FIELD OF THE INVENTION

The present invention refers to a novel process for the preparation of N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide, also known as agomelatine, Compound (I), and to a new crystalline form X of agomelatine.

BACKGROUND OF THE INVENTION

The compound N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide, also known as agomelatine (trade names Valdoxan, Melitor, Thymanax), presents hypnotic and antidepressant properties which make it suitable for clinical use (Pharmaprojects Access No. 19325 (27-1-2010)).

This compound was first described in EP 0447285 Bl (1991) and US 5225442 A (1992). It's preparation has been described, in addition to the aforementioned patents, in S. Yous, et al. J. Med. Chem. 35, 1484 (1992), as well as EP 1564202 Bl (2005), EP 1564203 Bl (2005), EP 1564204 Bl (2005), EP 1564205 Bl (2005), US 7470806 B2 (2005), US 7479569 B2 (2005), US 7476751 B2 (2005), US 2010/0036161 Al (2009), US 2010/0036163 Al (2009), and US 2010/0036162 Al (2009).

In addition, various crystalline forms of agomelatine such as forms II, III, IV, V and VI of agomelatine have been described in documents EP 1564202 Bl (2005), US 7250531 B2 (2005), EP 2008993 Al (2006), US 7635721 B2 (2006), US 7476751 B2

(2005) , US 7498465 (2007), and US 7498466 B2 (2007). AR 047741 Bl (2005) claims the crystalline form II of agomelatine. Other patent documents such as AR 057713

(2006) , AR 057714 (2006) and AR 057715 (2006) claim the crystalline forms III, IV and V of agomelatine. AR 47667 (2006) and AR 48235 (2006) also claim the intermediate synthesis products. Recently, crystalline forms A, B, and C have been described in WO 201 1/006387 Al (2010).

As mentioned in the literature, the synthetic pathway disclosed in United States Patent US 5225442 A, using 7-methoxy-l-tetralone as starting material, was improved over in simplicity, economy, and purity of yield by the industrial synthesis process described in patents EP 1564203 Bl , EP 1564204 Bl , and US 7479569 B2.

Later, another synthetic process was described in document WO 2009/053545 A2 (2008), using 7-methoxy-l -naphthoic acid as starting material. This process, significantly longer than the previous ones, implied a further reduction in production costs due to the even lower cost of the new starting material used.

However, there is still a need for a synthetic process for the active ingredient agomelatine which not only provides improved economic performance but also simplifies the procedure without the need for special equipment, as in the case of high pressure hydrogenation, and without the need to isolate intermediate products for further purification.

SUMMARY OF THE INVENTION

The present invention concerns a novel process using 7-mefhoxy-tetralone as starting material for the preparation of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide, also known as agomelatine.

In a first embodiment of the invention, 7-methoxy-tetralone as processed in accordance with Scheme I to form agomelatine.

In a second embodiment of the invention, 7-methoxy-tetralone as processed in accordance with Scheme II to form agomelatine.

The invention further relates to a new crystalline form X of agomelatine and a process for its preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example and not limitation in the accompanying drawings in which:

Fig. 1 shows the XRPD of the novel Agomelatine Form X of the present invention,

Fig. 2 shows the IR of the novel Agomelatine Form X of the present invention, and Fig. 3 shows the DSC of the novel Agomelatine Form X of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel synthesis starts with 7-methoxy- 1 -tetralone.

In accordance with the first embodiment as shown in Scheme I, the first reaction of Scheme I comprises a condensation between the anion from a cyanomethyl phosphonic acid ester in the presence of a base such as NaH, LiOH, potassium tert- butoxide with 7-methoxy- 1 -tetralone to produce 7-methoxy-l-tetrahydro naphthalene acrylonitrile.

The phosphonic ester is a commercially available substance; it is created according to the usual techniques from bromine acetonitrile and triethyl phosphite.

To use in similar cases, please refer to (S. Durieux et al - Bioorganic & Medicinal Chemistry 17, 2963 (2009).

This condensation produces the exclusively exocyclic double bond substituted acrylonitrile, as it is shown by its NMR 1H spectrum, which simplifies its purification.

The double bond substituents geometry is not important, since the product will be reduced in the following step.

Through the use of metallic hydrides in the presence of salts, especially NaBH ₄ /NiCl2 , the double bond reduction is concomitant to that of the nitrile group.

In this way, a substituted naphthyl-ethylamine is obtained, the purification of which is very simple due to its basic properties.

