HK1229785B - Novel method for the synthesis of 7-methoxy-naphthalene-1-carbaldehyde and use thereof in the synthesis of agomelatine - Google Patents

Description

The present invention relates to a new industrial process for the 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 industrial synthesis of the compound of formula (I): - What?

The compound of formula (I) obtained by the process of the invention is useful in the synthesis of agomelatine or N-[2-(7-methoxy-1-naphtyl) ethyl]acetamide of formula (II): - What?

Agomelatine or N-[2-(7-methoxy-1-naphtyl) ethyl]acetamide has interesting pharmacological properties.

It has the dual characteristic of being both an agonist at the melatonin receptor and a 5-HT2C receptor antagonist. These properties give it activity in the central nervous system and more particularly in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue due to time difference, appetite disorders and obesity.

Agomelatine, its preparation and its therapeutic use are 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 high-performance synthesis process, easily transposable on an industrial scale, leading to agomelatine with good yield and excellent purity, from cheap and easily accessible raw materials.

Patent EP 0 447 285 describes the eight-step access to agomelatine from 7-methoxy-1-tetralone.

5-step preparation of 7-methoxy-naphthalene-1-carbaldehyde from 8-amino-naphthalene-2-ol (Kandagatla et al. Tetrahedron Lett. 2012, 53, 7125-7127) or 3-step preparation from 2-(7-methoxy-1-naphthyl) ethanol (FR 2 918 369) has also been described. 4-step preparation of 7-methoxy-naphthalene-1-carbaldehyde from 7-methoxy-tetralone (Garipati et al. Bioorg. Med. Chem. 1997, 7, 1421-1426). However, 7-methoxy-1-naphthalene-1-ol and 8-amino-naphthalene-2-ol are reactive raw materials and therefore the synthesis of new, particularly less reactive, pathways from them is still in the early stages of research.

The applicant continued its investigations and developed a new industrial synthesis which leads, in a reproducible manner and without the need for laborious purification, to agomelatine with a purity compatible with its use as a pharmaceutical active ingredient, from a cheaper and more easily accessible raw material.

In particular, the applicant has now developed a new industrial synthesis process which makes it possible to obtain 7-methoxynaphthalene-1-carbaldehyde in a reproducible manner and without the need for laborious purification, using 7-methoxynaphthalene-2-ol as the raw material. This new raw material has the advantage of being simple, easily available in large quantities at lower cost. 7-methoxynaphthalene-2-ol also has the advantage of having a naphthenic node in its structure, which avoids the integration of an aromatisation step, which is always a delicate step from an industrial point of view, into the synthesis.

More specifically, the present invention relates to a process for industrial synthesis of the compound of formula (I): - What? characterised by the reaction of 7-methoxynaphthalene-2-ol of formula (III): - What? wherein a formulation reaction is carried out on position 1 of the compound of formula (III) to yield the compound of formula (IV): - What? a formula (IV) which is subjected to a sulphonylation reaction to give the formula (V): where R is a grouping of -CH3, -CH2) 2-CH3, -CF3 or toluyl; a formula (V) compound which undergoes a deoxygenation reaction in the presence of a transition metal and a reducing agent to lead to the formula (I) compound which is isolated as a solid.

The compound of formula (III) is commercially available or readily available to the professional by conventional chemical reactions or described in the literature.

R is preferably a -CH3 or toluyl group.

In the process of the invention, the transformation of the compound of formula (III) into compound of formula (IV) consists of the action of ethyl orthoformiate in the presence of aniline followed by hydrolysis of the intermediate imine obtained.

In the process of the invention, the transformation of the compound of formula (IV) into a compound of formula (V) consists of a sulphonylation step by the action of a sulphonyl chloride, a sulphonyl anhydride or a sulfonimide.

In the process of the invention, the transformation of the compound of formula (V) into compound of formula (I) consists of a deoxygenation step in the presence of a transition metal and a reducing agent. The transition metal can be either in the form of a salt or in the form of a simple body.

