FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10; rule 13)
1. TITLE OF THE INVENTION-
PROCESS FOR THE PREPARATION OF AGOMELATINE
2. APPLICANT(S)
(a) NAME: MEHTA API PVT. LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 203, Centre Point, J B Nagar, Andheri (East),
Mumbai 400059
3. PREAMBLE TO THE DESCRITION
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 improved processes useful for preparation of Agomelatine of formula (1). More specifically the present invention relates to a process suitable for industrial production of Agomelatine employing use of easy to handle and safe reagents along with simpler and fewer unit process operations. Furthermore the present invention relates to an improved process for controlling N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-acetamide impurity of formula (II).

BACKGROUND OF THE INVENTION
Agomelatine, N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, is a melatonin receptor agonist, and is a new antidepressant and antianxiety drug. EP0447285 discloses the chemical structure of Agomelatine. and the use of Agomelatine as an antianxiety drug, an antidepressant, and an antipsychotic drug. Agomelatine has a chemical structure represented by formula (i).
A number of methods for the preparation of Agomelatine have been reported. Patent specification EP0447285 describes production of Agomelatine by using pyridine as base for acylation. Use of pyridine is not feasible on industrial scale given its carcinogenic and neurotoxin properties. Also use of pyridine leads to increased ETP load thereby rendering process not environmentally friendly.
WO2012070025A1 and WO2012172387A1 discloses acylation by using Di-isopropyl ethyl amine and Triethylamine as base respectively. Use of organic bases like pyridine, thehtylamine, di-isopropylethyl amine and like is not advisable on industrial scale because of difficulty in handling as well as environment concerns during aqueous work-up and distillation of reaction mass having organic bases.
EP1564202 & WO2013080095A1 discloses process for acylation using sodium acetate as base in ethanol and methanol respectively at higher reflux temperatures and tedious workup involving concentration and aqueous extractions.
EP2580189A1 discloses process for acylation using sodium acetate as base in Tetrahydrofuran hence rendering the process economically as well as environmentally not . feasible on industrial scale.
WO2014001939 discloses acylation with acetic anhydride in acetic acid followed by quenching in water.
EP 2322508 B1 discloses acylation in using sodium acetate as base but involving tedious aqueous extraction workup.
EP2151427B1 discloses reductive acylation with hydrogen gas using raney nickel as catalyst in acetic anhydride at a higher temperature of 70°C and higher volume of acetic anhydride, approx 3 volumes of starting material followed by distillation of reaction mass. Given the safety and environmental concerns higher volumes and distillation of acetic

anhydride reaction mass is not advisable on industrial scale. Similarly various processes
have been reported most of which use organic bases or employ harsher reaction
conditions or tedious isolation.
WO2012093402 and US20100036161 discloses controlling N, N-Bis-[2-(7-methoxy-
napthalen-1-yl)-ethyl]-acetamide impurity of formula (II) by separate purification involving
crystallization of crude Agomelatine with different organic solvents thus resulting in yield
loss of the product as welt as increased processed time cycle and number of unit
operations for the process.
In view of the problems occurred in above methods, there remains a need for an improved
process, which is environment friendly and can be easily performed on an industrial scale
with shortened process timecycle along with lesser number of unit operations to give
better yield and quality of product.
All the referenced patents and applications are incorporated herein by reference in their
entirety. Furthermore, where a definition or use of a term in a reference, which is
incorporated by reference herein, is inconsistent or contrary to the definition of that term
provided herein, the definition of that term provided herein applies and the definition of
that term in the reference does not apply.
SUMMARY OF THE INVENTION
The present invention is directed to improved processes for the preparation of N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide (also known as Agomelatine), which overcomes the disadvantages of the formerly known methods.
According to one aspect of the invention, there is provided a process for preparation of Agomelatine which comprises of reduction of 2-(7-methoxynaphthalen-1 -yl) acetonitrile by hydrogen gas in the presence of Pd or Raney Ni catalyst in alkanolic solution of ammonia followed acylation of 2-(7-methoxynaphthalen-1 -yl) ethanamine using an acylating agent in organic solvent in presence of an inorganic alkali metal carbonate base.
According to another aspect of the invention, there is provided a process for preparation of Agomelatine by controlling formation of undesired dimer impurity N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-acetamide of formula (II), by employing use of alkanolic ammonia having appropriate concentration of ammonia, to give pure Agomelatine thereby avoiding further purifications.
According to still another aspect of the invention, there is provided a simpler process for isolating Agomelatine employing use of toluene, thereby avoiding the need for tedious work-up which involves aqueous extractions and separation followed by distillation of organic solvent.
Yet still another aspect of the invention, there is provided a process for preparation of the Agomelatine, which comprises the step of reacting 2-(7-methoxy-1-naphthyl)ethylamine or its salt with an acylating agent in presence of an inorganic alkali metal carbonate base to give Agomelatine
The process for the preparation of Agomelatine according to the invention provides for a number of advantages.. The synthetic route involves use of commercially available inexpensive inorganic bases instead of organic bases, thus avoiding the need for distillation to strip out organic bases from the reaction mass hence rendering process more environment friendly as organic bases lead to higher ETP load Also organic bases are difficult to handle on industrial scale given their irritant properties, in contrast to

