dissolves. The obtained solution is cooled to 5°C. Hexane (500 mL) is added and stirred for 4 hours at 5°C. The precipitated solid compound is obtained by filtration and washed with hexane (30 mL). The material is dried under suction. Yield: 17 g.

Example 3: Preparation of 1-(2-chloroethyl)-7-acetoxynaphthalene (compound of Formula IV):1-chloroacetyl-7-acetoxynaphthalene (20 g) and dichloromethane (100 mL) are charged into a round bottom flask at 30°C. Triethylsilane (29.1 mL) is added to the reaction mass dropwise in 10 minutes at 30°C. The reaction mass is cooled to 0°C and titanium tetrachloride (17 mL) diluted with dichloromethane (10 mL) is added dropwise at 5°C. The reaction mass is maintained for 2 hours at 30°C. The reaction mass is cooled to 0°C and dichloromethane (100 mL) is added to the reaction mass. Saturated solution of sodium bicarbonate (100 mL) is added dropwise to the reaction mass slowly in 1 hour at 5°C. The reaction mass is filtered. The layers are separated and the aqueous layer is extracted with dichloromethane (100 mL). The combined organic layer is washed with saturated solution of sodium bicarbonate (100 mL). The organic layer is dried on sodium sulphate and evaporated on a Rotavapour™ to obtain a residue. The residue is dissolved in acetonitrile (100 mL) and hexane (100 mL) is added to the solution at 30°C. The layers are separated and aectonitrile layer is washed with hexane (100 mL). The acetonitrile layer is evaporated to obtain the title compound as residue. Yield: 18 g.

Example 4: Preparation of 1-(2-chloroethyl)-7-methoxynaphthalene (compound of Formula V): 1-(2-chloroethyl)-7-acetoxynaphthalene (18 g) potassium carbonate (30 g) and methanol (144 ml) are charged into a round bottom flask at 30°C. Dimethyl sulphate (25.9 mL) is added slowly in 10 minutes at 30°C. The reaction mass is heated to 60°C and maintained for 1 hour 30 minutes at the same temperature. The reaction mass is cooled to 30°C. Water (90 mL) and dichloromethane (90 mL) are added to the reaction mass at 30°C and stirred for 10 minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (90 mL). The combined organic layer is washed with water (90 mL) with brine solution (100 mL) and dried over sodium sulphate. The organic layer is evaporated to a residue. The residue is purified by column chromatography. Yield: 9.2 g.

Example 5: Preparation of 2-(2-(7-methoxynaphthalen-1-yl)ethyl) isoindoline-1 3-dione (compound of Formula VI): 1-(2-chloroethyl)-7-methoxynaphthalene (9.2 g) and dimethylformamide (92 mL) are charged into a round bottom flask at 30°C. Potassium phthalimide (15.4 g) and potassium iodide (0.2 g) are added to the reaction mass at 30°C. The reaction mass is heated to 102°C and maintained for 2 hours at the same temperature. The reaction mass is cooled to 30°C water (360 mL) is added to the reaction mass and stirred for 30 minutes at 30°C. The precipitated solid is collected by filtration. The solid compound is slurried in a mixture of ethyl acetate (8 mL) and hexane (400 mL) filtered and washed with hexane. The compound is dried under suction. Yield: 13 g.

Example 6: Preparation of 1-(2-aminoethyl)-7-methoxynaphthalene (compound of Formula VII): 2-(2-(7-methoxynaphthalen-1-yl)ethyl)isoindoline-1 3-dione (15 g) and methanol (150 mL) are charged into a round bottom flask at 30°C. The reaction mass is stirred for 10 minutes at 30°C and hydrazine hydrate (19.4 mL) is added to the reaction mass at the same temperature. The reaction mass is heated to 65°C and maintained for 1 hour at the same temperature. The reaction mass is cooled to 30°C. The reaction mass is filtered and washed with dichloromethane (100 mL). Water (100 mL) is added to the filtrate and extracted with dichloromethane (3 X 100 mL). The layers are separated the organic layer is washed with brine and dried over sodium sulphate. The organic layer is evaporated to obtain the title compound as oil.