Preferably, the transition metal salt is a nickel salt or a palladium salt, more preferably a palladium salt. Preferably, the reducing agent is either a hydride such as sodium borohydride or lithium and aluminium hydride; or an aminoborane such as dimethylamine borane; or an alkoxysilan such as dimethoxymethylsilane; or an alkylsilan such as triethylsilane; or an alkaline earth metal such as magnesium or dihydrogen.The reducing agent is preferably dihydrogen obtained by decomposition of an ammonium formate. Another preferred method of production is the conversion of the compound of formula (V) to compound of formula (I) by a deoxygenation step in the presence of nickel, in particular a nickel salt, and a hydride, preferably sodium borohydride. Another preferred method of production is the transformation of the compound of formula (V) into compound of formula (I) by a deoxygenation step in the presence of palladium and dihydrogen. Another preferred method of production is the transformation of the compound of formula (V) into compound of formula (I) by a deoxygenation step in the presence of palladium and an alkaline earth metal,Preferably, the conversion reaction of the compound of formula (V) to the compound of formula (I) is carried out in dimethylformamide, dioxane, tetrahydrofuran and toluene and more preferably dimethylformamide. Preferably, the conversion reaction of the compound of formula (V) to compound of formula (I) is carried out between 25 °C and 110 °C, more particularly between 40 °C and 95 °C. Another preferred embodiment is the transformation of the compound of formula (V) into compound of formula (I) by a deoxygenation step in the presence of a transition metal, a reducing agent and a ligand.- What? The ligand can be either a phosphine ligand or a diaminocarbene ligand, more preferably a phosphine ligand and more specifically 1,3-bis (diphenylphosphino) propane or (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane).

An advantageous variant of the industrial synthesis process is that the compound of formula (IV) is directly transformed into a compound of formula (I), the sulphonylation reaction and the deoxygenation reaction in the presence of a transition metal being done in one-pot .

This method is particularly interesting for the following reasons: It allows the formula (I) compound to be obtained on an industrial scale with good yields from a simple and inexpensive raw material; it avoids a flavouring reaction since the naphthalene core is present in the starting substrate; it allows agomelatine to be obtained from 7-methoxy-naphthalene-2-ol with a reduced number of steps.

The formula (V) compounds obtained by the method of the invention are new and useful as intermediates for the synthesis of agomelatine and the formula (I) compound.

The following are the preferred formula (V) compounds: The following shall be indicated in the column 'C' of the column 'C' of the table:

The resulting compound of formula (I) is, if necessary, subjected to a series of conventional chemical reactions (e.g. reduction of the aldehyde to primary alcohol, cyanation, reduction and acetylation of the resulting primary amine) to give agomelatine of formula (II).

The following examples illustrate the invention, but do not limit it in any way. In order to validate the reaction pathways, the synthesis intermediates have been systematically isolated and characterized.

The structures of the described compounds were confirmed by the usual spectroscopic techniques: proton NMR (s = singlet; d = doublet; dd = doubled doublet); carbon NMR (s = singlet; d = doublet; q = quadruplet).

The following is the list of substances which are to be used in the preparation of the product: Stage A: 2-hydroxy-7-methoxynaphthaene-1-carbaldehyde

In a balloon equipped with a refrigerant, 7-methoxynaphthalene-2-ol (3.5 g; 20.11 mmol), ethyl orthoformiate (3.51 mL; 21.12 mmol) and aniline (1.83 mL; 20.11 mmol) are introduced. After agitation for 20 hours at the reflux and cooling, the solid is ground in an ethanol solution of hydrochloric acid 2 M (20 mL). After 30 minutes of agitation at 60 °C and cooling, the solid is collected by filtration to be washed with water and then dried by azeotropy with ethanol and used directly without further purification (2,95 g 73 %). The following spectroscopic analysis of RMN1H (CDCl3, δ in ppm) is performed: 13,17 (s, 1H); 10,74 (s, 1H); 7,88 (d, J = 9,1 Hz, 1H); 7,69 (d, J = 8,9 Hz, 1H); 7,65 (d, J = 2,4 Hz, 1H); 7,07 (dd, J = 8,9 and 2,4 Hz, 1H); 6,97 (d, J = 9,1 Hz, 1H); 3,95 (s, 3H).

Stage B: 4-methylbenzene sulphonate of 1-formyl-7-methoxynaphthalen-2-yl

To a solution of the previous Stage A product (1 g; 4.95 mmol) in dichloromethane (20 mL), triethylamine (826 μL; 5.94 mmol) and tosyl chloride (0.99 g; 5.2 mmol) are added. After 24 hours of agitation, the solvent is evaporated and the residue is re-absorbed in a water/ethyl acetate mixture. The organic phase is washed with a dilute solution of hydrochloric acid, water and brine, then dried on sodium sulphate and filtered.132 g; 65 per cent). The temperature of the liquid is approximately the same as that of the liquid, but the temperature of the liquid is not the same as that of the liquid. The temperature of the liquid is approximately the same as that of the liquid.The ECB shall be informed of any changes to the accounts of the ECB and of any changes to the accounts of the ECB .