inorganic bases which are easier to handle. The present invention also provides a process for controlling the formation of dimer impurity during reaction to give product of desired quality without requiring further purifications of final product. The reaction conditions are mild and easy to perform with much simpler isolation of final product thereby avoiding the need for tedious conventional work-up involving aqueous extractions and separation followed by distillation of organic solvent leading to significant reduction of time cycle required for the processes. In addition, the process according to the invention is suitable for industrial use.
DETAILED DESCRIPTION OF THE INVENTION

with hydrogen gas under pressure in presence of Pd/Raney Ni catalyst in alkanolic solution of ammonia having appropriate concentration to obtain 2-(7-methoxynaphthalen-1 -yl) ethanamine of formula (IV).

2-(7-methoxynaphthaien-1 -yl) ethanamine (formula il) is optionally isolated as its acid addition salt of formula (V).

In accordance with the present invention to provide the process for the preparation of Agomelatine the synthetic steps comprises of, reducing 2-(7-methoxynaphthalen-1 -yl) acetonitrile of formula (III),
2-(7-methoxynaphthalen-1 -yl) ethanamine or its acid addition salt on acetylating in suitable organic solvent in presence of inorganic base yields Agomelatine (formula I). The present invention is further elaborated below:
In accordance with one aspect of the present invention to provide the process for the preparation of Agomelatine the synthetic steps comprises of,
A) reducing 2-(7-methoxynaphthalen-1 -y!) acetonitrile of formula (III), with hydrogen gas under pressure in presence of Pd/Raney Ni catalyst in alkanolic ammonia solution having appropriate concentration to give 2-(7-methoxynaphthalen-1 -yl) ethanamine of formula (IV).
After the completion of reaction the catalyst is recovered from the reaction mass by filtration followed by concentration of filtrate to give concentrated mass of 2-(7~ methoxynaphthaien-1 -yl) ethanamine of formula (IV), which is further proceeded to acyiation.
The alkanol used in stage-A is selected from a group comprising of methanol, ethanol, isopropanol, n-butanol, or a combination thereof. Alkanol used in stage-A is preferably methanol.

