HK1141007B - New process for the synthesis of agomelatine - Google Patents

Description

novel method for synthesizing agomelatine

The technical field is as follows:

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):

background art:

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

In fact, it has a dual property, which is, on the one hand, an agonist of receptors of the melatoninergic system and, on the other hand, 5-HT_2CAn antagonist of the receptor. These properties confer central nervous system activity and more particularly activity for the treatment of major depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and its use in therapy have been described in european patents EP 0447285 and EP 1564202.

In view of the pharmaceutical value of the compound, it is important to be able to prepare this compound with an efficient industrial synthesis process which can be easily transferred to the industrial scale and which provides agomelatine in good yields and excellent purity.

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

In patent specification EP1564202, the applicant has established a more efficient and more industrialisable synthesis route starting from 7-methoxy-1-tetralone which allows agomelatine in a well-defined crystalline form to be obtained in a highly reproducible manner, in only four steps.

However, the search for new synthetic routes, especially starting from starting materials which are less expensive than 7-methoxy-1-tetralone, is still of great interest at present.

The applicant has established, by continuing research, a new process for the synthesis of agomelatine starting from 7-methoxy-1-naphthol: the advantage of this new starting material is that it is simple and can be easily obtained in large quantities at low cost. In addition, 7-methoxy-1-naphthol also has the advantage of having a naphthalene ring structure in its structure, which avoids the inclusion of an aromatization step in the synthesis, and thus the aromatization step has been problematic from an industrial point of view.

Furthermore, this new process makes it possible to obtain agomelatine in a reproducible manner and without the need for laborious purification, the agomelatine obtained having a purity compatible with its use as pharmaceutical active ingredient.

Disclosure of Invention

In particular, the present invention relates to a process for the industrial synthesis of compounds of formula (I):

the process is characterized in that 7-methoxy-1-naphthol of formula (II) is reacted:

after conversion of its hydroxyl function into a leaving group such as a halogen, tosylate or triflate group, it is reacted with a compound of formula (III) in the presence of palladium: CH (CH)₂(iii) condensation of (CH-R), (III),

wherein R represents a group

Wherein R 'and R' may be the same or different and each represents a straight chain or a branched chain (C)₁-C₆) Alkyl or R 'and R' together form a (C)₂-C₃) The alkylene chain and the ring formed may be fused to a phenyl group,

to obtain a compound of formula (IV):

wherein R is as defined above, and wherein,

subjecting it to catalytic hydrogenation, thereby obtaining a compound of formula (V):

wherein R is as defined above, and wherein,

subjecting it to base or acid hydrolysis or treatment with a binary reducing agent/acid system to give a compound of formula (VI):

it is treated with sodium acetate and then acetic anhydride to give the compound of formula (I), which is isolated as a solid.

According to the process of the invention, the compound of formula (III) is preferably a phthalimide compound, more preferably N-vinylphthalimide. The compound of formula (III) is also preferably acrylamide.

The condensation reaction of the compound of formula (III) according to the invention for obtaining the compound of formula (IV) is advantageously carried out with tetrakis (triphenylphosphine) palladium, preferably under reflux of toluene.

The hydrogenation of the compounds of the formula (IV) to compounds of the formula (V) is preferably carried out with palladium on carbon, in particular with palladium on carbon having a palladium content of at least 5%.

The hydrolysis of the compound of formula (V) is preferably carried out with a binary reducing agent/acid system such as NaBH₄And acetic acid, or, when R represents C (O) NH₂When present, the conversion of the compound of formula (V) to the compound of formula (VI) is preferably carried out with a base such as NaOBr or NaOCl.

This method is particularly valuable for the following reasons:

it makes it possible to obtain the compound of formula (I) on an industrial scale, starting from simple, low-cost starting materials, in excellent yields;

the operating conditions chosen according to the invention allow complete control of the regioselectivity during the coupling with the compound of formula (III);

the presence of a naphthalene ring system in the starting substrate makes it possible to avoid aromatization reactions;

finally, the compound of formula (I) obtained in a reproducible manner has the crystalline characteristics described in patent specification EP 1564202.

The compound of formula (IV) obtained according to the process of the present invention is new and can be used as an intermediate in the synthesis of agomelatine, in which it is subjected to a reduction reaction, then to a hydrolysis reaction, and then to a coupling reaction with acetic anhydride.

Detailed Description

The invention is illustrated in a non-limiting manner by the following examples.

