Field of Invention:

The present invention relates to an improved process for the. préparation of N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide, represented by the structural formula-1. The present invention also provides novel crystalline forms of its intermediate compounds.

Background of the Invention:

N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide (commonly known as agomelatine) and process for its préparation was first disclosed in US 5225442. The disclosed process involves eight steps, starting from 7-methoxy-l-tetralone. The said process involves the reaction of ethyl bromo acetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-l-naphthyl)acetonitrile, this being followed by réduction, and then condensation of the acetyl chloride. As the said process involves more number of steps, it makes the process more expensive and time-consuming. Hence there is a need to provide a process with less number of steps.

Synthetic communication 2001, 31(4), 621-629 disclosed a process for the préparation of 2-(l -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile. The disclosed process involves the reaction of 7-methoxy-l-tetralone with acetonitrile in the presence of n-butyl lithium. Further, the said compound obtained was purified by chromatography techniques, which is difficult to perform on a large scale. Hence there is a need to avoid chromatographic purification.

US 5922771 disclosed a process for the préparation of 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine. The process disclosed a two step synthesis from 2- ( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile, which involves dehydration using an acid or a base catalyst, followed by réduction. As the said process istime-consuming and requires additional solvents and reagents, which results in theprocess to be more expensive.

Henceforth, there is a need in the art to provide a cost-effective process for the
préparation of pure agomelatine with high yield in shorter reaction time, which can
reliably carried out in large scale.

Brief description of the Invention:

The fïrst aspect of the present invention is to provide a process for the préparation
of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and/orits acid addition sait compound of général formula-6, comprising of:

a) Treating 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 with hydrogen gas in the presence of a métal catalyst, in asuitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) optionally, treating the compound of formula-5 with an acid provides its
corresponding acid addition sait compound of général formula-6.

The second aspect of the present invention is to provide a process for the
préparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-1 (2H)-ylidene)ethanamine
compound of formula-8 and/or its acid addition sait compound of général formula-9,
comprising of:

a) Treating 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 with hydrogen gas in the presence of a métal catalyst, in asuitable solvent in the presence or absence of an acid or a base provides (E)-2-(7-methoxy-3,4-dihydronaphthalen-1 (2H)-ylidene)ethanamine compound of formula-8,

b) optionally, treating the compound of formula-8 with an acid provides its
corresponding acid addition sait compound of général formula-9.

The third aspect of the present invention is to provide 2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethanamine hydrochloride sait compound of formula-6a and itscrystalline form.

The fourth aspect of the present invention is to provide (È)-2-(7-methoxy-3,4-
dihydro naphthalen-l(2H)-ylidene)ethanamine hydrochloride sait compound of formula- 9a and its crystalline form.

The fîfth aspect of the present invention is to provide a process for préparation of agomelatine compound of formula-1, comprising of aromatizing the N-(2-(7-methoxy- 3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7- methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula-10 with a suitable aromatizing agent in a suitable solvent to provide agomelatine compound of formula-1.

The sixth aspect of the present invention is to provide a process for the préparation of agomelatine compound of formula-1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7- methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionally purifying it in a suitable hydrocarbon solvent to provide pure compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in the presence of a métal catalyst, in a suitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5, optionally converting it into its acid addition sait compound of général formula-6,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in a suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthàlen-l-yl)ethyl) acetamide compound of formula-7,

d) optionally, isolating the compound obtained in step-c) from a suitable hydrocarbon solvent to provide compound of formula-7 as a solid,

e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a suitable solvent provides agomelatine compound of formula-1.

The seventh aspect of the present invention is to provide a process for the préparation of agomelatine compound of formula-1, comprising of: a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4,optionally purifying it in a suitable hydrocarbon solvent to provide pure compoundof formula-4,

b) treating the compound of formula-4 with hydrogen gas in the presence of a métalcatalyst, in a suitable solvent in the presence or absence of an acid or a base to
provide (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine
compound of formula-8, optionally converting it into its acid addition sait compound
of général formula-9,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in asuitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-
ylidene)ethyl)acetamide compound of formula-10,

d) aromatizing the compound of formula-10 with a suitable aromatizing agent in asuitable solvent provides agomelatine compound of formula-1.

The eighth aspect of the present invention is to provide a process for the
purification of 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 by using cyclohexane as a solvent.

The ninth aspect of the present invention is to provide N-(2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid and its
process for préparation.

The tenth aspect of the present invention is to provide one pot process for the
préparation of agomelatine compound of formula-1 through 2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethanamine compound of formula-5 starting from 2-(l-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile compound of formula-4.

The eleventh aspect of the present invention is to provide one pot process for the
préparation of agomelatine compound of formula-1 through (E)-2-(7-methoxy-3,4-
dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8 starting from 2-(l-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile compound of formula-4.

The twelfth aspect of the present invention is to provide a process for the
purification of agomelatine using a suitable solvent and .aqueous base.

The thirteenth aspect of the present invention is to provide a process for the
purification of agomelatine by converting it into its acid addition sait compound of
général formula-2.

Advantages of the present Invention:

• Provides highly pure agomelatine with high yield.

• Avoids the usage of chromatographic purification.

• Provides agomelatine compound of formula-1 from 7-methoxy-l-tetralone
compound of formula-3 in less number of steps, which in-turn makes the process
time-saving, cost-effective and eco-friendly.

• Provides the 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound offormula-5 and/or (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)
ethanamine compound of formula-8 from 2-(l-hydroxy-7-methoxy-1,2,3,4-
tetrahydronaphthalen- l-yl)acetonitrile compound of formula-4 in a single step,
which makes the process time-saving and cost-effective.

Brief description of drawings:

Figure-1: Illustrated the DSC thermogram of crystalline form of 2-(7-methoxy-3,4-
dihydro naphthalen-1 -yl) ethanamine hydrochloride sait compound of formula-6a.
Figure-2: Illustrated the DSC thermogram of crystalline form of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride sait compound of formula-9a

Detailed Description of the Invention:

The present invention relates to an improved process for thè préparation of pure
agomelatine compound of formula-1 and novel crystalline forms of its intermediate
compounds.

