OA12900A - Novel synthesis method and new crystalline form of agomelatine as well as pharmaceutical compositions containing it. - Google Patents

Description

012900

The present invention relates to a process for the industrial synthesis of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide of formula (I):

The present invention also relates to crystalline form II of agomelatine, its method of preparation as well as pharmaceutical compositions containing it. Agomelatine or AL [2- (7-methoxy-1-naphthyl) ethyl] acetamide has interesting pharmacological properties.

It has the dual feature of being on the one hand agonist on the receptors of the melatoninergic system and on the other hand antagonist of the 5-HT2C receptor. These properties give it an activity in the central nervous system and more particularly in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue due to jet lag, appetite disorders and obesity. Agomelatine, its preparation and its therapeutic use have been described in European Patent EP 0 447 285.

Given the pharmaceutical interest of this compound, it was important to be able to access it with a high-performance industrial synthesis process, easily transposable on an industrial scale, leading to agomelatine with good yield and excellent purity. It was also important to be able to access the agomelatine in a crystalline form well defined, perfectly reproducible and having interesting characteristics filtration and ease of formulation. -2- 1 2900

EP 0 447 285 discloses the eight-step access to agomelatine from 7-methoxy-1-tetralone with an average yield of less than 30%.

This process involves the action of ethyl bromoacetate, followed by aromatization and apathing to yield the corresponding acid, which is then converted to acetamide and then dehydrated to yield (7-methoxy-1-naphthyl) acetonitrile, followed by reduction and then condensation of the acetyl chloride.

In particular, the access to (7-methoxy-1-naphthyl) acetonitrile involves six steps and, transposed on an industrial scale, it was quickly highlighted difficulties of implementation of this process due mainly to problems of Reproducibility of the first step constituted by the action of ethyl bromoacetate on 7-methoxy-1-tetralone according to the Réformatsky reaction leading to (7-methoxy-3,4-dihydro-1 (27) -naphthalenylidene ) ethyl ethanoate.

In addition, the following step of aromatization of ethyl (7-methoxy-3,4-dihydro-1 (277) -naphthalenylidene) ethanoate was often partial and after saponification led to a difficult to purify product mixture.

The literature describes the three-step access to (7-methoxy-1-naphthyl) acetonitrile from 7-methoxy-1-tetralone by the action of LiCELCN followed by dehydrogenation with DDQ (2,3-dichloro-5, 6-dicyano-1,4-benzoquinone) and finally dehydration in an acid medium (Synthetic Communication, 2001, 31 (4), 621-629). However the overall yield is average (76%) and especially the DDQ used in the dehydrogenation reaction as well as the reflux of benzene needed in the third stage do not meet the industrial constraints of cost and environment.

The Applicant has now developed a new industrial synthesis process which yields, in a reproducible manner and without the need for laborious purification, agomelatine with a purity which is compatible with its use as an active pharmaceutical ingredient.

An alternative to the difficulties encountered with the process described in patent EP 0 447 285 was obtained by directly condensing a cyano derivative on 7-methoxy-1-tetralone. 012900 -3-

It was also necessary that the condensation compound obtained could easily be aromatized to yield (7-methoxy-1-naphthyl) acetonitrile without requiring drastic conditions and allowing the use of reagents compatible with the industrial requirements of cost and environment. It has been found that (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile would be an ideal synthetic intermediate meeting the requirements of direct synthesis from 7-methoxy-1-tetralone and would be an excellent substrate for the étaped'aromatisation.

Direct condensations of tetralones with acetonitrile or acetonitrile derivatives are described in the literature. In particular, US Pat. No. 3,992,403 describes the condensation of cyanomethylphosphonate with 6-fluoro-1-tetralone, and US Pat. No. 3,931,188 describes the condensation of acetonitrile with tetralone leading to the cyan intermediate which is directly involved in the following reaction. .

When applied to 7-methoxy-1-tetralone, the condensation of acetonitrile leads to a mixture of isomers "exo" majority and "endo" minority according to FIG.

Figure 1

"exo" majority "endo" minority this mixture requiring subsequent conditions of drastic aromatisation noncompatible with industrial requirements to continue the synthesis of agomelatine.

