HK1189571B - Process and intermediates for synthesizing agomelatine - Google Patents

Description

Process and intermediates for the synthesis of agomelatine

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

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

It has in fact the dual properties of being an agonist of the melatoninergic system receptors on the one hand and of being 5-HT on the other hand_2CAn antagonist of the receptor. These properties provide it with activity in the central nervous system and more particularly in the treatment of major depression, seasonal affective disorder, 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 therapeutics have been described in european patent specifications EP0447285 and EP 1564202.

In view of the pharmaceutical value of this compound, it has been important to be able to produce it using an efficient industrial synthesis process which is easy to convert to industrial scale and provides agomelatine in good yield and excellent purity.

Patent specification EP0447285 describes the production of agomelatine in eight steps starting from 7-methoxy-1-tetralone.

In patent specification EP1564202, the applicant developed a new synthesis route, much more efficient and industrializable, starting from 7-methoxy-1-tetralone, in only four steps, which makes it possible to obtain agomelatine in perfect crystalline form in a highly reproducible manner.

However, the search for new synthetic routes, especially starting from starting materials which are less expensive than 7-methoxy-1-tetralone, is currently still appropriate.

The applicant has continued his research and developed a new process for the synthesis of agomelatine starting from allylnitrile and xanthate compounds: these new raw materials have the advantage of being simple and readily available in large quantities at lower cost.

This synthetic route is based on the proceeding of radical reactions which are not very common but which are very efficient. The use of continuous flow reactors to convert these reactions to commercial scale is promising as it becomes simpler to control the growth of the chain reaction.

Furthermore, the new process makes it possible to obtain agomelatine in a reproducible manner without requiring troublesome purifications, the purity of which can be matched to its use as pharmaceutically active ingredient. In fact, agomelatine can therefore be synthesized in six steps, during which only two of the intermediates are isolated.

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

the process is characterized in that an allylnitrile of the formula (II):

with a compound of formula (III) in the presence of a free radical initiator:

wherein Xa represents a group-S-C (S) -OR, wherein R represents a linear OR branched C₁-C₆Alkyl to give a compound of formula (IV):

wherein Xa is as defined above and wherein,

wherein the latter compound may optionally be isolated and then subjected to a cyclisation reaction in the presence of a free radical initiator to form a compound of formula (V):

the compound of formula (V) may also optionally be isolated,

subjecting the compound of formula (V) to a reductive dehydration reaction to give a compound of formula (VI):

the compound of formula (VI) is then subjected to an aromatization reaction to provide a compound of formula (VII):

the compound of formula (VII) is subjected to reduction with hydrogen in a polar protic medium in the presence of raney nickel and reacted with acetic anhydride to give the compound of formula (I), which is isolated in solid form.

In a preferred embodiment of the invention, the compound of formula (VII) is then subjected to reduction with hydrogen in the presence of raney nickel in an ammoniacal ethanol medium and then converted into a salt with hydrochloric acid, giving the compound of formula (VIII):

the compound of formula (VIII) is subjected to the action of sodium acetate and then acetic anhydride in that order to give the compound of formula (I), which is isolated as a solid.

Alternatively, the compound of formula (VII) may be subjected to hydrogen reduction in the presence of raney nickel in a medium comprising acetic anhydride in a polar protic medium to give the compound of formula (I), which is isolated in solid form.

In preferred compounds of formula (III), Xa represents the group-S-C (S) -OC₂H₅。

In the process of the invention, the initiation of the free-radical reaction is carried out thermally. The reaction mixture is preferably heated to a temperature of 50-140 ℃. Even more preferably at a temperature of 130 ℃ and 135 ℃.

Peroxides are particularly suitable as free radical initiators for carrying out the step of addition of a compound of formula (II) with a compound of formula (III) or for carrying out the cyclisation of a compound of formula (IV) to form a compound of formula (V). For example, mention may be made in particular of diisobutyryl peroxide, cumyl peroxyneodecanoate, tert-amyl peroxyneodecanoate, di (2-ethylhexyl) peroxydicarbonate, tert-butyl peroxyneodecanoate, dibutyl peroxydicarbonate, dicetyl peroxydicarbonate, dimyristyl peroxydicarbonate, tert-butyl peroxyneoheptanoate, tert-amyl peroxypivalate, didecanoyl peroxide, tert-amyl peroxy-2-ethylhexanoate, tert-butyl peroxyisobutyrate, 1, 4-bis (tert-butylperoxycarbonyl) cyclohexane, tert-butyl peroxyacetate, tert-butyl peroxybenzoate, di-tert-amyl peroxide, tert-butylcumyl peroxide, di-tert-butyl peroxide, dicumyl peroxide, dilauroyl peroxide (DLP) or di (4-tert-butylcyclohexyl) peroxydicarbonate.

