FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF AGOMELATINE"
DISHMAN PHARMACEUTICALS AND CHEMICALS LTD
BHADR-RAJ CHAMBERS, SWASTIK CROSS ROADS
NAVRANGPURA, AHMEDABAD-380009
GUJRAT-INDIA
The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Agomelatine, as represented in Formula I.

BACKGROUND OF THE INVENTION
Agomelatine is chemically known as (N-[2-(7-methoxynaphthalen-l-yl)ethyl]acetamide, as represented in Formula I and is marketed under the brand name Valdoxan® / Thymanax®.
Agomelatine has dual pharmacological effects, which is not only the agonist of melatonergic system receptors, but also the antagonist of 5HT2C receptor. Said properties confer activity in the central nervous system, especially in the treatment of major depression, seasonal affective disorders, dyssomnia, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin type antidepressive agent, which can effectively treat depressive disorders, improve the sleep parameters and maintain sexual function.
US 5225442 describes a process for the preparation of Agomelatine starting from 7-methoxy tetralone, in which yields are less than 30%. This process involves the reaction of ethyl bromoacetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-1 -naphthyl) acetonitrile, which on reduction to amine and subsequent reaction with acetylchloride to give Agomelatine of formula I. The process is as illustrated below:


In particular, the conversion of (7-methoxy-1-naphthyl)acetamide to (7-methoxy-1-naphthyl)acetonitrile involves the use of Trifluoroacetic anhydride, which is onerous during the large scale manufacturing of Agomelatine. Further, special precautions has to be taken for handling this reagent and hence this process is not industrially and commercially cost effective.
WO2014/001939 discloses a process for the preparation of (7-methoxy-1 -naphthyl)acetonitrile, comprising dehydration of (7-methoxy- l-naphthyl)acetamide using a dehydrating agent selected from the group consisting of POC13 or combination of Ethyldichlorophsophate and DBU or P205 or mixture there of in presence of a non-polar solvent selected from Toluene, Xylene, n-heptane, n-hexane and cylohexane.
The present inventors found that if the content of dehydrating agent is greater than 0.8 mole the color of the product is observed as pale brown and additional purification is required to remove the color.

Further, the prior art processes involve the use of expensive reagents, additional purifications and laborious process for the preparation of Agomelatine. Hence, there is a need in the art to develop an improved process for the preparation of Agomelatine.
The present inventors have now found an improved process for the preparation of Agomelatine, which is simple, industrially applicable and yields Agomelatine in high purity.
DISADVANTAGES OF PRIOR ART
The present inventors has repeated the above process and found the following disadvantages:
> most of them involve highly costly, toxic, flammable and hazardous reagents.
> Unwanted reactions observed during the formation of nitrile intermediate of formula (II), with the use of more dehydrating reagent
> most of the reactions do not provide high purity and good yield of Agomelatine.
> most of the reactions are taking place at high temperature.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for preparation of Agomelatine, which facilitate significantly high yield and significantly high purity Agomelatine.
Yet another objective of the present invention is to provide an improved process for preparation of (7-methoxy-l-naphthyl)acetonitrile, which is simple, industrially applicable and economically viable.
Yet another objective of the present invention is to provide an improved process for preparation of (7-methoxy-l-naphthyl)acetonitrile, which is carried out at room temperature and does not involve additional purification.
Yet another objective of the present invention is to provide an improved process for Agomelatine, which is simple and industrially applicable.

Yet another objective of the present invention is to provide an improved process for preparation of Agomelatine, which is economic and viable.
SUMMARY OF INVENTION
The present invention relates to an improved process for preparation of Agomelatine, as represented in Formula I.

