WO2018051042A1 - Novel method for the synthesis of agomelatine - Google Patents

Abstract

The invention relates to a method for the industrial synthesis of the compound of formula (I).

Description

 NEW PROCESS FOR THE SYNTHESIS OF AGOMELATIN

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

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

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-HT _2C 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 and obesity disorders.

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 high-performance industrial synthesis process, easily transposable on an industrial scale, leading to agomelatine with good yield, and excellent purity. EP 0 447 285 discloses the eight-step access to agomelatine from 7-methoxy-1-tetralone. In patent EP 1 564 202, the applicant has developed a new route of synthesis much more efficient and industrializable, in just four steps from 7-methoxy-1-tetralone, and to obtain the agomelatine of very reproducible way in a well-defined crystalline form. However, the search for new short synthetic routes, in particular from raw materials less expensive than 7-methoxy-1-tetralone, is still relevant.

The applicant has continued its investigations and has developed a new process for synthesizing agomelatine from 1-iodo-7-methoxy-naphthalene. There exists in the prior art a process for the synthesis of agomelatine using this raw material but it uses explosive reagents, such as nitromethane, which limit use on an industrial scale (Kandagatla et al., Tetrahedron Letters 2012, 53 , 7125-7127). Another process for synthesizing agomelatine claims the use of 1-iodo-7-methoxynaphthalene to convert it to organomagnesium to react with ethylene oxide, known to be genotoxic and carcinogenic (CN 102531956). ). However, 1-iodo-7-methoxy-naphthalene has the advantage of being simple, easily accessible in large quantities with lower costs compared to 7-methoxy-1-tetralone and to possess in its structure a naphthalene nucleus. , which avoids to integrate in the synthesis a stage of aromatisation, always delicate step from an industrial point of view.

Preliminary work on the coupling of β-aminoalkyl-organozinc derivatives on an aromatic ring according to the Hunter method (Hunter et al J. Chem Soc Perkin Trans, 2000, 219-223) showed a low reactivity of the -iodo-7-methoxy-naphthalene after curing the zinc complex and then catalyzed palladium coupling on the aromatic ring. Surprisingly, the new process developed by the Applicant makes it possible to obtain agomelatine in a few steps by means of a "one-pot" coupling of a β-aminoethylorganozincic derivative on the iodo-7-methoxy-naphthalene without maturation of the zinc complex.

This new reproducible process does not use explosive or toxic reagents, does not require laborious purification and allows to obtain agomelatine in a single step with a purity that is compatible with its use as a pharmaceutical active ingredient. More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I):

caractérisé en ce que l'on réalise les étapes suivantes :

characterized in that the following steps are carried out:

^■ is activated metallic zinc;

^■ are successively introduced a palladium complex and the compound of formula (II):

 NHR

 (II) wherein R represents an acetyl group or a protecting group of the primary amine function;

 and finally the compound of formula (III):

 all the reagents being in solution in an aprotic polar solvent;

^■ then heated the reaction mixture at a temperature between 40 and 80 ° C; to drive :

 or, when R represents the acetyl group, directly to the compound of formula (I) which is isolated in the form of a solid;

dans laquelle R' est un groupement protecteur de la fonction aminé primaire, sur lequel on effectue une réaction de déprotection de la fonction aminé primaire et on réalise une réaction d'acétylation, pour conduire au composé de formule (I) que l'on isole sous forme d'un solide. or to the compound of formula (IV):

in which R 'is a protecting group of the primary amine function, on which a deprotection reaction of the primary amine function is carried out and an acetylation reaction is carried out, to yield the compound of formula (I) which is isolated in the form of a solid.

The compounds of formula (II) and (III) are 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 metallic zinc can be activated in the first step by the diiod or by the sequential treatment with 1,2-dibromoethane followed by trimethylsilyl chloride. Preferably, the metallic zinc is activated by diiod. The metallic zinc is preferably powdered.

Advantageously, the compound of formula (II) is that for which R represents an acetyl group.

The polar aprotic solvent may be chosen from pyridine, N-methyl-2-pyrrolidone, N, N-dimethylformamide and N, N-dimethylacetamide, alone or as a mixture. Advantageously, the aprotic polar solvent is N, N-dimethylformamide or N, N-dimethylacetamide. Preferably, the aprotic polar solvent is N, N-dimethylacetamide.

The palladium complex may be chosen from the tris (dibenzylideneacetone) dipalladium / tris (o-tolyl) phosphine pair, the tris (dibenzylideneacetone) dipalladium / tricyclohexylphosphine pair, tetrakis (triphenylphosphine) palladium, palladium (II) acetate or [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] dichloride (3-chloropyridyl) palladium. According to a preferred embodiment, the palladium complex is [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride (Pd-PEPPSI-z ^' Pr complex). .

