HK1078563B

HK1078563B - New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it

Info

Publication number: HK1078563B
Application number: HK05110484.7A
Authority: HK
Inventors: Souvie Jean-Claude; Gonzalez Blanco Isaac; Thominot Gilles; Chapuis Genevieve; Horvath Stephane; Damien Gerard
Original assignee: Les Laboratoires Servier
Priority date: 2004-02-13
Filing date: 2005-11-21
Publication date: 2007-09-21

Description

New synthesis method, new crystal form and pharmaceutical composition of agomelatine

no marking

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

the invention also relates to the crystal form II of agomelatine, a preparation method thereof and a pharmaceutical composition containing the same.

Agomelatine, or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, has valuable pharmacological properties.

In fact, it is characterized by being an agonist of receptors of the melatoninergic system on the one hand, and a 5-HT on the other hand_2CAn antagonist of the receptor. These properties make it active in the central nervous system and in particular in the treatment of major depressive disorders, seasonal affective disorders, sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and its therapeutic use have been described in european patent specification EP 0447285.

In view of the pharmaceutical value of the compound, it is important to be able to obtain it in an efficient industrial synthesis process, i.e. a process which can be easily converted to the industrial scale and which gives agomelatine in good yields and extremely high purity.

It is also important to be able to obtain agomelatine in a well-defined crystalline form, with excellent reproducibility and, consequently, with valuable characteristics in terms of filtration and ease of formation.

Patent specification EP 0447285 describes the synthesis of agomelatine starting from 7-methoxy-1-tetralone in eight reaction steps with an average yield of less than 30%.

The process comprises the action of ethyl bromoacetate followed by aromatization and saponification to give the corresponding acid, which is then converted to acetamide and subsequently dehydrated to give (7-methoxy-1-naphthyl) acetonitrile, followed by reduction and then condensation of acetyl chloride.

In particular, the synthesis of (7-methoxy-1-naphthyl) acetonitrile involves 6 reaction steps and, when converted to industrial scale, it soon turned out to be difficult to carry out the process, mainly due to reproducibility problems of the first step. The first step consists in reacting 7-methoxy-1-tetralone with ethyl bromoacetate according to the reformatsky reaction, yielding ethyl (7-methoxy-3, 4-dihydro-1 (2H) -naphthylene) acetate.

Furthermore, the subsequent step of aromatization of ethyl (7-methoxy-3, 4-dihydro-1 (2H) -naphthylene) acetate is often incomplete and after saponification gives a product mixture which is difficult to purify.

The literature describes a three-step process for obtaining (7-methoxy-1-naphthyl) acetonitrile comprising: taking 7-methoxy-1-tetralone as a starting material, and passing LiCH₂CN, followed by dehydrogenation using DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) and finally dehydration in an acidic medium (Synthetic Communication, 2001, 31(4), 621-. The overall yield is relatively general (76%), however, the use of DDQ in particular in the dehydrogenation step and the necessity of benzene reflux in the third step, are not satisfactory from the point of view of cost and environment.

The applicant has now developed a new industrial synthesis process which proceeds in a reproducible manner and which, without the need of carrying out cumbersome purifications, gives agomelatine in a purity which is tolerable for its use as pharmaceutical active ingredient.

A further solution to overcome the problems encountered in the process described in patent specification EP 0447285 was obtained by direct condensation of a cyano compound with 7-methoxy-1-tetralone. Further, it is also necessary that the obtained condensation compound be easily subjected to aromatization without drastic conditions to obtain (7-methoxy-1-naphthyl) acetonitrile, and that reagents meeting the requirements for industrial production in terms of cost and environment can be used.

It is clear that (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile is an ideal synthetic intermediate satisfying the requirement for synthesis directly from 7-methoxy-1-tetralone and is an excellent substrate in the aromatization step.

The direct condensation of tetralone with acetonitrile or acetonitrile compounds has been described in the literature. In particular, patent specification US 3992403 describes the condensation of cyanomethyl phosphonate with 6-fluoro-1-tetralone and patent specification US 3931188 describes the condensation of acetonitrile with tetralone to give a cyano intermediate which is used directly in the subsequent reaction.

