WO2001072739A1 - Method for preparing 3-(4-hydroxy-1h-indol-5-ylmethyl)-pyridinium compounds via enones - Google Patents

Abstract

The invention concerns a novel method for preparing 3-(4-hydroxy-1h-indol-5-ylmethyl)-pyridinium compounds via enones.

Description

PROCESS FOR THE PREPARATION OF COMPOUNDS 3 - (4-HYDR0XY- 1H- IND0L- 5-YLMETHYL) - PYRIDINIUM PASSING THROUGH ENONES

The present invention relates to a new process for the preparation of 3- (4- hydroxy-1 H-indol-5-ylmethyl) -pyπdιnιums compounds of formula (I) via enones

3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyπdιnιums are known raw materials used in the dye industry. For example, 3- (4-hydroxy-1- methylsulfate) met yl-1 H-indol-5-ylmethyl) -1-methyl-pyπdιnιum can be used as coupler in compositions for the oxidation dyeing of keratin fibers, see patent application FR-A-2 783 520

The synthesis of 3- (4-hydroxy-1-alkyl-1 H-indol-5-ylmethyl) -1-alkyl-pyrιdιnιums is generally carried out in several stages, according to the simplified reaction scheme given below

consisting in a first step of reacting a 1-alkyl-1, 5,6,7-tetrahydro-ιndol-4- one, (compound (A)), with 3-pyrιdιnecarboxaldehyde, (compound (B)), in an organic solvent such as, for example, t-butanol, in the presence of a corresponding to the reflux temperature of the solvent used, to obtain a compound (C), see in particular the process described in patent application EP 0 377 450. The compound (C) thus obtained is then quaternized by an alkyl radical, according to the conventional methods of quaternization of pyridines, to lead to a 3- (4-hydroxy-1-alkyl-1 H-indol-5-ylmethyl) -1-alkyl-pyridinium of formula (D).

The yield indicated in this European patent application for the first step is 9% when the alkyl radical of the compound (A) is methyl. This very low yield during the first stage results in an overall yield of the order of approximately 9%. In addition, this first step preferably uses potassium tert-butoxide as a base, however this compound involves laborious handling conditions. On the other hand, this process requires high temperature conditions. Finally, acidification, often exothermic, followed by purification by chromatography, is compulsory in order to arrive at the expected compound (C). Therefore, this process is not transferable from an industrial point of view, and a more efficient synthesis method is desirable.

It is by seeking to remedy these problems that the Applicant discovered the process which is the subject of the invention.

The present invention therefore relates to a new process for the synthesis of 3- (4-hydroxy-1H-indol-5-ylmethyl) -pyridiniums of formula (I) below:

dans laquelle : - R_T représente un atome d'hydrogène ; un radical alkyle en C C₆ ; un radical aralkyle en C₇-C₁₂, un radical monohydroxyalkyle en C C₆ ; un radical polyhydroxyalkyle en C₂-C₆ ; un radical alcoxy(C C₆)alkyle en C C₆ ; un radical hydroxyalcoxy(C_rC₆)alkyle en C C₆ ; un radical aminoalkyle en C C_δ ; un radical aminoalkyle en C_rC₆ dont l'aminé est mono ou disubstituée par un radical alkyle en C_rC₆, par un radical acétyle, par un radical monohydroxyalkyle en C C₆ ou par un radical polyhydroxyalkyle en C₂-C₆ ; un radical alkyl(C_r C₆)thioalkyle en C_rC₆, un radical monohydroxyalkyl(C C₆)thioalky!e en C C₆ ; un radical polyhydroxyalkyl(C₂-C₆)thioalkyle en C,-C₆ ; un radical carboxyalkyle en C C₆ ; un radical alcoxy(C₁-C₅)carbonylalkyle en C_rC₆, un radical acétylaminoalkyle en

