FR3014433A1 - NOVEL PROCESS FOR THE SYNTHESIS OF 7-METHOXY-NAPHTHALENE-1-CARBALDEHYDE AND APPLICATION TO THE SYNTHESIS OF AGOMELATIN - Google Patents

Abstract

Process for the industrial synthesis of the compound of formula (I):

Description

The present invention relates to a new process for the industrial synthesis of 7-methoxynaphthalene-1-carbaldehyde and its application to the industrial production of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide. . More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I): CHO MeO The compound of formula (I) obtained according to the process of the invention is useful in the synthesis of agomelatine or N- [2- (7-Methoxy-1-naphthyl) ethyl] acetamide of formula (II): MeO NHCOMe (H) 1 () Agomelatine or N42- (7-methoxy-1-naphthyl) ethyl] acetamide has properties interesting pharmacological It has indeed the double peculiarity 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, pathologies of the digestive system, insomnia and fatigue due to jet lag. , appetite disorders and obesity. The agomelatine, its preparation and its therapeutic use have been described in European patents EP 0 447 285 and EP 1 564 202. Given the pharmaceutical interest of this compound, it was important to be able to access it. with a powerful synthesis process, easily transferable on an industrial scale, leading to agomelatine with a good yield and excellent purity, from cheap and easily accessible raw materials. EP 0 447 285 discloses the eight-step access to agomelatine from 7-methoxy-1-tetralone. However, transposed on an industrial scale, it was quickly demonstrated difficulties in implementing this process.

The literature describes 5-step access to 7-methoxy-naphthalene-1-carbaldehyde from 8-amino-naphthalen-2-ol (Kandagatla et al Tetrahedron Lett 2012, 53, 7125-7127). The 4-step preparation of 7-methoxy-naphthalene-1-carbaldehyde from 7-methoxy-tetralone has also been described (Garipati et al Bioorg, Chem Chem Lett, 1997, 7, 14211426). However, 7-inethoxy-1-tetralone and 8-amino-naphthalen-2-ol are expensive raw materials and, therefore, the search for new synthetic routes, especially from cheaper reagents, is still topical. The applicant has continued its investigations and has developed a new industrial synthesis which leads, in a reproducible manner and without requiring laborious purification, to agomelatine with a purity which is compatible with its use as a pharmaceutical active ingredient, starting from a raw material less expensive and more easily accessible. In particular, the Applicant has now developed a new industrial synthesis process to obtain 7-methoxy-naphthalene-1-carbaldehyde reproducibly and without requiring laborious purification, using as raw material naphthalene-2, 7-diol. This new raw material has the advantage of being simple, easily accessible in large quantities with lower costs. The naphthalene 2,7-diol also has the advantage of having in its structure a naphthalene nucleus, which avoids integrating into the synthesis an aromatization step, a step which is always difficult from an industrial point of view. More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I): CHO MeO (I), characterized in that the naphthalene-2,7-diol of formula (III) is reacted: HO OH on which a formylation reaction and a sulfonylation reaction of the aromatic alcohols are carried out to yield the compound of formula (IV): CHO RO 2 SO OSO 2 R in which R represents a group -CH 3, - (CH 2) 2 -CH 3, -CF 3 or toluyle; compound of formula (IV) which undergoes a regioselective deoxygenation reaction in the presence of a transition metal and a reducing agent to yield the compound of formula (V): CHO -4 RO2SO (V) wherein R represents a grouping -CH3, - (CH2) 2 -CH3, -CF3 or toluyl; compound of formula (V) which is then subjected to a desulfonylation reaction followed by a methylation reaction to yield the compound of formula (I) which is isolated in the form of a solid. R preferably represents a -CH3 or toluyl group. The compound of formula (III) is commercially available or readily accessible to those skilled in the art by conventional chemistry reactions or described in the literature. In the process according to the invention, the conversion of the compound of formula (III) into a compound of formula (IV) consists of the action of ethyl orthoformate in the presence of aniline to give an intermediate imine, followed by a sulfonylation reaction of the aromatic alcohols and terminated by hydrolysis of the imine. In the process according to the invention, the conversion of the compound of formula (III) into a compound of formula (IV) consists of the action of ethyl orthoformate in the presence of aniline to give an intermediate imine, followed by hydrolysis of the imine and terminated by a sulfonylation reaction of the aromatic alcohols. Said sulfonylation step is carried out by the action of a sulfonyl chloride, a sulfonic anhydride or a sulfonimide. According to a preferred embodiment, this sulphonylation step is carried out thanks to the action of a sulphonyl chloride and, in particular, tosyl chloride or mesyl chloride. Said hydrolysis reaction of the imine is carried out in a basic or acidic medium. In the process according to the invention, the conversion of the compound of formula (IV) into a compound of formula (V) consists of a deoxygenation step in the presence of a transition metal and a reducing agent.