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

Step A: trifluoromethanesulfonic acid 7-methoxy-1-naphthyl ester

In one reactor, 2.7g 7-methoxy-1-naphthol, 1.1 equivalents triflic anhydride and 1.1 equivalents 2, 6-di-tert-butyl-4-methyl-pyridine were introduced into dichloromethane (45 ml). The mixture was heated at reflux for 12 hours, then filtered, and the liquid was washed with 1N HCl solution and then with saturated NaCl solution. The organic phase is evaporated and the residue is purified by chromatography on silica gel (eluent: CH)₂Cl₂Methyl-cyclohexane 1/9) to give the title product in 91% yield as an oil with a chemical purity of more than 99%.

Step B: 2- [2- (7-methoxy-1-naphthyl) ethenyl]-1H-isoindole-1, 3(2H) -dione

In one reactor, 2g of the compound obtained in step A, 2 equivalents of N-vinylphthalimide, 1.25 equivalents of diisopropylethylamine and 0.05 equivalents of tetrakis (triphenylphosphine) palladium were introduced into toluene and heated at reflux. The reaction was allowed to continue at reflux for 12 hours, then the reaction mixture was cooled to ambient temperature. To this was added ethyl acetate, which was then washed with water and 1N HCl solution. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (eluent: dichloromethane/heptane 1/1, then dichloromethane) to obtain the title product in 80% yield with a chemical purity higher than 95%.

Melting Point：146℃

Step C: 2- [2- (7-methoxy-1-naphthyl) ethyl]-1H-isoindole-1, 3(2H) -dione

In a reactor, 2g of the compound obtained in step B and 1g of 5% palladium on carbon are introduced into a mixture of methanol/THF 1/2 under hydrogen pressure and at ambient temperature. After allowing to react for 8 hours, the reaction mixture was filtered. After evaporation of the solvent, the title product was obtained in quantitative yield with a chemical purity of 95%.

Melting Point：154℃

Step D: 2- (7-methoxy-1-naphthyl) ethylamine

In one reactor, 1g of the compound obtained in step C and 5 equivalents of NaBH₄Was introduced into a mixture of 2-propanol/water 6/1 and the mixture was stirred at ambient temperature. Then, acetic acid (0.2 eq) was added thereto and the reaction mixture was heated at 80 ℃ for 8 hours. After evaporation of the solvent and co-evaporation of water and toluene, the crude residue obtained was used directly for acetylation without further purification.

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

In one reactor, 5g of the compound obtained in step D and 2g of sodium acetate are introduced into ethanol. The mixture was stirred, then 2.3g of acetic anhydride was added thereto, the reaction mixture was heated to reflux and 20ml of water was added thereto. The reaction mixture was brought back to ambient temperature, the resulting precipitate was filtered off and washed with a mixture of ethanol/water 35/65 to obtain the title product in 80% yield (both in steps D and E) with a chemical purity higher than 99%.

Melting Point：108℃

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

Step A: 3- (7-methoxy-1-naphthyl) -2-acrylamide

A solution of the compound obtained in step A of example 1 (12.1g) in 80mL of DMF was degassed by bubbling nitrogen gas at 20 ℃ for 10 minutes. To the resulting solution were added triethylamine (6.6mL), acrylamide (5.6g), Neocopper reagent hydrate (454mg) and Pd (OAc) in this order₂(445 mg). The mixture was heated at 100 ℃ for 1 hour and then allowed to cool to 20 ℃. Dilute with AcOEt (100mL) and add saturated NH₄After the Cl solution, the phases are separated. The organic phase was concentrated under reduced pressure and the residue was diluted with AcOEt (50 mL). The precipitate was filtered off to give the title compound in powder form.

Step B: 3- (7-methylhydroyl-1-naphthyl) propanamide

0.12g of 5% Pd/C (50% humidity) was added to a solution of the compound obtained in step A (0.5g) in a mixture of MeOH (6.5mL)/THF (6.5 mL). The mixture was purged with nitrogen and then hydrogen, and then heated at 50 ℃ for 1 hour under atmospheric pressure. The suspension was then filtered through celite and the filter was washed with a MeOH (5mL)/THF (5mL) mixture. The liquid was concentrated under reduced pressure to give the title product as a solid, which was used directly in the next step without further purification.

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

Iodosobenzene diacetate (0.88g) was added to a solution of water (3 mL)/acetonitrile (3 mL). Stirring it at 20 deg.CAfter 10 minutes, the compound obtained in step B (500mg) was added in portions, and the mixture was left at 20 ℃ for 2 hours. After the starting material had been consumed, the acetonitrile was distilled off under reduced pressure. The residue is taken up in H₂O (10mL), then treated with concentrated HCl solution (0.4 mL). After filtration, the resulting precipitate was washed with ethyl acetate and then dried in an oven to give the title product.

