HK1079187B - New process for the synthesis of (7-methoxy-1-naphthyl)acetonitrile and application in the synthesis of agomelatine - Google Patents

Description

Novel synthesis method of (7-methoxy-1-naphthyl) acetonitrile and application thereof in synthesis of agomelatine

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The invention relates to a novel method for the industrial synthesis of (7-methoxy-1-naphthyl) acetonitrile and the use of this compound in 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 compounds of formula (I):

the compounds of formula (I) obtained according to the process of the invention can be used for the synthesis of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (II):

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

In fact, it is characterized by being an agonist of receptors of the melatoninergic system on the one hand, and a 5-HT on the other hand_2CAn antagonist of the receptor. These properties make it active in the central nervous system and in particular in the treatment of major depressive disorders, seasonal depressive disorders, sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and its therapeutic use have been described in european patent specification EP 0447285.

In view of the pharmaceutical value of the compound, it is important to be able to obtain it in an efficient industrial synthesis process, i.e. a process which can be easily converted to the industrial scale and which gives agomelatine in good yields and extremely high purity.

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

The process comprises the action of ethyl bromoacetate followed by aromatization and saponification to give the corresponding acid, which is then converted to acetamide and subsequently dehydrated to give (7-methoxy-1-naphthyl) acetonitrile, followed by reduction and then condensation of acetyl chloride.

In particular, the synthesis of (7-methoxy-1-naphthyl) acetonitrile involves 6 reaction steps and, when converted to industrial scale, it soon turned out to be difficult to carry out the process, mainly due to reproducibility problems of the first step. The first step consists in reacting 7-methoxy-1-tetralone with ethyl bromoacetate according to the reformatsky reaction, yielding ethyl (7-methoxy-3, 4-dihydro-1 (2H) -naphthylene) acetate.

Furthermore, the subsequent step of aromatization of ethyl (7-methoxy-3, 4-dihydro-1 (2H) -naphthylene) acetate is often incomplete and after saponification gives a product mixture which is difficult to purify.

The literature describes a three-step process for obtaining (7-methoxy-1-naphthyl) acetonitrile comprising: taking 7-methoxy-1-tetralone as a starting material, and passing LiCH₂CN, followed by dehydrogenation using DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) and finally dehydration in an acidic medium (Synthetic Communication, 2001, 31(4), 621-. The overall yield is relatively general (76%), however, the use of DDQ in particular in the dehydrogenation step and the necessity of benzene reflux in the third step, are not satisfactory from the point of view of cost and environment.

The applicant has now developed a new industrial synthesis process which proceeds in a reproducible manner and which, without the need of carrying out cumbersome purifications, gives agomelatine in a purity which is tolerable for its use as pharmaceutical active ingredient.

A further solution to overcome the problems encountered in the process described in patent specification EP 0447285 was obtained by direct condensation of a cyano compound with 7-methoxy-1-tetralone. Further, it is also necessary that the obtained condensation compound be easily subjected to aromatization without drastic conditions to obtain (7-methoxy-1-naphthyl) acetonitrile, and that reagents meeting the requirements for industrial production in terms of cost and environment can be used.

It is clear that (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile is an ideal synthetic intermediate satisfying the requirement for synthesis directly from 7-methoxy-1-tetralone and is an excellent substrate in the aromatization step.

The direct condensation of tetralone with acetonitrile compounds has been described in the literature. In particular, patent specification US 3992403 describes the condensation of cyanomethyl phosphonate with 6-fluoro-1-tetralone and patent specification US 3931188 describes the condensation of acetonitrile with tetralone to give a cyano intermediate which is used directly in the subsequent reaction.

According to FIG. 1, when applied to 7-methoxy-1-tetralone, the condensation of acetonitrile gives an isomeric mixture in which the exo form (exo) makes up the majority and the endo form (endo) makes up the minority.

FIG. 1 shows a schematic view of a

More parts of "exterior" and less parts of "interior"

The resulting mixture then requires drastic aromatization conditions which are incompatible with the industrial requirements for carrying out the agomelatine synthesis.