Preferably, the transition metal is nickel, palladium or platinum. The transition metal may be in the form of a salt or in the form of a single body. Preferably, the transition metal salt is a nickel salt or a palladium salt, more preferably a palladium salt. Advantageously, the reducing agent is either a hydride such as sodium borohydride or lithium aluminum hydride; an aminoborane such as dimethylamine borane; an alkoxysilane such as dimethoxymethylsilane; an alkylsilane such as triethylsilane; an alkaline earth metal such as magnesium; either dihydrogen. In a preferred manner, the reducing agent is dihydrogen which is used directly in its gaseous form or is indirectly obtained by decomposition of an ammonium formate. The reducing agent is preferably the dihydrogen obtained by decomposition of an ammonium formate. According to another preferred embodiment, the conversion of the compound of formula (IV) into a compound of formula (V) consists of a deoxygenation step in the presence of nickel, in particular a nickel salt, and a hydride, preferentially the sodium borohydride. According to another preferred embodiment, the conversion of the compound of formula (IV) into a compound of formula (V) consists of a deoxygenation step in the presence of palladium and dihydrogen. According to another preferred embodiment, the conversion of the compound of formula (IV) into a compound of formula (V) consists of a deoxygenation step in the presence of palladium and an alkaline earth metal, preferentially magnesium. Advantageously, the conversion reaction of the compound of formula (IV) into a compound of formula (V) is carried out in dimethylformamide, dioxane, tetrahydrofuran and toluene and, more preferably, toluene. Preferably, the conversion reaction of the compound of formula (IV) into a compound of formula (V) is carried out between 25 ° C and 75 ° C, more particularly between -30 ° C and 60 ° C and, more particularly, between 40 ° C and 50 ° C. According to another preferred embodiment, the conversion of the compound of formula (IV) into a compound of formula (V) consists of a deoxygenation step in the presence of a transition metal, a reducing agent and a ligand.

The ligand may be either a phosphine ligand or a diaminocarbene ligand, more preferably a phosphine ligand and, more particularly, 1,3-bis (diphenylphosphon) propane. This process is particularly interesting for the following reasons: it makes it possible to obtain on an industrial scale the compound of formula (I) with good yields from a simple and inexpensive raw material; it makes it possible to avoid an aromatisation reaction since the naphthalenic nucleus is present in the starting substrate; it makes it possible to obtain agomelatine from 2,7-dihydroxy-naphthalene with a reduced number of steps.