As used herein the present invention, the term "suitable solvents" wherever
necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropylacetate; "ether solvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether;"hydrocarbon solvents" like toluene, hexane, heptane, pet.ether and cyclohexane; "polaraprotic solvents" like dimethylformamide, dimethyl acetamide, dimethyl sulfoxide,acetonitrile; "ketone solvents" like acetone, methyethyl ketone, methyl isobutyl ketone;"alcohol solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycoland isobutanol; "chloro solvents" like dichloromethane, chloroform, and dichloroethane;and "polar solvents" like water; and also mixtures thereof.

The term "base" herein the present invention is selected from inorganic bases like
alkali métal, and alkaline earth métal alkoxides, hydroxides, carbonates and bicarbonatessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodiumbicarbonate and potassium bicarbonate; and organic bases like ammonia, triethylamine,tributyl aminé, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N-methyl morpholine, diisopropyl methylamine, diisopropyl aminé, diisopropyl ethylamine,cyclohexyldimethyl aminé, piperidine, dimethyl amino pyridine, pyridine, lithiumhexamethyldisilazidem (LiHMDS), sodium hexamethyldisilazide (NaHMDS) andtetraalkyl ammonium hydroxide such as tetrabutyl ammonium hydroxide.-

The term "acid" herein the present invention is selected from inorganic acids like
hydrochloric acid and hydrobromic acid; and organic acid like acetic acid, oxalic acid.
The term "aromatization process" as used herein the present invention refers to a
dehydrogenating process for converting alicyclic compounds into aromatic compounds.

The said process can be carried out using a suitable aromatizing agent is selected from agroup consisting of but not limited to, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ)or a proton acceptor selected from nitro alkanes or nitro arenes such as nitromethane,nitro ethane, nitro benzene and the like, optionally in the presence of a base selected fromalkali métal or alkaline earth métal or tetraalkyl ammonium hydroxides, alkoxides,carbonates and bicarbonates; and a phase transfer catalyst.

As used herein the present invention, the term "phase transfer catalyst" such as
alkyl ammonium and alkyl phosphonium salts, especially bromide or other halides.
Wherein, the alkyl group is straight chain or branched containing 1-20 carbon atoms,
most commonly 1-12 carbon atoms such as tetramethyl, tetraethyl, tetrabutyl, tetrapentyl,methyl-trialkyl, butyltripropyl, heptyltriethyl, octyltriethyl and the like.

The fïrst aspect of the present invention is to provide a process for the préparation
of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 and/orits acid addition sait compound of général formula-6, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrilecompound of formula-4with hydrogen gas in the presence of a métal catalyst, in a suitable solvent in thepresence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-1 -yl) ethanamine compound of formula-5,

b) optionally, treating the compound of formula-5 with an acid provides its
corresponding acid addition sait compound of général formula-6.

wherein, in step-a) the métal catalyst is Raney-Ni or Pd-C; and the step a) of the
above process is carried out at a temperature of above 40°C, preferably at 45-70°C,
more preferably at 45-60°C.

In a preferred embodiment of the present invention is to provide a process for the
préparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of
formula-5 and its hydrochloride sait compound of formula-6a, comprising'of:

a) Treating 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrilecompound of formula-4 with hydrogen gas in the presence of Raney-Ni, in aqueousmethanol in presence of ammonia at 45-60°C provides 2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) treating the compound of formula-5 with hydrochlorîc acid in ethylacetate provides2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine hydrochloride sait
compound of formula-6a.

US 5922771 described a two step process for the préparation of 2-(7-methoxy-3,4-
dihydro naphthalen-l-yl)ethanamine compound of formula-5. Whereas the present
invention provides a process for préparation of compound of formula-5 in a single step.

this makes the process more cost-effective and time-saving. Moreover, the purity of
compound of formula-5 is enhanced by converting it into its hydrochloride sait
compound of formula-6a, which is useful in the synthesis of highly pure agomelatine
compound of formula- l.Hence the present invention is more advantageous over the priorart process.

The second aspect of the present invention is to provide a process for the
préparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidène)ethanamine
compound of formula-8 and/or its acid addition sait compound of général formula-9,
comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrilecompound of formula-4 with hydrogen gas in the presence of a métal catalyst, in asuitable solvent in the presence or absence of an acid or a base provides (E)-2-(7-methoxy-3,4-dihydro naphthalen-l(2H)-ylidene)ethanamine compound of formula-8,

b) optionally, treating the compound of formula-8 with an acid to provide its
corresponding acid addition sait compound of général formula-9.


Wherein, in step-a) the métal catalyst is Raney-Ni or Pd-C; and the step-a) of the
above process is carried out at a temperature below 40°C, preferably at 25-40°C,
more preferably at 25-35°C.

In a preferred embodiment of the present invention is to provide a.process for the
préparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-1 (2H)-ylidene)ethanamine
compound of formula-8 and its hydrochloride sait compound of formula-9a,
comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)
acetonitrile compound of formula-4 with hydrogen gas in the presence of Raney-Ni
and ammonia in aqueous methanol at 25-35°C provides (E)-2-(7-methoxy-3,4-
dihydronaphthalen- 1 (2H)-ylidene)ethanamine compound of fofmula-8,

b) treating the compound of formula-8 with hydrochloric acid in ethyl acetate to
provide (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine
hydrochloride sait compound of formula-9a.

US Patent US 6235789 described a two-step process for the préparation of (E)-2-
(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8.

Whereas, the present invention provides the process for préparation of compound of
formula-8 in a single step, which makes the process more cost-effective and time-saving.

Moreover, the purity of compound of formula-8 is enhanced by converting it into its
hydrochloride sait compound of formula-9a, which is useful in the synthesis of highly
pure agomelatine compound of formula-1. Hence the present invention is more
advantageous over the prior art process.

The third aspect of the present invention is to provide 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride sait compound of formula-6a. Further, the present invention also provides the crystalline form of 2-(7-methoxy-3,4- dihydronaphthalen-l-yl)ethanamine hydrochloride sait compound of formula-6a. The crystalline form of compound of formula-6a is characterized by its DSC thermogram showing endotherm peak at 151.12°C substantially as shown in figure-1.

