WO2014064706A1

WO2014064706A1 - Processes for the preparation of agomelatine using novel intermediates

Info

Publication number: WO2014064706A1
Application number: PCT/IN2012/000694
Authority: WO
Inventors: Dodda Mohan Rao; Ambati Anna Reddy
Original assignee: Symed Labs Limited
Priority date: 2012-10-22
Filing date: 2012-10-22
Publication date: 2014-05-01
Also published as: AR093245A1; EP2909166A4; EP2909166A1

Abstract

Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of Agomelatine or a salt thereof, in high yield and purity, using novel intermediates.

Description

PROCESSES FOR THE PREPARATION OF AGOMELATINE USING NOVEL

INTERMEDIATES

FIELD OF THE INVENTION

The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of agomelatine or a salt thereof, in high yield and purity, using novel intermediates.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,225,442 (hereinafter referred to as the '442 patent) 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. Among them, 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 5HT₂c 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 '442 patent and its corresponding European equivalent Patent No. EP 0447285 Bl . Various pjOcesses_fot-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; PCT Publication Nos. WO 2011/054917, WO 201 1/153939, WO 2011/154140, WO2012/046253, WO2012/093402, WO2012/127483, WO 2012/093225, WO 2012/1 13999 and WO 2012/070025; and Journal of Medicinal Chemistry 1992, 35(8), 1484-1486; and Synthetic Communications 2001, 31(4), 621-629.

According to the '442 patent, N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide (Agomelatine) is prepared by a process as depicted in scheme 1 :

Scheme 1:

7- ethoxy-1 -tetrlone Et ylbromo acetate HCI , Pj0₅

Ethyl (7-methoxy-1 ,2,3,4-tetrahydro- 1 -na hthylidene)acetate

Ethyl (7-methoxy- 1-naphthyl)acetate (7- ethoxy-1 -naphthyl)

acetic acid

(7-Methoxy-1-naphthyl) (7-Methoxy-1 -naphthyl) (7-Methoxy-1 -naphthyl) acetyl chloride acetamide acetonitrile

Ethanolic ammonia

Raney Ni, H₂

2-(7- ethoxy-1 -naphthyl) N-[2-(7-Methoxynaphth-1-yl)

ethylamine ethyrjacetamide

(Agomelatine) As per the process described in the '442 patent, agomelatine is prepared by reacting

7-methoxy-l-tetralone with ethylbromo acetate in the presence of activated zinc filings and benzene to produce ethyl (7-methoxy-l,2,3,4-tetrahydro-l-naphthylidene)acetate,_which_is- then subjected to dehydro-aromatization with sulfur at 215°C to produce ethyl (7-methoxy- l-naphthyl)acetate, followed by hydrolysis and subsequent acyl chlorination with thionyl chloride in chloroform to produce (7-methoxy-l-naphthyl)acetyl chloride, and then ammonification with aqueous ammonia to produce (7-methoxy-l-naphthyl)acetamide, which is then reacted with triflic anhydride in the presence of triethylamine to produce (7- methoxy-l-naphthyl)acetonitrile, followed by reduction with Raney Nickel under hydrogen pressure to produce 2-(7-methoxy-l-naphthyl)ethyl amine, which is finally acetylated with acetyl chloride in pyridine to produce agomelatine.

The process for the preparation of agomelatine disclosed in the '442 patent suffers from various disadvantages such as the use of highly corrosive and toxic reagents like thionyl chloride, benzene, chloroform and pyridine; and involves the use of tedious and cumbersome procedures since it requires eight steps to synthesize agomelatine, thereby rendering the overall yield being less than 30% and making the process commercially unfeasible. Agomelatine obtained by the process described in the '442 patent does not have the satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities are generally formed along with agomelatine. Most of the methoxy intermediates compounds, obtained according to the process described in the '442 patent, exist in the form of residues, which are not isolated as solids, and thus leading to the formation of unacceptable amounts of impurities which are persistent impurities and cannot be removed at final stage.

According to U.S. Patent No. 7,544,839 (hereinafter referred to as the '839 patent),

Agomelatine is prepared by a process as depicted in scheme 2:

Scheme 2:

As per the process described in the '839 patent, 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 in the presence of hydrogenation catalyst Pd/C with allyl methacrylate as the dehydrogenating agent to produce (7-methoxy-l-naphthyl)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-naphthyl)ethanamine hydrochloride, followed by acetylation to produce agomelatine. The reported overall yield of the product is 72%.

The process described in the '839 patent requires the use of expensive noble metal catalysts like Palladium on carbon and hazardous reagents like allyl methacrylate, which causes a lot of environmental pollution, for dehydrogenation of (7-methoxy-3,4-dihydro-l- naphthalenyl)acetonitrile to produce (7-methoxy-l-naphthyl)acetonitrile. Moreover, this step of dehydrogenation is difficult to reproduce and the yield of the resulting amine compound is very low.

Furthermore, the methoxy intermediates obtained according to the process described in the '839 patent suffer from disadvantages since these methoxy intermediates are characterized by having low melting points. For example, the reported melting point for (7-methoxy-3,4-dihydro-l-naphthalenyl)acetonitrile is 48-50°C, and the reported melting point for (7-methoxy-i-naphthyl)acetonitrile is 83°C. Hence, the known methoxy intermediate compounds are not stable and they decompose at higher temperatures due to their low melting points, for example, when sulfur (which is a cheaper aromatizing agent) is employed as reagent for aromatization of (7-methoxy-3,4-dihydro-l- naphthalenyl)acetonitrile (this reaction requires heating the reactants at higher temperature 180-200°C) to produce (7-methoxy-l-naphthyl)acetonitrile, thus leading to the formation of unacceptable amounts of impurities, thereby decreasing the yield and purity of the product. Hence, the aromatization of (7-methoxy-3,4-dihydro-l-naphthalenyl)acetonitrile must be carried out at low temperatures and requires the use of expensive noble metal catalysts like palladium on carbon and additional hazardous reagents like allyl methacrylate. Therefore, the cheaper aromatizing agents like sulfur cannot be used for aromatization of known methoxy intennedjate _compounds The— time— periods—for completion of the reaction between 7-methoxy-l-tetralone and cyanoacetic acid takes around 30 hours at reflux temperature.

According to U.S. Patent No. 8,212,077 (hereinafter referred to as the Ό77 patent), Agomelatine is prepared by a process as depicted in scheme 3:

Scheme 3:

2-(7-Methoxy-1 -naphthyl) Agomelatine

ethanamine

According to PCT Publication No. WO 2012/046253 (hereinafter referred to as the '253 application), 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 crystallized from cyclohexane to produce pure compound, which is then treated with hydrogen gas in the presence of Raney Ni, in aqueous methanol in the presence of ammonia at 45-60°C to provide 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine, followed by treatment with hydrochloric acid in ethylacetate-to-produee-its-hydrochloride^{^} salt, which 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, isolating the compound as a solid from cyclohexane, followed by aromatizing the compound with DDQ in dichloromethane to produce agomelatine.

According to PCT Publication No. WO 2011/154140 (hereinafter referred to as the ' 140 application), Agomelatine is prepared by a process as depicted in scheme 4:

Scheme 4:

MeO. -A, Sodium hydride

Diethyl cyanomethyl

tetralone P^h°sPⁿ°ⁿa>e ^NaBH<

Tetrahydrofuran 7-Methoxy-1,2,3,4-tetrahydro Methanol 1 -(2-Aminoethyl)-7-methoxy- naphthylidene acetonitrile Q_0nc 1 ,2,3,4-tetrahydro naphthalene

Acetic anhydride

Methanol

methoxy-1 ,2,3,4-tetrahydro

naphthalene

According to U.S. Patent No. 8,143,449 (hereinafter referred to as the '449 patent), Agomelatine is prepared by a process as depicted in scheme 5:

Scheme 5:

3-Methoxyacenaphtho

(7-Methoxy-1 -naphthyl) Acetonitrile

quinone

(oxo)acetic acid

2-(7-Methoxy-1-naphthy!)-

2-(7-Methoxy-1 -naphthyl)- ethanamine Agomelatine 2-oxoacetamide According to Journal of Medicinal Chemistry 1992, 35(8), 1484-1486 (hereinafter referred to as the 'JMC article'), Agomelatine is prepared by a process as depicted in scheme 6:

Scheme 6:

(7-Methoxy-1-Naphthyl) (7-Methoxy-1-Naphthyl) (7-Methoxy-1-Naphthyl) acetic acid acetamide acetonitrile

LiAIH₄, Ether a) H_j, Raney Ni

b) HCI, Ether

The processes for the preparation of N-[2-(7-methoxy-l- naphthalenyl)ethyl]acetamide (Agomelatine) described in the aforementioned prior art suffer from several disadvantages such as the use of highly flammable, corrosive and hazardous reagents like thionyl chloride, pyridine, triflic anhydride, allyl methacrylate, sodium hydride, sodamide, n-butyl lithium and lithium aluminium hydride; use of expensive reagents such as diethyl cyanomethyl phosphonate, 2,6-di-tert-butyl-4-methyl- pyridine, N-vinylphthalimide, Palladium tetrakis(triphenylphosphine), hydrogenation catalysts such as Pd/C, acrylamide, Neocuproine hydrate, 18-crown-6-ether, propylphosphonic anhydride; use of additional and excessive amounts of reagents; use of multiple solvents and in excess amounts; use of highly flammable and/or hazardous solvents like benzene, pyridine, chloroform and dimethylsulfoxide; and involve the use of tedious and cumbersome procedures like prolonged reaction time periods, very low temperature conditions, multiple process steps, column chromatographic purifications, multiple isolations/ re-crystallizations, and thus resulting in a poor product yield and quality Methods involving column chromatographic plifificafions are generally- undesirable for large-scale operations, thereby making the process commercially unfeasible.

The major drawback of the processes for the preparation of agomelatine described in the aforementioned prior art is that the processes involve the use of highly flammable, corrosive and hazardous reagents like thionyl chloride, pyridine, triflic anhydride, allyl methacrylate, sodium hydride, sodamide, n-butyl lithium and lithium aluminium hydride, thereby requiring very strict control of reaction conditions at low temperatures. Handling of these reagents is very difficult at lab scale and in commercial scale operations. Moreover, the yields and purities of the product obtained according to the prior art processes are low to moderate.

The processes for the preparation of Agomelatine, N-[2-(7-methoxy-l- naphthalenyl)ethyl]acetamide, of formula I described in the above mentioned prior art have the following disadvantages and limitations:

a) the melting points of the known methoxy intermediate compounds are low;

b) the methoxy intermediates decompose at higher temperatures due to their low melting points, hence, the aromatization of methoxy intermediates such as (7-methoxy-3,4- dihydro- 1 -naphthalenyl)acetonitrile and N-[2-(7-methoxy-3 ,4-dihydronaphthalen- 1 - yl)ethyl]acetamide must be carried out at low temperatures and requires the use of expensive noble metal catalysts like palladium on carbon and additional hazardous reagents like allyl methacrylate, and expensive reagents like DDQ;

c) the cheaper aromatizing agents like sulfur cannot be employed for aromatization of known methoxy intermediate compounds;

d) the reaction between 7-methoxy-l-tetralone and cyanoacetic acid takes around 30 hours at reflux temperature for reaction completion;

e) most of the known methoxy intermediates compounds exist in the form of residues, which are not isolated as solids, and thus leading to the formation of impurities which are persistent impurities, thereby requiring additional purification steps which effects the yield of the product;

f) longer reaction times, low yields and low purities of the products; g) the processes involve the use of highly flammable, corrosive and hazardous reagents like thionyl chloride, pyridine, trifilc anhydride, allyl methacrylate, sodium hydride, sodamide, n-butyl lithium and lithium alumimium hydride;

h) the processes involve the use of expensive reagents such as diethyl cyanomethyl phosphonate, 2,6-di-tert-butyl-4-methyl-pyridine, N-vinylphthalimide, Palladium tetrakis(triphenylphosphine), hydrogenation catalysts such as Pd/C, acrylamide, Neocuproine hydrate, 18-crown-6-ether, propylphosphonic anhydride;

i) the processes involve the use of highly flammable and hazardous solvents like benzene, pyridine, chloroform arid dimethylsulfoxide;

j) the processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, very low temperature conditions, multiple process steps, column chromatographic purifications, multiple isolations/ re-crystallizations;

k) the overall processes generate a large quantity of chemical waste which is difficult to treat.

Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide (Agomelatine) at lab scale and in commercial scale operations.

A need remains for an improved, commercially viable and environmentally friendly process of preparing Agomelatine with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large- scale preparation. 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 with high yield.

SUMMARY OF THE INVENTION

The present inventors have surprisingly and unexpectedly found that Agomelatine, N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide, of formula I or a salt thereof can be prepared in high purity and with high yield by reacting 7-hydroxy-l-tetralone with cyanoacetic acid in the presence of a suitable reagent to produce (7-hydroxy-3,4-dihydro- l-naphthalenyl)acetonitrile or a salt thereof, which is_then_subjected-to-reduction^{^} ¥itir suitable reducing agent to produce 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine or a salt thereof, followed by aromatization with a suitable reagent to produce 2-(7- hydroxy-l-naphthyl)ethanamine or an acid addition salt thereof, which is then subjected to acetylation with a suitable acetylating agent to produce N-[2-(7-hydroxy-l- naphthyl)ethyl]acetamide, followed by reaction with a methylating agent to produce agomelatine.

In one aspect, provided herein are efficient, industrially advantageous and environmentally friendly processes for the preparation of agomelatine in high yield and with high purity using novel intermediates. The processes disclosed herein avoid the tedious and cumbersome procedures of the prior processes, thereby resolving the problems associated with the processes described in the prior art, which are more convenient to operate at lab scale and in commercial scale operations.

In another aspect, provided herein is a novel intermediate compound, (7-hydroxy- 3,4-dihydro-l-naphthalenyl)acetonitrile, of formula III:

or a salt thereof.

In another aspect, provided herein is a novel intermediate compound, 2-(7- hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine, of formula IV:

or an acid addition salt thereof. In another aspect, provided herein is a novel intermediate compound, 2-(7- hydroxy-l-naphthyl)ethanamine, of formula V:

or an acid addition salt thereof, wherein the acid addition salt does not include hydrobromide salt.

In another aspect, provided herein is a novel intermediate compound, (7-hydroxy- l-naphthyl)acetonitrile, of formula VII:

or a salt thereof.

In another aspect, provided herein is a novel intermediate compound, N-[2-(7- hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide, of formula VIII:

or a salt thereof.

In another aspect, provided herein is a novel intermediate compound, 2-(7- hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine, of formula XII:

or an acid addition salt thereof.

In another aspect, provided herein is a novel intermediate compound, N-[2-(7- hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethyl]acetamide, of formula XIII:

or a salt thereof.

In another aspect, the present invention also encompasses the use of the novel compounds of formulae III, IV, V, VII, VIII, XII and XIII disclosed herein for preparing Agomelatine.

The process for the preparation of Agomelatine disclosed herein have the following advantages over the processes described in the prior art:

i) the processes involve the use of novel hydroxy intermediates of formulae III, IV, V, . VII, VIII, XII and XIII;

ii) the novel hydroxy intermediate compounds are characterized by having higher melting points when compared with that of the known methoxy intermediates;

iii) the processes involve the use of less expensive and/or cheaper reagents;

iv) the novel hydroxy intermediate compounds are isolated as solid state forms in substantially pure form;

v) the reaction between 7-hydroxy-l-tetralone and cyanoacetic acid takes around 10 hours for completion of the reaction;

vi) the overall processes involve a reduced number of process steps and shorter reactions times;

vii) the processes avoid the use of highly flammable, corrosive and hazardous reagents like thionyl chloride, pyridine, triflic anhydride, allyl methacrylate, sodium hydride, sodamide, n-butyl lithium and lithium aluminium hydride;

viii) the processes avoid the use of highly toxic or hazardous chemicals like benzene, pyridine and chloroform; ix) the processes avoid the use of tedious and cumbersome procedures like prolonged reaction time periods, very low temperatures, multiple process steps, column chromatographic purifications, multiple isolations, use of additional and excess amounts of solvents;

x) the processes avoid the use of expensive reagents such as diethyl cyanomethyl phosphonate, 2,6-di-tert-butyl-4-methyl-pyridine, N-vinylphthalimide, Palladium tetrakis(triphenylphosphine), hydrogenation catalysts such as Pd/C, acrylamide, Neocuproine hydrate, 18-crown-6-ether, propylphosphonic anhydride;

xi) the processes involve easy work-up methods and simple isolation processes, and there is a reduction in chemical waste;

xii) the purity of the product is increased without additional purifications; and

xiii) the overall yield of the product is increased.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a novel process for the preparation of Agomelatine, N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy- 1 -tetralone of formula II:

with cyanoacetic acid of formula X:

or a salt thereof, to produce (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof;

b) reducing the compound of formula III with a suitable reducing agent to produce 2-(7- hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof;

c) subjecting the compound of formula IV or an acid addition salt thereof to aromatization by reacting with a suitable reagent to produce 2-(7-hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof;

d) acetylating the compound of formula V with a suitable acetylating agent to produce N- [2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof; and

e) reacting the compound of formula VI with a methylating agent to produce the agomelatine of formula I.

The compounds of formulae III, IV, V, VII, VIII, XII and XIII disclosed herein are novel and constitute another aspect of the present invention.

The use of the novel intermediate compounds of formulae III, IV, V, VII, VIII, XII and XIII, or a salt thereof, in the preparation of agomelatine of formula I is novel and forms further aspect of the present invention.

Advantageously, the novel intermediate compounds of Agomelatine disclosed herein are obtained as solid state forms in substantially pure form.

The term "substantially pure" as used herein refers to the solid state form of agomelatine intermediates, disclosed herein, having a purity of greater than about 97 wt%, specifically greater than about 98 wt%, more specifically greater than about 99 wt%, and still more specifically greater than about 99.5 wt%. The purity is preferably measured by High Performance Liquid Chromatography (HPLC). For example, the purity of solid state form of agomelatine intermediates obtained by the processes disclosed herein can be about 97% to about 99.5%, or about 98% to about 99.9%, as measured by HPLC.

Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.

Acid addition salts, as used herein, include the salts that are derived from organic and inorganic acids. For example, 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, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, di- p-toluoyl-L-(+)-tartaric acid, malic acid, ascorbic acid, and the like.

Base addition salts may be derived from an organic or an inorganic base. For example, 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.

Exemplary acid addition salts of the compounds of formulae IV and V include, but are not limited to, hydrochloride, hydrobromide,^uJphate,_nitrate,--phosphate7-acetate propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. Specific acid addition salts are hydrochloride and hydrobromide, and most specifically hydrochloride salt.

Base addition salts of the compound of formula X as used herein include the salts that are derived from an organic or an inorganic base. Exemplary base addition salts of the compound of formula X include, but are not limited to, sodium salt, calcium salt, potassium salt, magnesium salt and ammonium salt.

The reaction in step-(a) is carried out in the presence or absence of a solvent. In one embodiment, the reaction in step-(a) is carried out in the presence of a first solvent. The term solvent also includes mixture of solvents.

Exemplary first solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, and mixtures thereof.

In one embodiment, the first solvent used in step-(a) is a reaction solvent that has a boiling temperature higher than or equal to that of water, and more preferably that forms an azeotrope with water.

Specifically, the first solvent used in step-(a) is selected from the group consisting of toluene, xylene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene, mesitylene, and mixtures thereof; more specifically the first solvent is toluene or xylene; and a most specific solvent is toluene.

In one embodiment, the reaction in step-(a) is carried out in the presence of a carboxylic acid and an organic amine. In another embodiment, the carboxylic acid and the organic amine compounds are employed in catalytic amounts.

Exemplary carboxylic acids used in step-(a) include, but are not limited to, a linear or branched alkyl carboxylic acid, an unsubstituted or substituted aryl carboxylic acid, or an unsubstituted or substituted linear or branched aralkyl carboxylic acid.

Exemplary organic amines used in step-(a) include, but are not limited to, a linear or branched alkyl amine, an unsubstituted or substituted aryl amine, or an unsubstituted or substituted linear or branched aralkyl amine.

The term "alkyl", as used herein, denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl groups have 3 to 10 carbon atoms in the chain. The alkyLmay be substituted with one or more "cycloalkyl groups". Exemplary alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, hexyl and heptyl.

The term "cycloalkyl", as used herein, denotes a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "aryl", as used herein, 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, naphthyl or biphenyl group.

The term "aralkyl", as used herein, 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.

Specifically, the carboxylic acid used in step-(a) is an unsubstituted or substituted aryl carboxylic acid; and a most specific carboxylic acid is 4-hydroxybenzoic acid.

Specifically, the organic amine used in step-(a) is an unsubstituted or substituted linear or branched aralkyl amine; more specifically the organic amine is morpholine or benzyl amine; and a most specific organic amine is benzyl amine.

The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.

In one embodiment, the reaction in step-(a) is carried out at a temperature of about 25 °C to the reflux temperature of the solvent used, specifically at a temperature of about 60°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 10 hours to about 40 hours, and most specifically about 25 hours to about 30 hours.

In another embodiment, the cyanoacetic acid of formula X is used in a molar ratio of about 1 to 3 equivalents, specifically about .1 to 1.5 equivalents, with respect to the 7- hydroxy-l-tetralone of formula II in order to ensure a proper course of the reaction.

The reaction mass containing the (7-hydroxy-3,4-dihydro-l- naphthalenyl)acetonitrile of formula III obtained in step-(a) may subjected to usual work up such as a washing, an extraction, a pH adjustment, jm_evaporation, a layer separation,^~a decolorization, or a combination thereof. The reaction mass may be used directly in the next step to produce the amine compound of formula IV or the compound of formula III may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III is isolated in the form of a solid.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III 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 (7-hydroxy-3,4- dihydro-l-naphthalenyl)acetonitrile of formula III 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. 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.

In one embodiment, the reduction in step-(b) is carried out in the presence of a second solvent. The term solvent also includes mixture of solvents.

Exemplary second solvents used in step-(b) include, but are not limited to, water, an alcohol, an ester, a hydrocarbon solvent, an ether, and mixtures thereof.

Specifically, the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; more specifically, the second solvent is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof; and a most specific second solvent is methanol or ethanol. Exemplary reducing agents used in step-(b) include, but are not limited to, hydrogenation catalysts (metal catalysts) such as platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, and the like; hydride agents such as lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), and the like; and other reducing agents such as borane, borane-THF complex, and the like.

It has been surprisingly found that the reduction in step-(b) is advantageously and efficiently carried out by employing the less expensive hydride agents such as sodium borohydride when the reaction is performed in the presence of a Lewis acid. The use of hydride agents in the presence of Lewis acid in the reduction process leads to the resulting product with high purity and in good yield.

Exemplary Lewis acids used in step-(b) include, but are not limited to, aluminium chloride, calcium chloride, boron triflouride and zinc chloride, nickel chloride, and the like. Specific Lewis acids are aluminium chloride and nickel chloride.

The reduction in step-(b) may be carried out in the presence or absence of hydrogen gas. A most specific reducing agent used in step-(b) is Raney-Nickel.

The reduction in step-(b) is optionally carried out in the presence of ammonia. In one embodiment, ammonia used may be in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent. The organic solvent used for saturating ammonia is selected from the group consisting of ethanol, methanol, isopropyl alcohol and ethyl acetate.

In one embodiment, the reduction in step-(b) 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 more specifically at about 25°C to about 65°C. The reaction time may vary between about 3 hours to about 8 hours, and most specifically about 5 hours to about 6 hours.

In another embodiment, the reducing agent is used in an amount of about 5%w/w to 50%w/w, specifically about 5%w/w to 10%w/w, with respect to the (7-hydroxy-3,4- dihydro-l-naphthalenyl)acetonitrile of formula III in order to ensure a proper course of the reaction.

The reaction mass containing the 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV obtained in step-(b) may subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the amine compound of formula V or the compound of formula IV may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV obtained in step-(b) is converted into its acid addition salts by treatment with a suitable acid.

Exemplary acids suitable for forming acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, di-p-toluoyl-L-(+)- tartaric acid, malic acid, ascorbic acid, and the like. Most specific acids are hydrochloric acid and hydrobromic acid.

For example, hydrochloric acid used may be in the form of aqueous hydrochloric acid or in the form of hydrogen chloride gas or hydrogen chloride dissolved in an organic solvent. The organic solvent used for dissolving hydrogen chloride gas or hydrogen chloride is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.