The compounds of formula (IV) and (V) obtained according to the process of the invention are new and useful as an intermediate for the synthesis of agomelatine and the compound of formula (I). The preferred compounds of formula (IV) are the following: 1-formylnaphthalene-2,7-diyl bis (4-methylbenzenesulfonate); I-formylnaphthalene-2,7-diethyl dimethanesulfonate. The preferred compounds of formula (V) are the following: 8-formylnaphthalen-2-yl 4-methylbenzenesulphonate; 8-formylnaphthalen-2-yl methanesulphonate. The compound of formula (I) thus obtained is, if appropriate, subjected to a series of conventional chemical reactions to lead to agomelatine. The examples below illustrate the invention, but do not limit it in any way. In order to validate the reaction paths, the synthesis intermediates have been systematically isolated and characterized. However, it is possible to significantly optimize the processes by limiting the number of isolated intermediates. The structures of the described compounds were confirmed by the usual spectroscopic techniques: proton NMR (s = singlet, d = doublet, dd = doubled doublet, m - multiplet); Carbon NMR (s = singlet, d = doublet, q = quadruplet). EXAMPLE 1 7-Methoxynaphthalene-1-carbaldehyde Step A: 1 - [(E) - (phenylimino) methylinaphialene-2,7-diol In a flask, naphthalene-2,7-diol (8 g, 50 mmol) is introduced ), aniline (5.06 mL, 55 mmol), ethyl orthoformate (10 mL, 60 mmol). After stirring for 5 hours at 125 ° C, ethanol (100 mL) is added and the mixture is brought to boiling. After cooling, the yellow solid obtained is filtered (8.53 g, 65%) and is used directly for the next step. 1 H NMR spectroscopic analysis (DMSO-d 6, 300.13 MHz, 8 ppm): 15.65 (d, J = 4.7 Hz, 1H); 9.83 (s, 111); 9.44 (d, J = 4.7 Hz, 1H); 7.77 J = 9.1 Hz, 1H); 7.7 (d, 1.7 Hz, 1H); 7.62-7.57 (in, 3H); 7.5-7.45 (m, J = 7.9 Hz, 2H); 7.29 (m, J = 7.3 Hz, 11-1); 6.89 (dd, 8.7 and 2.1 Hz, 111); 6.75 (d, J = 9.1 Hz, 1H). Stage B: 1-formylnaphthalene-2,7-diyl bis (4-methylbenzenesulfonate) The product of the previous Step A (2.135 g, 8.12 mmol), triethylamine (2.7 mL; 19.5 mmol) and tosyl chloride (3.25 g, 17.05 mmol). After stirring for 72 hours at room temperature, the solvent is evaporated and the residue is solubilized in ethyl acetate. The organic phase is washed with water and brine, dried over sodium sulfate and filtered. After evaporation of the solvents, the crude is dissolved in tetrahydrofuran (40 mL) and an aqueous solution of 2 M hydrochloric acid (10 mL) is added. After 30 minutes of heating at 60 ° C, the solvents are evaporated and the residue is dissolved in ethyl acetate. The organic phase is washed three times with water and once with brine, dried over sodium sulfate and filtered. Evaporation of the solvent gives a clean off-white solid (3.53 g, 88%). NMRIII spectroscopic analysis (CDCl3, 300.13 MHz, S in ppm): 10.3 (s, 1H); 8.73 (d, J = 2.5 Hz, 1H); 8.03 (d, J = 9.1 Hz, 1H); 7.83 (d, J = 9.1 Hz, 1H); 7.75 (d, J = 8.3 Hz, 2H); 7.73 (d, J = 8.3 Hz, 2H); 7.39-7.31 (m, 6H); 2.47 (s, 3H); 2.44 (s, 3H). Eeciroscopic analysis of 13C ± CDCl3 NMR, 75 MHz, S en_p_pp): 189.2 (d); 154.0 (s); 150.8 (s); 146.8 (s); 145.8 (s); 136.4 (d); 132.3 (s); 131.2 (s); 131.1 (s); 130.6 (s); 130.4 (d x 2); 130.2 (d); 130.0 (d x 2); 128.63 (d x 2); 128.60 (d x 2); 122.9 (d); 122.7 (s); 122.0 (d); 118.4 (d); 22.0 (q); 21.9 (q).

Stage 8 4-formylnaphthalen-2-yl 4-naphthenesulphonate In an oven-dried flask purged with argon, the product of Step B above (248 mg, 0.5 mmol), acetate is added. of palladium (2.2 mg, 0.01 mmol), 1,3-bis (diphenylphosphino) propane (4.1 mg, 0.01 mmol), toluene (1 mL), triethylamine (280 μL; mmol) and formic acid (75 μL, 2 mmol). After stirring for 2 hours at 45 ° C., the solution is diluted with ethyl acetate and the organic phase is washed with a 1 M aqueous hydrochloric acid solution and with brine, dried over sodium sulfate and evaporated. The crude is purified by filtration on neutral alumina (eluent: ethyl acetate) to give the title product directly used in the next step.