Preferably the reaction is initiated in the presence of dilauroyl peroxide.

The amount of dilauroyl peroxide used in the cyclization is preferably 1-2.5 equivalents.

In a preferred embodiment of the invention, dilauroyl peroxide is added to the medium in stages.

The addition and/or cyclization reactions are carried out in solvents commonly used in free radical chemistry such as 1, 2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene, chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butanol, and mixtures thereof.

Preferably, ethyl acetate is used in the step of addition of the compound of formula (II) to the compound of formula (III), while the cyclisation of the compound of formula (IV) to form the compound of formula (V) is advantageously carried out in chlorobenzene, ethyl acetate or ethyl butyrate. In this latter reaction, chlorobenzene is more particularly preferred.

The conversion of the compound of formula (V) into the compound of formula (VI) is advantageously carried out in the presence of a lewis acid such as aluminum isopropoxide or samarium isopropoxide. Furthermore, the conversion is preferably carried out in an alcohol (primary or secondary), even more preferably isopropanol.

Once all the tetralone (V) has been consumed at the end of the conversion of the compound of formula (V) to the compound of formula (VI), a catalytic amount of p-toluenesulfonic acid is preferably added to the mixture.

The aromatization of compound (VI) is carried out in the presence of a quinone, preferably in the presence of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or chloranil (TCQ). Even more preferably, the aromatization is carried out in the presence of TCQ under toluene reflux.

The compounds of the formula (II) can be obtained by means of conventional chemical reactions and/or chemical reactions described in the literature, as is known to the person skilled in the art.

This method is important for the following reasons, among others:

the compound of formula (I) can be obtained on an industrial scale in good yields starting from simple, low-cost starting materials;

only the intermediates of formulae (VI) and (VII) require purification and isolation steps.

The compounds of formulae (V) and (VI) obtained according to the process of the present invention are novel and can be used as intermediates in the synthesis of agomelatine.

The following examples illustrate the invention but do not limit it in any way.

To confirm this reaction pathway, synthetic intermediates were isolated and characterized programmatically. However, these procedures can be greatly optimized by limiting the number of intermediates isolated. Thus, example 2 given below corresponds to the same reaction route used in example 1, but differs only in the separation of (7-methoxy-1, 2-dihydro-1-naphthyl) acetonitrile and (7-methoxy-1-naphthyl) acetonitrile.

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

Step A: dithiocarbonic acid S- [ [1- (cyanomethyl) -4- (4-methoxyphenyl) -4-oxobutyl]]-O-ethyl ester

Allyl nitrile (4.8mL, 60.0mmol) and S- [2- (4-methoxyphenyl) -2-oxoethyl ] dithiocarbonate were placed under a nitrogen atmosphere]-O-ethyl ester¹A solution of (8.1g, 30.0mmol) in ethyl acetate (30mL) was heated at reflux for 15 min. To this solution was first added a certain amount of dilauroyl peroxide (10mol%) under reflux. An additional amount of dilauroyl peroxide (5mol%) was also introduced after 1 hour and 30 minutes. When the reagents have been completely consumed, the mixture is cooled to ambient temperature and concentrated under reduced pressure. Then passing through flash column chromatography (petroleum ether-ethyl acetate)Ester: 95-5 to 80-20) to give the title compound in 98% yield as an oil.

¹H NMR(，ppm)(CDCl₃，400MHz)：7.93(m，2H，CH-4)，6.93(m，2H，CH-3)，4.67-4.57(m，2H，CH₂-13)，3.99(m，1H，CH-9)，3.87(s，3H，CH₃-1)，3.15(t，2H，J=7.3Hz，CH₂-7)，2.95(dd，2H，J=17.0，6.0Hz，CH₂-10)，2.41-2.31(m，1H，CH₂-8)，2.19-2.08(m，1H，CH₂-8)，1.41(t，

_____________________

¹Dithiocarbonic acid S- [2- (4-methoxyphenyl) -2-oxoethyl]the-O-ethyl ester was obtained according to the procedure described in Batanero, b, et al, j. 3H, J =7.1Hz, CH₃-14)。

Step B: (7-methoxy-4-oxo-1, 2,3, 4-tetrahydro-1-naphthyl) acetonitrile

The compound of step a used without purification was re-dissolved in chlorobenzene (900mL) and the solution was refluxed for 15 minutes under nitrogen atmosphere. Dilauroyl peroxide was then added gradually to the solution at reflux (10mol% per 10 minutes). When the reaction was complete, the mixture was cooled to ambient temperature and concentrated under reduced pressure. Acetonitrile was then introduced to precipitate most of the dilauroyl peroxide. The mixture was then filtered, concentrated under reduced pressure and purified by flash column chromatography (petroleum ether-ethyl acetate: 60-40) to give the title compound in the form of a solid in a yield of 40%.