The fourth aspect of the present invention is to provide (E)-2-(7-methoxy-3,4- dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride sait compound of formula- 9a. Further, the present invention also provides the crystalline form of (E)-2-(7-methoxy- 3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine hydrochloride sait compound of formula-9a. The crystalline form of compound of formula-9a is characterized by its DSC thermogram showing endotherm peak at 136.87°C substantially as shown in figure-2.

The fifth aspect of the present invention is to provide a process for the préparation of agomelatine compound of formula-1, comprising of aromatizing the N-(2-(7-methoxy- 3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7- methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula-10 with a suitable aromatizing agent in a suitable solvent to provide agomelatine compound of formula-1.

US 5922771 disclosed a process for préparation of N-(2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethyl)acetamide compound of formula-7 and US 6235789 disclosed a process for the préparation of (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide compound of formula-10. Further, its conversion into agomelatine was not reported in the said patents.

The compounds of formula-7 and formula-10 are important intermediates in the synthesis of agomelatine and these have been aromatized using a suitable aromatizing agent like DDQ to pro vide agomelatine compound of formula-1.

A preferred embodiment of the present inventioti provides agomelatine compound of formula-1, which comprises of aromatizing N-(2-(7-methoxy-3,4-dihydronaphthalen- l-yl)ethyl)acetamide compound of formula-7 or (E)-N-(2-(7-methoxy-3,4-dihydro
naphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula-10 with DDQ in
dichloromethane to provide agomelatine compound of formula-1. .

The sixth aspect of the present invention is to provide a process for the
préparation of agomelatine compound of formula-1, comprising of:

a) Reacting the 7-methoxy-1 -tetralone compound of formula-3

with acetonitrile in the presence of a suitable base in a suitable solvent to provide 2-
( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile compound of
formula-4, optionally purifying it in a suitable hydrocarbon solvent to provide pure
compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas, in the presence of a métalcatalyst, in a suitable solvent in the presence or absence of an acid or a base provides2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,optionally converting it into its acid addition sait compound of général formula-6,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent in asuitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)
acetamide compound of formula-7,

d) optionally, isolating the compound obtained in step c) from a suitable hydrocarbonsolvent to provide compound of formula-7 as a solid,

e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a
suitable solvent to provide agomelatine compound of formula-1.

Wherein,

In step a) the suitable base used is sodium hexamethyldisilazide,

in step b) the suitable reducing agent used is Rançy-Ni or Pd-C; the acid used is

acetic acid; the base used is ammonia; the suitable solvent is selected from alcohol solvents or water or mixture thereof,

in step c) the suitable acetylating agent is selected fromacetyl halide, acetic anhydride and acetic acid; and the suitable solvent is selected from chloro solvents and hydrocarbon solvents,

The step b) of the above process is carried out at a temperature above 40°C, preferably at 45-70°C, more preferably at 45-60°C.

In a preferred embodiment of the present invention is to pro vide a process for the préparation of agomelatine compound of formula-1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in the presence of sodium hexamethyldisilazide in tetrahydrofuran to provide 2-(l- hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrile compound of formula-4, which is further crystallization in cyclohexane to provide pure compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in the presence of Raney-Ni, in aqueous methanol in presence of ammonia at 45-60°C to provide 2-(7-methoxy- 3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5 followed by treatment with hydrochloric acid in ethylacetate to provide its corresponding hydrochloride sait compound of formula-6a,

c) acetylating the compound of formula-6a with acetyl chloride in the presence of potassium carbonate in aqueous ethyl acetate to provide N-(2-(7-methoxy-3,4- dihydronaphthalen- 1 -yl)ethyl)acetamide compound of formula-7,

d) isolating the compound obtained in step c) from cyclohexane to provide compound. of formula-7 as a solid,

e) aromatizing the compound of formula-7 with DDQ in dichloromethane to provide agomelatine compound of formula-1,

In the present invention, during the process for the préparation of Agomelatine, some process impurities are formed in higher concentrations, which led to the decrease in the purity of agomelatine. The present invention provides a simple purification processes which reduces the impurities to lower level, preferably to the level of non détection inHPLC.

The following impurities 'A' and 'B' were formed in step a) which are listed below
along with their RRT and Area % of crude compound and recrystallized compound.

Table 1

These impurities 'A' and 'B' are reduced to the level of non détection after
recrystallization from cyclohexane and provides compound of formula-4 with purity
99.74% by HPLC.

The following impurity 'C' was formed in step b) which is listed below along
with its RRT and Area % of compound of formula-5, before and after sait formation.

Table 2

The impurity 'C' is reduced to the level of non détection, by converting the
compound of formula-5 into its hydrochloride sait compound of formula-6a with purityof 99.36% by HPLC.

The following impurity 'D'is formed in step c) which is listed below along with
its RRT and area %, before and after isolation from cyclohexane.

Table 3

The impurity 'D' is reduced to the level of non détection after isolating from
cyclohexane and provides compound of formula-7 with purity 97.48% by HPLC.

The following impurities 'E', 'F' and 'G', which can be formed in the synthesis of
agomelatine are listed below along with their RRT.

Table 4

The above impurities 'E', 'F' and 'G' are controlled almost to the level of non
détection in the present invention to provide agomelatine compound of formula-1 withpurity 99.86% by HPLC.

The seventh aspect of the present invention is to provide agomelatine compound
of formula-1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in thepresence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4, optionallypurifying itin a suitable hydrocarbon solvent to provide pure compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in presence of a métal
catalyst, in a suitable solvent in the presence or absence of a base or an acid provides

(E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of
formula-8, optionally converting it into its acid addition sait compound of général
formula-9,

c) acetylating the compound obtained in step-b) with a-suitable acetylating agent in asuitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-
ylidene)ethyl) acetamide compound of formula-10,

d) aromatizing the compound of formula-10 with a suitable aromatizing agent in asuitable solvent to provide agomelatine compound of formula-1.
Wherein, the reagents and solvents used in step-(a), (b) and (c) of the above process
is same as defined above;

The step b) of the present invention is carried out at a temperature below 40°C,
preferably at 25-40°C, more preferably at 25-35°C.