H NMR spectroscopic analysis (CDCl 3, 300 °, 13 MHz, 5 ppm): 10.09 (s, 1H); 8.69 (d, J = 2.4 Hz, 1H); 7.93 (d, J = 8.2 Hz, 1H); 7.83 (dd, J = 7.2 and 1.3 Hz, 1H); 7.74 (d, J = 8.9 Hz, 1H); 7.65 (d, J = 8.3 Hz, 2H); 7.5 (dd, J - 8.2 and 7.2 Hz, 1H); 7.24 (dd, J = 8.9 and 2.4 Hz, 1H); 7.19 (d, J = 8.3 Hz, 2H); 2.31 (s, 3H). Pectrosco Analysis, 13C NMR I3C ICDC13, 75 MHz, S en-cltp): 192.9 (d); 149.9 25 (s); 145.7 (s); 137.8 (d); 134.9 (d); 132.3 (s); 132.1 (s); 131.1 (s); 130.5 (s); 130.3 (d); 129.9 (d x 2); 128.6 (d x 2); 125.5 (d); 122.5 (d); 117.6 (d); 21.7 (q). Step D: 7-Hydroxynaphthalene-1-carbaldehyde To a solution of the product of Step C above (298 mg, 0.96 mmol) in absolute ethanol (5 mL) is added solid potassium hydroxide (270 g). mg, 4.805 mmol). After stirring for 4 hours at room temperature, the solution is acidified with the addition of a 1 M aqueous hydrochloric acid solution and the aqueous phase is extracted three times with ethyl acetate. The organic fractions are combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting crude is recrystallized from ethyl acetate to give the title product (73 mg, 44%). NMR spectroscopic analysis of rH (acetone-d6, 300.13 MHz in ppm): 10.3 (s, 1H); 9.08 (s, 1H, OH); 8.58 (d, J = 2.4 Hz, 1H); 8.13 (d, J = 9.0 Hz, 1H); 8.06 (d, J = 7.0 Hz, 1H); 7.93 (d, J = 8.9 Hz, 1H); 7.51 (dd, J 9.0 and 7.0 Hz, 1H); 7.26 (dd, J = 8.9 and 2.4 Hz, 1H). 13 C NMR spectroscopic analysis (455: 5 MHz acetone, S ppm - presence of rotamers): 194.5 (d); 159.4-159.2 (s); 139.0 (d); 135.9 (d); 133.0 (s); 131.3 (d) 130.9 (s); 129.8 (s); 12Z9 (d); 119.9-119.8 (d); 107.7-107.6 (d). Step E: 7-Methoxynaphthalene-1-carbocedaldehyde To a solution of the product of Step D above (37 mg, 0.215 mmol) in dimethylformamide (0.5 mL) is added sodium hydride (60% in the oil). mineral, 13 mg, 0.323 mmol). After stirring for 1 hour, the iodomethane is added (27 μL, 0.43 mmol). After stirring for a further 30 minutes, the solution is diluted with ethyl acetate and the organic phase is washed with water and then with brine, dried over sodium sulphate and filtered. Evaporation of the solvent gives a crude product which is then purified by chromatography on a column of silica gel (eluent: petroleum ether / ethyl acetate 90/10) to yield the expected product (39 mg, 98%).