The treatment of 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV with a suitable acid is carried out in a solvent selected from the group consisting of water, an ester, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ether, and mixtures thereof. 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; and most specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and mixtures thereof. The treatment of 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV with a suitable acid is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, and most specifically at a temperature of about 20°C to the reflux temperature of the solvent used.

In one embodiment, the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof is isolated in the form of a solid.

In one embodiment, the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof 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 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV is selected from the group as described 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-peritane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV prepared by the process described herein is 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride salt.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV prepared by the process described herein is 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrobromide salt.

Exemplary reagents suitable for facilitating the aromatization reaction in step-(c) include, but are not limited to, sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts such as 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, 2,3- dicyano-4-chlorobenzoquinone, 2,3-dicyanobenzoquinone; and other^quinone derfvatives^{^} such as 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil, o-floranil, and the like.

Specific aromatization reagents are sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil), 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) and raney nickel; and most specifically sulfur, aqueous hydrobromic acid and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil).

Specifically, the starting material 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV, in step-(c), is employed in the form of an acid addition salt, and most specifically in the form of its hydrochloride salt.

It has been surprisingly and unexpectedly found that the novel hydroxy intermediate compounds of formulae III, IV, V, VII and VIII, and their salts, disclosed herein, are characterized by having higher melting points when compared with that of the known methoxy intermediates. For example, the hydrochloride salt of 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV, obtained by the processes disclosed, 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 novel hydroxy intermediate compounds disclosed herein is advantageous since this property makes these compounds stable even at higher temperature (e.g. 185-190°C), thereby making it possible to advantageously employ the cheaper aromatization reagents such as sulfur for aromatizing the respective dihydro intermediates (e.g., the compound of formula IV) at higher temperature, for example, at 185-190°C. Whereas, the corresponding methoxy intermediates decompose at such higher temperatures due to their low melting points when aromatizing with sulfur thereby effecting purity and yield of the resulting products.

Therefore, the aromatization reaction in step-(c) is advantageously carried out by using cheaper aromatization reagent sulfur in the absence of a solvent.

The aromatization reaction in step-(c) is carried out in the presence or absence of a solvent. In one embodiment, the aromatization in step-(c) is carried out as a neat reaction in the absence of a solvent.

In another embodiment, the aromatization in step-(c) is optionally carried out in the presence of a third solvent. The term solvent also includes mixture of solvents.

Exemplary third solvents suitable for facilitating the aromatization in step-(c) include, but are not limited to, water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

Specifically, the third solvent is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, and mixtures thereof; and a most specific third solvent is toluene.

In one embodiment, the aromatization in step-(c) is carried out as a neat reaction, in the absence of solvents, by heating the contents at a temperature of about 160°C to about 200°C, and specifically at a temperature of about 180°C to about 190°C. The reaction time may vary between about 30 minutes to about 5 hours, and most specifically about 1 hour to about 2 hours.

In another embodiment, the aromatization in step-(c) is carried out in the presenceof the third solvent 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. The reaction time may vary between about 3 hours to about 30 hours, and most specifically about 5 hours to about 25 hours.

In another embodiment, the metal catalysts suitable for facilitating aromatization is used in a amount of about 5%w/w to about 50%w/w, specifically about 5%w/w to 20%w/w, with respect to the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof in order to ensure a proper course of the reaction. In another embodiment, the sulfur is used in a molar ratio of about 1 to 5 equivalents, specifically about 1 to 2 equivalents, with respect to the 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof in order to ensure a proper course of the reaction.

In another embodiment, the 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p- chloranil) is used in a molar ratio of about 1 to 5 equivalents, specifically about 1 to 2 equivalents, with respect to the 2-(7-hydroxy-3,4-dihydro-l-naphthalehyl)ethanamine of formula IV or an acid addition salt thereof in order to ensure a proper course of the reaction.

In another embodiment, the aqueous hydrobromic acid is used in an amount of about 1 to 5 times, specifically about 1 to 2 times, with respect to the 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof in order to ensure a proper course of the reaction.

The reaction mass containing the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof obtained in step-(c) may subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI or the compound of formula V may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V obtained in step-(c) is converted into its acid addition salts by treatment with a suitable acid as per the methods described hereinabove.

In another embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof obtained in step-(c) is isolated in the form of a solid.

In another embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof 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 2-(7-hydroxy-l- naphthyl)ethanamine of formula V or an acid addition salt thereof is selected from the group as described 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-butyXejher,„ethyTaGetate n-penfane n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-l- naphthyl)ethanamine of formula V prepared by the process described herein is 2-(7- hydroxy- l-naphthyl)ethanamine hydrochloride salt.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-l- naphthyl)ethanamine of formula V prepared by the process described herein is 2-(7- hydroxy-l-naphthyl)ethanamine hydrobromide salt.

Exemplary acetylating agents used in step-(d) include, but are not limited to, acetyl halide such as acetyl chloride, acetyl bromide, acetyl iodide; acetic anhydride, sodium acetate, and the like, or a combination thereof. A most specific acetylating agent is acetic anhydride.

In another embodiment, the reaction in step-(d) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.

Exemplary bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals; ammonia, collidine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine and 1-alkylimidazole. Specific bases 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 sodium hydroxide and potassium hydroxide.

In one embodiment, the acetylation in step-(d) is carried out in the presence of a fourth solvent.

Exemplary fourth solvents used in step-(d) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the fourth solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanoI,_eth-yl— acetate,^~methyT acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fourth solvents are methanol, ethanol, isopropanol, and mixtures thereof.

In one embodiment, the acetylating 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 2-(7 -hydroxy- 1- naphthyl)ethanamine of formula V or an acid addition salt thereof in order to ensure a proper course of the reaction.

In one embodiment, 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 20 minutes to about 3 hours, and specifically about 30 minutes to about 2 hours.

The reaction mass containing the N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide of formula VI obtained in step-(d) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula VI may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.

The solvent used for isolating and/or recrystallizing the N-[2-(7-hydroxy-l- naphthyl)ethyl]acetamide of formula VI is selected from the group as described hereinabove for such purpose.

Exemplary methylating agents used in step-(e) include, but are not limited to, dimethyl sulfate, methyl iodide, and the like. A most specific methylating agent is dimethyl sulfate.

In another embodiment, the reaction in step-(e) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base,

Specific bases 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.

In one embodiment, the methylation in step-(e) is carried out in the presence of a fifth solvent.

Exemplary fifth solvents used in step-(e) include, but are not limited to, water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the fifth solvent used in step-(e) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fifth solvents are water, acetone, and mixtures thereof.

In one embodiment, the methylating agent in step-(e) 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-naphthyl)ethyl]acetamide of formula VI in order to ensure a proper course of the reaction.

In one embodiment, the reaction in step-(e) 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.

In one embodiment, the isolation 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.

According to another aspect, there is provided a process for the preparation of (7- hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof, comprising reacting 7-hydroxy-l-tetralone of formula II:

with cyanoacetic acid of formula X:

a salt thereof, to produce the compound of formula III. The process for the preparation of (7-hydroxy-3,4-dihydro-l- naphthalenyl)acetonitrile of formula III disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a process for the preparation of 2-(7- hydroxy-3,4-dihydro-l -naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof, comprising reducing (7-hydroxy-3,4-dihydro-l- naphthalenyl)acetonitrile of formula III:

with a suitable reducing agent to produce the compound of formula IV or an acid addition salt thereof.

The process for the preparation of 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a process for the preparation of 2-(7- hydroxy- 1 -naphthyl)ethanamine of formula V:

or an acid addition salt thereof, comprising subjecting 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof, to aromatization by reacting with a suitable reagent to produce the compound of formula V or an acid addition salt thereof.

The process for the preparation of 2-(7-hydroxy-l-naphthyl)ethanamine of formula V disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a process for the preparation of N- [2-(7-hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof, comprising acetylating 2-(7-hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof, with a suitable acetylating agent to produce the compound of formula VI or a salt thereof.

The process for the preparation of N-[2-(7-hydroxy-l-naphthyl)ethyl]aeetamide of formula VI disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a process for the preparation of Agomelatine, N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising reacting N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof, with a methylating agent to produce the agomelatine of formula I.

The process for the preparation of Agomelatine, N-[2-(7-methoxy-l - naphthalenyl)ethyl]acetamide, of formula I disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a novel process for the preparation of Agomelatine, N-[2- 7-methoxy-l-naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy-l -tetralone of formula II:

with cyanoacetic acid of formula X:

HO

CN X

O or a salt thereof, to produce (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof;

or an acid addition salt thereof;

acetylating the compound of formula IV with a suitable "acetylating agent to prodi [2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide, of formula VIII:

or a salt thereof;

d) subjecting the compound of formula VIII to aromatization by reacting with a suitable reagent to produce N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI: ...

or a salt thereof; and

Unless otherwise specified, the reactions in the above process steps-(a), (b) and (e) are carried out by the methods as described hereinabove.

The reaction in step-(a) is carried out in the presence or absence of a solvent. In one embodiment, the reaction in step-(a) is carried out in the presence of a first solvent selected from the group as described above.

Specifically, the carboxylic acid used in step-(a) is an unsubstituted or substituted aryl carboxylic acid; and a most specific carboxylic acid is 4-hydroxybenzoic acid. Specifically, the organic amine used in step-(a) is an unsubstituted or substituted linear or branched aralkyl amine; more specifically the organic amine is morpholine or benzyl amine; and a most specific organic amine is benzyl amine.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III is isolated in the.form of a solid.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula HI is isolated and/or re-crystallized from a suitable solvent by the methods described hereinabove.

The solvent used for isolating and/or recrystallizing the pure (7-hydroxy-3,4- dihydro-l-naphthalenyl)acetonitrile of formula III is selected from the group as described hereinabove.

In one embodiment, the reduction in step-(b) is carried out in the presence of a second solvent selected from the group as described above.

Specifically, the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; more specifically, the second solvent is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof; and a most specific second solvent is methanol or ethanol.

Exemplary reducing agents used in step-(b) include, but are not limited to, hydrogenation catalysts (metal catalysts) such as platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, and the like; hydride agents such as lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), and the like; and other reducing agents such as borane, borane-THF complex, and the like.

It has been surprisingly found that the reduction in step-(b) is advantageously and efficiently carried out by employing the less expensive hydride agents-such-as sodiunT borohydride when the reaction is performed in the presence of a Lewis acid. The use of hydride agents in the presence of Lewis acid in the reduction process leads to the resulting product with high purity and in good yield.

The reduction in step-(b) is optionally carried out in the presence of ammonia as per the methods described hereinbefore.

In one embodiment, the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV obtained in step-(b) is converted into its acid addition salts by treatment with a suitable acid selected from the group described hereinbefore. Most specific acids are hydrochloric acid and hydrobromic acid.

In one embodiment, the 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof is isolated and/or re-crystallized from a suitable solvent by the methods described hereinbefore.

The solvent used for isolating and/or recrystallizing the pure 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV is selected from the group as described above.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine of formula IV prepared by the process described herein is 2-(7-hydroxy-3,4-dihydro-l -naphthalenyl)ethanamine hydrochloride salt.

Exemplary acetylating agents used in step-(c) include, but are not limited to, acetyl halide such as acetyl chloride, acetyl bromide, acetyl iodide; acetic anhydride, sodium acetate, and the like, or a combination thereof. A most specific acetylating agent is acetic anhydride.

In another embodiment, the reaction in step-(c) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.

In one embodiment, the acetylation in step-(c) is carried out in the presence of a fourth solvent selected from the group as described hereinbefore.

Exemplary fourth solvents used in step-(c) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the fourth solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fourth solvents are methanol, ethanol, isopropanol, and mixtures thereof.

In one embodiment, the reaction 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 20°C to the reflux temperature of the solvent used, and most„specifically-at^"th¾^fluj temperature of the solvent used. The reaction time may vary between about 20 minutes to about 3 hours, and specifically about 30 minutes to about 2 hours.

The reaction mass containing the N-[2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide, of formula VIII obtained in step-(c) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula VI, or the compound of formula VIII may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.

The solvent used for isolating and/or recrystallizing the N-[2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethyl]acetamide, of formula VIII is selected from the group as described hereinabove for such purpose.