The applicant has now developed a new industrial synthesis process which makes it possible to obtain (7-methoxy-1-naphthyl) acetonitrile from 7-methoxy-tetralone in only two steps, in a reproducible manner, without having to carry out cumbersome purifications, by using as synthesis intermediate (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile free from the "exo" impurities of formula (III):

this impurity cannot undergo subsequent aromatization under operating conditions compatible with the industrial requirements for carrying out the agomelatine synthesis.

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

characterized by 7-methoxy-1-tetralone of formula (IV):

with cyanoacetic acid of the formula (V),

with the proviso that the water formed is removed and that a catalytic amount of a compound of formula (VI) is present:

wherein R and R', which may be the same or different, each represent a linear or branched (C)₃-C₁₀) Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted straight or branched aryl (C)₁-C₆) An alkyl group, a carboxyl group,

(7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile of formula (VII) is obtained after filtration and washing with an alkali solution,

the compound of formula (VII) is reacted in the presence of an allyl compound and a hydrogenation catalyst,

after filtration and removal of the solvent by distillation, the compound of the formula (I) is obtained which is isolated in solid form after recrystallization,

wherein

Aryl is understood to mean phenyl, naphthyl and biphenyl,

the term "substituted" as used to define "aryl" and "arylalkyl" means that the aryl residues of these groups may be chosen from linear or branched (C)₁-C₆) Alkyl, hydroxy and straight or branched chain (C)₁-C₆) 1 to 3 identical or different radicals of alkoxy.

By "allyl compound" is understood any compound containing from 3 to 10 carbon atoms, and which may additionally contain from 1 to 5 oxygen atoms, and which contains at least 1-CH₂-CH＝CH₂A molecule of a group.

More particularly, in the reaction of converting the compound of formula (IV) into the compound of formula (VII), the water formed is removed by distillation. Preference is given to using reaction solvents having a boiling temperature greater than or equal to that of water, more preferably those which form azeotropes with water, such as xylene, toluene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene or 1, 3, 5-trimethylbenzene.

The conversion of the compound of formula (IV) to the compound of formula (VII) is preferably effected under toluene or xylene reflux conditions, more preferably under toluene reflux conditions.

In the conversion of the compound of formula (IV) to the compound of formula (VII), it is appropriate that one of the R or R' groups of the catalyst used represents a linear or branched (C)₃-C₁₀) Alkyl and the other represents aryl or arylalkyl. More particularly, preferred catalysts are of the formula (VI)_a) The compound of (1):

wherein R'_aRepresents unsubstituted or substituted by one or more straight or branched chains (C)₁-C₆) Alkyl-substituted phenyl, n is 0 or 1, R_aRepresents a straight chain (C)₃-C₁₀) An alkyl group.

Suitably is R'_aRepresents an unsubstituted or substituted phenyl group, more particularly an unsubstituted phenyl group.

Preferred radicals R_aIs hexyl.

It is preferable that n is 1.

According to the process of the invention, in the conversion of the compound of formula (IV) into the compound of formula (VII), the catalyst used is preferably benzylammonium heptanoate of formula (VIII):

advantageously, in the filtration and use of mineral or organic base solutions, e.g. NaOH, KOH, Ca (OH)₂、Sr(OH)₂Or NH₄OH, and particularly preferably after washing with sodium hydroxide solution, to give the compound of the formula (VII).

The conversion of the compound of formula (VII) to the compound of formula (I) is preferably effected under toluene or xylene reflux conditions, more preferably under toluene reflux conditions.

In the conversion of the compounds of the formula (VII) into the compounds of the formula (I), preference is given to using catalysts which are in the form of oxides or are supported, for example, on palladium, platinum, nickel, Al₂O₃And more particularly palladium. Preferably 1 to 20% palladium on carbon is used, more particularly 5% or 10% palladium on carbon. The amount of palladium on carbon used is preferably from 1 to 10% by weight, more particularly 5% by weight, based on the weight of the catalyst relative to the weight of the substrate.