which comprises:
a) treating (7-methoxy-1 -naphthyl)acetamide of Formula (II)

with a dehydrating agent in presence of a solvent at a temperature below 30°C to yield (7-methoxy-l-naphthyl)acetonitrile compound of Formula (III)

b) reducing the (7-methoxy-l-naphthyl)acetonitriIe compound of Formula (III) to give an amine intermediate of Formula (IV)


c) converting the amine intermediate of Formula (IV) to Agomelatine
The present invention further relates to an improved process for preparation of (7-methoxy-1 -naphthyl)acetonitrile compound of Formula (III), which is a useful as an intermediate in the preparation of Agomelatine comprises treating (7-methoxy-l-naphthyl)acetamide with a dehydrating agent in presence of a solvent at a temperature below 30°C.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Agomelatine.
Another aspect of the invention is to provide a process for preparation of (7-rnethoxy-l-naphthyI)acetonitrile compound of Formula (III).
The said process comprises of treating (7-methoxy-1-naphthyl)acetamide with a dehydrating agent, selected from POCI3 or combination of Ethyldichlorophsophate and DBU or P205 or mixture there of, preferably in the presence of POC13 in presence of a solvent selected from aprotic solvents such as dimethyl formamide, dimethyl acetamide, Tetrahydrofuran, Ethylacetate, Acetone, Acetonitrile, Dimethyl sulphoxide; Protic solvents such as methanol, ethanol, Isopropanol, n-butanol, nitromethane, n-propanol; hydrocarbons such as toluene or xylene, n-hexane, n-heptane, cyclohexane and water or mixture thereof; at a temperature below 30°C, preferably at a temperature ranging from 20 to 30°C; more preferably at 23 to 27°C to yield (7-methoxy-1-naphthyl)acetonitrile. The nitrile intermediate thus formed is carried for next stage.
The present inventors found that the use of dehydrating agent greater than 0.8 mole and use of non-polar solvent leads to the formation of pale brown colored product, which in term changes

the color of the final product. Hence, additional purification is required to remove the color, which is highly costly and decreases the percentage of the yield.
The present inventors found that if the content of dehydrating agent is less than 0.8 mole there is no color issue and the yield of the product is also improved, when compared to the prior art processes.
Further, the present inventors also found that if the content of dehydrating agent is less than 0.8 mole then the reaction is proceeding at a temperature below 30°C, preferably at a temperature ranging from 20 to 30°C; more preferably at 23 to 27°C, which is industrially feasible and cost effective.
The nitrile intermediate thus formed is reduced to give amine intermediate of Formula (IV), using a reducing agent selected from transition metals such as palladium-carbon, platinum oxide, Raney nickel in presence of hydrogen or hydrogen source selected from ammonium formate, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; esters such as ethyl acetate, methyl acetate; toluene; xylene; tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5-70°C. The amine intermediate thus formed is used for next stage
The amine intermediate of Formula (IV) thus formed is converted in to Agomelatine by treating with an acetyl chloride in presence of pyridine and a solvent selected from Isopropyl ether, methyl tertiary butyl ether, diethyl ether, preferably Isopropyl ether, at a temperature ranging from 30 to 50°C. The obtained Agomelatine is isolated and recrystallized using a suitable solvent.
The present inventors found that the present invention is advantageous over prior-art by avoiding use of more dehydrating agent and high temperature. The present inventors have found that the unwanted reactions are observed during the formation of nitrile intermediate of Formula (III) by using excess trifluoroacetic anhydride at high temperature. Further, the yield of the present invention is comparatively high when compared with the prior-art process.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Example-1
Preparation of 2-(7-Methoxynaphthyl)Acetonitrile
(7-methoxynaphth-l-yl)acetamide (85 gm, 0.39 mole) was suspended in Dimethyl formamide (170 ml, 2 vol). To the resulting solution Phosphorous Oxychloride (44.75 gm, 0.29 mole) was added at 25-30°C and maintained for 1 hour. The resulting reaction mass was charged into to pre-cooled DM Water (425 ml) at 0-5°C. Filtered the solid, washed with DM Water, recrystallized with methanol and dried to yield the title compound.
Yield: 57.5 gm
Chromatographic Purity (by HPLC): > 99.5 (% area)
Example-2
Preparation of 2-(7-methoxynaphthyl)ethanamine hydrochloride
A mixture of 2-(7-methoxynaphthyl)acetonitrile (65 gm, 0.33 mole), methanolic ammonia (975 ml), 26.15 gm of Raney Ni was stirred in hydrogen atmosphere (Hydrogen gas pressure up to 8 kg) at 38-40°C for 3 hours to 4 hours. Filtered the reaction mass and distilled out solvent completely. Isopropanol (520 ml) was added to the residue and then a mixture of Hydrochloric acid in Isopropanol(75.4 ml) was added at 25-30°C. The resulting mixture was sirred for one hour. Filtered the solid, washed with Isopropanol and dried to yield the title compound.
Yield: 55 gm
Chromatographic Purity (by HPLC): >99 (% area)