The eighth aspect of the present invention is to provide a process for the
purification of 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4, comprising of:

a) Dissolving the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)
acetonitrile compound of formula-4 in cyclohexane by heating to higher
temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture,

d) filtering the solid to provide pure compound of formula-4.

Synthetic communication, 2001, 31(4), 621-629 disclosed a process for the
préparation of 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 by using chromatographic technique, which is difïicult to carryout on large scale. Whereas, in the present invention the said compound is purified byrecrystallization from cyclohexane, which avoids the chromatographic purification.

The ninth aspect of the present invention is to provide N-(2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid and is
characterized by its DSC thermogram showing endotherm peak at 107.95°C.

In another embodiment of the present invention provides a process for préparation
of solid N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of
formula-7, comprising of:

Dissolving the N-(2-(7-methoxy-3,4-dihydronaphthalen-1 -yl)èthyl)acetamide
compound of formula-7 in cyclohexane by heating to higher temperature,

cooling the reaction mixture,

stirring the reaction mixture,

filtering the solid to provide compound of formula-7 as a solid.

The tenth aspect of the present invention is to provide one pot process for the
préparation of agomelatine compound of formula-1, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrilecompound of formula-4 with hydrogen gas in presence of a métal catalyst, in asuitable solvent in the presence or absence of an acid or a base provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine compound of formula-5,

b) acetylating the compound of formula-5 in-situ with a suitable acetylating agent in asuitable solvent to pro vide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)
acetamide compound of formula-7,

c) aromatizing the compound of formula-7 in-situ with a suitable aromatizing agent in asuitable solvent to pro vide agomelatine compound of formula-1.

Wherein, the step a) is carried out at a temperature above 40°C, preferably at 45-
70°C, more preferably at 45-60°C.

The eleventh aspect of the present invention is to provide one pot process for the
préparation of agomelatine compound of formula-1, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile
compound of formula-4 with hydrogen gas in presence of a métal catalyst, in a
suitable solvent in the presence or absence of an acid or a base provides (E)-2-(7-
methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8,

b) acetylating the compound of formula-8 in-situ with a suitable acetylating agent in a suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l-ylidene) ethyl)acetamide compound of formula-10,

c) aromatizing the compound of formula-10 in-situ with a suitable aromatizing agent in a suitable solvent to provide agomelatine compound of formula-1.

Wherein, the step a) is carried out at a temperature below 40°C, preferably at 25- 40°C, more preferably at 25-35°C.

The twelfth aspect of the present invention is to provide a process for the purification of agomelatine compound of formula-1, comprising of:

a) Dissolving agomelatine compound of formula-1 in a suitable solvent by stirring at higher temperature,

b) cooling the reaction mixture,

c) adding aqueous base,

d) filtering the solid and washing with a aqueous base,

e) dissolving the solid obtained in step d) in a suitable solvent by heating to higher temperature,

f) treating with carbon,

g) filtering the reaction mixture and washing with a suitable solvent,

h) filtrate is added to the aqueous base and stirring the reaction mixture,

i) filtering the solid and washing with a suitable solvent to get pure agomelatine compound of formula-1.

Wherein, the aqueous base used in the above process is aqueous sodium hydroxide and the suitable solvent is polar aprotic solvent.

The thirteenth aspect of the present invention is to provide a process for the purification of agomelatine compound of formula-1, comprising of:

a) Dissolving agomelatine compound of formula-1 in a suitable solvent by stirring at higher temperature,

b) adding aqueous acid solution,

c) cooling and stirring the reaction mixture,

d) filtering the solid and washing with a suitable solvent to get acid addition sait ofagomelatine compound of général formula-2,

e) adding a chloro solvent to the solid,

f) adjusting the pH of the reaction mixture to 9-10 by adding an aqueous base,

g) separating the layers and distilling ofF the solvent from the organic layer to get pureagomelatine compound of formula-1.

Wherein, in step a) the suitable solvent is selected from ester solvent, ketone solvent,
hydrocarbon solvent and polar aprotic solvent,
. •
In step b) the acid used is oxalic acid.

The purity and description of agomelatine compound of formula-1 was enhanced
by the above purification process disclosed in 12 and 13 aspects of the present invention.

Agomelatine compound of formula-1 obtained by the present invention is
dissolved in a suitable solvent and precipitating the solid by adding water to it to provideagomelatine crystalline form-I.

The suitable solvent used for the préparation of agomelatine crystalline form-I is
selected from DMF, DMSO, THF, acetonitrile, ketone solvents and alcohol solvents.
In the present invention 7-methoxy-l-tetralone compound of formula-3 can be
prepared as follows by treating the anisole with succiniç anhydride in the presence of acidcatalyst like aluminiumtrichloride in a suitable solvent such as chloro solvents provides

4-(4-methoxyphenyl)-4-oxobutanoic acid compound of formula-Il, which is reduced
with a suitable reducing agent in a suitable solvent to provide 4-(4-methoxyphenyl)
butanoic acid compound of formula-12. Cyclizing the compound of formula-12 as per theknown methods in the art (JP2004182660A) provided 7-methoxy-l-tetralone compoundof formula-3.

Wherein, the suitable reducing agent used is selected from hydrazine hydrate,
triethylsilane in combination with trifluoroacetic acid and Pd-C.

Agomelatine obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on différent forms of pharmaceutical composition requirements.

Compound of formula-6a and compound of formula-7 of present invention were analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Intersil ODS-4, 250 x 4.6 mm, 5 μm or équivalent; Flow rate: 1.0 ml/min; Wavelength: 220 μm; Temperature: 40°C; Injection volume: 10 μb; Run time: 55 minutes; Diluent: acetonitrile: water (90:10 v/v); Elution: Gradient; Buffer: 2.8 grams of sodium per chlorate mono hydrate into 1000 ml of water, adjust pH to 2.8 with dilute perchloric acid. Filtered this solution through 0.22 μm Nylon membrane filter paper and sonicate to degas it; solution-A: Buffer; solution-B: acetonitrile:methanol (80:20 v/v).