Concentration of ammonia in the alkanolic ammonia solution used in stage-A may be
ranging from but not limiting to about 10% to 40% w/v.
Concentration of ammonia in the alkanolic ammonia solution used is preferably about 30%
to 35% w/v.
Reducing agents that may be used in this stage include but are not limited to Pd on
carbon, raney nickel, or Pd(OH)2 under a hydrogen atmosphere.
The reduction may be carried out at temperature ranging from about 0°C to about 75°C or
higher.
The reduction temperature range is preferably 50°C to 55°C
The reaction may be carried out at a pressure ranging from about 0 kg/cm2 to about 12
kg/cm2 or higher.
The reaction pressure is preferably 10 kg/cm2
The reaction time and the temperature shouid be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products.
2-(7-methoxynaphthalen-1 -y!) ethanamine (formula IV) is optionally isolated as its acid addition salt of formula (V),by reacting the compound of (formula II) with acid optionally in suitable solvent.
The acid addition salt is prepared by using acid selected from a group of acids comprising of hydrochloric acid, sulfuric acid, phosphoric acid, p - toluenesulphonic acid, methanesulphonic acid, benzenesulphonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid.
The suitable solvent used as mentioned above is selected from a group of solvents comprising of halogenated solvents like dichloromethane, ethylene dichloride, chloroform, chlorobenzene, alcohols like methanol, ethanol, esters like ethyl acetate, isopropyl acetate, tertiary butyl acetate, hydrocarbons like cyclohexane, toluene, xylene, or mixtures thereof in various proportions.
B) 2-(7-methoxynaphthalen-1 -yl) ethanamine or its salt is reacted with an acetylating agent such as acetic anhydride acetic anhydride or acetyl chloride in presence of alkali metal carbonate base and suitable solvent to produce Agomelatine of formula
(I),
The suitable solvent used in Stage-B, is selected from a group of solvents comprising of
hydrocarbons like toluene, xylene, cyclohexane; halogenated solvents like
dichloromethane, ethylene dichloride, chloroform, chlorobenzene; alcohols like methanol,
ethanol; esters like ethyl acetate, isopropyl acetate, tertiary butyl acetate; or mixtures
thereof in various proportions.
The suitable solvent is preferably toluene, dichloromethane or mixtures thereof.
After the completion of reaction the inorganic base is filtered out from the reaction mass
and Agomelatine is isolated from suitable solvent.
Solvent used for isolation of Agomelatine is preferably toluene, ethyl acetate, or mixture
thereof.
The base used in Stage-B to produce Agomelatine is selected from a group of comprising
of alkali metal carbonates such as sodium carbonate, potassium carbonate and the likes;
alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate and the
likes.
The base used is Stage-B is preferably sodium bicarbonate.
The reaction may be carried out at temperatures ranging from about but not limiting to -
10°C to 30°C, preferably at 3°C to7°C.

In accordance with another aspect of the present invention, one embodiment provides a
process for controlling N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-acetamide impurity of formula (II) in the final product by controlling its precursor N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethy!]-amine impurity of formula (VI), formed during the reduction reaction,

by employing use of methanolic ammonia having appropriate concentration of ammonia affecting the control of impurity of formula (VI) during Stage-A, consequently controlling the impurity of formula(ll) in the final stage thereby avoiding additional purification to obtain the product of desired quality
It has been observed that during the reduction reaction to obtain the compound of formula (III), there is formed N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-amine impurity of formula (VI), which during further acylation reaction gets acylated to the corresponding N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-acetamide impurity of formula (II), rendering the need for additional purifications, thereby resulting in yield loss and increased unit process operations as well as process time cycle. Formerly known methods have employed separate purifications of the crude product obtained to get Agomeiatine with N, N-Bis-[2-(7-methoxy-napthalen-1-yl)-ethyl]-acetamide impurity of formula (I!) in specified limits. The applicant have investigated the effect of concentration of methanolic ammonia on the formation of the impurity of formula (VI), which gets further acylated during subsequent stages to form impurity of formula (II), and found that the percentage of the impurity of formula (VI) formed is dependent on the concentration of methanolic ammonia. The effect of concentration of ammonia in methanol on the formation of impurity of formula (VI) is studied in detail and is represented as below in the given Table I
Table I:

Sr.N
0. Concentration of
Ammonia
(%w/v) impurity of formula (Vl)(%) 2.78%
1 -35%

2 -30% 2.86% 3.68%
3 -25%

4 -20% 4.07% 4.68% "4.95%'
5 -15%

6 -10%

7 -0% 35.65%.
Concentration of ammonia in the methanolic ammonia solution used in stage-A may be ranging from but not limiting to about. 10% to 40% w/v.
Concentration of ammonia in the methanolic ammonia solution used is preferably about 35% w/v.
Another aspect of the invention provides a simpler process for isolating the Agomeiatine thereby avoiding the need for tedious work-up involving aqueous extractions and separation followed by distillation of organic solvent, comprises reacting 2-(7-