Exemplary reagents suitable for facilitating the aromatization reaction in step-(d) include, but are not limited to, sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, hydrogenation catalysts such as palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, and the like; quinone derivatives such as 2,3,5,6-tetrachlorocyclohexa-2,5rdiene-l,4-dione (p-Chloranil), p- bromanil, p-floranil, 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ), 2,3-dibromo-5,6- dicyano benzoquinone, 2,3- dicyano-4-chlorobenzoquinone, 2,3-dicyanobenzoquinone; and other quinone derivatives such as 1 ,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil, o-floranil, and the like.

Therefore, the aromatization reaction in step-(d) is advantageously carried out by using cheaper aromatization reagent sulfur in the absence of a solvent.

The aromatization reaction in step-(d) is carried out in the presence or absence of a solvent.

In one embodiment, the aromatization in step-(d) is carried out as a neat reaction in the absence of a solvent. In another embodiment, the aromatization in step-(d) is optionally carried out in the presence of a third solvent selected from the group as described hereinbefore.

Exemplary third solvents suitable for facilitating the aromatization in step-(d) include, but are not limited to, water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

In one embodiment, the aromatization in step-(d) is carried out as a neat reaction, in the absence of solvents, by heating the contents at a temperature' of about 160°C to about 200°C, and specifically at a temperature of about 180°C to about 190°C. The reaction time may vary between about 30 minutes to about 5 hours, and most specifically about 1 hour to about 2 hours.

In another embodiment, the aromatization in step-(d) is carried out in the presence of the third solvent 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. The reaction time may vary between about 3 hours to about 30 hours, and most specifically about 5 hours to about 25 hours.

The reaction mass containing the N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI or a salt thereof obtained in step-(d) may subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the agomelatine of formula I or the compound of formula VI may be isolated and/or recrystallized and then used in the next step.

In another embodiment, the N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI obtained in step-(d) is isolated in the form of a solid. In another embodiment, the N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI 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-l- naphthyl)ethyl]acetamide of formula VI is selected from the group as described 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.

In another embodiment, the reaction in step-(e) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base, selected from the group as described hereinabove.

Specifically, the fifth solvent used in step-(e) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-hutyLether^monogLym^ Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fifth solvents are water, acetone, and mixtures thereof.

The solvent used for isolating/recrystallizing the pure agomelatine of formula I is selected from the group as described herein above.

According to another aspect, there is provided a process for the preparation of N- [2-(7-hydroxy-3,4-dihydro-l-na hthalenyl)ethyl]acetamide of formula VIII:

or a salt thereof, comprising acetylating 2-(7-hydroxy-3,4-dihydro- 1 - naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof, with a suitable acetylating agent to produce the compound of formula VIII or a salt thereof. The process for the preparation of N-[2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide of formula VIII disclosed herein is carried out by the methods and parameters as described hereinabove.

or a salt thereof, comprising subjecting N-[2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethyl]acetamide of formula VIII:

to aromatization by reacting with a suitable reagent to produce the compound of formula VI or a salt thereof.

The process for the preparation of N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide of formula VI disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a novel process for the preparation of Agomelatine, N-[2-(7-methoxy- 1 -naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

-a)— reacting 7-hydroxy- tetralOne of "formula^"!!!

with cyanoacetic acid of formula X:

HO

CN X or a salt thereof, to produce (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof;

b) subjecting the compound of formula III to aromatization by reacting with a suitable reagent to produce (7-h droxy-l-naphthyl)acetonitrile, of formula VII:

or a salt thereof; and

c) reducing the compound of formula VII with a suitable reducing agent to produce 2-(7- hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof; d) acetylating the compound of formula V with a suitable acetylating agent to produce N- [2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof; and

Unless otherwise specified, the reactions in the above process steps-(a), (d) and (e) are carried out by the methods as described hereinabove.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitriIe of formula III is isolated in the form of a solid.

In one embodiment, the (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III is isolated and/or re-crystallized from a suitable solvent by the methods described hereinabove.

Exemplary reagents suitable for facilitating the aromatization reaction in step-(b) include, but are not limited to, sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, hydrogenation catalysts such as 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, 2,3- dicyano-4-chlorobenzoquinone, 2,3-dicyanobenzpquinone; and other quinone derivatives such as 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil, o-floranil, and the like.

Therefore, the aromatization reaction in step-(b) is advantageously carried out by using cheaper aromatization reagent sulfur in the absence of a solvent.

The aromatization reaction in step-(b) is carried out in the presence or absence of a solvent.

In one embodiment, the aromatization in step-(b) is carried out as a neat reaction in _the_absence_of.a-sol-vent In another embodiment, the aromatization in step-(b) is optionally carried out in the presence of a third solvent selected from the group as described hereinbefore.

Exemplary third solvents suitable for facilitating the aromatization in step-(b) include, but are not limited to, water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

In one embodiment, the aromatization in step-(b) is carried out as a neat reaction, in the absence of solvents, by heating the contents at a temperature of about 160°C to about 200°C, and specifically at a temperature of about 180°C to about 190°C. The reaction time may vary between about 30 minutes to about 5 hours, and most specifically about 1 hour to about 2 hours.

In another embodiment, the aromatization in step-(b) is carried out in the presence of the third solvent 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. The reaction time may vary between about 3 hours to about 30 hours, and most specifically about 5 hours to about 25 hours.

The reaction mass containing the (7-hydroxy-l-naphthyl)acetonitrile, of formula VII or a salt thereof obtained in step-(b) may subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the 2- (7-hydroxy-l-naphthyl)ethanamine of formula V or the compound of formula VII may be isolated and/or recrystallized and then used in the next step.

In another embodiment, the (7-hydroxy-l-naphthyl)acetonitrile, of formula VII obtained in step-(b) is isolated in the form of a solid. In another embodiment, the (7-hydroxy-l-naphthyl)acetonitrile, of formula VII 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 (7 -hydroxy- 1- naphthyl)acetonitrile, of formula VII is selected from the group as described 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.

In one embodiment, the reduction in step-(c) is carried out in the presence of a second solvent selected from the group as described above.

Specifically, the second solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; more specifically, the second solvent is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof; and a most specific second solvent is methanol or ethanol.

Exemplary reducing agents used in step-(c) include, but are not limited to, hydrogenation catalysts (metal catalysts) such as platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, and the like; hydride agents such as lithium aluminum hydride, sodium borohydride/Lewis acid, lithium · borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), and the like; and other reducing agents such as borane, borane-THF complex, and the like.

It has been surprisingly found that the reduction in step-(c) is advantageously and efficiently carried out by employing the less expensive hydride agents such as sodium borohydride whenjhej-eactiojLis _^performed- in-the-presenee-of-a-bewis^'acid: he^"u^"se^~"of hydride agents in the presence of Lewis acid in the reduction process leads to the resulting product with high purity and in good yield.

Exemplary Lewis acids used in step-(c) include, but are not limited to, aluminium chloride, calcium chloride, boron triflouride and zinc chloride, nickel chloride, and the like. Specific Lewis acids are aluminium chloride and nickel chloride.

The reduction in step-(c) may be carried out in the presence or absence of hydrogen gas. A most specific reducing agent used in step-(c) is Raney-Nickel.

The reduction in step-(c) is optionally carried out in the presence of ammonia as per the methods described hereinbefore.

In one embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V obtained in step-(c) is converted into its acid addition salts by treatment with a suitable acid selected from the group described hereinbefore. Most specific acids are hydrochloric acid and hydrobromic acid.

In one embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof is isolated in the form of a solid.

In one embodiment, the 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof is isolated and/or re-crystallized from a suitable solvent by the methods described hereinbefore.

The solvent used for isolating and/or recrystallizing the pure 2-(7-hydroxy-l- naphthyl)ethanamine of formula V is selected from the group as described above.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-l- naphthyl)ethanamine of formula V prepared by the process described herein is 2-(7- hydroxy-l-naphthyl)ethanamine hydrochloride salt.

In another embodiment, a most specific acid addition salt of 2-(7-hydroxy-l- naphthyl)ethanamine of formula V prepared by the process described herein is 2-(7- hydroxy- 1 -naphthyl)ethanamine hydrobromide salt.

Exemplary acetylating agents used in step-(d) include, but are not limited to, acetyl halide such as acetyl chloride, acetyl bromide, acetyl iodide; acetic anhydride, sodium acetate, and the like, or a combination thereof. A most specific acetylating agent is acetic anhydride. In another embodiment, the reaction in step-(d) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.

In one embodiment, the acetylation in step-(d) is carried out in the presence of a fourth solvent selected from the group as described hereinbefore.

Specifically, the fourth solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, ^■< 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fourth solvents are methanol, ethanol, isopropanol, and mixtures thereof.

In one embodiment, 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 20 minutes to about 3 hours, and specifically about 30 minutes to aJ?mrt 2_ho_urs.- The reaction mass containing the N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI obtained in step-(d) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the agomelatine of formula I, or the compound of formula VI may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.

Specifically, the fifth solvent used in step-(e) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyI tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fifth solvents are water, acetone, and mixtures thereof.

According to another aspect, there is provided a process for the preparation of (7- hydroxy-l-naphthyl)acetonitrile of formula VII:

or a salt thereof, comprising subjecting (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

to aromatization by reacting with a suitable reagent to produce the compound of formula VII or a salt thereof. The process for the preparation of (7-hydroxy-l-naphthyl)acetonitrile of formula VII disclosed herein is carried out by the methods and parameters as described hereinabove.

or an acid addition salt thereof, comprising reducing (7-hydroxy-l -naphthyl)acetonitrile of formula VII:

with a suitable reducing agent to produce the compound of formula V or an acid addition salt thereof.

The process for the preparation of 2-(7-hydroxy- l-naphthyl)ethanamine of formula

V disclosed herein is carried out by the methods and parameters as described hereinabove.

According to another aspect, there is provided a novel process for the preparation of Agomelatine, N-[2-(7-methoxy-l-naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising: a) reacting 7-hydrOTy^l ejr^one_of onnulaJI÷-

with cyanoacetic acid of formula X:

or a salt thereof;

b) subjecting the compound of formula III to aromatization by reacting with a suitable reagent to produce (7-hydroxy-l-naphthyl)acetonitrile, of formula VII:

or a salt thereof;

c) reacting the compound of formula VII with a methylating agent to produce (7- methoxy-l-naphthyl)acetonitrile of formula IX:

or a salt thereof; d) reducing the compound of formula IX with a suitable reducing agent to produce 2-(7- methoxy-l-naphthyl)ethanamine of formula XI:

or an acid addition salt thereof; and

e) acetylating the compound of formula XI with a suitable acetylating agent to produce the agomelatine of formula I.

Unless otherwise specified, the reactions in the above process steps-(a), (b), (d) and (e) are carried out by the methods as described hereinabove.

Exemplary reagents suitable for facilitating the aromatization reaction in step-(b) include, but are not limited to, sulfur or its derivatives, ^' selenium metal, aqueous hydrobromic acid, hydrogenation catalysts such as 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, 2,3- dicyano-4-chlorobenzoquinone, 2,3-dicyanobenzoquinone; and other quinone derivatives such as 1 ,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil, o-floranil, and the like.

Specific aromatization reagents are sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil), 2,3-dichloro-5,6-dicyano_:benzoquinone (DDQ) and raney nickel; and most specifically sulfur, aqueous hydrobromic acid and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil).

In one embodiment, the aromatization in step-(b) is carried out as a neat reaction in the„absencej>f a solvent.- In another embodiment, the aromatization in step-(b) is optionally carried out in the presence of a third solvent selected from the group as described hereinbefore.

In another embodiment, the (7-hydroxy-l-naphthyl)acetonitrile, of formula VII obtained in step-(b) is isolated in the form of a solid. In ^"another embodiment, the (7-hydroxy-l-naphthyl)acetonitrile, of formula VII 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 (7-hydroxy-l- naphthyl)acetonitrile, of formula VII is selected from the group as described 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.

Exemplary methylating agents used in step-(c) include, but are not limited to, dimethyl sulfate, methyl iodide, and the like. A most specific methylating agent is dimethyl sulfate.

In another embodiment, the reaction in step-(c) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base, selected from the group as described hereinabove.

In one embodiment, the methylation in step-(c) is carried out in the presence of a fifth solvent selected from the group as described above.

Exemplary fifth solvents used in step-(c) include, but are not limited to, water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the fifth solvent used in step-(c) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitnle,„prQpionitrile,-N_TN-dimethylfom Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific fifth solvents are water, acetone, and mixtures thereof.