; un radical cyanoalkyle en C_rC₆ ; un radical trifluoroalkyle en C C₆ ; un radical halogénoalkyle en C_rC₅ ; un radical phosphoalkyle en C_rC₆ ou un radical sulfoalkyle en C C₆ ;

in which : - R _T represents a hydrogen atom; a CC ₆ alkyl radical; a C ₇ -C ₁₂ aralkyl radical, a CC ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; alkoxy (CC ₆₎ alkyl, CC _6; a CC ₆ hydroxyalkoxy (C _r C ₆ ) alkyl radical; a CC _amino aminoalkyl radical; a C _r C ₆ aminoalkyl radical in which the amine is mono or disubstituted by a C _r C ₆ alkyl radical, by an acetyl radical, by a CC ₆ monohydroxyalkyl radical or by a C ₂ -C ₆ polyhydroxyalkyl radical; an alkyl (C _r -C ₆₎ thioalkyl, C _r C _6, a monohydroxy radical (CC ₆₎ thioalky e CC _6!; a polyhydroxyalkyl radical (C ₂ -C ₆₎ thioalkyl, C, -C ₆ alkyl; a CC ₆ carboxyalkyl radical; alkoxy (C ₁ -C ₅₎ alkoxycarbonyl C _r C _6, a acetylaminoalkyl radical

; a C _r C ₆ cyanoalkyl radical; a CC ₆ trifluoroalkyl radical; a C _r C ₅ haloalkyl radical; a phosphoalkyl radical C _r C ₆ or a sulfoalkyl radical CC _6;

- R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom; a CC ₆ alkyl radical; a C ₇ -C ₁₂ aralkyl radical or a CC ₆ alkoxy radical;

; un radical polyhydroxyalkyle en C₂-C₆ ; un radical nitro ; un radical cyano ; un radical cyanoalkyle en C_rC₆ ; un radical alcoxy en C,-C₆ ; un radical trialkyl(C_rC₆)silanealkyle en C_rC₆ ; un radical amido ; un radical carboxyle ; un radical alkylcarbonyle en C.,-C₆ ; un radical thio ; un radical thioalkyle en C C₆ ; un radical alkyl(C C₆)thio ; un radical amino ; un radical amino protégé par un radical alkyl(C C₆)carbonyle, carbamyle ou alkyl(C.,- C₅)sulfonyle ; ou un groupement NHR" ou NR"R"' dans lesquels R" et R'", identiques ou différents, représentent un radical alkyle en C_rC₆, un radical monohydroxyalkyle en C,-C₆ ou un radical polyhydroxyalkyle en C₂-C₆ ;- R ₄ represents a hydrogen or halogen atom; a hydroxyl radical; an alkyl radical in; a C ₇ -C ₁₂ aralkyl radical; a monohydroxyalkyl radical

; a C ₂ -C ₆ polyhydroxyalkyl radical; a nitro radical; a cyano radical; a C _r C ₆ cyanoalkyl radical; a C 1 -C ₆ alkoxy radical; a trialkyl radical (C _r C ₆₎ alkylsilane C _r C _6; an amido radical; a carboxyl radical; a C ₁ -C ₆ alkylcarbonyl radical; a thio radical; a CC ₆ thioalkyl radical; an alkyl radical (CC ₆ ) thio; an amino radical; an amino radical protected by an alkyl (CC ₆ ) carbonyl, carbamyl or alkyl (C., - C ₅ ) sulfonyl radical; or an NHR "or NR" R "'group in which R" and R'", identical or different, represent a C _r C ₆ alkyl radical, a C ₆ -C ₆ monohydroxyalkyl radical or a C ₂ polyhydroxyalkyl radical -C ₆ ;