In the conversion of the compound of the formula (VII) into the compound of the formula (I), the hydrogen acceptor used is preferably an allyl compound, more particularly allyl acrylate or allyl glycidyl ether. The preferred allyl acrylate for the process of the present invention is allyl methacrylate.

This method is particularly advantageous because:

the process allows to obtain exclusively the "endo" -type compound of formula (VII) on an industrial scale. In view of this type of reaction, it is generally reported in the literature that endo/exo mixtures are obtained (Tetrahedron, 1966,223021-. The reason for this result is the use of the compound of formula (VI) as a reaction catalyst instead of the ammonium acetate currently used in this reaction (ball. soc. chim. fr., 1949, 884-890).

The conversion of the compound of formula (IV) into the compound of formula (VII) is very high, exceeding 97%, unlike the conversion which does not exceed 75% with acetic acid.

The use of a hydrogenation catalyst for the conversion of the compound of formula (VII) into the compound of formula (I) in the presence of an allyl compound, unlike benzoquinones currently used, is completely satisfactory for industrial production in terms of cost and environment.

Moreover, the process enables the compound of formula (I), in particular the corresponding reduction product free of the structure of formula (IX), to be obtained exclusively on an industrial scale:

finally, a higher conversion of the compound of formula (VII) to the compound of general formula (I) is observed, exceeding 90%.

The compound of formula (VII) thus obtained is a new compound and can be used as an intermediate in the synthesis of agomelatine, in which it is subjected to aromatization and subsequent reduction and then coupled with acetic anhydride.

The compound of formula (I) thus obtained can be reduced, if desired, and then coupled with acetic anhydride to form agomelatine.

The following examples are intended to illustrate the invention, but in no way limit it.

Example 1: (7-methoxy-1-naphthyl) acetonitrile

Step A: (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile

85.0kg of 7-methoxy-1-tetralone, 60.3kg of cyanoacetic acid and 15.6kg of heptanoic acid in toluene were charged in the presence of 12.7kg of benzylamine in a 670 liter reactor. The mixture was heated under reflux. When all starting substrate had disappeared, the solution was cooled and filtered. The resulting precipitate was washed with toluene and then the resulting filtrate was washed with 2N sodium hydroxide solution and then with water until neutral. The solvent was removed by evaporation and the resulting solid was then recrystallized from a mixture of ethanol/water (80/20) to give the title product in 90% yield and chemical purity of over 99%.

Melting point: 48-50 deg.C

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

12.6kg of 5% palladium on carbon in toluene were added to a 670 liter reactor and heated under reflux; then 96.1kg of (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile in toluene and 63.7kg of allyl methacrylate were added. The reaction was continued under reflux conditions and then subjected to gas chromatography. When all the starting substrate had disappeared, the solution was cooled to room temperature and then filtered. The toluene was removed by evaporation and the solid residue obtained was then recrystallized from a mixture of ethanol/water (80/20) to give the title product in 91% yield and chemical purity of over 99%.

Melting point: 83 deg.C

Example 2: (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile

Step A: (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile

85.0kg of 7-methoxy-1-tetralone, 60.3kg of cyanoacetic acid and 15.6kg of heptanoic acid in toluene were placed in a 670 l reactor in the presence of 11.0kg of aniline. The mixture was heated under reflux. When all starting substrate had disappeared, the solution was cooled and filtered. The resulting precipitate was washed with toluene and then the resulting filtrate was washed with 2N sodium hydroxide solution and then with water until neutral. The solvent was removed by evaporation and the resulting solid was then recrystallized from a mixture of ethanol/water (80/20) to give the title product in 87% yield and chemical purity of over 99%.

Melting point: 48-50 deg.C

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

This step is the same as step B of example 1.

Claims (13)

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

characterized by 7-methoxy-1-tetralone of formula (IV):

with cyanoacetic acid of the formula (V),

with the proviso that the water formed is removed and that a catalytic amount of a compound of formula (VI) is present:

wherein R and R', which may be the same or different, each represent a linear or branched (C)₃-C₁₀) Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted straight or branched aryl (C)₁-C₆) An alkyl group, a carboxyl group,

(7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile of formula (VII) is obtained after filtration and washing with an alkali solution,

the compound of formula (VII) is reacted in the presence of an allyl compound and a hydrogenation catalyst,

after filtration and removal of the solvent by distillation, the compound of the formula (I) is obtained which is isolated in solid form after recrystallization,

wherein

Aryl is understood to mean phenyl, naphthyl and biphenyl,

the term "substituted" as used to define "aryl" and "arylalkyl" means that the aryl residues of these groups may be chosen from linear or branched (C)₁-C₆) Alkyl, hydroxy and straight or branched chain (C)₁-C₆) 1 to 3 identical or different radicals of alkoxy.

By "allyl compound" is understood any compound containing from 3 to 10 carbon atoms, and which may additionally contain from 1 to 5 oxygen atoms, and which contains at least 1-CH₂-CH＝CH₂A molecule of a group.

2. A process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (IV) into the compound of formula (VII) is carried out under toluene reflux.

3. A process as claimed in claim 1 for the synthesis of the compound of formula (I), wherein the catalyst used in the conversion of the compound of formula (IV) to the compound of formula (VII) is of formula (VI)_a) Of (a) a compound

Wherein R'_aRepresents unsubstituted or substituted by one or more straight or branched chains (C)₁-C₆) Alkyl-substituted phenyl, n is 0 or 1, R_aRepresents a straight chain (C)₃-C₁₀) An alkyl group.

4. A process for the synthesis of compounds of formula (I) according to claim 1, characterised in that R represents a hexyl group.

5. A process for the synthesis of a compound of formula (I) according to claim 1, characterized in that R' represents a benzyl group.

6. A process for the synthesis of the compound of formula (I) according to claim 1, characterized in that in the conversion of the compound of formula (IV) into the compound of formula (VII), the catalyst used is benzylammonium heptanoate of formula (VIII):

7. a compound of formula (VII), which is (7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile, useful as an intermediate in the synthesis of agomelatine.

8. A process for the synthesis of the compound of formula (I) according to claim 1, characterized in that the conversion of the compound of formula (VII) into the compound of formula (I) is carried out under toluene reflux.

9. A process as claimed in claim 1 for the synthesis of compounds of formula (I), characterized in that in the conversion of compounds of formula (VII) into compounds of formula (I), the hydrogenation catalyst used is palladium.

10. A process as claimed in claim 1 for the synthesis of compounds of formula (I), wherein in the conversion of compounds of formula (VII) to compounds of formula (I) the hydrogenation catalyst used is 5% palladium on carbon.

11. A process for the synthesis of compounds of formula (I) according to claim 1, characterized in that in the conversion of the compound of formula (VII) into the compound of formula (I), the amount of hydrogenation catalyst used is 5% by weight, based on the weight of catalyst relative to the weight of substrate.

12. Process for the synthesis of agomelatine from a compound of formula (VII), characterized in that a compound of formula (VII) is subjected to aromatization, followed by its reduction and then coupling with acetic anhydride.

13. A method for synthesizing agomelatine by using 7-methoxy-1-tetralone of formula (IV) as a raw material:

wherein 7-methoxy-1-tetralone of formula (IV) is reacted with cyanoacetic acid of formula (V),

with the proviso that the water formed is removed and that a catalytic amount of a compound of formula (VI) is present:

wherein R and R' may be the same or different and each represents a straight or branched chain C₃-C₁₀Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted straight or branched aryl C₁-C₆An alkyl group, a carboxyl group,

(7-methoxy-3, 4-dihydro-1-naphthyl) acetonitrile of formula (VII) is obtained after filtration and washing with an alkali solution,

said compound of formula (VII) being reacted with a hydrogenation catalyst in the presence of an allyl compound,

after filtration and removal of the solvent by distillation, the compound of formula (I):

the compound of formula (I) is isolated in solid form after recrystallization,

it is then reduced and then coupled with acetic anhydride.