In one embodiment, the reaction 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 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 (7-methoxy-l-naphthyl)acetonitrile of formula IX obtained in step-(c) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the 2-(7-methoxy-l- naphthyl)ethanamine of formula XI, or the compound of formula IX may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.

The solvent used for isolating and/or recrystallizing the (7-methoxy-l- naphthyl)acetonitrile of formula IX is selected from the group as described hereinabove for such purpose.

In one embodiment, the reduction in step-(d) is carried out in the presence of a second solvent selected from the group as described above.

Specifically, the second solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; more specifically, the second solvent is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof; and a most specific second solvent is methanol or ethanol.

Exemplary reducing agents used in step-(d) include, but are not limited to, hydrogenation catalysts (metal catalysts) such as platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, and the like; hydride agents such as lithium aluminum hydride, sodium borohydride/Lewis acid, lithium b^rohy^ng^,_sodlum_^cyanoboroh-ydr-ide diisobutylalum^{^}i tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), and the like; and other reducing agents such as borane, borane-THF complex, and the like.

It has been surprisingly found that the reduction in step-(d) is advantageously and efficiently carried out by employing the less expensive hydride agents such as sodium borohydride when the reaction is performed in the presence of a Lewis acid. The use of hydride agents in the presence of Lewis acid in the reduction process leads to the resulting product with high purity and in good yield.

Exemplary Lewis acids used in step-(d) include, but are not limited to, aluminium chloride, calcium chloride, boron triflouride and zinc chloride, nickel chloride, and the like. Specific Lewis acids are aluminium chloride and nickel chloride.

The reduction in step-(d) may be carried out in the presence or absence of hydrogen gas. A most specific reducing agent used in step-(d) is Raney-Nickel.

The reduction in step-(d) is optionally carried out in the presence of ammonia as per the methods described hereinbefore.

In one embodiment, the 2-(7-methoxy-l-naphthyl)ethanamine of formula -XI obtained in step-(d) is converted into its acid addition salts by treatment with a suitable acid selected from the group described hereinbefore. Most specific acids are hydrochloric acid and hydrobromic acid.

In one embodiment, the 2-(7-methoxy-l-naphthyl)ethanamine of formula XI or an acid addition salt thereof is isolated in the form of a solid.

In one embodiment, the 2-(7-methoxy-l-naphthyl)ethanamine of formula XI or an acid addition salt thereof is isolated and/or re-crystallized from a suitable solvent by the methods described hereinbefore.

The solvent used for isolating and/or recrystallizing the pure 2-(7-methoxy-l- naphthyl)ethanamine of formula XI is selected from the group as described above.

In another embodiment, a most specific acid addition salt of 2-(7-methoxy-l- naphthyl)ethanamine of formula XI prepared by the process described herein is 2-(7- methoxy-l-naphthyl)ethanamine hydrochloride salt. In another embodiment, a most specific acid addition salt of 2-(7-methoxy-l- naphthyl)ethanamine of formula XI prepared by the process described herein is 2-(7- methoxy- 1 -naphthyl)ethanamine hydrobromide salt.

Exemplary acetylating agents used in step-(e) include, but are not limited to, acetyl halide such as acetyl chloride, acetyl bromide, acetyl iodide; acetic anhydride, sodium acetate, and the like, or a combination thereof. A most specific acetylating agent is acetic anhydride.

In another embodiment, the reaction in step-(e) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.

In one embodiment, the acetylation in step-(e) is carried out in the presence of a fourth solvent selected from the group as described hereinbefore.

Exemplary fourth solvents used in step-(e) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the fourth solvent used in step-(e) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichlorom£thane,-dichloroethane chlorofom7 afld^_ mixtures thereof. Most specific fourth solvents are methanol, ethanol, isopropanol, and mixtures thereof.

In one embodiment, the reaction in step-(e) 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 20 minutes to about 3 hours, and specifically about 30 minutes to about 2 hours.

The reaction mass containing the agomelatirie 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.

According to another aspect, there is provided a process for the preparation of (7- methoxy- 1 -naphthyl)acetonitrile of formula IX:

or a salt thereof, comprising reacting (7-hydroxy-l-naphthyl)acetonitrile of formula VII:

or a salt thereof, with a methylating agent to produce the compound of formula IX.

The process for the preparation of (7-methoxy-l-naphthyl)acetonitrile of formula IX disclosed herein is carried out by the methods and parameters as described hereinabove. 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.

The novel hydroxyl intermediates of formulae III, IV, V, VII, VIII, XII and XIII disclosed employed for the preparation of agomelatine disclosed herein allows the product to be easily isolated and purified, thereby producing a product with 72-80% overall yield.

The highly pure agomelatine, or a pharmaceutically acceptable salt thereof, 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.

In one embodiment, 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.

In another embodiment, the highly pure agomelatine or a salt thereof obtained by the process 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. For example, 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%. According to another aspect, there is provided a novel intermediate compound, (7- hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile, of formula III:

or a salt thereof.

According to another aspect, there is provided a novel intermediate compound, 2- (7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine, of formula IV:

or an acid addition salt thereof.

According to another aspect, there is provided 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine hydrochloride salt of formula IVa:

According to another aspect, there is provided 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine hydrobromide salt of formula IVb:

According to another aspect, there is provided a novel intermediate compound, 2- (7-hydroxy-l-naphthyl)ethanamine, of formula V:

According to another aspect, there is provided 2-(7-hydroxy-l- naphthyl)ethanamine hydrochloride salt of formula Va:

According to another aspect, there is provided a novel intermediate compound, (7- hydroxy- 1 -naphthyl)acetonitrile, of formula VII:

or a salt thereof.

According to another aspect, there is provided a novel intermediate compound, N- [2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide, of formula VIII:

or a salt thereof.

Based on the extensive research and experimentation carried out by the present inventors, it has been surprisingly and unexpectedly found that the Hydrobromic acid (HBr) can also be used as a reagent for aromatization of 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof, to produce 2-(7-hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof. It has been further surprisingly and unexpectedly found that the above reaction also yields significant amounts of the respective tetrahydro intermediate, 2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine, of formula XII:

or an acid addition salt thereof (found in mother liquors) along with the compound of formula V.

According to another aspect, there is provided a process for the preparation of 2-(7- hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof, comprising:

a) reacting 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof with aqueous hydrobromic acid to produce a reaction mass containing 2-(7-hydroxy-l-naphthyl)ethanamine of formula V and 2-(7-hydroxy- l,2,3,4-tetrahydro-l-naphthyl)ethanamine of formula XII:

(V) (XII) or an acid addition salt thereof;

b) isolating and/or recovering the pure 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof from the reaction mass obtained in step-(a);

c) treating the mother liquors with a suitable base to adjust the pH to produce cause precipitation;

d) optionally, extracting the 2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine of formula XII obtained in step-(c) into an organic solvent;

e) isolating and/or recovering the pure 2-(7-hydroxy- 1,2,3, 4-tetrahydro-l- naphthyl)ethanamine of formula XII or an acid addition salt thereof from the reaction mass obtained in step-(c) or from the organic layer obtained in step-(d); and

f) subjecting the compound of formula XII or an acid addition salt to aromatization by reacting with a suitable reagent to produce the compound of formula V.

In one embodiment, the reaction in step-(a) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 60°C to the reflux temperature of the solvent used_?_andjriQr.e_specifieaily-at^_theTOflu) ^{^} temperature of the solvent used. The reaction time may vary between about 2 hours to about 5 hours.

In another embodiment, the reaction in step-(a) is optionally carried out in the presence of water-miscible organic solvents.

The base used in step-(c) is an organic or inorganic base selected from the group as described above.

Specifically, the base is an inorganic base, and most specifically, the base is aqueous ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a combination thereof.

Specifically, the pH of the mother liquors in step-(c) is adjusted to above 8, and more specifically between 8 and 9.

Exemplary organic solvents used in step-(d) include, but are not limited to, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a halogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the organic solvent used in step-(d) is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific organic solvents are ethyl acetate, toluene, dichloromethane, and mixtures thereof.

The reagents suitable for facilitating the aromatization reaction in step-(f) is selected from the group as described hereinbefore. Specific aromatization reagents are sulfur or its derivatives, selenium metal, 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil), 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) and Pd/C; and most specifically sulfur, 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil) and 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ).

In one embodiment, the isolation in step-(b) and step-(e) is carried out by 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 recovery in step-(b) and step-(e) is accomplished by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

According to another aspect, there is provided a process for the preparation of N- [2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethyl]acetamide of formula XIII:

or a salt thereof, comprising acetylating 2-(7-hydroxy-l,2,3,4-tetrahydro-l- naphthyl)ethanamine, of formula XII:

or an acid addition salt thereof, with a suitable acetylating agent to produce the compound of formula XIII or a salt thereof.

Exemplary acetylating agents include, but are not limited to, acetyl halide such as acetyl chloride, acetyl bromide, acetyl iodide; acetic anhydride, sodium acetate, and the like, or a combination thereof. A most specific acetylating agent is acetic anhydride.

In another embodiment, the acetylation is optionally carried out in the presence of a base selected from the group as described hereinbefore.

In one embodiment, the acetylation is carried out in the presence of a fourth solvent selected from the group as described hereinbefore.

In one embodiment, the acetylation 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 mass containing the N-[2-(7-hydroxy-l,2,3,4-tetrahydro-l- naphthyl)ethyl]acetamide of formula XIII 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.

According to another aspect, there is provided a novel intermediate compound, 2- (7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine, of formula XII:

or an acid addition salt thereof.

According to another aspect, there is provided a novel intermediate compound, 2- (7-hydroxy- 1 ,2,3,4-tetrahydro- 1 -naphthyl)ethanamine hydrochloride salt, of formula Xlla:

According to another aspect, there is provided a novel intermediate compound, N- [2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethyl]acetamide, of formula XIII:

or a salt thereof.

According to another aspect, the present invention also encompasses the use of the novel compounds of formulae III, IV, IVa, IVb, V, Va, VII, VIII, XII, Xlla and XIII disclosed herein for preparing Agomelatine. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of (7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile

7-Hydroxy-l-tetralone (100 gm), cyanoacetic acid (75 gm), 4-hydroxybenzoic acid (25.5 gm) and benzylamine (20 gm) were added to toluene (2 L) at room temperature (25-30°C). The mixture was heated to reflux temperature (108-1 10°C) for about 6 hours. The reaction mass was cooled to room temperature and then filtered. The resulting precipitate was washed with toluene (100 ml), followed by washing the filtrate with 10% sodium carbonate solution (2 x 100 ml) and subsequently with distilled water (100 ml). The resulting filtrate was subjected to evaporation to remove the solvent to produce 1 13 gm of (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile as a solid (Melting Range: 120 - 120°C; Yield: 99%; Purity by HPLC: 99%).

Infra-red (FT-IR) Data (KBr pellet): 3346 cm^"1 (-OH); 2262 cm^'1 (-CN); 1613 cm^-1 (-C=C, Ar); 2827-2918 cm^"1 (-CH₂).

Ή-NMR (DMSO-d6) δ: 2.193-2.260 (m, 2H), 2.574-2.627 (t, 2H), 3.732-3.735 (s, 2H), 6.147-6.177 (m, 1H), 6.595-6.995 (m, 3H), 9.279 (s, OH); Mass (m/z): 184 (M-l).

Example 2

Preparation of 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine

(7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile (100 gm) was added to a mixture of Raney nickel (50 gm), methanol (1000 ml) and ammonia solution (500 ml) at room temperature (25-30°C) in an autoclave. The reaction mixture was stirred under 5 kg m² hydrogen pressure at 40-45 °C for 5-6 hours. After completion of the reaction, the autoclave was cooled to 25-30°C. The reaction mass was filtered and washed with methanol. The solvent was distilled completely from the resulting filtrate, followed by co- distillation twice with methanol (200 ml). Ethyl acetate (500 ml) was added to the resulting residue at 25-30°C, followed by cooling the resulting solution to 0-5°C for 1 hour. The obtained solid was filtered and then dried to produce 97 gm_2-(7_^hydroxy-^"374^ihydro-l- naphthalenyl)ethanamine (Yield: 95.1%; and Melting Range: 140-145°C; Purity by HPLC: 99.1%).

Infra-red (FT-IR) Data (KBr pellet): 3340, 3287 cm^"1 (-NH2); 1602 cm^-1 (-C=C, Ar); 2826- 2928 cm^-1 (-CH₂).