R ₅ represents a C _r C ₆ alkyl radical; a C _r C ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a C ₇ -C ₁₂ aralkyl radical; a aryl radical; an aminoalkyl radical into a CC ₆ aminoalkyl radical, the amine of which is protected by a (C ₁ -C ₆ ) alkyl carbonyl radical. carbamyl or (C ₁ -C ₆ ) alkyl sulfonyl; a C 1 -C 6 carboxyalkyl radical; a C _r C ₆ cyanoalkyl radical; a C 1 -C ₆ carbamylalkyl radical; a C ₆ -C ₆ trifluoroalkyl radical; a trialkyl (CC ₆ ) silanealkyl radical in CC ₆ ; a CC ₆ sulfonamidoalkyl radical; an alkyl (C ₁ -C ₆₎ carboxyalkyl, C _r C _6; an alkyl radical (CC ₆₎ alkylsulphinyl CC _6; an alkyl radical (CC ₆₎ sulfonylalkyl CC _6; an alkyl (C _r -C ₆₎ alkylketo C _r C _6; an N-C ₁ -C ₆ carbamylalkyl C _r C ₆ radical; an N-C ₁ -C ₆ sulfonamidoalkyl radical in C _r C ₆ ;

R ₆ represents a hydrogen or halogen atom; a CC ₆ alkyl radical; a C 1 -C ₆ alkoxy radical; an acetylamino radical; a CC ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; alkoxy (CC ₆₎ C _r C _6; a thiophene radical; a furan radical; a phenyl radical; or a CC ₆ aralkyl radical;

- X represents a monovalent or divalent anion;

consisting in a first step, in reacting in a solvent containing at least one base, a 1,5,6,7-tetrahydro-indol-4-one of formula (II) below:

dans lequel R,, R₂, R₃ et R₆ ont les mêmes significations que celles indiquées ci- dessus pour les composés de formule (I), avec une 3-pyridinecarboxaldéhyde de formule (III) suivante :

in which R ,, R ₂ , R ₃ and R ₆ have the same meanings as those indicated above for the compounds of formula (I), with a 3-pyridinecarboxaldehyde of formula (III) below:

(III) in which R ₄ has the same meanings as those indicated above for the compounds of formula (I), to obtain an enone derivative of formula (IV) below:

in which R _{1 t} R ₂ , R ₃ , R ₄ and R ₆ have the same meanings as those indicated above for the compounds of formula (I), then in a second step, in reacting, in a solvent medium, said enone derivative of formula (IV) with a quaternizing agent R ₅ X in which R ₅ and X have the same meanings as those indicated above for the compounds of formula (I), to obtain a cyclohexenone of formula (V) next :

in which the radicals R ₁ to R ₆ and X ^' have the same meanings as those indicated above for the compounds of formula (I), then in a third step, in flavoring said cyclohexenone of formula (V) thus obtained, in a solvent medium and in the presence of a base, to obtain the expected compound of formula (I).

This synthesis process in accordance with the invention can be represented according to the synthesis scheme below:

The process for the synthesis of 3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridiniums of formula (I) according to the invention differs essentially from that described in the prior art by the fact that the conditions of temperature and the base used during the first step make it possible to arrive at a compound of formula (IV), in a secure manner, (the bases used do not require any particular handling conditions). In addition, the compounds of formula (I) are obtained with an overall yield greater than 45% while the overall yield of the prior process was only around 9%. Finally, the compounds of formula (I) do not require an additional purification step by chromatography. as is the case for the method of the prior art. These advantages make the synthesis process according to the invention perfectly transposable on an industrial level. According to the process of the invention, R ₁ and R ₅ , independently of one another, preferably represent a methyl, ethyl or 2-hydroxyethyl radical; R ₂ , R ₃ , R ₄ and R ₆ preferably represent a hydrogen atom or a methyl radical.

According to the invention, X ^" is preferably chosen from a halogen atom such as chlorine, bromine or iodine; a hydroxide; a hydrogen sulphate; an alkyl sulphate or a carboxylate.

Among the 3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridiniums of formula (I) which can be obtained by implementing the process of the invention, there may be mentioned in particular:

- 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methylpyridinium methylsulfate;

- 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methyl-pyridinium chloride; and

- 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1- (2-hydroxyethyl) chloride - pyridinium chloride.