The Applicant has now developed a new industrial synthesis process which makes it possible to obtain (7-methoxy-1-naphthyl) acetonitrile in a reproducible manner and without the need for laborious purification, in only two steps from 7-methoxy- 4-

tetralone using as synthetic intermediate (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile free of the "exo" impurity of formula (II):

which can not be subjected to the subsequent aromatization reaction under operating conditions compatible with the industrial requirements in order to continue the synthesis of agomelatine.

More specifically, the present invention relates to a process for the industrial synthesis of

Characterized in that the 7-methoxy-1-tetralone of formula (III) is reacted with:

with cyanoacetic acid of formula (IV): HO.

CN (IV) 012900 under conditions of removal of formed water in the presence of a catalytic amount of the compound of formula (V): +

O (V) in which R and R ', which may be identical or different, each represent a linear or branched (C 3 -C 10) alkyl group, an unsubstituted or substituted aryl group, or a linear or branched (C 1 -C 6) arylalkyl group; substituted or substituted, to conduct after filtration and washing with a basic solution of (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile of formula (VI):

(VI) compound of formula (VI) which is reacted with a hydrogenation catalyst in presence of an allyl derivative to yield the compound of formula (VII):

(VH) which is then subjected to reduction with hydrogen in the presence of Raney nickel in an ammoniacal ethanol medium and then salified with hydrochloric acid to yield the compound of formula (VIII):

which is successively subjected to the action of sodium acetate and then of acetic anhydride to give the compound of formula (I) which is isolated in the form of a solid, it being understood that: - by aryl is meant a phenyl, naphthyl or biphenyl group, the term "substituted" for the terms "aryl" and "arylalkyl" means that the aromatic part of these groups may be substituted by 1 to 3 groups, identical or different, selected from alkyl (Cj-Cô) linear or branched, hydroxy, and (C 1 -C 6) alkoxy linear or branched, the term "allyl derivative" means any molecule containing 3 to 10 carbon atoms and may contain in addition 1 to 5 oxygen atoms, and containing at least one -CH2-CH = CH2 unit.

More particularly, in the reaction reaction of the compound of formula (III) containing compound of formula (VI), the water formed is removed by distillation. Preferably, a reaction solvent having a boiling point greater than or equal to that of water is used, and even more preferably forming an azeotrope with water, for example xylene, toluene, anisole, ethylbenzene, tetrachlorethylene, cyclohexene, or mesitylene.

Preferably, the conversion reaction of the compound of formula (III) into a compound of formula (VI) is carried out under reflux of toluene or xylene and more preferably toluene.

Advantageously, in the reaction of conversion of the compound of formula (III) into a compound of formula (VI), one of the R or R 'groups of the catalyst used represents a linear or branched (C 3 -C 10) alkyl group. and the other represents an aryl or arylalkyl group. More particularly, a preferred catalyst is that of formula (Va): R '. Wherein R'a represents a phenyl group unsubstituted or substituted by one or more linear or branched (C 1 -C 6) alkyl groups, n is 0 or 1, and R a is an (C 3 -C 10) alkyl group; ) linear.

Very advantageously, R'a represents an unsubstituted or substituted phenyl group and more particularly an unsubstituted phenyl group.

The preferred group Ra is the hexyl group.

Z 10 The preferred value of n is 1.

The preferred catalyst used in the reaction of conversion of the compound of formula (III) into a compound of formula (VI) according to the process of the invention is the heptanoate debenzylammonium of formula (IX):

Advantageously, the compound of formula (VI) is obtained after filtration and washing with an organic or inorganic basic solution such as NaOH, KOH, Ca (OH) 2, Sr (OH) 2 or NH 4 OH, and more preferably with a hydroxide solution. sodium.

Preferably, the conversion reaction of the compound of formula (VI) containing formula (VII) is carried out at reflux of toluene or xylene and more preferably at reflux of toluene. 0129 π η

ϋ U -8-

The catalyst preferably used in the reaction of conversion of the compound of formula (VI) into a compound of formula (VII) is a catalyst in oxide or supported form such as for example palladium, platinum, nickel, Al 2 O 3 and more particularly the palladium. Advantageously, palladium on charcoal, more particularly palladium on charcoal of 1 to 20% and even more particularly 5% or 10% will be used. Preferentially, palladium on charcoal will be used in catalytic quantities, more particularly in amounts ranging from 1 to 10% by weight of catalyst relative to the weight of substrate and more preferably 5%. The hydrogen acceptor preferentially used in the reaction of conversion of the compound of formula (VI) into a compound of formula (VII) is an allyl derivative and more particularly an allyl acrylate or an allylglycidylether. The preferred allyl acrylate of the process according to the invention is allyl methacrylate.