Example 7: Preparation of 1-(N N-diformylaminoethyl)-7- methoxynaphthalene (compound of Formula VIII): formamide (10.2 g) and sodium methoxide (6 g) are charged into a round bottom flask at 30°C. The reaction mass is stirred for 3 hours at 30°C and then heated to 80°C and stirred for 1 hour 30 minutes. 1-(2-Chloroethyl)-7-methoxynaphthalene (5 g) dissolved in dimethyl formamide (50 mL) and catalytic amount of tetrabutylammonium iodide are added to the reaction mass at 80°C. The reaction mass is stirred for 30 minutes at 80°C. The reaction mass is heated to 100°C and stirred for 4 hours. The reaction mass is cooled to 30°C after completion of the reaction and water (100 mL) is added. Ethyl acetate (150 mL) is added to the reaction mass and stirred for 5 minutes at 30°C. The layers are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layer is washed with brine solution and dried over sodium sulphate. The solvent from the organic layer is evaporated to obtain the compound as crude. Yield: 6.7 g (wet).

Example 8: Preparation of 1-(2-aminoethyl)-7-methoxynaphthalene (compound of Formula VII): 1-(N N-diformylaminoethyl)-7-methoxynaphthalene (6.1 g) and methanol (60 mL) are charged into a round bottom flask at 30°C. Concentrate hydrochloric acid (12 mL 36.5%) is added to the reaction mass at 30°C. The reaction mass is heated to 70°C and stirred for 4 hours at the same temperature. The reaction mass is cooled to 30°C after completion of the reaction and concentrated under vacuum to remove the solvent. The obtained solid is stirred in a mixture of ethyl acetate and hexane (40+60 mL) for 3 hours at 30°C. The title compound as a hydrochloride salt is obtained by filtration and washed with hexane. Yield: 5 g.

Example 9: Preparation of 1-(2-nitroethyl)-7-methoxynaphthalene (compound of Formula IX): 1-(2-chloroethyl)-7-methoxynaphthalene (1 g) and dimethylformamide (10 mL) are charged into a round bottom flask at 30°C. Sodium nitrite (0.62 g) phloroglucinol (0.17 g) and tetrabutylammonium iodide (0.2 g) are added to the reaction mass at 30°C.The reaction mass is heated to 90°C and stirred for 3 hours at the same temperature. The reaction mass is cooled to 30°C after completion of the reaction and water (20 mL) is added. The reaction mass is extracted with ethyl acetate (2 X 20 mL). The combine organic layer is washed with water (20 mL) and brine (20 mL). The organic layer is dried over sodium sulphate and evaporated the solvent to obtain the product as a residue. Yield: 1 g.

Example 10: Preparation of 1-(2-aminoethyl)-7-methoxynaphthalene (compound of Formula VII): 1-(2-nitroethyl)-7-methoxynaphthalene (1 g) and methanol (40 mL) are charged into an autoclave at 30°C. Raney™ nickel (1 g) is added to the reaction mass at 30°C. The reaction mass is heated to 50°C and stirred for 5 hours under hydrogen pressure at 50°C. The reaction mass is cooled to 30°C after completion of the reaction. The reaction mass is filtered and washed with methanol (100 mL). The filtrate is concentrated under vacuum to obtain the title compound as residue. Yield: 0.9 g.

Example 11: Preparation of N-[2-(7-methoxy-1-naphthylen-1-yl)ethyl]acetamide (agomelatine): 1-(2-aminoethyl)-7-methoxynaphthalene (5.1 g) and ethanol (40 mL) ) are charged into a round bottom flask at 30°C. Sodium acetate (2.51 g) is added to the reaction mass at 30°C. Acetic anhydride (3.25 mL) is added to the reaction mass dropwise in 15 minutes at 30°C.The reaction mass is heated to 80°C and stirred for 2 hours at the same temperature. The reaction mass is cooled to 30°C after completion of the reaction and water (250 mL) is added. Dichloromethane (50 mL) is added to the reaction mass and stirred for 15 minutes at 30°C.