The pure good yield Agomelatine is easily obtained through acetylation and subsequent aromatization.

For the aromatization, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) is used, which does not require precious metals catalysts.

Scheme I

COMPOUND II COMPOUND III

COMPOUND IVa

COMPOUND Va COMPOUND I

The synthesis according to Scheme I has the following differences and advantages over the industrial synthesis process described in patents EP 1564203 Bl, EP 1564204 Bl, and US 7479569 B2, which renders it useful as a synthesis alternative:

• The intermediate products for both processes are different.

• In the condensation step of Scheme I, the presence of ammonium salts from relatively long side chain acids as catalyst is not necessary; only the presence of a base is necessary.

• In the synthesis of 7-methoxy- 1 -tetrahydronaphtalene-acrylonitrile, only the product with double exocyclic bond is obtained; the geometric isomerism is not important since the product will be reduced.

• The reduction of the nitrile and of the double bond is simultaneous.

• The reduction shown in Scheme I is done with an economic and simple reagent, without the need for special equipment, as in the case of a high pressure hydrogenation. • The acylation is done using an intermediate product neither protected by nor used in patents EP 1564203 Bl , EP 1564204 Bl , and US 7479569 B2.

• The final aromatization step is done by oxidation with DDQ, producing a clean and good yield product; the raw product obtained is purified by recrystallization in different solvents such as methanol, ethyl acetate, toluene, acetonitrile, ethanol, isopropanol, or mixtures thereof or with water.

As regards the product obtained by Scheme I, its physical parameters (fusion point and NMR 1H spectrum) relate to those described in documents J. Med. Chem. 35, 1484 (1992), EP 447285 Bl (1991) and US 5225442 A (1993).

In the second embodiment of the invention N-[2-(7-methoxy- l- naphthyl)ethyl]acetamide, also known as agomelatine, Compound (I), is produced according to Scheme II below:

Scheme II

COMPOUND V COMPOUND I

In this embodiment, the inventors developed a new process for the industrial esis of agomelatine, which is simplified and highly reproducible, and which provides high yield and does not involve the need to carry out troublesome isolation and purification procedures on intermediate compounds of the synthesis.

More specifically, the Scheme II involves a procedure for the synthesis of N-[2- (7-methoxy-l-naphthalenyl)ethyl]acetamide, Compound (I), comprising, in a first step, the condensation of 7-methoxy-tetralone, Compound (II), with an ester of the cyanomethylphosphonic acid ((RO) ₂ P(0)CH ₂ CN, wherein R= alkyl, aryl, alkyl aryl) in solution into an ether solvent, such as di-isopropyl ether, tetrahydrofuran, or dimethyl sulfoxide, preferably dimethyl sulfoxide (DMSO), and the addition of a base, such as NaH, Li ₂ 0, LiOH, NaOH, KOH or potassium tert-butoxide, preferably potassium hydroxide (KOH), to give (7-methoxy-3,4-dihydro-2H-naphthalene- l-ylidene)- acetonitrile, Compound (III).

COMPOUND III

Compound (III), (7-methoxy-3 ,4-dihydro-2H-naphthalene- 1 -ylidene)- acetonitrile, is then combined with metal hydrides in the presence of Lewis acids in an aprotic medium to give compound 2-(7-methoxy-3,4-dihydro-2H-naphthalene-ylidene)- ethylamine, which, without further isolation and through the action of an acid, isomerizes to a salt of 2-(7-methoxy-3,4-dihydro-naphthalene-l -yl)-ethylamine, Compound (IV), wherein the double bond is endoc clic.

COMPOUND IV

The 2-(7-methoxy-3,4-dihydro-naphthalene-l-yl)-ethylamine salt is then acetylated with an acetylating agent in order to produce the corresponding acetamide, Compound (V), wherein the endocyclic double bond is maintained.

COMPOUND V

Finally, in a fourth and last step, Compound (V) is oxidized to give Compound (I), named agomelatine, or N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide.

In a preferred aspect of the present invention for the obtention of Compound (IV), the pharmaceutically acceptable metal hydride used in the procedure of the invention is NaBH ₄ or LiAlH ₄ , preferably LiAlH ₄ .

Pharmaceutically acceptable Lewis acids used for the obtention of Compound (IV) in the invention include A1C1 ₃ , NiCl ₂ , or CoCl ₂ . Preferably, AICI3 is the pharmaceutically acceptable Lewis acid of choice in the present invention.