Compound of formula-4 of present invention was analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Inertsil ODS-4, 250 x 4.6 mm, 5 μm or équivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Temperature: 35°C; Injection volume: 10 |iL; Run time: 52 minutes; Diluent: acetonitrile: water (90:10 v/v); Elution: Gradient; Buffer: 2.8 grams of sodium per chlorate mono .hydrate into 1000 ml of water, adjust pH to 2.8 with dilute perchloric acid. Filtered this solution through 0.22 μm Nylon membrane filter paper and sonicate to degas it; solution-A: Buffer; solution-B: acetonitrile:methanol (80:20 v/v).

Compound of formula-1 of present invention was analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Inertsil C8-3, 250 x 4.6 mm, 5 μm or équivalent; Flow rate: 1.0 ml/min; Wavelength: 230 nm; Temperature: 45°C; injection volume : 10 μL; Run time: 52 minutes; Diluent: Acetonitrile:water (50:50 v/v); Elution: Gradient; Mobile phase-A : Buffer: acetonitrile (90:10 v/v); Mobile phase-B: water: acetonitrile (10:90 v/v); Buffer : 2.81 grams of sodium per chlorate mono hydrate into 1000 ml of water, adjust pH to 2.2 with phosphoric acid. Filtered this solution through 0.45 μm Nylon membrane filter paper and sonicate to degas it.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6
Build 290calorimeter. Samples of about 2 to 3 milligrams was held in a closed pan, andanalyzed at a heating rate of 10° per minute.

The present invention represented schematically as follows:

The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore shouldnot be construed as limitation of the scope of the invention.

Examples:

Example-1: Préparation of 2-(l-hydroxy-7methoxy-l,2,3,4-tetrahydronaphthalen-l-
yl) acetonitrile (Formula-4)

A solution of NaHMDS (498.5 ml) in tetrahydrofuran (500 ml) was cooled to -70
to -80°C under nitrogen atmosphère. To this solution, a mixture of 7-methoxy-l-tetralonecompound of formula-3 (100 g), tetrahydrofuran (200 ml) and acetonitrile (44.4 ml) wasadded at -70 to -80°C and then stirred for 45 minutes at -70 to -80°C.

After completion ofthe reaction, the reaction mixture was quenched with 10% ammonium chloride solutionand extracted the product into ethylacetate. Both the organic and aqueous layers wereseparated and the aqueous layer was extracted with ethylacetate. Both ethyl acetate layerswere combined and washed with 10% sodium chloride solution.Distilled off the solventand co-distilled with cyclohexane to obtain title compound as a residue.' Dissolving theobtained residue in cyclohexane (200 ml) by heating to 50-60°C and then cooled to 25-30°C. The reaction mixture was stirred for 1 ½ hour at 25-30°C. Filtered the obtainedsolid, washed with cyclohexane and then dried to get title compound. The purificationusing cyclohexane (1000 ml) was repeated another time to get highly pure titlecompound. Yield: 105 grams; MR: 83-93°C; purity: 99.74 % by HPLC

Example-2: Préparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine
hydrochloride sait (Formula-6a)2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 (100 g) was added to a mixture of Raney-Ni (50 g), methanolicammonia (600 ml) and water (25 ml) at 25-30°C in autoclave. Hydrogen gas (3-4 kg) wasbubbled to the reaction mixture. The reaction mixture was heated to 45-55°C and thenstirred for 6 hours at 45-50°C. After completion of the reaction, cool the autoclave to 25-30°C. Filtered the reaction mixture and washed with methanol. Distilled off the solventcompletely from the filtrate obtained and cooled to 25-30°C.Co-distilled the reactionmixture twice with methanol. Ethyl acetate was added to the obtained residue at 25-30°C
and then cooled to 10-15°C. The pH of the reaction mixture was adjusted to below 2.0
with ethylacetate-hydrochloride and stirred for 2 hours at 10-15°C. The obtained solid
was filtered, washed with ethylacetate and then dried to get the title compound.

Yield: 100 grams; MP: 151.12°C; purity: 99.36 % by HPLC.

Example-3: Préparation of N-(2-(7-methoxy-3,4-dihydronaphthglen-l-yl)ethyl)
acetamide (Formula-7)

A mixture of 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine
hydrochloride sait compound of formula-6a (100 g), ethylacetate (800 ml) and potassiumcarbonate (69.5 ml) was stirred for 15 minutes at 25-30°C and then cooled to 0-5°C.

Acetyl chloride (29.6 ml) was slowly added to the reaction mixture over a period of 1
hour and stirred for 1 hour at 0-5°C. After completion of the reaction, the temperature ofthe reaction was raised to 25-30°C. Water was added to the reaction mixture and stirredfor 15 minutes at 25-30°C. Both the organic and aqueous layers were separated andextracted the aqueous layer with ethyl acetate. Bcfth the ethylacetate layers were
combined and washed with 10% sodium chloride solution. Distilled off the solvent
completely from the organic layer and co-distilled with cyclohexane. The reaction
mixture was cooled to 25-30°C to get title compound as a residue. Cyclohexane (300 ml)was added to the obtained residue and then heated to 45-50°C. The reaction mixture wasstirred 45 minutes at 45-50°C and further stirred for 1 ½ hour at 25-30°C.

Filtered theobtained solid, washed with cyclohexane and then dried to get pure title compound.Yield: 95 grams; MR: 100-110°C; Purity: 97.48 % by HPLC.

Example-4: Préparation of agomelatine (Formula-1)

A solution of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide
compound of formula-7 (100 g) in dichloromethane (800 ml) was cooled to 0-5°C. A
solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added to the abovereaction mixture at 0-5°C and then stirred for 10-20 minutes. The temperature of thereaction mixture was raised to 25-30°C and then stirred for 14 hours at 25-30°C.