According to FIG. 1, when applied to 7-methoxy-1-tetralone, the condensation of acetonitrile gives an isomeric mixture in which the exo form (exo) is the major portion and the endo form (endo) is the minor portion,

FIG. 1 shows a schematic view of a

More parts of "exterior" and less parts of "interior"

The resulting mixture then requires drastic aromatization conditions which are incompatible with the industrial requirements for carrying out the agomelatine synthesis.

The applicant has now developed a new industrial synthesis process which makes it possible to obtain (7-methoxy-1-naphthyl) acetonitrile from 7-methoxy-tetralone in only two steps, in a reproducible manner, without having to carry out cumbersome purifications, by using as synthesis intermediate (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile free from the "exo" impurities represented by formula (II):

this impurity cannot undergo subsequent aromatization under operating conditions compatible with the industrial requirements for carrying out the agomelatine synthesis.

More particularly, the present invention relates to a process for the industrial synthesis of a compound of formula (I):

characterized by 7-methoxy-1-tetralone of formula (III):

with cyanoacetic acid of the formula (IV),

with the proviso that the water formed is removed and that a catalytic amount of a compound of formula (V) is present:

wherein R and R', which may be the same or different, each represent a linear or branched (C)₃-C₁₀) Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted straight or branched chain aryl (C)₁-C₆) Alkyl, preferably R represents hexyl and R' represents benzyl.

After filtration and washing with an alkaline solution, (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile represented by the formula (VI) is produced:

reacting a compound of formula (VI) with a hydrogenation catalyst in the presence of an allyl compound to produce a compound of formula (VII):

reduction thereof with hydrogen in the presence of raney nickel in an ammoniacal ethanol medium, followed by conversion to a salt using hydrochloric acid, to yield the compound of formula (VIII):

this is reacted successively with sodium acetate and acetic anhydride to give the compound of the formula (I) which is isolated in solid form.

Wherein:

aryl is understood to mean phenyl, naphthyl and biphenyl,

the term "substituted" as used to define "aryl" and "arylalkyl" means that the aryl residues of these groups may be chosen from linear or branched (C)₁-C₆) Alkyl, hydroxy and straight or branched chain (C)₁-C₆) Alkoxy is substituted by 1 to 3 identical or different radicals,

by "allyl compound" is understood any compound containing from 3 to 10 carbon atoms and containing at least 1-CH₂-CH＝CH₂Molecules of the group, which may additionally contain 1 to 5 oxygen atoms.

More particularly, in the reaction of converting the compound of formula (III) into the compound of formula (VI), the water formed is removed by distillation. Preference is given to using reaction solvents having a boiling temperature greater than or equal to that of water, more preferably those which form azeotropes with water, such as xylene, toluene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene or 1, 3, 5-trimethylbenzene.

The conversion of the compound of formula (III) to the compound of formula (VI) is preferably effected under toluene or xylene reflux conditions, more preferably under toluene reflux conditions.

In the conversion of the compound of the formula (III) into the compound of the formula (VI), it is appropriate that one of the R or R' groups of the catalyst used represents a linear or branched (C)₃-C₁₀) Alkyl radical and the otherRepresents aryl or arylalkyl. More particularly, preferred catalysts are of formula (V)_a) The catalyst shown is:

wherein R'_aRepresents unsubstituted or substituted by one or more straight or branched chains (C)₁-C₆) Alkyl-substituted phenyl, n is 0 or 1, R_aRepresents a straight chain (C)₃-C₁₀) An alkyl group.

Suitably is R'_aRepresents an unsubstituted or substituted phenyl group, more particularly an unsubstituted phenyl group.

Preferred radicals R_aIs hexyl.

N has a preferred value of 1.

According to the process of the present invention, in the conversion of the compound of formula (III) into the compound of formula (VI), the catalyst used is preferably benzylammonium heptanoate of formula (IX):

advantageously, in the filtration and use of inorganic or organic alkaline solutions, e.g. NaOH, KOH, Ca (OH)₂、Sr(OH)₂Or NH₄OH, and particularly preferably sodium hydroxide solution, to give the compound of the formula (VI).

The conversion of the compound of formula (VI) to the compound of formula (VII) is preferably effected under toluene or xylene reflux conditions, more preferably under toluene reflux conditions.

