Field of the Invention:

The present invention relates to novel crystalline form of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1 and process for its preparation. N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1 is commonly known as Agomelatine and is represented by the following structural formula

Background of the Invention:

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1, has valuable pharmacological properties. N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1, its preparation and its therapeutic use have been described in European Patent specification EP 0 447 285.

Indeed it has the double feature of being, on the one hand, an agonist of melatoninergic system receptors and, on the other hand, an antagonist of the 5-HT 2c receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity. In view of the pharmaceutical value of this compound, it has become an important to be able to obtain it with excellent purity, with well defined crystalline form, which is perfectly reproducible, which as a result exhibits valuable characteristics in terms of formulation and sufficiently stable to allow its storage for long periods without particular requirements for control of temperature, light, humidity or oxygen level.

Patent Specification US5225442 describes the preparation of Agomelatine in eight steps, starting from 7-methoxy-l-tetralone. In the said process agomelatine was finally recrystallized from isopropyl ether. The obtained agomelatine having melting range 109-1 10°C. The process for the preparation of agomelatine is also reported in JMC 1994, vol 37, 3231-3239. In the said process agomelatine was obtained as a crystalline solid from a mixture of toluene/hexane in the ratio of 2:1 having melting range 109-110°C. The PXRD of the obtained compound is shown in figure-2. The said crystalline form herein is designated as Form-I. The crystalline forms II, III, IV, V and VI are reported in US7498465, US7635721, US7465905, US7358395, US20090069434A1 respectively.

The present invention provides a novel crystalline form-M of Agomelatine and also the process for its prepeiration.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel crystalline form of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1, and process for its preparation. Herein after the novel crystalline form will be designated as Form-M.
The second aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1.

Brief description of the drawings:

Figure-l: Illustrates the PXRD of crystalline form-M of N-[2-(7-methoxy-l-naphthyl) ethyl]acetamide compound of formula-1.

Figure-2: Illustrates the PXRD of crystalline N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-l obtained as per the process disclosed in JMC 1994, vol 37, 3231-3239.

Detailed Description of the Invention:

As used herein the present invention, the term "suitable solvents" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropnol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and ethylene dichloride; polar solvents like water; and also mixtures thereof

The first aspect of the present invention is to provide a novel crystalline form of Agomelatine, which is characterized by its X-ray powder diffractogram having characteristic peaks at 11.20, 11.86, 19.55, 22.51 and 31.91 ± 0.2 degress 20; heremafter designated as form-M. The crystalline form-M of the present invention fiirther chacterised by its PXRD peaks at 11.20, 11.86, 17.54, 18.38, 18.54, 19.55, 19.73, 20.51, 21.78, 22.51, 23.04, 24.60, 25.39 and 31.91 ± 0.2 degress 20. The crystalline form may also be substantially similar to the PXRD pattern depicted in Figure-l.

The second aspect of the present invention provides a process for the preparation of crystalline form-M of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compoumd of formula-1 which comprises of the following steps,

a) Taking the N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1 in a suitable organic solvent selected from ketone solvents, ether solvents and alcoholic solvents, preferably ether solvents like methyl tertiary butyl ether.

b) heating the reaction mixture to 55° C to 80° C, preferably 65°C to 75°C and stirring,

c) cooling the reaction mixture to room temperature,

d) further cooling the reaction mixture to 0-5° C and stirring,

e) filtering the precipitated solid and washing with a suitable organic solvent,

f) drying the solid to get the crystalline form-M of agomelatine.

In a preferred embodiment, the process for the preparation of novel crystalline
Form-M of agomelatine of formula-1 comprises of the following steps,

a) Taking the N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide compound of formula-1 in methyl tertiary butyl ether,

b) heating the reaction mixture65-75°C and sturing for 90 min.,

c) cooling the reaction mixture to room temperature

d) further cooling the reaction mixture to 0-5° C and stirring for 2 hrs

e) filtering the precipitated solid and washing with methyl tertiary butyl ether

f) drying the solid at 55-65°C for 12-14 hrs to get crystalline form-M of agomeaitine.