Advantageously, the conversion reaction of the compound of formula (VII) into the compound of formula (VIII) according to the process of the invention is carried out between 20 and 40 ° C. and more preferably between 30 and 40 ° C., and even more advantageously at 40 ° C.

Advantageously, the conversion reaction of the compound of formula (VIII) containing formula (I) is carried out in an alcoholic medium and more particularly in ethanol medium.

This process is particularly interesting for the following reasons: it allows to obtain on an industrial scale the compound "endo" of formula (VI) exclusively. This result is quite surprising when considering the literature concerning this type of reaction, which most often refers to obtaining "exo" / "endo" mixtures (Tetrahedron, 1966, 22, 3021-3026). This result results from the use of a compound of formula (V) as reaction catalyst in place of the ammonium acetates commonly used in these reactions (Bull Soc Chim Fr, 1949, 884-890). The degree of conversion of the compound of formula (III) to the compound of formula (VI) obtained is very high, greater than 97%, contrary to what could be observed with the use of acetic acid for which this rate does not exceed 75%. the use of a hydrogenation catalyst in the presence of an allyl derivative and more particularly allyl methacrylate for the conversion of the compound of formula (VI) into a compound of formula (VII) is entirely compatible with the industrial requirements of cost and environment, unlike the quinonescurrently used. it furthermore makes it possible to obtain, on an industrial scale, the compound of formula (VII) exclusively, in particular free of the corresponding reduction product of formula (X):

lastly, the conversion rates of the compound of formula (VI) into compound of formula (VII) observed are high, greater than 90%. The hydrogenation of the compound of formula (VII) in the presence of Raney nickel in an ammoniacal ethanol medium is described (J. Med Chem, 1994, 37 (20), 3231-3239) but requires conditions which are difficult to transpose to On the industrial scale, the reaction is carried out at 60 ° C. and for 15 hours, and the final yield is less than 90%. Furthermore, the main drawback of this reaction is the concomitant formation of the "bis" derivative of formula (XI):

MeO

OMe (XI) - 10-

and the difficulty is to control the rate of formation of this impurity. The procedure developed by the Applicant allows to obtain the compound of formula (VIII) with a bis impurity content of less than 4% with experimental conditions compatible with industrial requirements since the reaction is carried out at between 30 ° and 40 ° C. lead to a yield greater than 90% and a chemical purity greater than 99.5%. the amidation step carried out in an alcoholic and more particularly ethanol medium makes it possible to isolate the compound of formula (I) very easily with quantitative efficiency. This result is totally surprising since this type of reaction is not very compatible with this solvent for which competitive consumption of acetic anhydride is expected.

The compound of formula (VI) obtained according to the process of the invention is new and is useful as an intermediate for the synthesis of agomelatine in which it is subjected to an aromatization reaction followed by a reduction and then coupling reaction. with acetic anhydride. The invention also extends to the crystalline form II of the agomelatine obtained according to the method described above. It is indeed important to be able to obtain a well-defined and perfectly reproducible crystalline form. The prior art EP0447285 and Yous et al. (Journal of Medicinal Chemistry, 1992, 35 (8), 1484-1486) provides access to agomelatine in a particular crystalline form which has been described in Tinant et al. (Acta Cryst., 1994, C50, 907-910).

The Applicant has now developed a process for obtaining agomelatine in a well-defined crystalline form, perfectly reproducible and thus presenting interesting characteristics of filtration and ease of formulation. 012900 - 11 -

More specifically, the present invention relates to the crystalline form II of agomelatine, characterized by the following parameters, obtained from the powder diagram carried out on the Bruker AXS high-resolution diffractometer D8 with a 3 ° -90 ° angle domain in 2Θ, a step 0.01 ° and 30 s in steps: - monoclinic crystalline mesh, - mesh parameters: a = 20.0903 Å, b = 9.3194 Å, c = 15.4796 Å, β = 108.667 ° space group : P2] / n - number of molecules in the mesh: 8 - mesh volume: Vmaine = 2746,742 Å3 - density: d = 1,13 g / cm3. Obtaining this crystalline form has the advantage of enabling particularly fast and efficient filtration, as well as the preparation of pharmaceutical formulations having a constant and reproducible composition, which is particularly advantageous when these formulations are intended for oral administration.