Son point: 65-67 ° C. Mectroscopic analysis of 1 H-NMR (CDCl 3, 300 °, 13 MHz, 8 ppm): 10.29 (s, 1H); 8.75 (d, J = 2.6 Hz, 1H); 7.99 (cl, J - 8.1 Hz, 1H); 7.9 (cl, J = 7.1Hz, 1H); 7.77 (d J = 8.9 Hz, 1H); 7.45 (dd, J = 8.1 and 7.1 II, 1H); 7.23 (dd, = 8.9 and 2.6 Hz, 1H); 3.98 (s, 3H). Spectroscopic 13 C NMR analysis fCDCl3, 75.5 MHz, δ (ppm): 194.1 (d); 160.7 (s); 138.3 (d); 135.1 (d); 132.2 (s); 130.2 (s); 129.9 (d); 129.3 (s); 122.5 (d); 119.8 (d); 103.6 (d); 55.6 (q). EXAMPLE 2: 7-Feethoxynaphthalene-1-carbaldehyde Step A: 2,7-Dihydroxynaphthalene-1-carbaldehyde The compound of Step A of Example 1 (5.38 g, 20.46 mmol) is dissolved in a solution. sodium hydroxide (8.18 g, 250 mmol) in water (200 mL). After evaporation of half of the water at atmospheric pressure for 2 hours, the reaction mixture is cooled and a 2M aqueous hydrochloric acid solution (100 ml) is added and then concentrated hydrochloric acid until a pH is obtained. acid. The resulting precipitate is filtered, washed extensively with water until neutralization of the mother liquors and azeotroped with ethanol to give the title product as a gray solid (3.769 g, 98%). NMR111 spectroscopic analysis (acetone-d6, 30013 MHz, 8 ppm): 13.16 (s, OH); 10.74 (s, 1H); 9.03 (s, 1H, OH); 8.02 (d, J = 8.9 Hz, 1H); 7.88 (d, J = 2.3 Hz, 1H); 7.79 (d, J = 8.7 Hz, 1H); 7.07 (dd, J = 8.7 and 2.3 Hz, 1H); 6.92 (d, J 8.9 Hz, 1H). Step B 1-Formylnaphthalene-2,7-dlyl B-dimethanesulfonate To a solution of the product of Step A above (1.565 g, 10.296 mmol) and triethylamine (3.15 mL, 22.65 mmol) in dichloromethane (40 mL) Methanesulfonyl chloride (1.63 mL, 21.11 mmol) was added at 0 ° C. After stirring for 2 hours at room temperature, the solvent is evaporated and the residue is solubilized while hot in ethyl acetate. The organic phase is rapidly washed three times with water. The precipitate that forms during these extractions is filtered and recovered. The organic phase is dried over sodium sulphate. Sodium sulfate is thoroughly washed with hot ethyl acetate. The organic phases are combined and evaporated to give a solid. This solid and the precipitates formed during the extractions were combined to finally be recrystallized from hot ethyl acetate to give the title product (2.574 g, 72%). Spectroscopic analysis of 1H NMR (DM-S0-4, 30 (2.13 MHz, 8 pptni: 10.62 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H); (D, J = 8.9 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.76 (cl, J = 8.9 Hz, 1H), 7.7; (dd, J = 8.9 and 2.3 Hz, 1H), 3.72 (s, 3H), 3.51 (s, 3H), 13 C NMR spectroscopic analysis, 1.13MSO-d, δ, 755 MHz, ppm): 190.7 (d), 152.8 (s), 149.9 (s), 137.3 (d), 131.3 (d), 130.6 (s), 130.5 (s); 122.6 (s), 122.5 (d), 122.3 (d), 117.2 (d), 38.2 (q), 37.7 (q), Step C: methanesulphonate 8 In an oven-dried flask purged with argon, the product of Step B above (172 mg, 0.5 mmol), palladium acetate (5.6 mg) is added. 0.25 mmol), 1,3-bis (diphenylphosphino) propane (10.3 mg, 0.025 mmol), toluene (1 mL), triethylamine (280 μM, 2 mmol) and formic acid (75 μM). After 2 hours of stirring at 60 ° C., the solution is diluted with ethyl acetate and the organic phase is washed with water. aqueous solution of 1 M hydrochloric acid and then with brine, dried over sodium sulfate and evaporated. The crude is purified by filtration on neutral alumina (eluent: ethyl acetate) to give the title product directly used in the next step (94 mg, 75%). Spectroscopic analysis of 1H NMR (CDC13L 300.13 MHz, 8 ppm): 10.3 (s, 1H); 9.2 (d, J = 2.4 Hz, 11-1); 8.11 (d, J = 8.2 HZ, 1H); 8.02 (dd, J = 7.1 and 1.2 Hz, 1H); 7.96 (d, J = 9.0 Hz, 1H); 7.67 (dd, J = 8.2 and 7.1 Hz, 1H); 7.56 (dd, J - 9.0 and 2.4 Hz, 1H); 3.25 (s, 3H). 13 C NMR spectroscopic analysis (CDCl 3, 75.5 MHz, 8 ppm): 193.5 (d); 149.7 (s); 138.3 (d); 135.1 (d); 132.4 (s); 131.2 (s); 130.7 (d); 130.7 (s); 125.7 (d); 122.6 (d); 117.3 (d); 37.8 (q). Stage D: 7-methoxynaphthalene-1-carbaldehyde The title product is obtained in two stages according to the processes described in Stages D and E of Example 1 starting from the product of Stage C above. Point of addition: 65-67 ° C. NMR analysis 111 (CDCl3, 300113 MHz, 8 ppm): 10.29 (s, 1H); 8.75 (d, J = 2.6 Hz, 1H); 7.99 (cl, J = 8.1Hz, 1H); 7.9 (cl, J = 7.1Hz, 1H); 7.77 (cl, 8.9 Hz, H1); 7.45 (cid, J = 8.1 and 7.1 Hz, 1H); 7.23 (dcl, J = 8.9 and 2.6 Hz, 1H); 3.98 (s, 3H). 13C NMR spectroscopy analysis fCDC13, 75.5 MHz, 8 ppm): 194.1 (d); 160.7 (s); 138.3 (d); 135.1 (d); 132.2 (s); 130.2 (s); 129.9 (d); 129.3 (s); 122.5 (d); 119.8 (d); 103.6 (d); 55.6 (q).