HRMS(EI，m/z)：C₁₃H₁₃NO₂Calculated values: 215.0946, respectively; measured value: 215.0946.

step C: (7-methoxy-1, 2-dihydro-1-naphthyl) acetonitrile

Aluminum isopropoxide (2.05g, 10.0mmol) was added to a solution of the compound obtained in step B (680mg, 3.15mmol) in isopropanol (15mL) at ambient temperature. Back flow reactionThe mixture is used. When the reagents were completely consumed, some p-toluenesulfonic acid monohydrate crystals were added and a Dean-Stark apparatus was installed at the top of the flask. The mixture was refluxed again for 1 hour, during which time the isopropanol was gradually replaced by toluene by means of a Dean-Stark apparatus. Then 1N HCl solution was added and the resulting phases were separated. The aqueous phase was extracted with ethyl acetate and the organic phase was saturated NaHCO₃The solution was washed with saturated NaCl solution and then MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to give the title product in the form of an oil in a yield of 85%.

HRMS(EI，m/z)：C₁₃H₁₃Calculated NO: 199.0997, respectively; measured value: 199.1001.

step D: (7-methoxy-1-naphthyl) acetonitrile

The method A comprises the following steps:

to a solution of the compound obtained in step C (1.0g, 5.0mmol) in dichloromethane (50mL) was added DDQ (1.4g, 6.0mmol) at ambient temperature. The reaction mixture was stirred for 2 days, then saturated NaHCO₃And (4) washing the solution. The aqueous phase is extracted with ethyl acetate and the organic phase is washed with saturated NaCl solution over MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to give the title product in the form of a solid in a yield of 55%.

The method B comprises the following steps:

to a solution of TCQ (615mg, 2.5mmol) in toluene (1.5mL) heated to 80 ℃ was added the compound obtained in step C (462mg, 2.3mmol) dissolved in toluene (3.5 mL). The mixture was then refluxed for 2.5 hours, then diluted with water and extracted with petroleum ether. The organic phase was washed with NaOH solution (30 wt%) and water, then over MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to give the title product in the form of a solid in a yield of 61%.

HRMS(EI，m/z)：C₁₃H₁₁Calculated NO: 197.0841, respectively; measured value: 197.0838.

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

The reaction was run in larger batches to optimize the resulting yields:

136g of Raney nickel, 2.06L of ethanol and 0.23L of water were introduced into an 8L reactor. The compound obtained in step D (0.8kg) dissolved in acetic anhydride (2.4L) was added slowly while stirring at 70 ℃ and 30 bar of hydrogen. At the end of the addition the reaction mixture was stirred under 30 bar of hydrogen for 1 hour, then the reactor was depressurized and the liquid filtered. After concentrating the mixture, the residue was crystallized from a mixture of ethanol/water 35/65 to give the title product in 89% yield and chemical purity of greater than 99%.Melting Point：108°C

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

Step A: (7-methoxy-1, 2-dihydro-1-naphthyl) acetonitrile

Allyl nitrile (6.75mL, 84.0mmol) and S- [2- (4-methoxyphenyl) -2-oxoethyl ] dithiocarbonate were placed under a nitrogen atmosphere]-O-ethyl ester¹A solution of (11.3g, 42.0mmol) in ethyl acetate (45mL) was heated at reflux for 15 min. To this solution was first added a certain amount of dilauroyl peroxide (10mol%) under reflux. An additional amount of dilauroyl peroxide (5mol%) was also introduced after 1 hour and 30 minutes. When the reagents have been completely consumed, the mixture is cooled to ambient temperature and concentrated under reduced pressure. The crude mixture was redissolved in chlorobenzene (640mL) and the solution was refluxed for 15 minutes under a nitrogen atmosphere. Dilauroyl peroxide was then added gradually to the solution at reflux (10mol% per 10 minutes). When the reaction was complete, the mixture was cooled to ambient temperature and concentrated under reduced pressure. Acetonitrile was then introduced to precipitate most of the dilauroyl peroxide. The mixture was then filtered and concentrated under reduced pressure. At ambient temperature underHalf of the crude oil thus obtained was redissolved in isopropanol (100mL) in the presence of aluminium propoxide (13.6g, 66.6 mmol). The reaction mixture was refluxed. When the reagents were completely consumed, some p-toluenesulfonic acid monohydrate crystals were added and a Dean-Stark apparatus was installed at the top of the flask. The mixture was refluxed again for 2 hours, during which time the isopropanol was gradually replaced by toluene by means of a Dean-Stark apparatus. Then 1N HCl solution was added and the resulting phases were separated. The aqueous phase was extracted with ethyl acetate and the organic phase was saturated NaHCO₃The solution was washed with saturated NaCl solution and then MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to give the title product in the form of an oil in a yield of 24%.