Example 3

Preparation of 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride

Ethyl acetate (200 ml) was added to 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine (50 gm), followed by adjusting the pH of the resulting mixture to below 2 with IPA-HC1 solution at 10-15°C and hexane (200 ml) was added. The reaction mass was stirred for 30 minutes at 0-10°C. The resulting solid was filtered and washed with n-hexane (50 ml) and then dried to yield 58 gm of 2-(7-hydroxy-3,4-dihydro- l-naphthalenyl)ethanamine hydrochloride (Yield: 97.3%; Melting Range: 195-200°C; Purity by HPLC: 99.5%).

Infra-red (FT-IR) Data (KBr pellet): 3380 on ¹ (-OH); 3027 cm^"1 (-NH₃ ⁺); 2824-2892 cm^"1 (-CH₂).

Ή-NMR (DMSO-d6) δ: 2.129-2.195 (m, 2H), 2.551-2.604 (m, 2H), 2.636-2.686 (m, 2H), 2.887-2.938 (m, 2H), 5-910-5.939 (t, 1H), 6.576-6.964 (m, 3H), 7.971 (s, -NH₃), 9.242 (s, OH); Mass (m/z): 190 (M+l). Example 4

Preparation of 2-(7-Hydroxy-l-naphthyl)ethanamine hydrochloride

Sulfur (8.5 gm) was added to 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride (50 gm), followed by heating the mixture to 185-190°C for 1-2 hours. The resulting mass was cooled to 50-55°C and then methanol (500 ml) was added. The reaction mixture was refluxed for 30 minutes, followed by treating with activated carbon (5 gm). The methanolic layer was distilled under vacuum to produce 48 gm of 2-(7-Hydroxy-l- naphthyl)ethanamine hydrochloride (Yield: 97%; Melting Range: 200-205°C; Purity by HPLC: 99.4%).

Infra-red (FT-IR) Data (KBr pellet): 3240-3460 cm^-1 (-OH); 2480-2720 cm^-1 (-NH₃ ⁺); 2950-3060 cm^'1 (-CH). Example 5

Preparation of N-[2-(7-Hydroxy-l-naphthyI)ethyl]acetamide

2-(7-Hydroxy-l-naphthyl)ethanamine hydrochloride (50 gm), sodium acetate (36.5 gm) and acetic anhydride (34 gm) were added to methanol (250 ml). The reaction mixture was heated to reflux temperature (65-68°C) for 15-20 minutes, followed by the addition of 10% sodium hydroxide solution (200 ml) under reflux. The reaction mixture was cooled to room temperature (25-30°C), followed by the addition of distilled water (250 ml). The resulting mixture was cooled to 0-10°C, followed by adjusting the pH to below 2 with concentrated hydrochloric acid. The resulting solid was filtered and then dried to produce 50 gm of the title compound, which was re-crystallized form water (500 ml) to yield 46 gm of the pure N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide (Yield: 90%; Melting Range: 123-125°C; Purity by HPLC: 99.6%).

Infra-red (FT-IR) Data (KBr pellet): 3347 cm^-1 (-OH); 1641 cm^"1 (-CO); 1626 crn ¹ (- C=C).

Example 6

Preparation of N-[2-(7-methoxy-l-naphthaIenyl)ethyI]acetamide (Agomelatine)

N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide (35 gm), potassium carbonate (30 gm) and dimethyl sulfate (20 gm) were added to acetone (175 ml) at room temperature (25-30°C). The reaction mixture was refluxed for 5 hours. After completion of the reaction, the reaction mass was cooled to room temperature and then added into water (200 ml). The resulting solid was filtered and then dried to produce 35 gm of agomelatine (Yield: 94.5%; Purity by HPLC: 99.93%). Example 7

Preparation of N-[2-(7-hydroxy-3,4-dihydro-l-naphthyl)ethyl]acetamide

The 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride (30 gm) was dissolved in methanol (150 ml), followed by the addition of sodium acetate (22 gm) and acetic anhydride (21 gm), and then heating the resulting mixture for 30 minutes at reflux temperature (65-68°C). 15% Sodium hydroxide solution (90 ml) was added to the reaction mass under reflux temperature, followed by maintainingJhe-resuliiag-mtxture^fbT^{^} rio aT reflux temperature. The reaction mass was cooled to room temperature, followed by the addition of distilled water (150 ml) and then cooling the mass to 0-10°C. The pH of the reaction mass was adjusted to below 2 with hydrochloric acid, followed by extracting the mass three times with dichloromethane (3 x 50 ml). The dichloromethane layer was washed with distilled water (50 ml) and the resulting dichloromethane layer was distilled to produce 30 gm of N-[2-(7-hydroxy-3,4-dihydro-l-naphthyl)ethyl]acetamide (Yield: 97.7%; Melting Range: 115-120°C; Purity by HPLC: 99.3%).

Infra-red (FT-IR) Data (KBr pellet): 3331 cnf¹ (-OH); 2824-2897 cm^"1 (-CH₂); 1642 cm (-CO-); 1606 cm^"1 (-C=C-).

Ή-NMR (DMSO-d6) δ: 1.795 (s, 3H), 2.101-2.164 (m, 2H), 2.430-2.454 (m, 2H), 2.546- 2.573 (m, 2H), 3.124-3.192 (m, 2H), 5.835-5.868 (t, 1H), 6.521-6.941 (m, 3H), 7.877- 7.926 (t, -NH), 9.124 (s, OH); Mass (m/z): 232 (M+ 1).

Example 8

Preparation of N-[2-(7-Hydroxy-l-naphthyl)ethyI]acetamide

N-[2-(7-Hydroxy-3,4-dihydro-l-naphthyl)ethyl]acetamide (5 gm) and sulfur (15 gm) were heated to 185-190°C for about 1-2 hours. The reaction mass .was cooled to 55-60°C, followed by the addition of methanol (500 ml) and then refluxing for 1 hour. The resulting hot methanolic layer was treated with activated carbon (5 gm), followed by distillation under vacuum to produce 50 gm of the crude N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide, which was then recrystallized from water (500 ml) to yield 45 gm of the pure compound (Yield: 90.9%; Melting Range: 123-125°C; Purity by HPLC: 99.6%).

Example 9

Preparation of (7-Hydroxy-l-naphthyI)acetonitrile

(7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile (10 gm) was dissolved in toluene (100 ml), followed by the addition of Pd/C (2.5 gm) and then heating the resulting mixture at reflux temperature for 30 hours. After completion of reaction, the mixture was filtered and the filtrate was distilled under vacuum to produce 9.5 gm of (7-hydroxy-l- naphthyl)acetonitrile (Yield: 96.9%; Melting Range: 110-115°C; Purity by HPLC: 99.2%). Infra-red (FT-IR) Data (KBr pellet): 3394 cm^"1 (-0H); 2267 cm^"1 (-CN); 1613 cm^"1 (-C=C, Ar).

Example 10

Preparation of (7-Hydroxy-l-naphthyl)acetonitrile

(7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile (5 gm) and sulfur (1.5 gm) were heated to 185-190°C for 1 hour. The reaction mixture was cooled to 55-60°C, followed by the addition of methanol (50 ml) and then heating the resulting mass at reflux for 30 minutes. Activated carbon (1.0 gm) was added to the reaction mass and then filtered through celite bed. The resulting filtrate was distilled under vacuum to produce 4.5 gm of (7-hydroxy-l-naphthyl)acetonitrile (Yield: 91.8%; Melting Range: 1 10-145°C; Purity by HPLC: 99.1%).

Example 11

Preparation of (7-hydroxy-l-naphthyl)acetonitriIe

(7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile (10 gm) was dissolved in toluene (100 ml), followed by the addition of chloranil (18.5 gm) and then heating the mixture at reflux temperature for about 20-24 hours. After completion of the reaction, the mixture was filtered and the filtrate was washed with saturated aqueous sodium carbonate solution (2 x 50 ml), and subsequently with water (50 ml). The resulting organic layer was distilled under vacuum to produce 9.5 gm of (7-hydroxy-l-naphthyl)acetonitrile (Yield: 96.9%; Melting Range: 1 10-115°C; Purity by HPLC: 98.7%).

Example 12

Preparation of (7-Hydroxy-l-naphthyl)ethanamine

(7-Hydroxy-l-naphthyl)acetonitrile (5 gm) was dissolved in methanol (500 ml), followed by the addition of aqueous ammonia solution (25 ml), Raney Nickel (5 gm). The reaction mixture was hydrogenated with hydrogen gas under 5 kg/m² pressure at 40°C until completion of the reaction. The reaction mass was cooled to room temperature, followed by filtration and then concentrating the mass to remove methanol to produce 5 gm of (7- hydroxy- l-naphthyl)ethanamine (Yield: 98%; Purity by HPLC: 99.3%). Example 13

Preparation of (7-Hydroxy-l-naphthyl)ethanamine hydrochloride salt

Step-1: Preparation of (7-Hydroxy-l-naphthyl)ethanamine hydrobromide

A mixture of 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride (50 gm) and 48% aqueous hydrobromic acid (100 ml) was heated at 95-100°C for 5 hours. After completion of the reaction, the reaction mass was cooled to 0-10°C, followed by maintaining the reaction mass at the same temperature for 1 hour. The resulting solid was filtered and washed with cold water (50 ml) and then dried to produce 25 gm of (7- hydroxy-l-naphthyl)ethanamine hydrobromide (Yield: 42%; Purity by HPLC: 99.5%). Step-2: Isolation of (7-Hydroxy-l,2,3i4-tetrahydro-l-naphthyl)ethanamine from Mother Liquors

The filtrate (mother liquors) obtained in step-1 was neutralized with 20% sodium hydroxide solution, followed by adjusting the pH to 8.9 with aqueous ammonia solution. The resulting aqueous layer was extracted into dichloromethane (3 x 150 ml) and the dichloromethane layer was washed with water (100 ml). The solvent was distilled off from the resulting organic layer to produce crude solid (20 gm). The resulting solid was taken in ethyl acetate (100 ml), followed by adjusting the pH to below 2.0 with isopropanolic-HCl solution at room temperature. The obtained clear solution was distilled under vacuum to produce 20 gm of the titled compound as hydrochloride salt (Purity by HPLC: 99.4%). Step-3: Preparation of (7-Hydroxy-l-naphthyl)ethanamine hydrochloride salt

Sulfur (6 gm) was added to (7-Hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine (20 g, obtained in step-2), followed by heating the mixture at 190-195°C for 10 hours. The resulting mass was cooled to 25-30°C and then methanol (100 ml) was added. The resulting mixture was heated at reflux temperature (65-70°C) for about 30 minutes. Charcoal (2 gm) was added to the reaction mass, followed by filtration through celite pad. The obtained filtrate was distilled under vacuum to produce 19 gm of (7-Hydroxy-l- naphthyl)ethanamine hydrochloride salt (Yield: 96.9%; Purity by HPLC: 99.5%).

Example 14

Preparation of (7-Methoxy-l-naphthyl)acetonitrile

(7-Hydroxy-l-naphthyl)acetonitrile (5 gm) was dissolved in acetone (50 ml), followed by the addition of potassium

resulting mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and then added into water (100 ml). The resulting mixture stirred for 30 minutes at 0-10°C and the separated solid was filtered and washed with water (50 ml) to produce 5 gm of (7- ethoxy-l-naphthyl)acetonitrile (Yield: 92.9%; Purity by HPLC: 99%).

Example 15

Preparation of N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide

N-[2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide (10 gm) was dissolved in toluene (100 ml), followed by the addition of Pd/C (2.5 gm). The resulting mixture was heated to reflux temperature and then maintained for 20-25 hours. After completion of reaction, the reaction mass was filtered and the filtrate was distilled under vacuum to produce 9 gm ofpure N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide (Yield: 90.9%; Melting Point: 123-125°C; Purity by HPLC: 98.9%). Example 16

Preparation of N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide

N-[2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide (10 gm) was dissolved in toluene (100 ml), followed by the addition of chloranil (12 gm).. The resulting mixture was heated to reflux temperature and then maintained for 20 hours. After completion of the reaction, the reaction mass was filtered and the filtrate was washed with saturated sodium carbonate solution (2 x 50 ml), and subsequently with water (50 ml). The resulting organic layer was distilled under vacuum to produce 8 gm of N-[2-(7 -hydroxy- 1- naphthyl)ethyl]acetamide (Yield: 80.8%; Purity by HPLC: 99.2%). Example 17

Preparation of N-[2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyI)ethyl]acetamide

2-(7-Hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine hydrochloride (10 gm), sodium acetate (8 gm) and acetic anhydride (6 gm) were added to methanol (100 ml). The reaction mixture was heated to reflux temperature (65-68°C) for 30 minutes. The reaction mixture was cooled to room temperature (25-30°C) and then added into water (150 ml). The resulting mixture was extracted into dichloromethane (3_x-5.0-ml)^d-the esulting^fganic Layer was washed with water (50 ml), the solvent was evaporated under vacuum to produce 12 gm of the pure N-[2-(7-hydroxy- 1 ,2,3, 4-tetrahydro-l -naphthyl)ethyl]acetamide (Yield: 98.4%; Purity by HPLC: 99.6%).