Claims (27)

REVENDICATIONS1. Process for the industrial synthesis of the compound of formula (I): C 0 MeO (I), characterized in that the naphthalene-2,7-diol of formula (III) is reacted: OH OH on which a reaction is carried out formylation and sulfonylation reaction of the aromatic alcohols to yield the compound of formula (IV): wherein R is -C1-13, - (CH2) 2 -CH3, -CF3 or toluyl; compound of formula (IV) which undergoes a regioselective deoxygenation reaction in the presence of a transition metal and a reducing agent to yield the compound of formula (V): ## STR2 ## wherein R represents a methyl or toluyl group; compound of formula (V) which is then subjected to a desulfonylation reaction followed by a methylation reaction to yield the compound of formula (I) which is isolated in the form of a solid. 2. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that, during the conversion of the compound of formula (III) into a compound of formula (IV), the sulfonylation step is carried out by a sulfonyl chloride, a sulfonic anhydride or a sulfonimide. to 3. Process for the industrial synthesis of the compound of formula (I) according to claim 2, characterized in that the sulphonylation step is carried out by the action of a sulphonyl chloride. 4. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that, during the conversion of the compound of formula (IV) into a compound of formula (V), the transition metal is nickel, palladium or platinum. 5. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that, during the conversion of the compound of formula (IV) into a compound of formula (V), the transition metal is a palladium salt. . 6. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out in dimethylformamide, dioxane, tetrahydrofuran or toluene. 7. Process for the industrial synthesis of the compound of formula (I) according to claim 6, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out in toluene. 8. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out between 25 ° C and 75 ° C. 9. Process for the industrial synthesis of the compound of formula (I) according to claim 8, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out between 40 ° C and 50 ° C. 10. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that, during the conversion of the compound of formula (IV) into a compound of formula (V), the reducing agent is dihydrogen. 11. Process for the industrial synthesis of the compound of formula (I) according to claim 10, characterized in that the dihydrogen is obtained by decomposition of an ammonium formate. 12. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out in the presence of palladium and dihydrogen. 13. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (IV) into a compound of formula (V) is carried out in the presence of 1,3-bis (diphenylphosphino). Propane.- 16- 14. Compound of formula (IV) according to claim 1 useful as an intermediate synthesis of the compound of formula (I). 15. A compound of formula (IV) according to claim 14 useful as an intermediate for synthesizing agomelatine of formula (II). 16. A compound of formula (IV) according to claims 14 and 15 selected from the following compounds: bis (4-methylbenzenesulfonate) 1-formylnaphthalene-2,7-diyl; 1-formylnaphthalene-2,7-diyl dimethanesulphonate. 17. Use of the compound of formula (IV) according to claims 14 to 16 in the synthesis of the compound of formula (I). 18. Use of the compound of formula (IV) according to claim 17 in the synthesis of agomelatine of formula (II). 19. Compound of formula (V) according to claim 1 useful as an intermediate for synthesizing the compound of formula (I). 20. Compound of formula (V) according to claim 19 useful as an intermediate for the synthesis of agomelatine of formula (II). 21. A compound of formula (V) according to claims 19 and 20 selected from the following compounds: - 8-formylnaphthalen-2-yl 4-methylbenzenesulphonate; 8-formylnaphthalen-2-yl methanesulphonate. 22. Use of the compound of formula (V) according to claims 19 to 21 in the synthesis of the compound of formula (I). 23. Use of the compound of formula (V) according to claim 22 in the synthesis of agomelatine of formula (II). 24. Use of the compound of formula (III) according to claim 1 in the synthesis of the compound of formula (I). 25. Use of the compound of formula (III) according to claim 24 in the synthesis of agomelatine of formula (II). 26. A process for synthesizing agomelatine from the compound of formula (IV), characterized in that the compound of formula (IV) is obtained by the synthesis method according to one of claims 1 to 3. 27. A method for synthesizing agomelatine according to claim 1 from the compound of formula (V), characterized in that the compound of formula (V) is obtained by the synthesis method according to one of claims 1 to 13.