Aftercompletion of the reaction, filtered the reaction mixture and washed with
dichloromethane. Filtrate was washed with 0.5% sodium hydroxide solution, followed by1% hydrochloride solution and followed by water. Distilled off the solvent completelyfrom the dichloromethane layer and co-distilled with acetone. The obtained residue wascooled to 25-30°C. Acetone (200 ml) was added to the obtained residue and then carbon(10 g) was added to the reaction mixture. The reaction mixture was heated to refluxtemperature and stirred for 20 minutes at the same temperature. Filtered the reaction mixture and washed with acetone. Filtrate was added to 2% sodium hydroxide solution at 10-15°C and then stirred for 2 hours at 10-15°C.

Filtered the obtained solid, washed with 2% sodium hydroxide and then washed with 0.5 % hydrochloric acid and followed by water to get title compound. Acetone (140 ) was added to the obtained solid and then heated to 45-50°C. The reaction mixture was stirred for 10 minutes at 45-50°C. Filtered the reaction mixture, washed with acetone. Filtrate was added to the water and then stirred for 2 hours at 25-30°C. Filtered the reaction mixture, washed with water and then dried to get the crystalline form-I of Agomelatine. Yield: 60 grams, MR: 97-103°C; Purity (by HPLC): 99.86 %.

ExampIe-5: Préparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene) ethanaminehydrochloride sait (Formula-9a)
2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)acetonitrilecompound of formula-4 (100 g) was added to a mixture of Raney-Ni (50 g), methanolic ammonia (600 ml) and water (25 ml) at 25-30°C in autoclave. Hydrogen gas (3-4 kg) was bubbled to the reaction mixture. The reaction mixture was heated to 25-30°C and then stirred for 6 hours at 25-30°C. After completion of the reaction, filtered the reaction mixture at 25- 30°C and washed with methanol. Distilled off the solvent completely from the filtrate obtained and cooled to 25-30°C.Co-distilled the reaction mixture twice with methanol.Ethylacetate was added to the obtained residue mixture at 25-30°C and then cooled to 10-15°C. The pH of the reaction mixture was adjusted to below 2.0 with ethylacetate-hydrochloride and stirred for 2 hours at 10-15°C. The obtained solid was filtered, washed with ethylacetate and then dried to get the title compound. Yield: 83 grams; MP: 136.87°C; Purity (by HPLC): 99.57 %.

Example-6: Préparation of (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)- ylidene)ethyl)acetamide (Formula-10)
A mixture of 2-(7-methoxy-3,4-dihydro naphthalen-l-yl)ethanamine hydrochloride sait compound of formula-6a (100 g), ethylacetate (800 ml) and potassium carbonate (69.5 ml) was stirred for 15 minutes at 25-30°C and then cooled to 0-5°C. Acetyl chloride (29.6 ml) was slowly added to the reaction mixture over a period of 1
hour and stirred for 1 hour at 0-5°C. After completion of the reaction, the temperature ofthe reaction was raised to 25-30°C. Water was added to the reaction mixture and stirredfor 15 minutes at 25-30°C. Both the organic and aqueous layers were separated andextracted the aqueous layer with ethyl acetate. Both the ethylacetate layers were
combined and washed with 10% sodium chloride solution. Distilled off the solvent
completely from the organic layer to get title compound. Yield: 76 grams.

Example-7: Préparation of agomelatine (Formula-1)
A solution of(E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)
acetamide compound of formula-10 (100 g) in dichloromethane (800 ml) was cooled to0-5°C. A solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added tothe above reaction mixture at 0-5°C and then stirred for 10-20 minutes. The temperatureof the reaction mixture was raised to 25-30°C and then stirred for 14 hours at 25-30°C.

After completion of the reaction, filtered the reaction mixture and washed with
dichloromethane. Filtrate was washed with 0.5% sodium hydroxide solution, followed by1% hydrochloride solution and followed by water. Distilled off the solvent completelyfrom the dichloromethane layer and co-distilled with acetone. The obtained residue wascooled to 25-30°C. Acetone (200 ml) was added to the obtained residue and then carbon(10 g) was added to the reaction mixture. The reaction mixture was heated to refluxtemperature and stirred for 20 minutes at the same temperature.

Filtered the reactionmixture and washed with acetone. Filtrate was added to 2% sodium hydroxide solution at10-15°C and then stirred for 2 hours at 10-15°C. Filtered the obtained solid, washed with2% sodium hydroxide and then washed with 0.5 % hydrochloric acid and followed bywater to get title compound. Acetone (140 ) was added to the obtained solid and thenheated to 45-50°C. The reaction mixture was stirred for 10 minutes at 45-50°C. Filteredthe reaction mixture, washed with acetone. Filtrate was added to the water and thenstirred for 2 hours at 25-30°C. Filtered the obtained solid, washed with water and thendried to get the crystalline form-I of Agomelatine. Yield: 55 grams, MR: 97-103°C.

Example-8: Préparation of 4-(4-methoxy phenyl) -4-oxobutanoic acid (Formula-Il)
Succinic anhydride (27.7 g) followed by anisole (30 g) were added to a solution
of Aluminium chloride (74.4 g) in dichloromethane (300 ml) at 0-5°C and stirred for 2hours at 0-5°C. After completion of the reaction, the reaction mixture was poured into amixture of ice water and hydrochloric acid.The reaction mixture was stirred for 2 hours at0-5°C. Filtered the solid, washed with water and then dried to get title compound.Yield: 55 grams.

Example-9: Préparation of 4-(4-methoxy phenyl)butanoic acid (Formula-12)
A mixture of 4-(4-methoxyphenyl)-4-oxobutanoic acid compound of formula-11
(15 g) and triethylsilane (41.46 g) was heated to 40-45°C and then stirred for 4 hours at40-45°C. After completion of the reaction, the reaction mixture was cooled to 25-30°Cand added water followed by ethylacetate. Both the organic and aqueous layers wereseparated and the aqueous layer was extracted with ethylacetate. Both the organic layerswere combined and washed with 10% sodium chloride solution. Distilled off the solventcompletely from organic layer and co-distilled with pet.ether.The reaction mixture wascooled to 25-30°C and pet.ether was added and further cooled to 0-5°C.

Filtered the solid,washed with pet.ether and then dried to get the title compound. Yield: 9 grams.

Example-10: Préparation of 7-methoxy-l-tetralone (Formula-3)
Préparation was similar to the process disclosed in JP 2004182660 A starting from
4-(4-methoxyphenyl)butanoic acid.

Example-11: Préparation of Agomelatine (Formula-1)
A solution of DDQ (27 g) in dichloromethane (125 ml) was added to pre-cooled
solution of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound offormula-7 (25 g) in dichloromethane (250 ml) at 10-15°C. The reaction mixture
temperature was raised to 25-35°C and stirred for 12 hours at 25-35°C. After completionof the reaction, distilled off the solvent from the reaction mixture to obtain residue.Andthen dissolved in dimethylformamide (25 ml) by stirring at 50-55°C. The reactionmixture was cooled to 25-35°C and further cooled to 10-15°C. 2% aqueous sodiumhydroxide (375 ml) was added to the reaction mixture and stirred for 2 hours at 10-15°C.

Filtered the solid and washed with 2% aqueous sodium hydroxide. Dissolved the
obtained solid in dimethylformamide (50 ml) by heating the reaction mixture to 50-55°C.

Carbon was added to the reaction mixture at 50-55°C and stirred for 15 minutes. Filteredthe reaction mixture through hyflow bed and washed with dimethylformamide. Thefiltrate was added to the pre-cooled 2% aqueous sodium hydroxide solution at 10-15°Cfor a period of 45 minutes. The reaction mixture was stirred for 2 hours at 10-15°C.

Filtered the obtained solid, washed with 2% aqueous sodium hydroxide solution and thendried to get title compound. Yield: 17 grams

Example-12: Préparation of Agomelatine (Formula-l)
Agomelatine (25 g) was dissolved in ethylacetate (50 ml) at 50-55°C. A solution
of oxalic acid (11.12 g) in water (50 ml) was added to the reaction mixture at 50-55°C.

The reaction mixture was stirred for 30 minutes at 50-55°C. The reaction mixture was
cooled to 0-5°C and stirred for 2 hours. Filtered the obtained solid, washed with water
and then dried to get agomelatine oxalate compound of formula-2a. Dichloromethane
followed by water were added to the obtained oxalate sait and the pH of the reaction
mixture was adjusted to 9.5 with 10% sodium carbonate. Both the organic and aqueouslayers were separated and distilled off the solvent from the organic layer to obtainagomelatine as a solid. Dissolved the obtained solid in dimethylformamide (50 ml) andthe reaction mixture was heated to 50-5 5 °C for 15 minutes. Further the reaction mixturewas cooled to 25-35°C and added to the pre-cooled water (250 ml) at 10-15°C. Thereaction mixture was stirred for 2 hours at 10-15°C. Filtered the solid, washed with waterand then dried to get agomelatine crystalline form-I. Yield: 20 grams

Example-13: Préparation of agomelatine (Formula-l)
DDQ (27.79 g) was added to a mixture of N-(2-(7-methoxy-3,4-
dihydronaphthalen-l-yl)ethyl) acetamide compound of formula-7 (25 g) and toluene (250ml) under nitrogen atmosphère and heated to 70-75°C. The reaction mixture was stirredfor 12 hours at 70-75°C and then cooled to 25-35°C. 2% sodium hydroxide solution wasadded to the reaction mixture and stirred for 30 minutes at 25-35°C. Both the toluene andaqueous layers were separated and the aqueous layer was extracted with toluene. Both thetoluene layers were combined and washed with water. Distilled off the solvent from thetoluene layer to get solid. Dissolved the obtained solid in dimethylformamide by heatingto 50-55°C. Carbon was added to the reaction mixture and stirred for 10-15 minutes at50-55°C. Filtered the reaction mixture and washed with dimethylformamide. The filtratewas added to the pre-cooled 2% aqueous sodium hydroxide solution at 10-15°C over aperiod of 30 minutes and stirred for 2 hours at 10-15°C. Filtered the solid, washed with2% aqueous sodium hydroxide solution and then dried to get title compound.Yîeld: 17 grams.

Example-14: Purification of agomelatine (Formula-1)

Dissolved the crude agomelatine (10 g) in dimethylformamide by heating to 50-55°C.
Carbon was added to the reaction mixture and stirred for 10-15 minutes at 50-55°C andfiltered the reaction mixture. The filtrate was added to the pre-cooled 2% aqueous sodiumhydroxide solution at 10-15°C over a period of 30 minutes and stirred for 2 hours at 10-15°C. Filtered the solid, washed with 2% aqueous sodium hydroxide solution and thendried to get title compound. Yield: 9 grams.

Example-15: Préparation of Agomelatine (Formula-1)

A solution of DDQ (27 g) in toluene (125 ml) was added to pre-cooled solution of
N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7
(25 g) in toluene (250 ml) at 10-15°C. The reaction mixture temperature was raised to 70-75°C and stirred for 12 hours. After completion of the reaction, distilled off the solventfrom the reaction mixture to obtain solid. Toluene (300 ml) was added to the obtainedsolid and then heated to 70-75°C. The reaction mixture was stirred for 45 minutes at 70-75°C and then cooled to 0-5°C. Further stirred for lA hour at 0-5°C. Filtered the obtainedsolid, washed with toluene and then dried to get pure title compound. Yield: 17 grams

Example-16: Préparation of Agomelatine (Formula-1)

A solution of DDQ (27 g) in toluene (125 ml) was added to pre-cooled solution of
N-(2-(7-methoxy-3,4-dihydronaphthalen- l-yl)ethyl)acetanlide compound of formula-7(25 g) in toluene (250 ml) at 10-15°C. The reaction mixture temperature was raised to 70-75°C and stirred for 12 hours. After completion of the reaction, distilled'off the solventfrom the reaction mixture to obtain solid. Methyl tertiary butyl ether (MTBE) (300 ml)was added to the obtained solid and then heated to 50-55°C. The reaction mixture wasstirred for 45 minutes at 50-55°C and then cooled to 0-5°C. Further stirred for lA hour at0-5°C. Filtered the obtained solid, washed with methyl tertiary butyl ether and then driedto get crystalline form-I of Agomelatine. Yield: 17 grams

1. A crystalline form of 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine
hydrochloride sait compound of formula-6a characterized by its DSC thermogram
showing endotherm peak at 151.12°C as illustrated in figure-1.