In the conversion of the compounds of the formula (VI) into compounds of the formula (VII), preference is given to using catalysts which are in the form of oxides or are supported, for example, on palladium, platinum, nickel, Al₂O₃And more particularly palladium. Preferably 1 to 20% palladium on carbon (hydrogenation catalyst), more particularly 5% or 10% palladium on carbon. The amount of palladium on carbon (hydrogenation catalyst) used is preferably from 1 to 10% by weight, more particularly 5%, based on the weight of the catalyst relative to the weight of the substrate.

In the reaction for converting the compound of the formula (VI) into the compound of the formula (VII), the hydrogen acceptor used is preferably an allyl compound, more particularly allyl acrylate or allyl glycidyl ether. The preferred allyl acrylate for the process of the present invention is allyl methacrylate.

The conversion of the compound of the formula (VII) into the compound of the formula (VIII) according to the process of the present invention is preferably carried out at from 20 to 40 ℃, more particularly at from 30 to 40 ℃ and even more preferably at 40 ℃.

The conversion of the compound of formula (VIII) into the compound of formula (I) is preferably carried out in an alcoholic medium, and more particularly in an ethanolic medium.

This method is particularly advantageous because:

the process enables the exclusive access to the "endo" form of the compound of formula (VI) on an industrial scale. This result is even more surprising in view of the fact that in this type of reaction it is generally well reported in the literature that endo/exo mixtures are obtained (Tetrahedron, 1966, 22, 3021-3026). The reason for this result is the use of the compound of formula (V) as a reaction catalyst instead of the ammonium acetate currently used in this reaction (ball. soc. chim. fr., 1949, 884-890).

The conversion of the compound of formula (III) into the compound of formula (VI) is very high, exceeding 97%, unlike the conversion which does not exceed 75% with acetic acid.

Unlike benzoquinones currently used, the use of hydrogenation catalysts in the presence of allyl compounds for the conversion of compounds of formula (VI) into compounds of formula (VII) completely meets the requirements of industrial production in terms of cost and environment.

Moreover, the process enables the compound of formula (VII) to be obtained exclusively on an industrial scale, in particular without the corresponding reduction product of formula (X):

finally, a higher conversion of the compound of formula (VI) to the compound of general formula (VII) is observed, exceeding 90%.

The hydrogenation of the compounds of formula (VII) in an ethanol medium containing ammonia in the presence of a Raney nickel catalyst has been described (J.Med.chem., 1994, 37(20), 3231-3239), but the conditions required for this reaction are difficult to apply on an industrial scale: the reaction was carried out at 60 ℃ for 15 hours with a final yield of less than 90%. Moreover, the main drawback of this reaction is also the concomitant formation of "bis" compounds of formula (XI):

and it is difficult to control the conversion of impurities. The process developed by the present inventors makes it possible to obtain compounds of formula (VIII) with impurity levels reduced to less than 4% under experimental conditions which are satisfactory for industrialization, since the reaction is carried out at 30 to 40 ℃ with yields of more than 90% and chemical purities of more than 99.5%.

The fact that the amidation is carried out in alcoholic solvents, more particularly in ethanolic solvents, makes it possible to isolate the compound of formula (I) very easily in quantitative yields, is surprising since this solvent is expected to be a competitive drain on acetic anhydride and is therefore not very suitable for this type of reaction.

The compounds of formula (VI) obtained according to the process of the present invention are novel and can be used as intermediates in the synthesis of agomelatine. In the synthesis process, the compound shown in the formula (VI) is subjected to aromatization, reduction and coupling with acetic anhydride.

The invention also relates to crystalline form II of agomelatine obtained according to the above process. In fact, it is very important to obtain crystalline forms that are well defined and have excellent reproducibility.

The prior art documents EP 0447285 and Yous et al (Journal of medicinal chemistry, 1992, 35(8), 1484-1486) make it possible to obtain agomelatine in a particular crystalline form which has been described by Tinant et al (Acta Crystal., 1994, C50, 907-910).

The present inventors have developed a process for the preparation of agomelatine which has a crystalline form which is well defined and very reproducible and therefore has valuable characteristics in terms of filtration and ease of formation.