methoxynaphthaien-1 -yt) ethanamine or its salt with an acetylating agent such as acetic anhydride or acetyl chloride In presence of alkali metal carbonate base in toluene to produce Agomelatine of formula (I)
One embodiment according to this aspect of the invention provides a process for preparing Agomelatine wherein Agomelatine precipitates out as the reaction forwards which is then isolated from reaction mass by filtration after the completion of reaction. The said embodiment of the invention comprises of:
1) reacting 2-(7-methoxynaphthalen-1 -yi) ethanamine or its salt with an acylating agent such as acetyl chloride or acetic anhydride in presence of alkali metal carbonate base in toluene.
2) after completion of the reaction, cooling the reaction mass to a temperature below 25°C, preferably at 0° + 2 C filtering the reaction mass, followed by water
. washings to the residue to provide Agomelatine of formula (I).
The reaction may be carried out at temperature ranging from about but not limiting to -
10°C to about 30°C.
The reaction temperature range is preferably 3°C to 7°C.
Another embodiment according to this aspect of the invention provides a process for
synthesizing Agomelatine comprising heating the reaction mass at about 30°C to 55 °C
after the completion of reaction in step 1), followed by water washing to the reaction mass
at same temperature. The resultant organic layer obtained after separation is cooled to a
temperature range of about but not limiting to 0°C to 5 °C to crystallize the product
followed by filtration to provide Agomelatine of formula (I).
The reaction mass is preferably heated to 50°C
Another embodiment according to this aspect of the invention provides a process for
preparing Agomelatine comprising heating the reaction mass at about 60°C to 80 °C after
the completion of reaction in step i), followed by filtration of reaction mass. Filtrate so
obtained is optionally given water washing and cooled but not limiting to about 0°C to 5
°C to crystallize the product and filtered to provide Agomelatine of formula (I) wherein the
isolated products exhibits the following XRD peaks expressed in terms of Bragg's Angle
20 at 10.47, 12.60, 15.27, 15.76, 17.12, 18.57. 18.98, 20.03, 20.08 and 24.16.
The reaction mass is preferably heated to 65°C
Thus the present invention provides an improved process with respect to simplified
process as well as better yield and quality.
EXAMPLES
The following examples are used to illustrate the invention, but are not intended to limit the invention in anyway.
Example I): Preparation of 2-(7-methoxynaphthalen-1 -yl) ethanamine, formula (IV) To (1000 ml) methanolic ammonia solution of concentration approx. 35%w/v in an autoclave vessel, is charged (100g) 2-(7-methoxynaphtha!en-1 -yl) acetonitrile of formula (III), raney nickel(1g). The reaction mass is heated to 50-55°C under hydrogen pressure of approx. 10±2Kg/cm and maintained at same temperature till the reaction complies. After the reaction complies, reaction mass is cooled to room temperature, filtered followed by concentration & degassing under vacuum at 40-45°C to obtain the title compound. Weight.-100.2gms (oily mass), HPLC:96.08%, Dimer impurity: 2.86%