Example 18

Preparation of N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide

N-[2-(7-hydroxy-l ,2,3,4-tetrahydro-l -naphthyl)ethyl]acetamide (10 gm) was dissolved in toluene (100 ml), followed by the addition of Pd/C (2.5 gm). The resulting mixture was heated to reflux temperature and then maintained for 20 hours. After completion of the reaction, the reaction mass was filtered and the filtrate was distilled under vacuum to produce 9.1 gm of pure N-[2-(7-Hydroxy-l -naphthyl)ethyl]acetamide.

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. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

We claim:

1. A process for the preparation of Agomelatine, N-[2-(7-methoxy-l- naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy-l-tetralone of formula II:

with cyanoacetic acid of formula X:

or a salt thereof;

25 b) reducing the compound of formula III with a suitable reducing agent to produce 2- (7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV:

_30.

or an acid addition salt thereof;

c) subjecting the compound of formula IV or an acid addition salt thereof to aromatization by reacting with a suitable reagent to produce 2-(7-hydroxy-l- naphthyl)ethanamine of formula V:

or an acid addition salt thereof;

d) acetylating the compound of formula V with a suitable acetylating agent to produce N-[2-(7-Hydroxy- 1 -naphthyl)ethyl]acetamide of formula VI:

or a salt thereof; and

2. The process of claim 1, wherein the reaction in step-(a) is carried out in the presence of a carboxylic acid and an organic amine; wherein the reaction in step-(a) is carried out in the presence of a first solvent; and wherein the reaction in step-(a) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used.

3. The process of claim 2, wherein the carboxylic acid used in step-(a) is a linear or branched alkyl carboxylic acid, an unsubstituted or substituted aryl carboxylic acid, or an unsubstituted or substituted linear or branched aralkyl carboxylic acid; wherein the organic amine used in step-(a) is a linear or branched alkyl amine, an unsubstituted or substituted aryl amine, or an unsubstituted or substituted linear or branched aralkyl amine; wherein the first solvent used in step-(a) is selected from the group consisting of a hydrocarbon solvent, a^iajogenated-hydrocarbon-solventr-an-etherrand mixtwes^' thereof; and wherein the reaction in step-(a) is carried out at a temperature of about 60°C to the reflux temperature of the solvent used.

The process of claim 3, wherein the carboxylic acid used in step-(a) is 4- hydroxybenzoic acid and wherein the organic amine used in step-(a) is benzyl amine or morpholine; wherein the first solvent used in step-(a) is selected from the group consisting of toluene, xylene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene, mesitylene, and mixtures thereof; and wherein the reaction in step-(a) is carried out at the reflux temperature of the solvent used.

The process of claim 1, wherein the reduction in step-(b) is carried out in the presence of a second solvent; wherein the reducing agent used in step-(b) is selected from the group consisting of hydrogenation catalysts (metal catalysts), hydride agents, borane and borane-THF complex; and wherein the reduction in step-(b) is optionally carried out in the presence of ammonia.

The process of claim 5, wherein the second solvent used in step-(b) is selected from the group consisting of water, an alcohol, an ester, a hydrocarbon solvent, an ether, and mixtures thereof; wherein the reducing agent used in step-(b) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2- methoxyethoxy)aluminium hydride (Vitride), borane and borane-THF complex; and wherein the ammonia is used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent.

The process of claim 6, wherein the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n- pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; and wherein the reducing agent used in step-(b) is Raney-Nickel.

8. The process of claim 1, wherein the acid addition salts of 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV prepared by the process are 2-(7-hydroxy-3,4- dihydro-l-naphthalenyl)ethanamine hydrochloride salt and 2-(7-hydroxy-3,4-dihydro- l-naphthalenyl)ethanamine hydrobromide salt.

9. The process of claim 1, wherein the reagent suitable for facilitating the aromatization reaction in step-(c) is selected from the group consisting of sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts and quinone derivatives; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV in step-(c) is employed in the form of an acid addition salt; and wherein the aromatization in step-(c) is optionally carried out in the presence of a third solvent.

10. The process of claim 9, wherein the reagent suitable for facilitating the aromatization reaction in step-(c) is selected from the group consisting of sulfur, selenium metal, aqueous hydrobromic acid, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, 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, 2,3-dicyano-4-chlorobenzoquinone, 2,3- dicyanobenzoquinone, 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil and o-floranil; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV in step-(c) is employed in the form of its hydrochloride salt; and wherein the third solvent used in step-(c) is selected from the group consisting of water, a halogenated hydrocarbon, ah ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

11. The process of claim 10, wherein the reagent suitable for facilitating the aromatization reaction in step-(c) is selected from the group consisting of sulfur, aqueous hydrobromic acid and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil); and wherein the third solvent used in step-(c) is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

12. The process of claim 1, wherein the aromatization in step-(c) is carried out as a neat reaction, in the absence of solvent; and wherein the acid addition salts of 2-(7-hydroxy- l-naphthyl)ethanamine of formula V prepared are 2-(7-hydroxy-l- naphthyl)ethanamine hydrochloride salt and 2-(7-hydroxy-l-naphthyl)ethanamine hydrobromide salt.

13. The process of claim 1, wherein the acetylating agent used in step-(d) is selected from the group consisting of acetyl chloride, acetyl bromide, acetyl iodide, acetic anhydride, sodium acetate, or a combination thereof; wherein the reaction in step-(d) is optionally carried out in the presence of a base; and wherein the acetylation in step-(d),is carried out in the presence of a fourth solvent selected from the group consisting of .water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar$aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

14. The process of claim 13, wherein the acetylating agent used in step-(d) is acetic anhydride or a combination with sodium acetate; wherein the base used in step-(d) is selected from the group consisting of aqueous ammonia, sodium hydroxide^ealcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide,-isodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate;llithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butox e; and wherein the fourth solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

15. The process of claim 1, wherein the methylating agent used in step-(e) is dimethyl sulfate or methyl iodide; wherein the reaction in step-(e) is optionally carried out in the presence of a base; and_wherein^the-methy-lation4n-step-(e)-is-carried -out in the presence of a fifth solvent selected from the group consisting of water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

16. The process of claim 15, wherein the methylating agent used in step-(e) is dimethyl sulfate; wherein the base used in step-(e) is selected from the group consisting of 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 wherein the fifth solvent used in step-(e) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

17. A process for the preparation of (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof, comprising reacting 7-hydroxy-l-tetralone of formula II:

with cyanoacetic acid of formula X:

or a salt thereof, to produce the compound of formula III.

18. The process of claim 17, wherein the reaction is carried out in the presence of a carboxylic acid and an organic amine; wherein the reaction is carried out in the presence of a first solvent selected from the group consisting of a hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, and mixtures thereof; and wherein the reaction is carried out at a temperature of about 25°C to the reflux temperature of the solvent used.

19. A process for the preparation of 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV:

20. The process of claim 19, wherein the reduction is carried out in the presence of a second solvent; wherein the reducing agent is selected from the group consisting of hydrbgenation catalysts (metal catalysts), hydride agents, borane and borane-THF complex; and wherein the reduction is optionally carried out in the presence of ammonia.

21. The process of claim 20, wherein the second solvent is selected from the group consisting of water, an alcohol, an ester, a hydrocarbon solvent, an ether, and mixtures

-thereof; wherein-the-redueing-is-seleeted~-fr^ palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), borane and borane-THF complex; and wherein the ammonia is used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent.

22. A process for the preparation of 2-(7-hydroxy-l-naphthyl)ethanamine of formula V:

23. The process of claim 22, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts and quinone derivatives; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV is employed in the form of an acid addition salt; and wherein the aromatization is optionally carried out in the presence of a third solvent.

24. The process of claim 23, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur, selenium metal, aqueous hydrobromic acid, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-

dibromo-5,6-dicyano benzoquinone, 2,3-dicyano-4-chlorobenzoquinone, 2,3- dicyanobenzoquinone, 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil and o-floranil; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV is employed in the form of its hydrochloride salt; and wherein the third solvent is selected from the group consisting of water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

25. The process of claim 24, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur, aqueous hydrobromic acid and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil); and wherein the third solvent is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

26. The process of claim 22, wherein the aromatization is carried out as a neat reaction, in the absence of solvent; and wherein the acid addition salts of 2-(7-hydroxy-l- naphthyl)ethanamine of formula V prepared are 2-(7-hydroxy-l-naphthyl)ethanamine hydrochloride salt and 2-(7-hydroxy-l-naphthyl)ethanamine hydrobromide salt.

27. A process for the preparation of N-[2-(7 -hydroxy- l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof, comprising acetylating 2-(7-hydroxy-l-naphthyl)ethanamine formula V:

28. The process of claim 27, wherein the acetylating is selected from the group consisting of acetyl chloride, acetyl bromide, acetyl iodide, acetic anhydride, sodium acetate, or a combination thereof; wherein the reaction is optionally carried out in the presence of a base; and wherein the acetylation is carried out in the presence of a fourth solvent selected from the group consisting of water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

29. The process of claim 28, wherein the acetylating agent is acetic anhydride or a combination with sodium acetate; wherein the base is selected from the group consisting of 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 wherein the fourth solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

30. A process for the preparation of Agomelatine, N-[2-(7-methoxy-l-naphthalenyl) ethyl] acetamide, of formula I:

31. The process of claim 30, wherein the methylating agent is dimethyl sulfate or methyl iodide; wherein the reaction is optionally carried out in the presence of a base; and wherein the methylation is carried out in the presence of a fifth solvent selected from the group consisting of water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

32. The process of claim 31, wherein the methylating agent is dimethyl sulfate; wherein the base is selected from the group consisting of 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 wherein the fifth solvent is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

33. A process for the preparation of agomelatine, N-[2-(7-methoxy-l-naphthalenyl) ethyl] acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy-l-tetralone of formula II:

with cyanoacetic acid of formula X:

or a salt thereof;

b) reducing the compound of formula III with a suitable reducing agent to produce 2- (7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof;

c) acetylating the compound of formula IV with a suitable acetylating agent to produce N-[2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethyl]acetamide, of formula VIII:

or a salt thereof;

d) subjecting the compound of formula VIII to aromatization by reacting with a suitable reagent to produce N-[2-(7-Hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

or a salt thereof; and

e) reacting the compound of formula VI with a methylating agent to produce the

agomelatine of formula I.

34. The process of claim 33, wherein the reaction in step-(a) is carried out in the presence of a carboxylic acid and an organic amine; wherein the reaction in step-(a) is carried out in the presence of a first solvent; and wherein the reaction in step-(a) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used.

35. The process of claim 34, wherein the carboxylic acid used in step-(a) is a linear or branched alkyl carboxylic acid, an unsubstituted or substituted aryl carboxylic acid, or an unsubstituted or substituted linear or branched aralkyl carboxylic acid; wherein the organic amine used in step-(a) is a linear or branched alkyl amine, an unsubstituted or substituted aryl amine, or an unsubstituted or substituted linear or branched aralkyl amine; wherein the first solvent used in step-(a) is selected from the group consisting of a hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, and mixtures thereof; and wherein the reaction in step-(a) is carried out at a temperature of about 60°C to the reflux temperature of the solvent used.

36. The process of claim 35, wherein the carboxylic acid used in step-(a) is 4- hydroxybenzoic acid and wherein the organic amine used in step-(a) is benzyl amine or morpholine; wherein the first solvent used in step-(a) is selected from the group consisting of toluene, xylene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene, mesitylene, and mixtures thereof; and wherein the reaction in step-(a) is carried out at the reflux temperature of the solvent used.