The successive introduction of the palladium complex and then of the compound of formula (II) and of the compound of formula (III), dissolved in an aprotic polar solvent, is preferably carried out at room temperature.

Then, the reaction medium is preferably heated to between 50 and 70 ° C and more particularly between 55 and 65 ° C.

The present invention also relates to the use of the compound of formula (II) for the synthesis of agomelatine. More particularly, the present invention relates to the use of the compound of formula (II) wherein R represents an acetyl group, for the synthesis of agomelatine.

The present invention also relates to the use of the compound of formula (II) for the synthesis of agomelatine obtained according to the method described by the preferred embodiments.

This process is particularly interesting for the following reasons:

 it allows to obtain on an industrial scale the compound of formula (I) with good yields from a simple raw material and inexpensive;

 it makes it possible to avoid an aromatization reaction, a step which is always difficult from an industrial point of view since the naphthalenic nucleus is present in the starting substrate;

it avoids the use of explosive or toxic reagents during the synthesis; it makes it possible to obtain, with a reduced number of steps and operating manipulations, agomelatine from 1-iodo-7-methoxy-naphthalene without prior curing of the zinc complex, which guarantees a saving of time, better productivity and no transfer of material. The example below illustrates the invention, but does not limit it in any way.

The structures of the described compounds were confirmed by the usual spectroscopic techniques: proton NMR (s = singlet, ls = large singlet, d = doublet, t = triplet, dd = double doublet, m = multiplet); Electrospray ionization mass spectrometry (ESI).

Preparation 1: 7-methoxynaphthalen-1-amine

 In a tricolor equipped with a nitrogen inlet adapter, is added sodium hydride (4.5 g, 113 mmol, 60% in mineral oil) and dimethylformamide (250 mL). The resulting suspension is then cooled to 0 ° C, 8-aminonaphthalen-2-ol (15 g, 94 mmol) is added portionwise. After the addition is complete, the solution is warmed to room temperature and is mixed until the release of dihydrogen ceases. The solution is then cooled to 0 ° C. and the methyl iodide (6 mL, 312 mmol) is added dropwise. After stirring for 30 minutes, the reaction is warmed to room temperature and is mixed for 2 hours. The solution is diluted with a mixture of ethyl acetate and saturated sodium carbonate solution and then washed with saturated sodium carbonate solution, dried over sodium sulfate and evaporated. The residue is recrystallized from petroleum ether to give Preparation 1 (13.5 g, 83%).

Preparation 2: 7-methoxynaphthalene-1-diazonium tetrafluoroborate

To a suspension of Preparation 1 (11 g, 63.6 mmol) in water (50 mL) is added a solution of 12 N hydrochloric acid (16 mL, 192 mmol). The mixture is cooled to 0 ° C and a solution of sodium nitrite (4.6 g, 66.8 mmol) in water (25 mL) is added dropwise. The reaction mixture is mixed for 1 hour and then the tetrafluoroboric acid (100 mL) is added. The green solid obtained was recovered by filtration, washed with water, ethanol and diethyl ether to give Preparation 2 (15.6 g, 90%) as a yellow solid. Preparation 3: 1-Iodo-7-methoxynaphthalene

 In a flask placed in an oven and purged with argon, are introduced Preparation 2 (1 g, 3.68 mmol), tetrabutylammonium iodide (1.5 g, 5.52 mmol), iodide copper (11 mg, 0.06 mmol) and acetonitrile (6 mL). After stirring for 6 hours at 40 ° C, the solution is cooled, diluted with ethyl acetate and washed with brine. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. The resulting crude is purified by chromatography (eluent: ethyl acetate / petroleum ether 10/90) to give Preparation 3 as a yellow solid (522 mg, 50%).

Melting point: 67-69 ° C.

1 H NMR (CDCl ₃ , 300 MHz, δ in ppm): 8.03 (dd, J = 7.5 and 1.1 Hz, 1H); 7.76 (d, J = 8.0 Hz, 1H); 7.68 (d, J = 8.9 Hz, 1H); 7.4 (d, J = 2.4 Hz, 1H); 7.16 (dd, J = 8.9 and 2.5 Hz, 1H); 7.05 (dd, J = 8.0 and 7.5 Hz, 1H); 3.99 (s, 3H).

¹³ C NMR (CDCl3, 75 MHz, δ in ppm): 159.13; 137.77; 135.6; 129.39; 128.61; 124.56; 119.48; 118.33; 110.48; 98.18; 55.38.