Example II): Preparation of 2-(7-rnethoxynaphthalen-1 -yl) ethanamine Hydrochloride,
formula (V)
To a solution of 100 gm 2-(7-rnethoxynaphthaien-1 -yl) ethanamine (oily mass) in (1000 ml) ethyl acetate is added 10% Ethyl acetate hydrogen chloride (200 ml) was added at 10-15°C. The reaction mixture was stirred at room temperature for 2 hr, filtered and evaporated to dryness to obtain 2-{7- methoxynaphthaien-1 -yl) ethanamine hydrochloride Dry Weight- 100.4gms. HPLC:96.75%, Dimer Impurity: 2.74%
Example HI): Preparation of Agomelatine, formula (I)
To (1000ml) MDC is charged (100gm) of compound of formula (IV), (115g) sodium bicarbonate and cooled to 0-5°C. To the reaction mass is added (53m!) acetic anhydride at 3 to 7°C & monitored by TLC. After the reaction complies, reaction mass is filtered. Filtrate so obtained is washed twice with 200 ml water followed by brine wash. Organic layer is concentrated and degassed under vacuum at 40-45°C. To the concentrated mass is charged (240 ml) toluene and cliarcoalised at 70±5°C. Then reaction mass is filtered through celite bed & washed with hot (60 ml) toluene and cooled to room temperature and further chilied to 0-5°C for 30 min & filtered. Residue is washed with chill (100ml) toluene. Wet cake so obtained is dried under vacuum at 45±50°C to give the title compound of formula (I). Dry wt. - 105gms, HPLC:99.94%: Dimer Impurity: 0.03%.
Example IV): Preparation of Agomeiatine, formula (I)
To (1000ml) Toluene is charged (100gm) of compound formula (IV), (115g) sodium
bicarbonate and cooled to 0-5°C. To the reaction mass is added (53ml) acetic anhydride
at 3 to 7°C & monitored by TLC. After the reaction complies, reaction mass is filtered and
residue washed with water. Wet cake so obtained is dried at 45±5°C to obtain title
compound of formula (I).
DryWt.-101gms, HPLC-99.50%, Dimer Impurity: 0.34%
Example V): Preparation of Agomelatine, formula (I)
To (1000m!) Toluene is charged (lOOgm) of compound of formula (IV), (115g) sodium bicarbonate and cooled to 0-5°C. To the reaction mass is added (53ml) acetic anhydride at 3 to 7°C & monitored by TLC. After the reaction complies, reaction mass is heated to 50-55°C, water washed and concentrated till approximately 30% of its Initial volume remains. Concentrated mass is then cooled to 0-5°C and filtered. Wet cake so obtained is dried at 45±5°C to obtain title compound of formula (I). DryWt. -102gms, HPLC-99.82%, Dimer Impurity: 0.12%
Example V): Preparation of Agomeiatine, formula (I)
To (1000ml) Toluene is charged (100gm) of compound of formula (IV), (115g) sodium
bicarbonate and cooled to 0-5°C. To the reaction mass is added (53ml) acetic anhydride
at 3 to 7°C & monitored by TLC. After the reaction complies, reaction mass is heated to
60-65°C and filtered. Filtrate so obtained is water washed and concentrated till
approximately 30% of its initial volume remains. Concentrated mass is then cooled to 0-
5°C and filtered. Wet cake so obtained is dried at 45±5°C to obtain title compound of
formula (I).
Dry Wt. - 107.7gms, HPLC-99.94%, Dimer Impurity: 0.03%

CLAIMS:
We Claim,
comprising:
a) reducing 2-(7-methoxynaphthalen-1 -yi) acetonitrile of formula (III),
1) A process for preparation of Agomelatine, of formula (I),


with hydrogen gas under pressure in presence of Pd or Raney Ni catalyst in alkanolic solution of ammonia to obtain 2-(7-methoxynaphthalen-1 -yl) ethanamine of formula (IV);

b) reacting the 2-(/-methoxynaphthalen-1 -yl) ethanamine of formula (IV) or its acid addition salt of formula (V),

with an acylating reagent in suitable solvent in presence of an inorganic base characterised in that the inorganic base is an alkali metal carbonate.
2) The process as claimed in claim 1), wherein the inorganic alkali metal carbonate is selected from a group comprising of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or the likes.
3) The process as claimed in claim 1), wherein the inorganic alkali metal carbonate base is sodium bicarbonate.
4) The process as claimed in claim 1), wherein the alkanolic ammonia solution is selected from a group comprising of methanolic ammonia, ethanolic ammonia, isopropanolic ammoina, n-buianolic ammonia or mixtures thereof.
5) The process as claimed in claim 1), wherein the alkanolic ammonia solution is methanolic ammonia.

6) The process as claimed in claim 1), wherein the concentration of methanolic
ammonia is within 10 to 40% W/V
7) The process as claimed in claim 1), wherein the concentration of methanolic ammonia is about 35%w/v.
8) The process as claimed in claim 1), wherein the suitable solvent is from a group of solvent comprising of halogenated solvents like dichloromethane, ethylene dichloride, chloroform, chlorohenzene, alcohols like methanol, ethanol, esters like ethyl acetate, isopropyl acetate, tertiary butyl acetate, hydrocarbons like cycfohexane, toluene, xylene, or mixtures thereof.
9) The process as claimed in claim 1), wherein suitable solvent is toluene, dichloromethane or mixtures thereof.
10)The process as claimed in claim 1), wherein the Agomelatine of formula (I) as isolated exhibits the XRD peaks expressed in terms of Bragg's Angle 2G at 10.47, 12.60, 15.27, 15.76, 17.12, 18.57, 18.98, 20.03, 20.08 and 24.16.