Advantageously, the solvent or solvents used in the various stages of the process according to the invention are inert solvents such as, for example, a lower C _r C ₄ alcohol such as methanol, ethanol, isopropanol or isobutanol; ethyl ether; tert-butyl methyl ether; tetrahydrofuran; toluene; hexane; heptane; ethyl acetate; chloroform; dichloromethane or acetonitrile; in the presence or absence of a phase transfer agent such as for example a quaternary ammonium or a salt of sulfosuccinic acid. Preferably, the solvent used is a CC ₄ alcohol such as methanol, ethanol, isobutanol; tetrahydrofuran or ethyl acetate.

The solvent used during the first step is preferably chosen from methanol, ethanol, tetrahydrofuran and toluene. The solvent used during the second step is preferably chosen from ethyl acetate and tetrahydrofuran.

The solvent used during the third step is preferably chosen from ethanol, isopropanol and isobutanol.

The base used during the first step is preferably chosen from sodium hydroxide, potassium hydroxide, and sodium methylate. The amount of base used is preferably of the order of two molar equivalents relative to the number of moles of compound of formula (II) to be reacted.

The base used during the third step is preferably chosen from triethylamine and piperidine. The amount of base used is preferably of the order of two and a half equivalents relative to the number of moles of compound of formula (V) to be reacted.

The quaternizing agent used during the second step is preferably chosen from dimethyl sulphate and chloromethane.

According to an advantageous embodiment of the process of the invention, the reaction temperature during the first step is between 0 and 60 ° C approximately and preferably between 20 and 30 ° C approximately. A particularly preferred temperature is around 25 ° C.

Of course, during the first step, and depending on the nature of the different radicals present on the starting compound of formula (II), those skilled in the art will take care to protect certain substituents so that they do not intervene not in the continuation of the reactions. Thus, and by way of example, when a compound of formula (II) in which R ₄ represents a hydroxyl radical is used, it will then be necessary to protect said hydroxyl radical with the aid of a protective group by forming the corresponding benzil ether. When the reaction is complete, the expected products, such as for example 3- (4-hydroxy-1-methyl-1H-indol-5-ylmethyl) -1-methyl-pyridinium methyl sulfate, may, if necessary, be recovered by methods well known in the state of the art such as filtration or crystallization.

The compounds of formula (I) obtained according to the process in accordance with the invention can be used as finished products in any type of industry such as the cosmetic industry, in particular as a coupler for the oxidation dyeing of keratin fibers.

The enone derivatives of formula (IV) and (V) formed respectively at the end of the first stage and of the second stage of the synthesis process in accordance with the invention are new compounds, and as such constitute another subject of the invention.

Among these enone derivatives of formula (IV) and (V) there may be mentioned in particular:

- 1-methyl-5-pyridin-3-ylmethylene-1, 5,6,7-tetrahydro-indol-4-one;

- 1-methyl-3- (1-methyl-4-oxo-1,4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium methyl sulfate; - 1-methyl-3- (1-methyl-4-oxo-1, 4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium chloride; and

- 1- (2-hydroxyethyl) -3- (1-methyl-4-oxo-1, 4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium chloride.

These new enone derivatives of formulas (IV) and (V) can of course be used in any type of industry, chemical, cosmetic, food, pharmaceutical or other. They can in particular be used as intermediate compounds in the synthesis of the compounds of formula (I) as defined above.

The example of preparation which follows is intended to illustrate the invention. EXAMPLES

EXAMPLE 1 Synthesis of 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methyl-pyridinium methyl sulfate

a) Step 1: Preparation of 1-methyl-5-pyridin-3-ylmethylene-1, 5,6,7- tetrahvdro-indol-4-one

In a 250 ml flask, 4.5 g of 1-methyl-1,5,6; 7-tetrahydro-indol-4-one (0.03 mole) and 9.8 g of pyridine-3- were dissolved. carboxaldehyde (0.09 mole) in 15 ml of toluene. 11 ml of a solution of sodium methoxide in 30% methanol (0.06 mol) were then added to the reaction medium, while cooling using an ice / water bath. The reaction medium was stirred at 25 ° C for 4 hours. The reaction medium was then evaporated under vacuum almost to dryness. The residue obtained was mixed with 30 ml of water, then cooled to 4 ° C for 1 hour. The solid obtained was then rinsed with 2 times 20 ml of water. After drying, 4.6 g of a white powder were obtained with a yield of 64% and whose melting point (Kofler) was 159 ° C. ¹ H NMR analysis (CDCI ₃ , 200 MHz) in accordance with the expected product was as follows:

8.49 (d, J = 2Hz, 1H); 8.39 (dd, J = 2.5 Hz, 1 H); 7.5 (m, 2H);

7.19 (dd, J = 5.8 Hz, 1 H); 6.51 (d, J = 3 Hz, 1 H); 6.46 (d, J = 3 Hz, 1 H);

3.44 (s, 3H); 2.95 (t, J = 6Hz, 2H); 2.68 (t, J = 6Hz, 2H). b) Step 2: Preparation of 1-methyl-3- (1-methyl-4-oxo-1, 4,6,7-tetrahvdro-indol-5-ylidenemethyl) -pyridinium methyl sulfate

10 g of 1-methyl-5-pyridin-3-ylmethylene-1, 5,6,7-tetrahydro-indol-one (42 mmol) obtained according to the protocol described in the previous step were suspended in 100 ml ethyl acetate. Then 4.5 ml (47.3 mmol) of dimethyl sulfate with a density d = 1.325 was added. The heterogeneous mixture was heated at reflux for 2 hours and then cooled to room temperature. The yellow solid obtained was filtered, rinsed three times with 30 ml of ethyl acetate. 15.1 g of expected product were obtained with a yield of 99%, and whose melting point (Kofler) was 170 ° C. ¹ H NMR analysis (DMSO, 200 MHz) in accordance with the expected product was as follows:

9.21 (s, 1H); 9.01 (d, J = 6Hz, 1H); 8.70 (d, J = 8Hz, 1H); 8.24 (dd, 8Hz, 1H); 7.55 (s, 1H); 6.96 (d, J = 3 Hz, 1 H);

6.50 (d, J = 3 Hz, 1 H); 4.45 (s, 3H); 3.80 (s, 3H); 3.45 (s, 3H); 3.13 (t, J = 6Hz, 2H); 2.97 (t, J = 6Hz, 2H).

c) Step 3: Preparation of 3- (4-hvdroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methyl-pyridinium methyl sulfate

12.0 g (33mmol) of 1-methyl-3- (1-methyl-4-oxo-1, 4,6,7-tetrahydro-indol-5-ylidenemethyl) methyl sulfate are introduced into a 250 ml flask ) -pyridinium obtained above in the previous step and 90 ml of absolute ethanol. It was heated under nitrogen at reflux to obtain a homogeneous solution. 12 ml (86 mmol) of triethylamine with a density d = 0.726 were then added. The reaction mixture was continued to reflux for about 16 hours. The reaction medium was then cooled to room temperature. The solid obtained was filtered, then rinsed three times with 30 ml of absolute ethanol. There was obtained, with a yield of 82.5%, 9.9 g of the expected product in the form of a dark yellow solid which melted 215 ° C (Kofler). The ¹ H NMR analysis in accordance with the expected product was as follows: , 25 (s, 1H); 8.96 (s, 1H); 8.84 (d, J = 6HZ, 1H); 8.40 (d, J = 8HZ, 1H); .06 (dd, J = 6.8Hz, 1H); 7.21 (d, J = 3Hz, 1H); 7.08 (d, J = 7 Hz, 1 H); , 94 (d, J = 7 Hz, 1 H); 6.70 (d, J = 3Hz, 1H); 4.38 (s, 3H); 4.22 (s, 2H); , 77 (s, 3H); 3.44 (s, 3H).

Claims

1. Process for the synthesis of 3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridiniums of formula (I) below:

in which : - Ri represents a hydrogen atom; an alkyl radical in

; a C ₇ -C ₁₂ aralkyl radical, a C 1 -C ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; alkoxy (CC ₆₎ alkyl, CC _6; a hydroxyalkoxy radical (C ₁ -C ₆₎ alkyl, CC _6; a CC ₆ aminoalkyl radical; a CC ₆ aminoalkyl radical in which the amine is mono or disubstituted by a CC ₆ alkyl radical, by an acetyl radical, by a C 1 -C ₆ monohydroxyalkyl radical or by a C ₂ -C ₆ polyhydroxyalkyl radical; an alkyl (C _r C _s) thioalkyl, C _r C _6, a monohydroxy radical (CC ₆₎ thioalkyl, C _ι -C ₆ alkyl; a polyhydroxyalkyl radical (C ₂ -C ₆₎ thioalkyl, C, -C ₆ alkyl; a carboxyalkyl radical in; alkoxy (CC ₆₎ carbonylalkyl _r C alkyl, a radical acetylaminoalkyl C _r C _6; a C _r C ₆ cyanoalkyl radical; a CC ₆ trifluoroalkyl radical; a C ₁ -C ₆ haloalkyl radical; a phosphoalkyl radical in

or a CC ₆ sulfoalkyl radical; R ₂ and R ₃ , identical or different, represent a hydrogen or halogen atom; an alkyl radical in

; a C ₇ -C ₁₂ aralkyl radical or a CC ₆ alkoxy radical; R ₄ represents a hydrogen or halogen atom; a hydroxyl radical; an alkyl radical in

; a C ₇ -C ₁₂ aralkyl radical; a radical monohydroxyalkyl in

; a C ₂ -C ₆ polyhydroxyalkyl radical; a nitro radical; a cyano radical; a C 1 -C ₆ cyanoalkyl radical; a C C6 alkoxy radical; a tri (C ₁ -C ₆₎ alkylsilane C _r C _6; an amido radical; a carboxyl radical; a C _r C ₆ alkylcarbonyl radical; a thio radical; a CC ₆ thioalkyl radical; an alkyl radical (CC ₆ ) thio; an amino radical; an amino radical protected by a C ₁ -C ₆ alkyl, carbonyl, carbamyl or (CC ₆ ) sulfonyl alkyl radical; or an NHR "or NR" R "'group in which R" and R "", which are identical or different, represent a C ₁ -C ₃ alkyl radical, a C _r C ₆ monohydroxyalkyl radical or a C ₂ polyhydroxyalkyl radical -C ₆ ; - R ₅ represents an alkyl radical in

; a CC ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a C ₇ -C ₁₂ aralkyl radical; an aryl radical; a C ₁ -C ₆ aminoalkyl radical, a C _r C ₆ aminoalkyl radical the amine of which is protected by a (C ₁ -C ₆ ) carbonyl, carbamyl or (C ₁ -C ₆ ) alkyl sulfonyl radical; a CC ₆ carboxyalkyl radical; a C _r C ₆ cyanoalkyl radical; a carbamylalkyl radical to a CC ₆ trifluoroalkyl radical; a thalkyl (C ₁ -C ₆ ) silanealkyl radical in

; a sulfonamidoalkyl radical in; an alkyl (C ₁ -C ₆₎ carboxyalkyl, C _r C _6; an alkyl (C _{r C6)} alkylsulphinyl C _r C _6; a CC ₆ alkyl (C Cs) sulfonylalkyl radical; a CC ₆ alkyl (C _r C ₆ ) ketoalkyl radical; an N-alkyl (C _ι -C ₆ ) carbamylalkyl radical CC ₆ ; an N-alkyl (Cι-C ₆ ) sulfonamidoalkyl radical in C, -C ₆ ; - R ₆ represents a hydrogen or halogen atom; a CC ₆ alkyl radical; a C 1 -C ₆ alkoxy radical; an acetylamino radical; a monohydroxyalkyl radical in; a C ₂ -C ₆ polyhydroxyalkyl radical; an alkoxy radical (C ₁ -C ₆ ) alkyl in

; a thiophene radical; a furan radical; a phenyl radical; or a CC ₆ aralkyl radical; - X represents a monovalent or divalent anion; consisting in a first step, in reacting in a solvent containing at least one base, a 1,5,6,7-tetrahydro-indol-4-one of formula (II) below:

in which R _{1 (} R ₂ , R ₃ and R ₆ have the same meanings as those indicated above for the compounds of formula (I), with a 3-pyridinecarboxaldehyde of formula (III) below:

(III) in which R ₄ has the same meanings as those indicated above for the compounds of formula (I), to obtain an enone derivative of formula (IV) below:

in which R ^ R ₂ , R ₃ , R ₄ and R ₆ have the same meanings as those indicated above for the compounds of formula (I), then in a second step, in reacting, in solvent medium, said derivative of enone of formula (IV) with a quaternizing agent R ₅ X in which R ₅ and X have the same meanings as those indicated above for the compounds of formula (I), to obtain a cyclohexenone of formula (V) below :

in which the radicals Ri to R ₆ and X ^" have the same meanings as those indicated above for the compounds of formula (I), then in a third step, to flavor said cyclohexenone of formula (V) thus obtained, in medium solvent and in the presence of a base, to obtain the compound of formula (I) expected. 2. Method according to claim 1, characterized in that R and R ₅ , independently of one another, represent a methyl, ethyl or 2-hydroxyethyl radical and R ₂ , R ₃ , R ₄ and R ₆ represent a hydrogen atom or a methyl radical. 3. Method according to claim 1 or 2, characterized in that X ^" is chosen from a halogen atom; a hydroxide; a hydrogen sulphate; an alkyl sulphate or a carboxylate. 4. Method according to any one of claims 1 to 3, for the preparation of 3- (4-hydroxy-1-methyl-1 H-indol-5-yimethyl) -1-methylpyridinium methyl sulfate; 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methyl-pyridinium chloride or 3- (4-hydroxy-1-methyl-1 H-indol-5 chloride -ylmethyl) -1- (2-hydroxyethyl) -pyridinium. 5. Method according to any one of the preceding claims, characterized in that the solvent (s) are chosen from methanol, ethanol, isopropanol or isobutanol; ethyl ether; tert-butyl methyl ether; the tetrahydrofuran; toluene; hexane; heptane; ethyl acetate; chloroform; dichloromethane or acetonitrile; whether or not a phase transfer agent is present. 6. Method according to claim 5, characterized in that the solvent used during the first step is chosen from methanol, ethanol, tetrahydrofuran and toluene. 7. Method according to claim 5, characterized in that the solvent used during the second step is chosen from ethyl acetate and tetrahydrofuran. 8. Method according to claim 5, characterized in that the solvent used during the third step is chosen from ethanol, isopropanol and isobutanol. 9. Method according to any one of the preceding claims, characterized in that the base used during the first step is chosen from sodium hydroxide, potassium hydroxide, and sodium methylate. 10. Method according to any one of the preceding claims, characterized in that the base used during the third step is preferably chosen from triethylamine and piperidine. 11. Method according to any one of the preceding claims, characterized in that the quaternizing agent used during the second step is chosen from dimethylsulfate and chloromethane. 12. Method according to any one of the preceding claims, characterized in that the reaction temperature during the first step is between 0 and 60 ° C. 13. The method of claim 12, characterized in that the reaction temperature during the first step is between 20 and 30 ° C. 14. The method of claim 13, characterized in that the reaction temperature during the first step is 25 ° C. 15. Enone derivatives of formula (IV) and (V) as defined in any one of claims 1 to 3. 16. Derivatives according to claim 15, characterized in that they are chosen from: - 1-methyl-5-pyridin-3-ylmethylene-1, 5,6,7-tetrahydro-indol-4-one; - 1-methyl-3- (1-methyl-4-oxo-1,4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium methyl sulfate; - 1-methyl-3- (1-methyl-4-oxo-1, 4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium chloride; and - 1- (2-hydroxyethyl) -3- (1-methyl-4-oxo-1, 4,6,7-tetrahydro-indol-5-ylidenemethyl) -pyridinium chloride. 17. Use of the enone derivatives of formula (IV) and / or (V) as defined in claim 15 or 16, as intermediate compounds in the synthesis of the compounds of formula (I) as defined in any one of claims 1 to 4.