The shape thus obtained is sufficiently stable to allow its prolonged storage without special conditions of temperature, light, humidity or oxygen content. The pharmacological study of the form thus obtained showed an important activity on the central nervous system as well as microcirculation which makes it possible to establish its utility in the treatment of stress, sleep disorders, anxiety, major depression, seasonal depression, cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to jet lag, laschizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, only in disorders of the cerebral circulation. In another area of activity, it appears that in the treatment, form II of agomelatine can be used in sexual dysfunctions, that it possesses properties of ovulation inhibitors, immunomodulators and that It is likely to be used in cancer treatment.

The crystalline form II of agomelatine will preferably be used in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, hemorrhagic disorders. appetite and obesity. The invention also extends to pharmaceutical compositions containing as the active ingredient crystalline form II agomelatine with one or more inert, non-toxic and suitable excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injectable preparations, oral suspensions and chewables.

The useful dosage is adaptable depending on the nature and severity of the condition, the route of administration as well as the age and weight of the patient. This dosage varies from 0.1 mg to 1 g per day in one or more doses.

The examples below illustrate the invention, but do not limit it in any way. Example 1: 7V- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide

Step A: (7-Methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile

In a reactor of 670 l are introduced 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of acidecyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 12.7 kg of -13 - 01290 benzylamine. The medium is brought to reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and the filtrate obtained is washed with a 2N sodium hydroxide solution and then with water until neutral. After evaporation of the solvent, the solid obtained is recrystallized from an ethanol / water (80/20) mixture to yield the title product with a yield of 90% and a chemical purity higher than 99%.

Melting point: 48-50 ° C

Stage B: (7-Methoxy-1-naphthyl) acetonitrile

In a 670 reactor, 12.6 kg of 5% palladium on carbon in toluene are introduced and refluxed, followed by 96.1 kg of (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile. toluene solution are added as well as 63.7 kg of methacrylated allyl. The reaction is continued at reflux and is followed by vapor phase chromatography.

When all the starting substrate has disappeared, the reaction medium is cooled to room temperature and filtered. After evaporation of the toluene, the solid residue obtained is recrystallized from an ethanol / water (80/20) mixture to yield the title product with a yield of 91% and a chemical purity greater than 99%.

Melting point: 83 ° C

Stage C: 2- (7-Methoxy-1-naphthyl) ethanamine hydrochloride

In a reactor of 1100 l are introduced 80.0 kg of the compound obtained in stage B and 24.0 kg of Raney nickel in ethanol and 170 l of ammonia. The medium is stirred and put under a hydrogen pressure of 30 bar, then heated to 40 ° C. When all the starting substrate has disappeared, the solvent is evaporated and the residue obtained is redissolved in ethyl acetate and 41.5 l of an 11N hydrochloric acid solution are added. After filtration, the precipitate obtained is washed with ethyl acetate and then dried in an oven to yield the title product with a yield of 95.3% and a chemical purity higher than 99.5%. - 14-

f 3

Melting point: 243 ° C

Stage D: N- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide

In a 1600 l reactor, 173 kg of the compound obtained in Stage C and 66 kg of sodium acetate in ethanol are introduced. The mixture is stirred and then 79 kg of acetic anhydride are added, the reaction mixture is refluxed and 600 l of water are added. The reaction is allowed to return to ambient temperature and the precipitate obtained is filtered, washed with a 35/65 ethanol / water mixture to yield the title product with a yield of 92.5% and a chemical purity higher than 99%.

Melting point: 108 ° C. Example 2: A- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide

Step A: (7-Methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile

In a reactor of 670 l are introduced 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of acidecyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 11.0 kg of aniline. The medium is brought to reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and the filtrate obtained is washed with a 2N sodium hydroxide solution and then with water until neutral. After evaporation of the solvent, the solid obtained is recrystallized from an ethanol / water (80/20) mixture to give the title product with a yield of 87% and a chemical purity greater than 99%.