More specifically, the present invention relates to crystalline form II of agomelatine, which can be characterized by the following parameters, which are obtained from a powder diagram obtained using a Bruker AXS D8 high resolution diffractometer having an angle 2 θ ranging from 3 ° to 90 ° in steps of 0.01 °, 30s per step:

monoclinic crystal lattice

-lattice parameter: 20.0903 Å, 9.3194 Å, 15.4796 Å and 108.667 degree

-space group: p2₁/n

-number of molecules in unit cell: 8

-unit cell volume: v_{Unit cell}＝2746.742Å³

-density: d is 1.13g/cm³。

The advantage of obtaining this crystalline form is that it can be filtered extremely rapidly and efficiently, and that the preparation of a pharmaceutical formulation has consistent and reproducible components, which is extremely advantageous when the pharmaceutical formulation is intended for oral administration.

The crystalline form thus obtained is sufficiently stable and can therefore be stored for a long period of time without particular restrictions on temperature, light, humidity or oxygen content.

Pharmacological studies on the crystalline form thus obtained show a remarkable activity on the central nervous system and the microcirculatory system, and thus it can be confirmed that crystalline form II of agomelatine is useful for the treatment of stress, sleep disorders, anxiety disorders, major depression, seasonal affective disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue due to jet lag, schizophrenia, phobias, melancholia, appetite disorders, obesity, insomnia, pain, confusion, epilepsy, diabetes, parkinson's disease, senile dementia, various diseases associated with normal or pathological aging, migraine, amnesia, alzheimer's disease, and cerebral circulation diseases. In another active area, crystalline form II of agomelatine is useful for the treatment of sexual dysfunction, which has ovulation-inhibiting and immune-modulating properties, and which is useful in the treatment of cancer.

Crystalline form II of agomelatine is preferably used for the treatment of major depressive disorder, seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jet lag, appetite disorders and obesity.

The invention also relates to a pharmaceutical composition comprising crystalline form II of agomelatine as active ingredient, together with one or more inert, non-toxic suitable excipients. In the pharmaceutical compositions according to the invention, mention may be made, more particularly, of those suitable for oral, parenteral (intravenous or subcutaneous) injection or by intranasal use, tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, emulsions, ointments, dermatives, injectable preparations, oral liquids and disintegratable pastes.

The invention also relates to the use of the pharmaceutical composition described above for the manufacture of a medicament for the treatment of disorders of the melatoninergic system.

The dosage to be administered should be selected according to the characteristics and severity of the disease, the route of administration, and the age and weight of the patient, and the dosage of 0.1mg to 1g should be administered in one or more divided doses per day.

The following examples are intended to illustrate the invention, but in no way limit it.

Example 1: n- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide

Step A: (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile

85.0kg of 7-methoxy-1-tetralone, 60.3kg of cyanoacetic acid and 15.6kg of heptanoic acid in toluene were charged in the presence of 12.7kg of benzylamine in a 670 liter reactor. The mixture was heated under reflux. When all starting substrate had disappeared, the solution was cooled and filtered. The resulting precipitate was washed with toluene and then the resulting filtrate was washed with 2N sodium hydroxide solution and then with water until neutral. The solvent was removed by evaporation and the resulting solid was then recrystallized from a mixture of ethanol/water (80/20) to give the title product in 90% yield and chemical purity of over 99%.

Melting Point：48-50℃

Step B: (7-methoxy-1-naphthyl) acetonitrile

12.6kg of 5% palladium on carbon in toluene were added to a 670 liter reactor and heated under reflux; then 96.1kg of (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile in toluene and 63.7kg of allyl methacrylate were added. The reaction was continued under reflux conditions and then subjected to gas chromatography. When all the starting substrate had disappeared, the solution was cooled to room temperature and then filtered. The toluene was removed by evaporation and the solid residue obtained was then recrystallized from a mixture of ethanol/water (80/20) to give the title product in 91% yield and chemical purity of over 99%.