Stage C: 7-methoxynaphthalene-1-carbaldehyde

In a balloon that has been ovenised and purged with argon, the previous Stage B product (356 mg; 1 mmol), palladium acetate (4.5 mg; 0.02 mmol), 1,3-bis (diphenylphosphino) propane (8.2 mg; 0.02 mmol), dimethylformamide (2 mL), triethylamine (556 μL; 4 mmol) and formic acid (150 μL; 4 mmol) is introduced into the balloon. The vial is placed in a bath heated to 90 °C for 1.5 hours. After cooling, the mixture is diluted in ethyl acetate and the organic phase is washed with a solution of 1 M hydrochloric acid and dry salt, sodium sulphate and filtered saline.After evaporation of the solvent, the crude is purified by filtration on neutral alumina to give the titer product (139 mg; 75%). The melting point is 65-67 °C. Spectroscopic analysis of RMN1H (CDCl3, 300,13 MHz, δ in ppm): 10, 29 (s, 1H) ; 8,75 (d, J = 2,6 Hz, 1H) ; 7,99 (d, J = 8,1 Hz, 1H) ; 7, 9 (d, J = 7,1 Hz, 1H) ; 7,77 (d, J = 8,9 Hz, 1H) ; 7,45 (dd, J = 8,1 and 7,1 Hz, 1H) ; 7, 23 (dd, J = 8, 9 and 2,6 Hz, 1H) ; 3,(s, 3H).Spectroscopic analysis of RMN13C (CDCl3, 75.5 Mhz, δ in 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 98 6 (q).

The following is the list of substances which are to be used in the preparation of the product: Stage A: 1-formyl-7-methoxynaphthalen-2-yl methanesulfonate

To a solution of the compound obtained in Step A of Example 1 (300 mg; 1,485 mmol) in dichloromethane (5 mL), triethylamine (250 μL; 1,782 mmol) and mesyl chloride (120 μL) are added. After one hour of agitation, the solvent is evaporated and the residue is taken up in an ethyl acetate/water mixture. The organic fraction is washed twice with water and then with brine, dried on sodium sulphate and filtered. Evaporation of the solvent gives the product the title of the product (416 mg; 95%) without the need for purification. The test chemical is a chemical that is used to produce a specific chemical.The following are the parameters for the calculation of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the value of the0 (d) ; 55,7 (q) ; 38,5 (q).

Stage B: 7-methoxynaphthalene-1-carbaldehyde

The product of the title (84%) is obtained by the process described in Step C of Example 1 from the product of the previous Step A and a reaction time of 4 hours at 90 °C instead of 1.5 hours. The melting point is 65-67 °C. Spectroscopic analysis of RMN1H (CDCl3, 300,13 MHz, δ in ppm) is 10.29 (s, 1H) ; 8.75 (d, J = 2.6 Hz, 1H) ; 7.99 (d, J = 8.1 Hz, 1H) ; 7.9 (d, J = 7.1 Hz, 1H) ; 7.77 (d, J = 8.9 Hz, 1H) ; 7.45 (dd, J = 8.1 and 7.1 Hz, 1H) ; 7.23 (dd, J = 8.9 and 2.6 Hz, 1H) ; 3.98 (s, 3H).Spectroscopic analysis of RMN13C (CDCl3, 75,5 MHz, δ in ppm) is 194.1 (d) 160,7 (s) 138,3 (d) ; 135,1 ; 135,2 ; 139,2 ; 129,3 (s) 129,6 (s) 129,6 (s) 129,6 (s) 129,6 (s) 129,8 (s) 129,6 (s) 129,6 (s) 129,8 (s) 129,9 (s) 129,9 (s) 129,9 (s) 129,9 (s) 129,9 (s) 129,9 (s) 129,12 (s) 129,12 (s) 129,12 (s) 129,12 (s) 129,12 (s) 129,12 (s) 129, (s) 129,12 (d) 129, (d) 12 (d) 129, (d) 129, (d) 12 (d) 12 (d) 12 (d) 12 (d) 12 (d)