Also preferred in the present invention for the obtention of Compound (IV) is the use of a pharmaceutically acceptable aprotic solvent, such as an ether compound, selected from the group consisting of di-isopropyl ether, tetrahydrofuran (THF), or mixtures thereof with toluene.

Also, the pharmaceutically acceptable acid used for the isomerization and obtention of the salt of compound (IV) is an aqueous acid selected from the group consisting of HC1, H ₂ S0 ₄ , or HBr, preferably HC1.

In another particular aspect of the present invention, for the obtention of Compound (V), the pharmaceutically acceptable acylating agent used in the procedure of the invention is acetic anhydride/sodium acetate.

In another particular aspect of the present invention, for the obtention of Compound (V), the pharmaceutically acceptable acylating agent used in the procedure of the invention is acetyl chloride in the presence or absence of a base such as triethylamine, pyridine, potassium carbonate, sodium acetate, or the like.

In a further particular aspect of the present invention, for the obtention of Compound (I), the pharmaceutically acceptable oxidizing agent used in the procedure of the invention is 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). In a further preferred aspect of the present invention, for the obtention of Compound (I), oxidation takes place through catalysis with Pd/C, without further addition of co-catalyzers, in hydrocarbonated alkyl or aryl solvents.

The invention also refers to a procedure for the purification of Compound (I), obtained according to the procedure described herein, comprising a crystallization process wherein the crystallization solvent is selected from the group consisting of an alcohol of up to 4 carbon atoms, ethyl acetate, methyl-ethyl-ketone, acetone, isopropyl ether, toluene, acetonitrile, or mixtures thereof, with the possible addition of water.

The invention also refers to Compound (I), obtained according to the procedure described herein, and whose physical parameters, as well as its melting point, correspond to those described in prior art documents.

Finally, the Applicant has now developed a new synthesis process that allows agomelatine to be obtained in a well defined reproducible new crystalline form, which especially exhibits valuable characteristics for formulations.

More specifically, the present invention relates to the crystalline form X of the Compound (I), characterized by the following X-ray Powder Diffraction Diagram, measured using a Philips model X ^' Pert PW3710 (Philips, The Netherlands) with a wavelength of 1.54060 (K-Alpha) and expressed in terms of inter-planar distance d, Bragg' s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray).

2-Theta (°) d (A) Intensity (%)

5.79 15.251 1.94

9.56 9.246 12.64

9.85 8.969 15.46

1 1.90 7.432 8.48

12.81 6.905 30.54

13.83 6.399 18.75

15.14 5.846 14.58

16.14 5.487 27.13

17.33 5.1 14 16.45

18.56 4.776 100.00 19.10 4.644 33.0

19.80 4.480 9.45

20.84 4.258 98.52

21.18 4.192 44.12

22.02 4.034 13.59

22.24 3.994 15.31

22.94 3.874 13.41

23.82 3.733 77.39

24.23 3.671 18.55

25.70 3.463 15.12

25.79 3.451 13.53

27.91 3.195 9.28

28.28 3.154 12.1 1

28.52 3.127 12.67

29.28 3.047 14.28

30.10 2.966 22.47

30.46 2.932 12.24

30.84 2.897 9.37

This new crystalline form is also characterized by its IR spectrum (KBr) presenting characteristic absorption signals at 3235, 3061 , 3048, 2941 , 1640, 1627, 1600, 1540, 151 1, 1437, 1308, 1297, 1216, 1 184, 1031, 827, 755 cm ^"1 (FT-IR Shimadzu IRAffinity/l).

The new crystalline form X is also characterized by DSC (Differential Scanning Calorimetry) (Q-100 TA INSTRUMENTS equipment at 10°C/min).

The invention also refers to a pharmaceutical composition comprising, as an active ingredient, Compound (I) and the crystalline form X of compound (I), obtained according to the procedure described herein, and one or more pharmaceutically acceptable excipients, such as those described in the Handbook of Pharmaceutical Excipients, 2 ^nd Edition, American Pharmaceutical Association; The Theory & Practice of Industrial Pharmacy, 2 ^nd Edition, Lachman Leon, 1976; Pharmaceutical Dosage Forms: Tablets, Volume 1, 2 ^nd Edition, Lieberman, Hebert A, et al, 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T. 1 79: and Remington 's Pharmaceutical Sciences, 15 ^th Edition, 1975, for their use in the preparation of a medicament for the treatment of depression and sleep disorders, among others.