PXRD analysis of agomelatine was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

ExampIe-l:Preparation of Form-M of Agomelatine

5g of Agomelatine was dissolved in methyl tertiary butyl ether( 100ml) and heated the reaction mixture to 55-58 °C and stirred for 90 min. Then the reaction mixture was slowly cooled to room termperature and further cooled to 0-5°C. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the precipitated crystals and washed with MTBE. Dried the compound to get the crystalline form-M of Agomelatine.

Yield: 3grams

Exainple-2:Preparation of Form-1 of Agomelatine

0.01ml of 2-(7-methoxynaphth-l-yl)etylamine is dissolved m 6ml of pyridine.The mixture was cooled in an ice bath with stirring, and 0.012 mol of acetylchloride was added dropwise.The stirring was continued for 30minutes, and then the reaction mass was poured onto ice.The formed precipitate was washed and dried and recrystallised from Isopropylether. Yield: 92%

Example-3: Preparation of Form-II of Agomelatine

Potassiumcarbonate(2.8g) was added to a solution of 2-(7-methoxynaphth-l-yl)etylamine(2.38g) in water(40ml) and chloroform(60ml).The reaction mixture was cooled to 0° C and was added acetylchloride dropwise at same temperature. The reaction mixture was stirred for 30min at 0°C. The oraganic layer was separated, washed with water and evaporated under reduced pressure. The obtained residue was crystallized from toluene/hexane in the ratio of 2:1 to get the title compound. Yield: 2.0 grams

Example-4: Preparation of Form-M of Agomelatine.

Potassiumcarbonate(2.8g) was added to a solution of 2-(7-methoxynaphth-l-yl)ethylamine(2.38g) in water(40ml) and chloroform(60ml).The reaction mixture was cooled to 0° C and was added acetylchloride dropwise at same temperature. The reaction mixture was stirred for 30min at 0°C. The organic layer was separated, washed with water and evaporated under reduced pressure. The obtained residue was crystallized from methyl tertiary butyl ether to get the title compound. Yield: 2.0 grams

Claims:

1. Crystalline form-M of agomelatine compound of formula-1
characterized by its powder X-ray diffractogram having characteristic peaks peaks at 11.20, 11.86, 19.55,22.51 and 31.91 ± 0.2 degress 2θ..

2. The crystalline form-M of agomelatine is further characterized by its powder X-ray diffractogram having peaks at about 11.20, 11.86, 17.54, 18.38, 18.54, 19.55, 19.73, 20.51, 21.78,22.51,23.04, 24.60,25.39 and 31.91 ± 0.2 degress 2θ.

3. A process for the preparation of novel crystalline form-M of agomelatine comprising of the following steps;

a) Taking the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide compound of formula-1 in a suitable organic solvent selected from ketone solvents, ether solvents and alcoholic solvents, preferably ether solvents like methyl tertiary butyl ether.

b) heating the reaction mixture to 55° C to 80° C, preferably 65°C to 75°C and stirring,

c) cooling the reaction mixture to room temperature,

d) further cooling the reaction mixture to 0-5° C and stirring,

e) filtering the precipitated solid and washing with a suitable organic solvent,

f) drying the solid to get the crystalline form-M of agomelatine.

4. A process for the preparation of novel crystalline Form-M of agomelatine comprises of the following steps;

a) Taking the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide compound of formula-l in methyl tertiary butyl ether,

b) heating the reaction mixture65-75°C and stirring for 90 min.,

c) cooling the reaction mixture to room temperature,

d) further cooling the reaction mixture to 0-5° C and stirring for 2 hrs,

e) filtering the precipitated solid and washing with methyl tertiary butyl ether,

f) drying the solid at 55-65°C for 12-14 hrs to get crystalline form-M of agomealtine.

5. A process for the preparation of crystaline agomelatine comprises of recrystallization of agomelatine from a suitable organic solvent selected from ether solvents or ketone solvents.

6. A process according to claim 5, wherein the organic solvent used for recrystallization of agomelatine is methyl tertiary butyl ether.

7. Use of crystalline form-M of Agomelatine as an active pharmaceutical ingredient in the preparation of pharmaceutical composition.