MS (ESI, m / z (%)): 284 (100) [M] ^{+ *} ; 241 (35), 114 (30).

EXAMPLE 1: V- (2- (7-Methoxynaphthalen-1-yl) ethyl) acetamide

Zinc powder (69 mg, 1.1 mmol) is introduced into a flask and heated under vacuum. N, N-dimethylacetamide (0.4 mL) is then added under nitrogen followed by diiodine (18 mg, 0.07 mmol). After stirring at room temperature (23 ° C.) until the red color disappeared, [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride (6 mg 0.009 mmol) and a solution containing N- (2-iodoethyl) acetamide (149 mg, 0.7 mmol) and Preparation 3 (0.1 g, 0.35 mmol) in N, N-dimethylacetamide (0). , 6 mL) are added successively. After stirring for 12 hours at 60 ° C., the mixture is then cooled, diluted with ethyl acetate and filtered through Celite. The filtrate is washed with 1M hydrochloric acid solution and with brine. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. The crude product obtained is purified by chromatography (eluent: ethyl acetate) to give the title product as a white solid (81 mg, 61%).

 Melting point: 106-108 ° C (pentane).

1H NMR (CD ₃ OD, 300 MHz, δ in ppm): 8.21 (bs, 1H); 7.74 (d, J = 8.9 Hz, 1H); 7.65 (d, J = 8.0 Hz, 1H); 7.52 (d, J = 2.5 Hz, 1H); 7.31-7.2 (m, 2H); 7.11 (dd, J = 8.9 and 2.5 Hz, 1H); 3.96 (s, 3H); 3.52-3.44 (m, 2H); 3.23-3.18 (m, 2H); 1, 94 (s, 3H).

¹³ C NMR (CD ₃ OD, 75 MHz, δ in ppm): 173.4; 159.4; 135.1; 134.6; 131.2; 130.8; 128.2; 127.9; 124.2; 119.3; 103.2; 55.9; 41.4; 34.2; 22.6.

MS (ESI, m / z (%)): 243 (29) [M] ^{+ *} ; 184 (100); 171 (70); 128 (35).

Claims

1. Process for the industrial synthesis of the compound of formula (I)

characterized in that the following steps are carried out: ^■ is activated metallic zinc; ^■ are successively introduced a palladium complex and the compound of formula (II):  NHR  (II) wherein R represents an acetyl group or a protecting group of the primary amine function;  and the compound of formula (III):

all the reagents being in solution in an aprotic polar solvent; ^■ then heated the reaction mixture at a temperature between 40 and 80 ° C; to drive :  or, when R represents the acetyl group, directly to the compound of formula (I) which is isolated in the form of a solid; or to the compound of formula (IV):

in which R 'is a protecting group of the primary amine function, on which a deprotection reaction of the primary amine function is carried out and an acetylation reaction is carried out, to yield the compound of formula (I) which is isolated in the form of a solid. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the step of activating metallic zinc is carried out by diiod or by sequential treatment with 1,2-dibromoethane followed by trimethylsilyl chloride. Process for the industrial synthesis of the compound of formula (I) according to claim 2, characterized in that the activation step of the metallic zinc is carried out by the diiodode. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that R represents an acetyl group. Process for the industrial synthesis of the compound of formula (I) according to Claim 1, characterized in that the aprotic polar solvent is chosen from pyridine, N-methyl-2-pyrrolidone, N, N-dimethylformamide and N, N-N-dimethylformamide. dimethylacetamide, alone or in admixture. Process for the industrial synthesis of the compound of formula (I) according to claim 5, characterized in that the aprotic polar solvent is N, N-dimethylacetamide. 7. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the palladium complex is chosen from the tris (dibenzylideneacetone) dipalladium / tris (o-tolyl) phosphine pair, the tris (dibenzylideneacetone) pair. dipalladium / tricyclohexylphosphine, tetrakis (triphenylphosphine) palladium, palladium (II) acetate or [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride. 8. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the palladium complex is [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] dichloride. -chloropyridyl) palladium. 9. Process for the industrial synthesis of the compound of formula (I) according to claim 1, characterized in that the temperature of the reaction medium is between 50 and 70 ° C. 10. Process for the industrial synthesis of the compound of formula (I) according to claim 1 characterized in that the temperature of the reaction medium is between 55 and 65 ° C. 11. Use of the compound of formula (II)

wherein R represents an acetyl group or a protecting group of the primary amine function, for the synthesis of agomelatine. 12. Use of the compound of formula (II)

 in which R represents an acetyl group or a protecting group of the primary amine function, for the synthesis of the agomelatine obtained according to the method of claims 1 to 10.