The invention relates also to a process for the preparation of the crystalline form X of Agomelatine, which process is characterised in that Agomelatine is dissolved into acetone and the obtained solution is poured into a cool mixture of acetone:water.

Examples

After having described the method for the obtention of agomelatine, there follow preparation examples for illustrative purposes only, which aim at showing the processes involved and the possibilities thereto.

Example 1: 7-Methoxy-l,2,3 _i 4-tetrahydro naphthylidene acetonitrile, Compound III (Scheme I)

In a 2 L capacity three necked round flask, placed in a water bath and provided with condenser, thermometer, mechanic stirrer, addition funnel and nitrogen flow, sodium hydride (17.81 g - 60% w/w) and tetrahydrofuran (135 ml) are added. A soft nitrogen flow is kept while diethyl cyanomethyl phosphonate (80 g) in tetrahydrofuran (70 ml) is slowly added at room temperature. Gas release is observed together with a slight exothermic reaction. During the addition, the internal temperature is kept between 20-30°C. A slightly colored suspension is obtained.

Once the addition of the phosphonate solution is finished, the addition of a 7- Methoxytetralone (43 g) in tetrahydrofuran (80 ml) solution is started, keeping internal temperature between 30-35°C.

The suspension is stirred at room temperature for 1-2 hours and controlled by TLC (mobile phase: toluene (Rf 7-MT: 0.3; Rf product 0.35; Rf phosphonate: 0)).

Once the reaction is finished, it is cooled at 0-5°C and water is added (270 ml). Ethyl acetate (1 x 270 ml and 2 x 135 ml) is added and the organic layers are combined.

The solvent is evaporated until just reaching dryness at reduced pressure, thereby obtaining a viscous oil (58 g) (Titration: 75%) Yield: 90%.

This oil can be used directly in the following step without further purification.

A sample of the oil is treated with methanol, placed in an ice bath and obtaining a crystallized solid which, after filtration and drying, shows a purity above 92% (HPLC) and is characterized by spectroscopy. NMR 1H: (δ) 2.87 or 2.58 (E/Z) (2H, dt, J=1.6 and 6.4 Hz) (CH ₂ allyl); 5.70 and 5.27 (E/Z) (2H, t, J= 1.5 and 1.4 Hz); 7.03 or 7.86 (E/Z) (1H, d, J=2.8 or 2.6 Hz) (H-8).

Example 2: l-(2-aminoethyl)-7-methoxy-l,2,3,4-tetrahydro naphthalene, Compound IVa (Scheme I)

The product obtained in the previous step is dissolved (1.2 g containing approximately 0.8 g of 7-Methoxy-l ,2,3,4-tetrahydro naphthylidene acetonitrile) in methanol (10 ml) and anhydrous NiCl ₂ (0.52 g, 4 mmol) is added.

Then, NaBH ₄ (0.83 g, 22 mmol) is added while stirring and cooling (exothermic reaction with plenty of gas release).

The black colored reaction mixture is stirred for 12 hours at room temperature until the starting material is disappeared by TLC.

The solution is filtered through celite, and the cake is washed with three portions of 50 ml ethyl acetate (AcOEt).

The solvent is evaporated, water is added (20 ml), and the solution is extracted with three portions of AcOEt.

The organic phases are combined, dried over Na ₂ S0 ₄ , filtered and evaporated to dryness.

The residue obtained is suspended in 15 ml concentrated HCl; the suspension is stirred at room temperature for 30 minutes and then it is extracted with three fractions of 10 ml AcOEt, and the organic phase is washed with concentrated HCl (2 x 10 ml).

The acid phases are combined and concentrated NaOH aqueous solution (16 g in 50 ml, final pH > 12) is slowly added in an ice bath until alkaline. The aqueous phase is extracted with AcOEt (4 x 20 ml), the organic phase is dried over Na ₂ S0 ₄ and the solvent is evaporated.

The result is 0.82 g of product containing approximately 85% amine (calculated by NMR 1H). (Yield: 85 %).

NMR Ή: (6) 2.82 (2H, t, J= 5.6 Hz) (alpha H to amine group); 2.82 (1H, overlaying m) (benzyl H); 6.71 (1H, d, J- 2.6 Hz) (H-8).