Melting point: 48-50 ° C. Stage B: (7-Methoxy-1-naphthyl) acetonitrile

The procedure is as in Step B of Example 1. Melting point: 83 ° C 012900 -15-

Stage C: 2- (7-Methoxy-1-naphthyl) ethanamine hydrochloride

The procedure is as in Step C of Example 1.

Melting point: 243 ° C

Step D: N- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide The procedure is as in Step D of Example 1.

Melting point: 108 ° C.

Example 3: Crystalline Form II of N- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide The recording of the data was carried out on the Bruker AXS high-resolution diffractometer D8 with the following parameters: an angular domain 3 ° - 90 ° at 20, a pitch of 0.01 ° and 30 s in steps. The Ar- [2- (7-methoxy-1-naphthyl) ethyl] acetamide powder obtained in Example 1 was deposited on a carrier for transmission mounting. The X-ray source is a copper tube (LCuKai = 1.54056 Å). The assembly includes a front monochromator (Ge crystal (ll 1)) and a solid energy-resolved detector (MXP-Dl, Moxtec-SEPH). The compound is well crystallized: the width of the lines at mid-height is of the order of 0.07 ° in 2Θ.

The following parameters were thus determined: - monoclinic crystal lattice, - mesh parameters: a = 20.0903 Å, b = 9.3194 Å, c = 15.4796 Å, β = 108.667 ° space group: P2i / n 20 - number of molecules in the mesh: 8 - volume of the mesh: V average = 2746.742 Å3 - density: d = 1.13 g / cm3. 012900 -16-

Example 4: Pharmaceutical composition

Preparation formula for 1000 tablets 25 mg doses:

Composed of example 3 ............................................ .................................................. .... 25 g

Lactose monohydrate ................................................ ............................................... 62 g 5 Magnesium Stearate ............................................... ............................................. 1.3 g

Corn starch............................................... .................................................. ...... 26 g

Maltodextrins ................................................. .................................................. ...... 9 g

Anhydrous colloidal silica ............................................... ....................................... 0.3 g

Pre-gelatinised maize starch type A ............................................ .......................... 4 g 10 Stearic acid ................... .................................................. ................................... 2.6 g

Example 5: Pharmaceutical composition

Preparation formula for 1000 tablets 25 mg doses:

Composed of example 3 ............................................ .................................................. .... 25 g

Lactose monohydrate ................................................ ............................................... 62 g 15 Magnesium Stearate ............................................... ............................................. 1.3 g

Povidone ............................. ................... 1 .................................................. ............... 9 g

Anhydrous colloidal silica ............................................... ....................................... 0.3 g

Cellulose sodium glycolate ............................................... ...................................... 30 g

Stearic acid ................................................ .................................................. ... 2.6 g 20

Claims (20)