HRMS(EI，m/z)：C₁₃H₁₃Calculated NO: 199.0997, respectively; measured value: 199.1001.

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

The procedure was similar to step D of example 1.

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

The procedure was analogous to step E of example 1.

Claims (20)

1. A method for the industrial synthesis of a compound of formula (I):

characterized in that an allylnitrile of formula (II):

with a compound of formula (III) in the presence of a free radical initiator:

wherein Xa represents a group-S-C (S) -OR, wherein R represents a linear OR branched C₁-C₆Alkyl to give a compound of formula (IV):

wherein Xa is as defined above and wherein,

wherein the latter compound may optionally be isolated and then subjected to a cyclisation reaction in the presence of a free radical initiator to form a compound of formula (V):

the compound of formula (V) may also optionally be isolated,

subjecting the compound of formula (V) to a reductive dehydration reaction to give a compound of formula (VI):

the compound of formula (VI) is then subjected to an aromatization reaction to provide a compound of formula (VII):

reduction of the compound of formula (VII) in the presence of raney nickel in a polar protic medium with hydrogen and reaction with acetic anhydride gives the compound of formula (I) which is isolated in solid form, wherein the radical initiator is a peroxide.

2. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the compound of formula (VII) is then subjected to reduction with hydrogen in the presence of raney nickel in an ethanol medium containing ammonia, and then converted into a salt with hydrochloric acid, obtaining the compound of formula (VIII):

the compound of formula (VIII) is subjected to the action of sodium acetate and then acetic anhydride in that order to give the compound of formula (I), which is isolated as a solid.

3. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the compound of formula (VII) is subjected to a hydrogen reduction in the presence of raney nickel in a medium comprising acetic anhydride in a polar protic medium, obtaining the compound of formula (I), which is isolated in solid form.

4. Process for the synthesis of compounds of formula (I) according to claim 1, characterized in that the group Xa ═ -S-c (S) -OC₂H₅。

5. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the radical reaction is initiated thermally at a temperature of 50-140 ℃.

6. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the cyclisation of the compound of formula (IV) is carried out at a temperature of 130-135 ℃.

7. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the step of addition of the compound of formula (II) with the compound of formula (III) and the step of cyclization of the compound of formula (IV) are initiated in the presence of dilauroyl peroxide.

8. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the step of addition of the compound of formula (II) with the compound of formula (III) is carried out in chlorobenzene.

9. Process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the step of cyclisation of the adduct of formula (IV) to form the compound of formula (V) is carried out in ethyl acetate.

10. The synthesis according to claim 1, characterized in that the conversion of the compound of formula (V) into the compound of formula (VI) is carried out in the presence of aluminum isopropoxide.

11. Synthesis according to claim 1, characterized in that the conversion of the compound of formula (V) into the compound of formula (VI) is carried out in isopropanol.

12. The synthesis according to claim 1, characterized in that a catalytic amount of p-toluenesulfonic acid is added to the mixture at the end of the conversion of the compound of formula (V) to the compound of formula (VI).

13. The synthesis process according to claim 1, characterized in that the aromatization of the compound of formula (VI) is carried out in the presence of quinones.

14. The synthesis process according to claim 1, characterized in that the aromatization of the compound of formula (VI) is carried out in the presence of TCQ under toluene reflux.

15. A compound of formula (V) according to claim 1.

16. Use of a compound of formula (V) according to claim 15 in the synthesis of agomelatine.

17. A compound of formula (VI) according to claim 1.

18. Use of a compound of formula (VI) according to claim 17 in the synthesis of agomelatine.

19. 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 according to the synthesis process of any one of claims 1 to 10.

20. Process for the synthesis of agomelatine according to claim 1 starting from the compound of formula (VI), characterized in that the compound of formula (VI) is obtained according to the synthesis process of any one of claims 1 to 14.