Melting Point：243℃

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

In one reactor, 5g of the compound obtained in step C and 2g of sodium acetate are introduced into ethanol. The mixture was stirred, then 2.3g of acetic anhydride was added thereto, the reaction mixture was heated to reflux and 20ml of water was added thereto. The reaction mixture was allowed to return to ambient temperature and the resulting precipitate was filtered off and washed with a mixture of ethanol/water 35/56 to give the title product.

Melting Point：108℃

Example 3: the compound obtained in examples 1 and 2 is N- [2- (7-methoxy-1-naphthyl) ethyl]Determination of acetamide Crystal form

Data recording was performed with a D8 high resolution diffractometer from Bruker AXS, using the following parameters: a 2 theta angle range of 3 deg. -90 deg., a span of 0.01 deg. and 30 seconds each. The N- [2- (7-methoxy-1-naphthyl) ethyl group obtained in examples 1 and 2]Acetamide powder was placed on a transport fixture support. The X-ray source being a copper tube (lambda CuK)_α1＝1.54056). The mount includes a front monochromator (Ge (111) crystal) and energy resolving solid state detector (MXP-D1, Moxtec-SEPH). The compound crystallizes well: the half-height line width was 0.07 ° (in terms of 2 θ).

The following parameters were determined accordingly:

-crystal structure of unit cell: the crystal is a monoclinic crystal,

-unit cell parameters: 20.0903b＝9.3194c＝15.4796β＝108.667°

-space group: p2₁/n

-number of molecules in unit cell: 8

Volume of unit cell: v_Cell＝2746.742

-density: d is 1.13g/cm³。

Example 4: n- [2- (7-methoxy-1-naphthyl) ethyl radical obtained in examples 1 and 2 by X-ray powder diffractometry]Crystal form determination of acetamide Compound

The crystalline form of the compound obtained in examples 1 and 2 was characterized by the following X-ray powder diffractogram, measured with a Siemens D5005 diffractometer (copper on cathode) and expressed in interplanar spacing D, Bragg's angle 2 θ and relative intensity (expressed as a percentage with respect to the most intense line):

Claims (11)

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

The process is characterized in that 7-methoxy-1-naphthol of formula (II) is reacted:

after converting its hydroxyl function into a leaving group, it is reacted with a compound of formula (III) in the presence of palladium: CH (CH)₂(iii) condensation of (CH-R), (III),

wherein R represents a group

Wherein R 'and R' may be the same or different and each represents a straight chain or a branched chain (C)₁-C₆) Alkyl or R 'and R' together form a (C)₂-C₃) An alkylene chain and the ring formed may be fused with a phenyl group to give a compound of formula (IV):

wherein R is as defined above, and wherein,

subjecting it to catalytic hydrogenation, thereby obtaining a compound of formula (V):

wherein R is as defined above, and wherein,

subjecting it to base or acid hydrolysis or treatment with a binary reducing agent/acid system to give a compound of formula (VI):

or when R represents a groupWhen the conversion of the compound of formula (V) into the compound of formula (VI) is carried out with iodosobenzene diacetate,

the compound of formula (VI) is treated with sodium acetate and then acetic anhydride to give the compound of formula (I), which is isolated as a solid.

2. The method of synthesizing the compound of formula (I) according to claim 1 wherein said leaving group is selected from the group consisting of halogen, tosylate or triflate groups.

3. The method of synthesizing the compound of formula (I) according to claim 1 wherein the compound of formula (III) is N-vinyl phthalimide.

4. The process for synthesizing the compound of formula (I) according to claim 1, wherein the compound of formula (III) is acrylamide.

5. The process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the condensation reaction of the compound of formula (III) to obtain the compound of formula (IV) is carried out with tetrakis (triphenylphosphine) palladium.

6. A compound of formula (IV) according to claim 1 for use as an intermediate in the synthesis of agomelatine.

7. Use of a compound of formula (IV) according to claim 6 for the synthesis of agomelatine.

8. Use of a compound of formula (II) according to claim 1 for the synthesis of agomelatine.

9. Use of a compound of formula (V) according to claim 1 for the synthesis of agomelatine.

10. Process for the synthesis of agomelatine according to claim 1, starting from the compound of formula (IV), characterized in that the compound of formula (IV) is obtained with a synthesis process according to any one of claims 1 to 5.

11. Process for the synthesis of agomelatine according to claim 1, starting from the compound of formula (V), characterized in that the compound of formula (V) is obtained with a synthesis process according to any one of claims 1 to 5.