The following is the list of substances which are to be used in the preparation of the product:

After 30 minutes of agitation at room temperature, tosyl chloride is then added in several portions (190.5 mg; 0.36 mmol). After 4 hours of agitation at room temperature, 1,3-bisphenolphosphene) salts (7.1 mg; 0.017 mmol), palladium acropropyl (3,9 mg; 0.073 mmol), triethylamine (192 μL) and sodium acetate (1,38 mmol; 1.50 mmol; 1.50 mmol); sodium acetate and sodium triethylamide are added in several portions (190.5 mg; 0.36 mmol). After 1 hour of agitation at room temperature, 1,3-bisphenolphosphene) salts (7.1 mg; 0.017 mmol), palladium acetate (3.9 mg; 0.073 mmol), triethylamine (192 μL) and sodium acetate (1.6 mmol; 1.50 mmol) are added in a neutral phase (6 hours) and the mixture is then washed with the solution and filtered to a temperature of 1.5 °C. After 1 hour of reaction, the mixture is diluted with sodium acetate and the product is filtered with sodium acetate (1,5 mg; 1.50 mmol) and 1 mg (1 mmol for the reaction time of 90 °C. After 1 hour, the mixture is washed with the solution and filtered with the solution, the mixture is filtered to 95 °C. Melting point: 65 to 67 °C.

Claims (22)

1. Process for the industrial synthesis of the compound of formula (I): characterised in that 7-methoxy-naphthalen-2-ol of formula (III): is reacted, wherein a formyl group is introduced at position 1 to yield the compound of formula (IV): which compound of formula (IV) is subjected to a sulfonylation reaction to yield the compound of formula (V): wherein R represents a group -CH₃, -(CH₂)₂-CH₃, -CF₃ or toluyl; which compound of formula (V) is subjected to a deoxygenation reaction in the presence of a transition metal and a reducing agent 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, characterised in that R represents a group -CH₃ or toluyl.
3. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by the action of a sulfonyl chloride, a sulfonic anhydride or a sulfonamide.
4. Process for the industrial synthesis of the compound of formula (I) according to claim 3, characterised in that the conversion of the compound of formula (IV) into the compound of formula (V) is carried out by the action of a sulfonyl chloride.
5. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that, in the conversion of the compound of formula (V) into the compound of formula (I), the transition metal is nickel, palladium or platinum.
6. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that, in the conversion of the compound of formula (V) into the compound of formula (I), the transition metal is a palladium salt.
7. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out in dimethylformamide, dioxane, tetrahydrofuran or toluene.
8. Process for the industrial synthesis of the compound of formula (I) according to claim 7, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out in dimethylformamide.
9. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out between 25°C and 110°C.
10. Process for the industrial synthesis of the compound of formula (I) according to claim 9, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out between 40°C and 95°C.
11. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that, in the conversion of the compound of formula (V) into the compound of formula (I), the reducing agent is dihydrogen.
12. Process for the industrial synthesis of the compound of formula (I) according to claim 11, characterised in that the dihydrogen is obtained by decomposition of an ammonium formate.
13. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out in the presence of palladium and dihydrogen.
14. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterised in that the conversion of the compound of formula (V) into the compound of formula (I) is carried out in the presence of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) or 1,3-bis(di-phenylphosphino)propane.
15. Compound of formula (V) according to claim 1 for use as an intermediate for the synthesis of the compound of formula (I).
16. Compound of formula (V) according to claim 15 for use as an intermediate for the synthesis of agomelatine of formula (II).
17. Compound of formula (V) according to claims 15 and 16 chosen from the following compounds:

    - 1-formyl-7-methoxynaphthalen-2-yl 4-methylbenzenesulfonate;

    - 1-formyl-7-methoxynaphthalen-2-yl methanesulfonate.
18. Use of the compound of formula (V) according to claims 15 to 17 in the synthesis of the compound of formula (I).
19. Use of the compound of formula (V) according to claim 18 in the synthesis of agomelatine of formula (II).
20. Use of the compound of formula (III) according to claim 1 in the synthesis of the compound of formula (I).
21. Use of the compound of formula (III) according to claim 20 in the synthesis of agomelatine of formula (II).
22. Process for the synthesis of agomelatine from the compound of formula (V), characterised in that the compound of formula (V) is obtained by the synthesis process according to any one of claims 1 to 4.