Example 3: l-(2-N-acethyl aminoethyl)-7-methoxy-l,2,3,4-tetrahydro naphthalene, Compound Va (Scheme I) The mass obtained in the previous step (containing approximately 0.7 g amine) is dissolved in 3 ml methanol and 1.5 ml acetic anhydride, and is stirred for 12 hours under reflux (Rf acetamide 0.1 ; mobile phase AcOEt/hexane 1 :2).

The solution is evaporated under reduced pressure to eliminate the acetic acid. Methanol is added and the solution is evaporated to dryness.

It is obtained 0.82 g of product containing approximately 0.76 g amine calculated by NMR 1H. (Yield: 90 %).

NMR Ή: (δ) 1.95 (3H, s) (CH ₃ CO); 3.2-3.5 (2H, m) (alpha H to NH); 2.80 (1H, tt, J= 9.2 and 5.0 Hz) (benzyl H); 3.76 (3H, s) (CH ₃ 0); 6.7 (1H, d, J=2.6 Hz) (H-8).

Example 4: Agomelatine, Compound I (Scheme I)

The acetylated product (0.82 g containing approximately 0.76 g amide) is dissolved in 10 ml anhydrous tetrahydrofuran (THF) and 9 mMol DDQ are added. The solution is stirred and heated under reflux for 12 hours until the starting material disappeared (TLC: Rf GML: 0.12, Rf acetamide: 0.1, mobile phase AcOEt/hexane 1 :2).

The solvent is evaporated, 10 ml of a sodium bisulfite solution (2 g in 10 ml distilled water) are added, and the solution is stirred at 40°C for 30 minutes.

Then, 20 ml of a NaOH 1.25M aqueous solution are added until alkaline. The product is extracted with three portions of 30 ml AcOEt, and the solvent is evaporated resulting in a yellow solid (0.4 g). (Yield: 53 %).

A sample of this solid (0.1 g) is recrystallized in a methanol: water mixture, obtaining a melting point of 108-109 °C.

The NMR 1H spectrum coincides with that of a standard Agomelatine.

Part of this solid (0.1 g) is dissolved in hot methanol, charcoal is added. Then it is hot filtered through a celite bed, and is crystallized by the water adding. It is left in the refrigerator overnight.

The solid (0.08 g) is dried for 3 hours at 50 °C and 1 Torr. MP: 108-109 °C. (EP 447285 Bl Ex.1 provides melting point: 109-1 10 °C).

Example 5: (7-Methoxy-3,4-dihydro-2H-naphthalene-l-ylidene)-acetonitril e, Compound (III) (Scheme II)

Dimethyl sulfoxide (6.4 1) is placed into a 50-liter reactor and potassium hydroxide (1.28 kg; 22.85 M) is added. A solution of cyanomethyl diethyl phosphonate (3.4 1; 21.03 M) in tetrahydrofuran (3.4 1) is added to the suspension and kept under stirring for 1 hour at 15 - 25°C.

Then, a solution of 7-methoxy-l-tetralone (2 kg; 1 1.4 M) in tetrahydrofuran (3.8 1) is added, keeping the temperature between 15 - 25°C. The suspension is stirred for 2½ hours.

Water (15 1) is added, while the temperature is maintained between 15 - 25°C. Then, the reaction mixture is distilled under reduced pressure at a temperature lower than 50°C until the tetrahydrofuran is removed.

The reaction mixture is cooled at room temperature and extracted with toluene (3 x 10 1).

The combined organic phase is washed with sodium chloride aqueous solution 35% (w/v), and the organic phase is concentrated at reduced pressure at 60°C up to a final volume of approximately 4-5 1.

This solution contains around 2.15 kg (95%) (analyzed by HPLC) of (7- methoxy-3,4-dihydro-2H-naphthalene-l-ylidene)-acetonitrile, Compound (III), which is used as it is in the next step.

Example 6: 2-(7-Methoxy-3,4-dihydro-naphthalene-l-yl)-ethyIamine

Hydrochloride, Compound (IV) (Scheme II)

A suspension of LiAlH ₄ (107 g) in tetrahydrofuran (2200 ml) is placed in a 3- necked, 12-liter flask, equipped with stirrer, condenser and mild nitrogen flow.

AICI3 (240 g) in tetrahydrofuran (2200 ml) is added to the suspension.

After that, a solution of (7-methoxy-3,4-dihydro-2H-naphthalene-l-ylidene)- acetonitrile, Compound (III) (440 g with an 80% titration, equivalent to 352 g) in toluene (2000 ml) is added under stirring at room temperature. A slightly colored suspension is obtained.

After 4 hours, methanol (880 ml) and then water (880 ml) are added.