The layers are separated and the aqueous layer is extracted with dichloromethane (50 mL). The combined organic layer is washed with brine solution and dried over sodium sulphate. The solvent from the organic layer is evaporated to obtain a residue. The obtained residue is evaporated with hexane to obtain the product as crude (solid). The crude product is recrystallized in mixture of dichloromethane and hexane. Yield: 3 g.

Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

While particular embodiments of the present invention have been illustrated and described it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

CLAIMS:

1. A process for preparing 1-(2-chloroethyl)-7-hydroxynaphthalene, a compound of Formula IVa comprising:

a) reacting 2-naphthol with an acetylating agent to provide 7-acetoxynaphthalene, a compound of Formula II;

b) reacting the compound of Formula II with chloroacetyl chloride to obtain 1-chloroacetyl-7-acetoxynaphthalene, a compound of Formula III;

hormuia in c) reducing the compound of Formula III to provide 1-(2-chloroethyl)-7-
acetoxynaphthalene, a compound of Formula IV; and

f-ormuia iv d) deacylating the compound of Formula IV to produce 1-(2-chloroethyl)-7-
hydroxynaphthalene, a compound of Formula IVa:

Formula IVa 2. A process for preparing 1-(2-chloroethyl)-7-methoxynaphthalene, a compound of
Formula V comprising:

a) reacting 2-naphthol with an acetylating agent to provide 7-acetoxynaphthalene, a compound of Formula II;

b) reacting the compound of Formula II with chloroacetyl chloride to obtain 1-chloroacetyl-7-acetoxynaphthalene, a compound of Formula III;

c) reducing the compound of Formula III to provide 1-(2-chloroethyl)-7-acetoxynaphthalene, a compound of Formula IV; and

d) hydrolyzing the compound of Formula IV followed by methylation with dimethylsulphate to produce the compound of Formula V.

3. A process for preparing agomelatine comprising;

a) methylating the compound of Formula IVa obtained according to the process of claim 1, with a methylating agent to provide compound of Formula V;

b) reacting the compound of Formula V obtained in step a) with an alkali diformylamide salt to provide a compound of Formula VIII;

c) hydrolyzing the compound of Formula VIII to provide 1-(2-aminoethyl)-7-methoxynaphthalene, a compound of Formula VII or its salts; and

d) converting the compound of Formula VII or its salts into agomelatine.

4. A process for preparing agomelatine comprising;

a) reacting 1-(2-chloroethyl)-7-methoxynaphthalene, a compound of Formula V obtained according to the process of claim 2, with an alkali diformylamide salt to provide 1-(N, N-diformylaminoethyl)-7-methoxynaphthalene, a compound of Formula VIII;

b) hydrolyzing the compound of Formula VIM to provide a compound of Formula VII or its salts; and

c) converting 1-(2-aminoethyl)-7-methoxynaphthalene, a compound of Formula VII or its salts into agomelatine.

5. A process for preparing agomelatine comprising;

a) preparing 1-chloroacetyl-7-acetoxynaphthalene from 7-acetoxynaphthalene; and

b) converting 1-chloroacetyl-7-acetoxynaphthalene into aglomelatine.

6. A process for preparing agomelatine comprising;

a) preparing 1-chloroacetyl-7-acetoxynaphthalene from 7-acetoxynaphthalene;

b) reducing 1-chloroacetyl-7-acetoxynaphthaleneto produce 1-(2-chloroethyl)-7-
acetoxynaphthalene; and

c) converting 1-(2-chloroethyl)-7-acetoxynaphthalene into aglomelatine.

7. 1-chloroacetyl-7-acetoxynaphthalene, a compound of Formula III.

8. 1-(2-chloroethyl)-7-acetoxynaphthalene, a compound of Formula IV. rui muid iv

9. 1-(N, N-diformylaminoethyl)-7-methoxynaphthalene, a compound of Formula VIM.

10. Use of compounds of Formula III, IV and VIM according to the claims 7, 8 or 9 for the preparation of Agomelatine.