- 17- 012900 CLAIMS 1. Process for the industrial synthesis of the compound of formula (I) (I) characterized in that the 7-methoxy-1-tetralone of formula (III) is reacted with: with cyanoacetic acid of formula (IV): HO CN (IV) under conditions of elimination of the water formed, in the presence of a catalytic quantity of the compound of formula (V): + R 1 -NH 3 (V) wherein R and R ', which may be identical or different, each represent a linear or branched (C 3 -C 10) alkyl group, an unsubstituted or substituted aryl group, or a linear or branched (C 1 -C 6) arylalkyl group; unsubstituted or substituted, to conduct after filtration and washing with a basic solution of (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile of formula (VI): (VI) compound of formula (VI) which is reacted with a hydrogenation catalyst in the presence of an allyl derivative to yield the compound of formula (VII): (VII) which is then subjected to reduction with hydrogen in the presence of Raney nickel in an ammoniacal ethanol medium and then salified with hydrochloric acid to yield the compound of formula (VIII): which is successively subjected to the action of sodium acetate and then of acetic anhydride to give the compound of formula (I) which is isolated in the form of a solid, it being understood that: -19- Ο 1290 C - aryl means a phenyl, naphthyl or biphenyl group, - the term "substituted" for the expressions "aryl" and "arylalkyl" means that the aromatic portion of these groups may be substituted with 1 to 3 groups, identical or different, selected from linear or branched (CrC 6) alkyl, hydroxy, and linear or branched (C 1 -C 6) alkoxy - "allyl derivative" means any molecule containing 3 to 10 carbon atoms and may also contain 1 to 5 oxygen atoms and containing at least one -CH2-CH = CH2 moiety. 2. Process for synthesizing the compound of formula (I) according to claim 1, characterized in that the conversion reaction of the compound of formula (ΠΙ) into a compound of formula (VI) is carried out under reflux of toluene. 3. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that R represents a hexyl group. 4. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that R 'represents a benzyl group. 5. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the catalyst used for the conversion reaction of the compound of formula (III) into a compound of formula (VI) is the compound of formula (Va) Wherein R'a represents a phenyl group unsubstituted or substituted by one or more linear or branched (C 1 -C 6) alkyl groups, n is 0 or 1; and Rarepresents a linear (C3-C10) alkyl group. -20- 012900 6. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the catalyst used for the conversion reaction of the compound of formula (ΠΙ) into a compound of formula (VI) is benzylammonium heptanoate of formula (IX): 7. A compound of formula (VI) which is (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile, useful as an intermediate for the synthesis of agomelatine. 8. Process for synthesizing the compound of formula (I) according to claim 1, characterized in that the conversion reaction of the compound of formula (VI) into compound of formula (VII) is carried out under reflux of toluene. 9. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the hydrogenation catalyst used in the conversion reaction of the compound of formula (VI) into a compound of formula (VII) is palladium. 10. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the hydrogenation catalyst used in the reaction of conversion of the compound of formula (VI) to a compound of formula (VIT) is palladium on 5% coal. 11. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the amount of hydrogenation catalyst used in the reaction of conversion of the compound of formula (VI) to a compound of formula (VII) is 5%. in weight of catalyst relative to the weight of the substrate. 12. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion reaction of the compound of formula (VII) into compound of formula (VIII) is carried out at 40 ° C. Û12900 -21 - 13. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the reaction of conversion of the compound of formula (VIII) into compound of formula (I) is carried out in ethanol. 14. Process for the synthesis of agomelatine from the compound of formula (VI), characterized in that the compound of formula (VI) is obtained by the synthesis method according to any one of claims 1 to 6, and subject to an aromatization reaction followed by reduction and then coupling with acetic anhydride. 15. Process for synthesizing agomelatine from the compound of formula (VII), characterized in that the compound of formula (VH) is obtained by the synthesis method according to any one of claims 1 to 6 and 8. at 11, and which is subjected to reduction and then coupling with acetic anhydride. 16. Process for the synthesis of agomelatine from the compound of formula (VIII), characterized in that the compound of formula (VIII) is obtained by the method of synthesis according to any one of claims 1 to 6 and 8 to 12 and which is subjected to coupling with acetic anhydride. 17. Crystalline form II of agomelatine of formula (I): characterized by the following parameters, obtained from the powder chart on the Bruker AXS D8 high resolution diffractometer with an angular range of 3 ° -90 ° in 2Θ, a pitch of 0.01 ° and 30 s in steps: - mesh monoclinic crystalline, - mesh parameters: a = 20.0903 Å, b = 9.3194 Å, c = 15.4796 Å, β = 108.667 ° -22- 012900 - space group: P2i / n - number of molecules in the mesh: 8 - mesh volume: Vmaiiie - 2746,742 Â3 □ - density: d = 1,13 g / cm. 18. Pharmaceutical compositions containing as active ingredient the crystalline form II of Tagomelatine according to claim 17, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 19. Pharmaceutical compositions according to claim 18 useful for the manufacture of medicaments for treating disorders of the melatoninergic system. 20. Pharmaceutical compositions according to claim 18, useful for the manufacture of medicaments for the treatment of sleep disorders, stress, anxiety, seasonal disorders or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue. time differences, schizophrenia, panic attacks, lamelancolence, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, dementia, various disorders related to normal or pathological aging, lamigraine, memory loss, Alzheimer's disease, cerebral circulation disorders, as well as sexual dysfunction, as ovulation inhibitors , immunomodulators and in the treatment of cancers.