2. A crystalline form of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)
ethanamine hydrochloride sait compound of formula-9a characterized by its DSC
thermogram showing endotherm peak at 136.87°C as illustrated in fîgure-2.

3. A process for the préparation of 2-(7-methoxy-3,4-dihydronaphthalen-l-
yl)ethanamine compound of formula-5 and/or its acid addition sait compound of
général formula-6, comprising of:

a) Treating the 2-(l-hydroxy-7-methoxy-l,2;3,4-tetrahydronaphthalen-l-yl)
acetonitrile compound of formula-4 with hydrogen gas in presence of a métal
catalyst, in a suitable solvent in the presence or absence of an acid or a base at
45-60°C to provide 2-(7-methoxy-3,4-dihydronaphthalen-1 -yl)ethanamine
compound of formula-5,

b) optionally, treating the compound of formula-5 with an acid to provide its
corresponding acid addition sait compound of général formula-6.

4. A process for the préparation of (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethanamine compound of formula-8 and/or its acid addition sait compound ofgénéral formula-9, comprising of:

a) Treating the 2-( 1 -hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalen-1 -yl)
acetonitrile compound of formula-4 with hydrogen gas in presence of a métal
catalyst, in a suitable solvent in the presence or absence of an acid or a base at
25-35°C to provide (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)
ethanamine compound of formula-8,

b) optionally, treating the compound of formula-8 with an acid to provide its
corresponding acid addition sait compound of général formula-9.

5. A process for the préparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide
compound of formula-1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile in
the presence of a base in a suitable solvent to provide 2-(l-hydroxy-7-methoxy-
l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4,
optionally purifying it in a suitable hydrocarbon solvent to provide pure
compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in presence of a métal
catalyst, in a suitable solvent in the presence or absence of an acid or a base at
45-70°C provides 2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethanamine
compound of formula-5, optionally converting it into its acid addition sait
compound of général formula-6,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent ina suitable solvent to provide N-(2-(7-methoxy-3,4-dihydronaphthalen-l-
yl)ethyl)acetamide compound of formula-7,

d) optionally, isolating the compound obtained in step c) form a suitable
hydrocarbon solvent to provide compound of formula-7 as a solid,

e) aromatizing the compound of formula-7 with a suitable aromatizing agent in a
suitable solvent to provide N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide
compound of formula-1.

6. A process for the préparation of A^-[2-(7-methoxy-l-naphthyl)ethyl]acetamide
compound of formula-1, comprising of:

a) Reacting the 7-methoxy-l-tetralone compound of formula-3 with acetonitrile inthe presence of a suitable base in a suitable solvent to provide 2-(l-hydroxy-7-
methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)acetonitrile compound of formula-4,
optionally purifying it in a suitable hydrocarbon solvent to provide pure
compound of formula-4,

b) treating the compound of formula-4 with hydrogen gas in presénce of a métal
catalyst, in a suitable solvent in the presence or absence of an acid or a base at
25-35°C provides (E)-2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)
ethanamine compound of formula-8, optionally converting it into its acid
addition sait compound of général formula-9,

c) acetylating the compound obtained in step-b) with a suitable acetylating agent ina suitable solvent to provide (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-
ylidene)ethyl)acetamide compound of formula-10,

d) aromatizing the compound of fonnula-10 with a suitable aromatizing agent in a suitable solvent to provide JV-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1.

7. A process according to claims 5 and 6, wherein, in step a) the suitable base is selected from sodium hexamethyl disilazide, lithium hexamethyl disilazide, in step b) the métal catalyst is Raney-Ni or Pd/C,

in step-c) the suitable acetylating agent is selected from acetyl halide, acetic
anhydride and acetic acid.

8. A process for the préparation of jV-[2-(7-methoxy-l-naphthyl)ethyl]acetamide
compound of formula-1, comprising of:

a) Aromatizing the N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide
compound of formula-7 (or) (E)-N-(2-(7-methoxy-3,4-dihydronaphthalen-l(2H)-ylidene)ethyl)acetamide compound of formula-10 with a suitable aromatizing agent in a suitable solvent to provide 7V-[2-(7-methôxy-1 -naphthyl)ethyl]
acetamide compound of formula-1,

b) optionally, purifying the compound obtained in step-a) in a suitable solvent to
provide pure compound of formula-1.

9. A process for the purification of 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydro
naphthalen-l-yl)acetonitrile compound of formula-4, comprising of:

a) Dissolving the 2-(l-hydroxy-7-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)
acetonitrile compound of formula-4 in cyclohexane by heating to higher
temperature,

b) cooling the reaction mixture,
c) stirring the reaction mixture,
d) filtering the solid to provide pure compound of formula-4.

10. N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 as a solid characterized by its DSC thermogram showing endotherm peak at
107.95°C.

11. A process for the purification of N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamidecompound of formula-1, comprising of:

a) Dissolving N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide compound of formula-1 in a suitable solvent by stirring at higher temperature,

b) cooling the reaction mixture,
c) adding aqueous base,
d) filtering the solid and washing with an aqueous base,
e) dissolving the solid obtained in step d) in a suitable solvent by heating to higher temperature,
f) treating with carbon,
g) filtering the reaction mixture and washing with a suitable solvent,
h) filtrate is added to the aqueous base and stirring the reaction mixture,
i) filtering the solid and washing with a suitable solvent to get pure compound of formula-1.

12. A process for the purification of jV-[2-(7-methoxy-l-naphthyl)ethyl]acetamide
compound of formula-1, comprising of:
a) Dissolving N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide compound of formula-1 in a suitable solvent by stirring at higher temperature,
b) adding aqueous oxalic acid solution,
c) cooling and stirring the reaction mixture,
d) filtering the solid and washing with a suitable solvent to get acid addition sait of agomelatine compound of général formula-2,
e) adding a chloro solvent to the solid,
f) adjusting the pH of the reaction mixture to 9-10 by adding an aqueous base,
g) separating the layers and distilling off the solvent from the organic layer to get pure compound of formula-1.