The suspension obtained is filtered, and the insoluble material is washed with methanol. The methanolic filtrates are treated with concentrated hydrochloric acid (HC1) (around 150 ml) until pH less than 1.

The acid solution is distilled at atmospheric pressure up to a volume of 1 100 ml and then heated under reflux (80°C) for 1 hour.

Toluene (1320 ml) is added, and the suspension is cooled to 0-5°C. The solid is isolated by filtration and dried at 60°C.

This procedure yields 371 g (88%) of 2-(7-methoxy-3,4-dihydro-naphthalene-l- yl)-ethylamine hydrochloride, Compound (IV), whose Ή-NMR is coincident with that of a standard.

Its retention time in a chromatogram (HPLC) is coincident with that of a standard, and its purity is higher than 97.5%.

Example 7: N-[2-(7-Methoxy-3,4-dihydro-naphthalene-l-yl)-ethyl]-acetami de, Compound (V) (Scheme II)

2-(7-Methoxy-3,4-dihydro-naphthalene- 1 -yl)-ethylamine hydrochloride, Compound (IV) (300 g, 1.25 moles) is placed in a 3-necked, 3-liter flask, equipped with stirrer, condenser, addition funnel and with mild nitrogen flow. Toluene (1200 ml) is added to obtain a suspension. After that, anhydrous sodium acetate (108 g, 1.31 moles) is added.

Then acetic anhydride (124.6 ml, 1.31 moles) is added at 20-25°C.

After 1 hour at room temperature, the suspension is filtered and the solid is washed with toluene.

Sodium hydroxide aqueous solution 10% w/v (1200 ml) is added to the filtrates.

The phases are separated, and the organic phase is washed with water until pH 6.

The toluene phase is concentrated at reduced pressure to a final volume of about 900 ml and hexane is added.

The suspension is cooled below 5°C for 1 hour; the solid is filtered, washed, and dried at 60°C.

257 g (84%) of N-[2-(7-methoxy-3,4-dihydro-naphthalene-l-yl)-ethyl]- acetamide, Compound (V) is obtained, which is used as it is for the final step.

Example 8: N-[2-(7-Methoxy-l-naphthyl)ethyl]acetamide (agomelatine) (Scheme Π)

To a solution of N-[2-(7-methoxy-3,4-dihydro-naphthalene-l-yl)-ethyl]- acetamide, Compound (V) (250 g, 1.02 moles) in tetrahydrofuran (2 1), DDQ (255 g, 1.12 moles) is added.

During the addition the internal temperature is kept around 20°C.

The reaction mixture is distilled at reduced pressure, replacing the solvent by toluene. The final suspension is filtered at room temperature, and the obtained solid is suspended again in toluene at 40-45°C.

The combined toluene solution is distilled at reduced pressure to a final volume of about 250 ml.

The resulting suspension is cooled at 0-5°C and then filtered and dried in an oven at 60°C.

The solid obtained, whose Ή-NMR spectrum coincides with that of a purified sample, is dried at 60°C.

Yield: 198 g (80%). Titration (HPLC): > 98%.

Example 9: N-[2-(7-Methoxy-l-naphthyl)ethyl]acetamide (agomelatine) (Scheme II)

A suspension of N-[2-(7-methoxy-3,4-dihydro-naphthalene-l-yl)-ethyl]- acetamide, Compound (V) (200 g, 0.82 moles) and 10% Pd/C (10.2 g, 10 mmol) in toluene is heated under reflux until the starting product disappears.

The reaction mixture is filtered to separate the catalyzer, and the solution is distilled to a final volume of about 200 ml.

This suspension is cooled at 0-5°C for one hour and then filtered. The solid is dried in an oven at 60°C.

159 g (80%) of agomelatine, similar quality of that in Example 8 is obtained.

Example 10: Crystalline form X

Agomelatine (6 kg) was dissolved into acetone (18 1) under reflux and the solution was cooled at 35-40 °C.

This solution was transferred to a second reactor vessel containing a mixture of acetone (12 1): water (60 1) at 0 °C.

The solution of Agomelatine was then poured under stirring into this mixture; a suspension was immediately observed.

This suspension was kept for 30 minutes at 0-5 °C.

The crystalline solid was filtered and dried at 60 °C in an oven until constant weight. Yield: 90 %.

Having described and determined the nature of the present invention, and the way in which it may be put into practice, exclusive rights and property over the following is claimed: