FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
Titles: An Improved Process For The Preparation Of Agomelatine
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Nationality: Indian
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad 380009. Gujarat. India.
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to process for preparation of N-[2-(7-methoxy naphthalan-1-yl) ethyl] acetamide commonly known as agomelatine of following formula

The present invention also relates to purification of agomelatine.

Bis-[2-(7-methoxynaphthalen-1 -yl)-ethyl]amine
N,N-Bis-[2-(7-methoxynaphthalene-l-yl)-ethyl]acetamide
The process also provides highly pure agomelatine substantially free of impurity of formula (II) and of formula (III)


BACKGROUND OF THE INVENTION
Agomelatine is the international non-proprietary name of N-[2-(7-methoxy naphthalen-l-yl)ethyl]acetamide; it is known for its antidepressant activity. Agomelatine is also a potent agonist at melatonin receptor which makes it the first melatonergic antidepressant.
Agomelatine was first disclosed in EP 0447285. Preparative process described in EP'285 patent comprises eight steps of synthesis. The process involves reaction of ethyl bromoacetate with 7-methoxy-3,4-dihydronaphtha!ene-l(2H)-one; followed by aromatisation and saponification to yield 7-methoxynaphthalen-l-ylacetic acid which is then converted to acetamide and subsequently dehydrated to obtain (7-methoxy-1-naphthyl) acetonitrile. followed by reduction to obtain ethanamine (V). In the last step of synthesis ethanamine (V) is coupled with acetyl chloride to obtain agomelatine.
Subsequently various processes are disclosed for preparation of agomelatine such as US 7,470,806; US 7,479,569; US 7,544,839: US 7,498,460; US 7,498,465; US 2010/0036162 and US 2010/0036161. The general synthetic route of agomelatine can be depicted by following scheme:


According to our search acetyl chloride or acetic anhydride is commonly used for coupling with ethanamine of formula (V) however use of these reagents can not be considered appropriate from industrial point of view due to their hazardous nature. Use of acetyl chloride generates acidic fumes which are not found to be suitable on industrial scale as it leads to corrosion of stainless steel lining of the reactor causing severe damages. Moreover the product is obtained with undesired impurities which are difficult to remove. In addition to this acetyl chloride and acelic anhydride both suffers from drawback of being hygroscopic and the reaction with these reagents is highly exothermic. These reagents decompose instantly therefore the rate of reaction is slowed or many times the reaction does not go for completion due to unavailability of the reagents.

Furthermore acetic anhydride is very difficult to handle on industrial scale owing to its irritant and flammable properties.
To evade the problems of prior art processes the present invention provides an improved process to prepare agomelatine comprising reaction of ethanamine (II) with acetic acid. Acetic acid is easily available, inexpensive and very safe to use on large scale; furthermore the generation of hazardous acidic fumes can be avoided by using acetic acid.
Since acetic acid does not decompose the reaction goes for completion which eventually results in good yield and purity of the final product i.e. agomelatine.
Besides, the process for preparation of agomelatine suffers from drawback of. formation of impurity of formula (II). This impurity is named as bis[2-(7-mehoxy)-naphthalen-l-yl)-ethylamine and is also disclosed in US 2007/0197829 and US 2010/0003161. The impurity (II) generates during the step of reduction of 7-methoxy-nphthalen-1-yl-acetonitrile (IV) to obtain 2-(7-methoxy-naphthalen-l-yl)-ethylamine (V). Acetylation of compound of formula (V) obtains agomelatine.
US 2007/0197829 disclosed that impurity of formula (II) can be controlled below 4% by the process disclosed therein. The process includes reduction of compound of formula (IV) in presence of Raney Nickel and recrystallization of compound of formula (V) and final product i.e. agomelatine from ethanoi/water. US 2010/0003161 disclose one pot reaction for preparation of Agomelatine.
The impurity (II) is formed by dimerization of two reaction intermediates and is very difficult to remove from the reaction mixture or from the product. Agomelatine obtained by the processes described in the prior art do not have satisfactory purity

for pharmaceutical use. Thus there is a need in the art for a process of obtaining pure Agomelatine substantially free of impurity {II).
It has been observed by the present inventors that purification of compound of formula (V) or the final product i.e. Agomelatine by various solvents does not result into removal of impurity (II) to the level acceptable for pharmaceutical ingredient.
The present inventors have also observed that if the compound of formula (V) is taken forward for acetylation without purification; the impurity (II) also gets acetylated and get converted in to acetylated impurity of formula (III). Acetylated impurity (III) can be removed by purification of crude Agomelatine from selected solvents.
Hence the present application provides a process for preparation of highly pure Agomelatine which is substantially free of impurity (II) and impurity (III). The process of the present application is also simple, industrially feasible and results into high yield of Agomelatine.
Thus the present invention provides simple, safe and robust process to prepare agomelatine.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for preparation of agomelatine and its purification.
Another object of the invention is to provide pure agomelatine, substantially free of impurity (II) and (III)

Another object of the present invention is to provide a safe, cost effective and industrially viable process for preparation of agomelatine.
SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of agomelatine According to an aspect of the invention the process comprises reacting 2-(7-methoxy naphthalen-l-yl)ethanamine (V) or its acid addition salt with acetic acid to obtain agomelatine.
In another aspect the process of present application comprises purification of crude Agomelatine from aromatic hydrocarbon solvents.
The invention also provides highly pure Agomelatine substantially free of dimer impurity of formula (II) and acetylated dimer impurity of formula (III).
In another aspect the present invention provides an isolated acetylated dimer impurity of formula (III).
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 is a Mass Spectrum of acetylated dimer impurity (III) is a characteristic NMR of acetylated dimer impurity of formula (111).
Figure 2 is a characteristic infrared (IR) spectrum of acetylated dimer impurity (III)
Figure 3 is a characteristic NMR of acetylated dimer impurity of formula (III).

DETAILED DESCRIPTION
In accordance with the invention, there is an improved process for preparing agomelatine (1) from 2-{7-methoxy naphthalen-1-yl) ethanamine (V) or its salt (VA) by reacting with acetic acid. Preferably, the reaction is carried out in presence of a coupling agent. The process can be depicted by following scheme.

The first step in preparation comprises hydrogenation of (7-Methoxynaphthalen-l-yl)-acetonitrile of formula (IV). Hydrogenation can be carried out by any conventionally known process such as the process disclosed in EP 0447285 or by the process provided by present invention.
Preferably the reducing agent employed in present process is raney nickel but any other reducing agent suitable for the process can be used. The reaction is carried out in presence of solvent and base. The solvent can be selected from any conventional solvent especially preferred solvents are alcohols such as C1-C4 straight or branched chain alcohol preferably methyl alcohol is used in present process.

The base employed in step of hydrogenation can be selected appropriately from known base preferably ammonia is used in present process.
The reaction may be carried out at suitable temperature, either under heating or reflux the preferred temperature for hydrogenation is 50-70 °C.
On completion of reaction the product can be isolated as free amine of formula (V) or it can be converted to its acid addition salt.
For isolation of free amine (V) the catalyst can be separated by filtration followed by concentration of filtrate to give compound of formula (V). Alternatively the compound of formula (V) can be convened to its acid addition salt (VA). The process for preparing acid addition salt (VA) comprises reacting ethanamine of formula (V) with desired acid.
The acid may be selected from any known ones such as inorganic acid for example hydrochloric, hydrobromic or organic acids for example acetic acid or maleic acid. Especially preferred acid is hydrochloric acid. If desired the salts thus obtained can be converted to their free form by methods known conventionally.
The intermediate of formula (V) or its acid addition salt (VA) obtained as above is converted to agomelatine the reaction comprises coupling with acetic acid. Preferably the process is carried out in presence of a coupling agent: if required a base can also be used.
The process surpasses use of hazardous reagents which makes it safe to handle on large scale.

The suitable coupling agent, which may be used in present invention can be any known coupling agent used for acid amine coupling reaction. Preferably the coupling agent may be selected from carbodimide derivatives such as dicyclohexyl carbodimide. N-N'-ditertbutyl carbodimide. N-N'-diisopropyl carbodimide, 1.3-di-p-tolyl carbodimide. I-tert-butyl-3-ethyl carbodimide, N-(3-dimethyi aminopropyl)-N'-ethyl carbodimide preferably dicyclohexyl carbodimide commonly known as DCC is used for this purpose.
Suitably the reaction is carried out in presence of a solvent. The solvent may be any organic solvent. The base employed in the reaction may be selected from an organic or inorganic class of compound.
The process may be carried at suitable temperature, either under cooling or at ambient temperature, heating or reflux temperature of the solvent.
On completion of the reaction, the reaction mixture can be cooled and the product i.e. agomelatine (I) can be recovered from the reaction by conventional manner such as by concentrating the reaction mixture.
Agomelatine thus obtained can be purified by any suitable solvent such as alcohol or ether for example diisopropyl ether; alkyl nitrile; ketone or combination with water or mixture thereof in various proportions.
To remove impurity (III) the crude agomelatine is preferably purified/recrystallised from aromatic hydrocarbon.

Accordingly, the invention provides a process for preparing highly pure agomelatine. comprising purification of crude agomelatine from solvent selected from group consisting of aromatic hydrocarbon especially toluene.
It was observed by present inventors that it is difficult to remove dimer impurity (I!) to the desired level thai is almost below 0.15% (to meet the ICH i.e. international conference on harmonization of technical requirement for registration of pharmaceutical for human use) by purification from solvents. The dimer impurity (II) generated in step I (scheme 1) gets converted into acetylated impurity (111) during the process of step II (scheme I). After extensive experimentation it was observed that impurity (III) can be removed to a desired level by purification from selected solvents. During the process of step II. the impurity (11) almost completely gets converted to impurity (III) so there does not remain any need to remove impurity (II) neither from intermediate of formula (V) nor from the final product Agomelatine.
Thus the process comprises taking intermediate of formula (V) for acetylation without purification. The intermediate (V) generally contains 2-7% of dimer impurity (II). In the process the dimer impurity (II) also gets acetylated and converts to impurity (III) which is referred here as acetylated impurity of Agomelatine.
After completion of reaction of step II (scheme I), the crude Agomelatine is taken in a solvent. The exemplary solvents used for purification of crude Agomelatine include but not limited to aromatic hydrocarbons such as toluene, benzene, xylene etc. and mixture thereof
The suspension obtained by mixing crude Agomelatine and desired solvent can be heated to obtain clear reaction mixture. The reaction mixture can be heated from 30

°C till reflux of the solvent used and can be maintained at the same for 30 minutes to 5 hours. The pure Agomelatine can be isolated from the reaction mixture by cooling the reaction mixture. The reaction mixture can be cooled to a temperature lower than reflux temperature of the solvent used. Preferably the reaction mixture can be cooled to 0-30 °C. The pure Agomelatine can be isolated from the reaction solution by filtration, decantation or centrifugation,
The highly pure Agomelatine thus obtained may be further dried for example in vacuum dryer or any generally known technique.
The total purity of the Agomelatine obtained by the process disclosed herein is of greater than 99.5%, specifically about 99.9%.
In one embodiment, the highly pure Agomelatine disclosed herein comprises acetylated impurity of formula (III) in an amount less than 0.1 area %., more specifically less than 0.05 area % still more specifically free of acetylated impurity (III).
In another embodiment the highly pure Agomelatine disclosed herein is substantially free of dimer impurity more specifically essentially free of dimer impurity (II).
In an embodiment there is provided an isolated impurity (III). Agomelatine acetylated dimer impurity formed during synthesis of agomelatine has been identified, isolated and synthesized. The impurity (III) was detected and resolved from agomelatine by HPLC with RRT of 2.55. The structure of compound (III) was deduced with the aid of '1H. Mass. and IR spectroscopy.

The process of present application is very simple and efficient and provides pure Agomelatine without any need for laborious purification and the product is obtained in high yield.
The starting material (7-Methoxynaphthalen-l-yl)-acetonitri!e. can be prepared by methods known in art such as by process disclosed in EP 0447285.
EXAMPLES:
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.
Example 1: Preparation of 2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride (III)
100g of (7-methoxynaphthalen-l-yl)-acetonitrile; 200ml of liq. ammonia; 30g raney nickel and 500 ml of methanol were taken in autoclave. The reaction mixture was stirred at 55°C-60°C under hydrogen pressure 6-8 kg/cm2 .The reaction was monitored by TLC; after completion of reaction the reaction mixture was filtered to separate the catalyst. The filtrate was concentrated to yield residue. The residue was dissolved in 400 ml of ethyl acetate followed by addition of hydrochloric acid to obtain salt. The reaction mixture was cooled to 0-5 °C followed by filtration to obtain solid. The solid thus obtained was dried to obtain 95 g of title compound.
Example 2: Preparation of N-[2-(7-methoxy naphthalene -1-yl) ethyl]acetamide
10g of 2-(7-methoxynaphthalen-1-yl)elhanamine or hydrochloride. 100ml dichloromethane. 10.76g. dicyclohexylcarbodimide. 1.21g dimethylaminopyridine

and 3.28g acetic acid were taken in a round bottom flask, the reaction mixture was stirred for 2 hours while maintaining the temperature between 25-3 5°C. after completion of reaction the reaction mixture was cooled to 0-5°C followed by filtration to separate undissolved material. The filtrate was washed with IN HCI solution and than concentrated under vacuum, the solid thus obtained was dried to obtain 8g of title compound.
Example 3: Preparation of N,N-Bis-[2-(7-methoxy naphthalcne-1-yl)-ethyl]-acetaamide (HI)
10g of Bis-[2-(7-methoxy-naphthalen-l-yl)-ethyl]-amine (II) or Hydrochloride, 100ml dichloromethane, 6.42g. dicyclohexylcarbodimide, 0.63 g dimethylaminopyridine and 2.02g acetic acid were taken in a round bottom flask, the reaction mixture was refluxed for 4-6 hours, after completion of reaction the reaction mixture was cooled to 0-5°C followed by filtration to separate undissolved material. The filtrate was washed with IN HC1 solution and then concentrated under vacuum; the solid thus obtained was dried to obtain 7.8g of title compound.
Example 4: Purification of Agomelatine (I)
Crude Agomelatine (90g) was taken in 270ml of toluene. The suspension thus obtained was heated to 60-65 °C, The clear reaction mixture thus obtained was stirred at the same temperature for 2 hours. The reaction mixture was cooled to 0-5 °C. The separated solid was filtered, washed with toluene (20.0 ml) and then dried under vacuum at 55-60 °C for 8-10 hours to obtain 80g of the title compound with purity 99.9%.

Example 5: Purification of Agomelatine (I)
50 g of compound as obtained by following example 3 and methanol 200ml were taken in a round bottom flask; the mixture was stirred for 30 minutes at 25-30°C. 400 ml water was added to the reaction mixture and it was cooled to 3 0-15°C.Tbe reaction mixture was filtered and the solid thus obtained was washed with aqueous methanol; followed by drying to obtain 45 g of title compound.


CLAIMS:
1. A process for preparation of agomelatine (1)
which comprises reacting 2-{7-methoxynaphthalen-l-yl)ethanamine) (V) or its acid addition salt

HA-Acid capable of forming salts, with acetic acid.
2. A process as claimed in claim 1. wherein acid addition salt is selected from salt of inorganic acid or organic acid.
3. A process according to claim 7, wherein inorganic acid is selected from hydrochloric acid or hydrobromic acid.
4. A process according to claim 2, wherein organic acid is selected from acetic acid or maleic acid.
5. A process of claim 1 further comprises purification of agomelatine from aromatic hydrocarbon.

6. A process as claimed in claim'6, wherein aromatic hydrocarbon is selected from toluene, xylene.
7. Agomelatine (I) substantially free of impurity of formula (III).
8. Agomelatine (I) substantially free of impurity (II).
9. An impurity of formula (III)

10. A process for preparing agomelatine substantially free of impurity (III) comprising
a. providing a solution of agomelatine in a solvent;
b. recovering pure agomelatine.