Example-3
Preparation of Agomealtine
A mixture of 2-(7-methoxynaphthyl)ethanamine hydrochloride (50 gm), methylene chloride (225 ml), water (50 ml), aqueous Potassium carbonate solution (69.55 gm Potassium carbonate in 100 ml water) was stirred at 25-30°C. The mixture was cooled in an ice bath with agitation and acetyl chloride (19.75 gm) was added drop wise. Maintain stirring till the completion of reaction. Separate the organic layer, washed with brine solution and distilled off the solvent completely under vacuum to yield the Agomelatine. Recrystallized with Toluene:Hexane (2:1) to yield Agomelatine in crystalline Form I.
Yield: 47 gm
Chromatographic Purity (by HPLC): > 99. 9 (% area)

We claim:
1) An improved process for preparation of Agomelatine, as represented in Formula I.

which comprises:
d) treating (7-methoxy-1 -naphthyl)acetamide of Formula (II)

with a dehydrating agent in presence of a solvent at a temperature below 30°C to yield (7-methoxy-1-naphthyl)acetonitrile compound of Formula (III)

e) reducing the (7-methoxy-1-naphthyl)acetonitrile compound of Formula (III) to give an amine intermediate of Formula (IV)

f) converting the amine intermediate of Formula (IV) to Agomelatine
2) The process according to claim 1, wherein dehydrating agent, selected from POC13 or combination of Ethyldichlorophsophate and DBU or P205 or mixture there of, preferably in the presence of POC13

3) The process according to claim 1, wherein solvent selected from aprotic solvents such as
dimethyl formamide, dimethyl acetamide, Tetrahydrofuran, Ethylacetate, Acetone,
Acetonitrile, Dimethyl sulphoxide; Protic solvents such as methanol, ethanol,
Isopropanol, n-butanol, nitromethane, n-propanol; hydrocarbons such as toluene or
xylene, n-hexane, n-heptane, cyclohexane and water or mixture thereof;
4) The process according to claim 1, wherein reducing agent selected from transition metals such as palladium-carbon, platinum oxide, Raney nickel in presence of hydrogen or hydrogen source selected from ammonium formate, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; esters such as ethyl acetate, methyl acetate; toluene; xylene; tetrahydrofuran; dioxane or mixture thereof
5) An improved process for preparation of (7-methoxy-1 -naphthyl)acetonitrile compound of Formula (III), which is a useful as an intermediate in the preparation of Agomelatine comprises treating (7-methoxy-l-naphthyl)acetamide with a dehydrating agent in presence of a solvent at a temperature below 30°C.

6) The process according to claim 5, wherein the use of dehydrating agent is not greater than 0.8 mole.
7) The process according to claim 5, wherein the use of dehydrating agent is preferably 0.7 to 0.8 mole.
8) The process according to claim 5, wherein dehydrating agent, selected from POC13 or
combination of Ethyldichlorophsophate and DBU or P205 or mixture there of, preferably
in the presence of POC13
9) The process according to claim 5, wherein solvent selected from aprotic solvents such as
dimethyl formamide, dimethyl acetamide, Tetrahydrofuran, Ethylacetate, Acetone,
Acetonitrile, Dimethyl sulphoxide; Protic solvents such as methanol, ethanol, Isopropanol,

n-butanol, nitromethane, n-propanol; hydrocarbons such as toluene or xylene, n-hexane, n-heptane, cyclohexane and water or mixture thereof;
10) A process for the preparation of Agomelatine substantially as herein described with reference to the examples.