Melting point: 83 deg.C

Step C: 2- (7-methoxy-1-naphthyl) ethylamine hydrochloride

80.0kg of the compound obtained in step B, 24.0kg of Raney nickel in ethanol and 170 l of ammonium hydroxide are introduced into a 1100 l reactor. The mixture was stirred under a hydrogen pressure of 30 bar and then heated to 40 ℃. When all the starting substrate had disappeared, the solvent was distilled off, the residue obtained was redissolved in ethyl acetate, and 41.5 l of 11N hydrochloric acid solution was added. After filtration, the precipitate obtained was washed with ethyl acetate and dried in an oven to give the title product in 95.3% yield and chemical purity of over 99.5%.

Melting Point：243℃

Step D: n- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide

173kg of the compound obtained in step C and 66kg of sodium acetate in ethanol are placed in a 1600 l reactor, the mixture is stirred and then 79kg of acetic anhydride are added. The reaction mixture was heated to reflux and 600 liters of water were added. The reaction mixture was brought to room temperature and the resulting precipitate was filtered off and washed with 35/65 of an ethanol/water mixture to give the title product in 92.5% yield and more than 99% chemical purity.

Melting Point：108℃

Example 2: n- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide

Step A: (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile

85.0kg of 7-methoxy-1-tetralone, 60.3kg of cyanoacetic acid and 15.6kg of heptanoic acid dissolved in toluene were charged in the presence of 11.0kg of aniline in a 670 liter reactor, and the mixture was heated under reflux. When all starting substrate had disappeared, the solution was cooled and filtered. The resulting precipitate was washed with toluene, and the resulting filtrate was washed with a 2N sodium hydroxide solution, and then washed with water to neutrality. The solvent was removed by evaporation and the resulting solid was recrystallized from an ethanol/water (80/20) mixture to give the title product in 87% yield and in more than 99% chemical purity.

Melting Point：48-50℃

Step B: (7-methoxy-1-naphthyl) ethaneNitrile

The operation is the same as in step B of example 1.

Melting Point：83℃

Step C: 2- (7-methoxy-1-naphthyl) ethylamine hydrochloride

The procedure is the same as in step C of example 1.

Melting Point：243℃

Step D: n- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide

The procedure is the same as in step D of example 1.

Melting Point：108℃

Example 3: n- [2- (7-methoxy-1-naphthyl) ethyl]Crystalline form II of acetamide

Data were recorded using a Bruker AXS D8 high resolution diffractometer with the following parameters: the 2 theta angle ranges from 3 deg. to 90 deg., steps of 0.01 deg., for 30s each step. N- [2- (7-methoxy-1-naphthyl) ethyl obtained in the examples]Acetamide powder is placed on a transport table support. The X-ray source is a copper tube (lambda CuK)_α11.54056 Å). The bench includes a front monochromator (Ge (111) crystal) and an energy resolving solid state detector (MXP-D1, Moxtec-SEPH).

The compound has good crystallization: the half-height ray width is about 0.07 deg. (2 theta). The following parameters were determined:

monoclinic crystal lattice

-lattice parameter: 20.0903 Å, 9.3194 Å, 15.4796 Å and 108.667 degree

-a spatial group: p2₁/n

-number of molecules in unit cell: 8

-unit cell volume: v_{Unit cell}＝2746.742Å³

-density: d is 1.13g/cm³

Example 4: pharmaceutical composition

1000 tablets, each containing a 25mg dose, are formulated as follows:

compound of example 3 25g

Lactose monohydrate 62g

Magnesium stearate 1.3g

Corn starch 26g

Maltodextrin 9g

Silica, anhydrous colloid 0.3g

Type A starch glycolate 4g

Stearic acid 2.6g

Example 5: pharmaceutical composition

1000 tablets, each containing a 25mg dose, are formulated as follows:

compound of example 3 25g

Lactose monohydrate 62g

Magnesium stearate 1.3g

Povidone 9g

Silica, anhydrous colloid 0.3g

Cellulose glycolate 30g

Stearic acid 2.6g

Claims

1. Crystalline form II of agomelatine of formula (I):

the characteristics can be expressed in the following parameters, obtained from a powder diagram obtained using a Bruker AXS D8 high resolution diffractometer with 2 θ angles ranging from 3 ° to 90 ° in steps of 0.01 °, 30s per step:

monoclinic crystal lattice

-lattice parameter: 20.0903 Å, 9.3194 Å, 15.4796 Å and 108.667 degree

-space group: p2₁/n

-number of molecules in unit cell: 8

-unit cell volume: v_{Unit cell}＝2746.742Å³

-density: d is 1.13g/cm³。

2. Process for the industrial synthesis of crystalline form II of agomelatine of formula (I) according to claim 1:

characterized by 7-methoxy-1-tetralone of formula (III):

with cyanoacetic acid of the formula (IV):

with the proviso that the water formed is removed and that a catalytic amount of a compound of the formula (V) is present:

wherein R and R' may be the same or different and each represents a straight or branched C₃-C₁₀Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted straight or branched aryl C₁-C₆An alkyl group, a carboxyl group,

reacting with sodium acetate and acetic anhydride successively to obtain compound of formula (I), and separating in solid form,

wherein:

aryl is understood to mean phenyl, naphthyl and biphenyl,

the term "substituted" as used to define "aryl" and "arylalkyl" means that the aryl residue of these groups may be chosen from linear or branched C₁-C₆Alkyl, hydroxy and straight or branched C₁-C₆Alkoxy is substituted by 1 to 3 identical or different radicals,

3. Process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the conversion from the compound of formula (III) to the compound of formula (VI) is carried out under reflux of toluene.

4. Process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that R represents a hexyl group.

5. Process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that R' represents a benzyl group.

6. Process for the synthesis of the crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the catalyst used for the conversion of the compound of formula (III) into the compound of formula (VI) is of formula (V)_a) A compound shown in the formula (I):

wherein R'_aRepresents C which is unsubstituted or substituted by one or more straight or branched chains₁-C₆Alkyl-substituted phenyl, n is 0 or 1, R_aRepresents linear C₃-C₁₀An alkyl group.

7. Process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the catalyst used for the conversion of the compound of formula (III) into the compound of formula (VI) is benzylammonium heptanoate of formula (IX):

8. process for the synthesis of the crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the conversion from the compound of formula (VI) to the compound of formula (VII) is carried out under reflux of toluene.

9. Process for the synthesis of the crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the hydrogenation catalyst used in the conversion of the compound of formula (VI) into the compound of formula (VII) is palladium.

10. The process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the hydrogenation catalyst used in the conversion of the compound of formula (VI) into the compound of formula (VII) is 5% palladium on carbon.

11. The process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that in the conversion of the compound of formula (VI) into the compound of formula (VII), the amount of hydrogenation catalyst used is 5% by weight, based on the weight of catalyst relative to the weight of substrate.

12. Process for the synthesis of the crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the conversion from the compound of formula (VII) to the compound of formula (VIII) is carried out at 40 ℃.

13. Process for the synthesis of crystalline form II of agomelatine of formula (I), according to claim 2, characterized in that the conversion from the compound of formula (VIII) to the compound of formula (I) is carried out in ethanol.

14. A process for the synthesis of the crystalline form II of agomelatine of formula (I) starting from the compound of formula (VI), characterized in that the compound of formula (VI) is aromatized, then reduced and coupled with acetic anhydride.

15. Process for the synthesis of crystalline form II of agomelatine of formula (I) starting from a compound of formula (VII), characterized in that the compound of formula (VII) is reduced and then converted into a salt using hydrochloric acid, yielding the compound of formula (VIII):

which is then acted upon with sodium acetate and acetic anhydride.

16. A process for the synthesis of the crystalline form II of agomelatine of formula (I) starting from the compound of formula (VIII), characterized in that the compound of formula (VIII) is acted on with sodium acetate and acetic anhydride.

17. A pharmaceutical composition containing the crystalline form II of agomelatine according to claim 1 as active agent, together with one or more pharmacologically acceptable, inert, non-toxic excipients.

18. Use of a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the treatment of disorders of the melatoninergic system.

19. Use of a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the treatment of: sleep disorders, stress, anxiety disorders, seasonal affective disorders or major depression, cardiovascular diseases, digestive disorders, jet lag induced insomnia and fatigue, schizophrenia, phobias, depression, appetite disorders, obesity, insomnia, confusion, epilepsy, diabetes, parkinson's disease, senile dementia, diseases associated with normal or pathological ageing, migraine, amnesia, alzheimer's disease, cerebral circulation disorders and sexual dysfunction, as ovulation inhibitors and immunomodulators, for the treatment of cancer.