37. The process of claim 33, wherein the reduction in step-(b) is carried out in the presence of a second solvent; wherein the reducing agent used in step-(b) is selected from the group consisting of hydrogenation catalysts (metal catalysts), hydride agents, borane and borane-THF complex; and wherein the reduction in step-(b) is optionally carried out in the presence of ammonia.

38. The process of claim 37, wherein the second solvent used in step-(b) is selected from the group consisting of water, an alcohol, an ester, a hydrocarbon solvent, an ether, and mixtures thereof; wherein the reducing agent used in step-(b) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2- methoxyethoxy)aluminium hydride (Vitride), borane and borane-THF complex; and wherein the ammonia is used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent.

39. The process of claim 38, wherein the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2- methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, and mixtures thereof; and wherein the reducing agent used in step-(b) is Raney-Nickel.

40. The process of claim 33, wherein the acetylating agent used in step-(c) is selected from the group consisting of acetyl chloride, acetyl bromide, acetyl iodide, acetic anhydride, sodium acetate, or a combination thereof; wherein the reaction in step-(c) is optionally carried out in the presence of a base; and wherein the acetylation in step-(c) is carried out in the presence of a fourth solvent selected from the group consisting of water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

41. The process of claim 40, wherein the acetylating agent used in step-(c) is acetic anhydride or a combination with sodium acetate; wherein the base used in step-(c) is selected from the group consisting of 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 wherein the fourth solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

42. The process of claim 33, wherein the reagent suitable for facilitating the aromatization reaction in step-(d) is selected from the group consisting of. sulfur or its derivatives,

wherein the starting material 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV in step-(d) is employed in the form of an acid addition salt; and wherein the aromatization in step-(d) is optionally carried out in the presence of a third solvent.

43. The process of claim 42, wherein the reagent suitable for facilitating the aromatization reaction in step-(d) is selected from the group consisting of sulfur, selenium metal, aqueous hydrobromic acid, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, 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, 2,3-dicyano-4-chlorobenzoquinone, 2,3- dicyanobenzoquinone, 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil and o-floranil; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV in step-(d) is employed in the form of its hydrochloride salt; and wherein the third solvent used in step-(d) is selected from the group consisting of water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

44. The process of claim 43, wherein the reagent suitable for facilitating the aromatization reaction in step-(d) is selected from the group consisting of sulfur, aqueous hydrobromic acid and 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (p-Chloranil); and wherein the third solvent used in step-(d) is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

45. The process of claim 33, wherein the aromatization in step-(d) is carried out as a neat reaction, in the absence of solvent.

46. The process of claim 33, wherein the methylating agent used in step-(e) is dimethyl sulfate or methyl iodide; wherein the reaction- in step-(e) is optionally carried out in the presence of a base; and wherein the methylation in step-(e) is carried out in the presence of a fifth solvent selected from the group consisting of water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

47. The process of claim 46, wherein the methylating agent used in step-(e) is dimethyl sulfate; wherein the base used in step-(e) is selected from the group consisting of 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 wherein the fifth solvent used in step-(e) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

48. A process for the preparation of N-[2-(7-hydroxy-3,4-dihydro-l-naphthalenyl) ethyl]acetamide of formula VIII:

or a salt thereof, comprising acetylating 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV:

or an acid addition salt thereof, with a suitable acetylating agent to produce the compound of formula VIII or a salt thereof.

49. The process of claim 48, wherein the acetylating is selected from the group consisting of acetyl chloride, acetyl bromide, acetyl iodide, acetic anhydride, sodium acetate, or a combination thereof; wherein the reaction is optionally carried out in the presence of a base; and wherein the acetylation is carried out in the presence of a fourth solvent selected from the group consisting of water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof

50. The process of claim 49, wherein the acetylating agent is acetic anhydride or a combination with sodium acetate; wherein the base is selected from the group consisting of 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 wherein the fourth solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

51. A process for the preparation of N-[2-(7-hydroxy-l-naphthyl)ethyl]acetamide of formula VI:

52. The process of claim 51, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts and quinone derivatives; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV is employed in the form of an acid addition salt; and wherein the aromatization is optionally carried out in the presence of a third solvent.

53. The process of claim 52, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur, selenium metal, aqueous hydrobromic acid, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, 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, 2,3-dicyano-4-chlorobenzoquinone, 2,3- dicyanobenzoquinone, 1 ,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil and o-floranil; wherein the starting material 2-(7-hydroxy-3,4-dihydro-l- naphthalenyl)ethanamine of formula IV is employed in the form of its hydrochloride salt; and wherein the third solvent is selected from the group consisting of water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

54. The process of claim 51, wherein the aromatization is carried out as a neat reaction, in the absence of solvent.

55. A process for the preparation of agomelatine, N-[2-(7-methoxy-l- naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy- 1 -tetralone of formula II :

with cyanoacetic acid of formula X:

HO.

CN or a salt thereof, to produce (7-hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile of formula III:

or a salt thereof;

b) subjecting the compound of formula III to aromatization by reacting with a suitable reagent to produce (7-hydroxy- l-naphthyl)acetonitrile, of formula VII:

or a salt thereof; and c) reducing the compound of formula VII with a suitable reducing agent to produce 2- (7-hydroxy- 1 -naphthyl)ethanamine of formula V:

or an acid addition salt thereof;

or a salt thereof; and

56. The process of claim 55, wherein the reagent suitable for facilitating the aromatization reaction in step-(b) is selected from the group consisting of sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts and quinone derivatives; and wherein the aromatization in step-(b) is optionally carried out in the presence of a third solvent.

57. The process of claim 56, wherein the reagent suitable for facilitating the aromatization reaction in step-(b) is selected from the group consisting of sulfur, selenium metal, aqueous hydrobromic acid, palladium on carbon in various percentages, platinum oxide, raney nickel, palladium oxide, 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, 2,3-dicyano-4-chlorobenzoquinone, 2,3- dicyanobenzoquinone, 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil

_ _and Q-flQranil;_and_wherein he hird-solvent-used n-step-(b)-is seleeted-from the group consisting of water, a halogenated hydrocarbon, an ester, a hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.

58. The process of claim 55, wherein the aromatization in step-(b) is carried out as a neat reaction, in the absence of solvent.

59. The process of claim 55, wherein the reduction in step-(c) is carried out in the presence of a second solvent; wherein the reducing agent used in step-(c) is selected from the group consisting of hydrogenation catalysts (metal catalysts), hydride agents, borane and borane-THF complex; and wherein the reduction in step-(c) is optionally carried out in the presence of ammonia.

60. The process of claim 59, wherein the second solvent used in step-(c) is selected from the group consisting of water, an alcohol, an ester, a hydrocarbon solvent, an ether, and mixtures thereof; wherein the reducing agent used in step-(c) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride/Lewis acid, lithium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), lithium tri-tert-butoxyaluminum hydride, sodium bis(2- methoxyethoxy)aluminium hydride (Vitride), borane and borane-THF complex; and wherein the ammonia is used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent.

61. A process for the preparation of (7-hydroxy-l-naphthyl)acetonitrile of formula VII:

or a salt thereof, comprising subjecting (7-hydroxy-3,4-dihydro-l- naphthalenyl)acetonitrile of formula III:

to aromatization by reacting with a suitable reagent to produce the compound of formula VII or a salt thereof.

62. The process of claim 61, wherein the reagent suitable for facilitating the aromatization reaction is selected from the group consisting of sulfur or its derivatives, selenium metal, aqueous hydrobromic acid, metal catalysts and quinone derivatives; and wherein the aromatization is optionally carried out in the presence of a third solvent.

63. A process for the preparation of 2- 7-hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof, comprising reducing (7-hydroxy-l- naphthyl)acetonitrile of formula VII:

64. The process of claim 63, wherein the reduction is carried out in the presence of a second solvent; wherein the reducing agent is selected from the group consisting of hydrogenation catalysts (metal catalysts), hydride agents, borane and borane-THF complex; and wherein the reduction is optionally carried out in the presence of ammonia.

65. A process for the preparation of agomelatine, N-[2-(7-methoxy-l- naphthalenyl)ethyl]acetamide, of formula I:

or a salt thereof, comprising:

a) reacting 7-hydroxy- 1 -tetralone of formula II:

with cyanoacetic acid of formula X:

or a salt thereof;

b) subjecting the compound of formula III to aromatization by reacting with a

reagent to produce (7-hydroxy- l-naphthyl)acetonitrile, of formula VII:

or a salt thereof;

c) reacting the compound of formula VII with a methylating agent to produce (7- methoxy- 1 -naphthyl)acetonitrile of formula IX:

or a salt thereof;

d) reducing the compound of formula IX with a suitable reducing agent to produce 2- (7-methoxy-l-naphthyl)ethanamine of formula XI:

or an acid addition salt thereof; and

66. The process of claim 65, wherein the methylating agent used in step-(c) is dimethyl sulfate or methyl iodide; wherein the reaction in step-(c) is optionally carried out in the presence of a base; and wherein the methylation in step-(c) is carried out in the presence of a fifth solvent selected from the group consisting of water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

67. The process of claim 66, wherein the methylating agent used in step-(c) is dimethyl sulfate; wherein the base used in step-(c) is selected from the group consisting of 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 wherein the fifth solvent used in step-(c) is selected from the group consisting of water, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

68. -A-process-for he-prepar-ation-of-(-7-methoxy^naphthyl)ae

69. The process of claim 68, wherein the methylating agent is dimethyl sulfate or methyl iodide; wherein the reaction is optionally carried out in the presence of a base; and wherein the methylation is carried out in the presence of a fifth solvent selected from the group consisting of water, a hydrocarbon solvent, an ester, a ketone, an ether, a nitrile, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

70. A compound, (7-Hydroxy-3,4-dihydro-l-naphthalenyl)acetonitrile, of formula III:

or a salt thereof.

71. A compound, 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine, of formula IV:

or an acid addition salt thereof.

72. A compound, 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrochloride salt, of formulajVaL

73. A compound, 2-(7-Hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine hydrobromide salt, of formula IVb:

74. A compound, 2-(7-Hydroxy-l-naphthyl)ethanamine, of formula V:

75. A compound, 2-(7-hydroxy-l-naphthyl)ethanamine hydrochloride salt, of formula Va:

76. A compound, (7-hydroxy-l-naphthyl)acetonitrile, of formula VII:

or a salt thereof.

A compound, N-[2-(7-hydroxy-3,4-dihydro- 1 -naphthalenyl)ethyl]acetamide, formula VIII:

or a salt thereof.

78. Use of the compounds of formulae III, IV, IVa, IVb, V, Va, VII and VIII as claimed in claims 70 to 77, in the process for manufacture of agomelatine or a salt thereof.

79. A compound, 2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine, of formula XII:

or an acid addition salt thereof.

80. A compound, 2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine hydrochloride salt, of formula Xlla:

81. A compound, N-[2-(7-hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethyl]acetamide, of formula XIII:

or a salt thereof—

82. Use of the compounds of formulae XII, Xlla and XIII as claimed in claims 79 to 81, in the process for manufacture of agomelatine or a salt thereof.

83. A process for the preparation of 2-(7-hydroxy-l-naphthyl)ethanamine of formula V:

or an acid addition salt thereof, comprising:

a) reacting 2-(7-hydroxy-3,4-dihydro-l-naphthalenyl)ethanamine of formula IV or an acid addition salt thereof with aqueous hydrobromic acid to produce a reaction mass containing 2-(7-hydroxy-l-naphthyl)ethanamine of formula V and 2-(7- hydroxy-l,2,3,4-tetrahydro-l-naphthyl)ethanamine of formula XII:

(V) (XII) or an acid addition salt thereof;

b) isolating and/or recovering the pure 2-(7-hydroxy-l-naphthyl)ethanamine of formula V or an acid addition salt thereof from the reaction mass obtained in step- (a);

e) isolating and/or recovering the pure 2-(7-hydroxy-l,2,3,4-tetrahydro-l- naphthyl)ethanamine of formula XII or an acid addition salt thereof from the reaction mass obtained in step-(c) or from the organic layer obtained in step-(d); and f) subjecting the compound of formula XII or an acid addition salt to aromatization by reacting with a suitable reagent to produce the compound of formula V.

84. A process for the preparation of N-[2-(7 -hydroxy- 1,2,3, 4-tetrahydro-l-naphthyl)ethyl] acetamide of formula XIII: