WO2001074803A1 - Method for preparing 3-(4-hydroxy-1h-indol-ylmethyl)-pyridinium compounds using an aldolisation reaction - Google Patents

Abstract

The invention concerns a novel method for preparing 3-(4-hydroxy-1H-indol-5-ylmethyl)-pyridinium compounds using an aldolisation reaction.

Description

PROCESS FOR THE PREPARATION OF 3 - (4-HYDR0XY- 1H- IND0L-YLMETHYL) - PYRIDINIUMS COMPOUNDS USING AN ALDOLIZATION REACTION

The present invention relates to a new process for the preparation of 3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridinium compounds of formula (I) using an aldolization reaction.

3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridiniums are known raw materials used in the dye industry. 3- (4-Hydroxy-1-methyl-1 H-indol-5-ylmethyl-pyridinium methylsulfate can in particular be used as a 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-pyridiniums is generally carried out in several stages, according to the simplified reaction scheme f

consisting in a first step of reacting a 1-alkyl-1, 5,6,7-tetrahydro-indol-4-one, (compound (A)), with 3-pyridinecarboxaldehyde, (compound (B)), in an organic solvent such as, for example, t-butanol, in the presence of a base such as potassium tert-butoxide, and at an elevated temperature corresponding to the reflux temperature of the solvent used, to obtain a compound (C), see in particular the process described in the patent application EP 0 377 450. The compound (C) thus obtained is then quaternized by an alkyl radical, according to 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, an often exothermic acidification followed by purification by chromatography are mandatory to arrive at the expected compound (C). Therefore, this process is not industrially transferable, 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 subject of the present invention is therefore a new process for the synthesis of 3- (4-hydroxy-1 H-indol-5-ylmethyl) -pyridiniums of formula (I) below:

in which

Ft represents a hydrogen atom; an alkyl radical in

; a C ₇ -C ₁₂ aralkyl radical; a C 1 -C ₆ alkoxy ^ -C ^ alkyl radical; a radical alkyl (C _r -C ₆₎ thioalkyl CC _6; alkoxy (C ₁ -C ₆₎ alkoxycarbonyl, C _r C _6; an O, -Cg cyanoalkyl radical; a C ₆ -C ₆ trifluoroalkyl radical; a C _1-6 haloalkyl radical; a C _r C ₆ phosphoalkyl radical or a C _r C ₆ sulfoalkyl radical;

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

- R ₄ represents a hydrogen or halogen atom; a hydroxyl radical; a C _r C ₆ alkyl radical; a C ₇ -C ₁₂ aralkyl radical; a C _r C ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a nitro radical; a cyano radical; a C 1 -C ₆ cyanoalkyl radical; a C 1 -C ₆ alkoxy radical; a trialkyl (C _r C ₆ ) silanealkyl radical in

; a CC ₆ alkylcarbonyl radical; a C _r C ₆ thioalkyl radical; an alkyl radical (CC ₆ ) thio;

- R ₅ represents a C ₁ -C ₆ alkyl radical; a C ₁ -C ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a C ₇ -C ₁₂ aralkyl radical; an aryl radical; an aminoalkyl radical at 0, -Cg, an aminoalkyl radical at CC ₆ , the amine of which is protected by an alkyl ^ -C ^ carbonyl, carbamyl or alkyl (CC ₆ ) sulfonyl radical; a C ₁ -C ₆ carboxyalkyl radical; a C _r C ₆ cyanoalkyl radical; a C ₁ -C ₆ carbamylalkyl radical; a trifluoroalkyl radical in

; a trialkyl (C _r C ₆ ) silanealkyl radical in

; a C _r C ₆ sulfonamidoalkyl radical; a CC ₆ -C ₁ -C ₆ carboxyalkyl alkyl radical; a C ₁ -C ₆ sulfinylalkyl C ₁ -C ₆ alkyl radical; an alkyl radical (C _r C ₆ ) sulfonylalkyl in

; a C ₆ -C ₆ alkyl (CC ₆ ) ketoalkyl radical; an N-alkyl (CC ₆ ) carbamylalkyl radical CC ₆ ; an N-alkyl (C _r C ₆₎ alkylsulphonamido C, -C ₆ alkyl;

R ₆ represents a hydrogen or halogen atom; an alkyl radical in; a C _r C ₆ alkoxy radical; aicoxy a (C ₁ -C ₆₎ alkyl, C, -C ₆ alkyl; a thiophene radical; a furan radical; a phenyl radical; or an aralkyl radical in C _ï C₆ alkyl;

X ^" represents a monovalent or divalent anion;

consisting in a first step, to carry out in a solvent containing at least one base, an aloioiisation reaction between a 1,5,6,7-tetrahydro-indol-4- one of formula (II) below:

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

(Ml) in which R ₄ has the same meanings as those indicated above for the compounds of formula (I), while trapping the alcoholate resulting from said alkalization reaction with an anhydride or an acid chloride, for obtain a 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) and R ₇ represents a radical R ' ₇ CO or R " ₇ SO ₂ in in which R ' ₇ represents a linear or branched, saturated or unsaturated C _r C ₅ alkyl radical, an aryl radical or a C ₇ -C ₁₂ aralkyl radical, and R " ₇ represents a linear or branched CC ₆ alkyl radical, saturated or unsaturated, an aryl radical or a C ₇ -C ₁₂ aralkyl radical, then in a second step, reacting, in a solvent medium, said 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 compound of following formula (V):

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) and in which the radical R ₇ has the same meanings as those indicated above for the compounds of formula (IV), then in a third step, transforming the compound of formula (V) thus obtained, in a solvent medium and in the presence of a base, to obtain the compound of formula (I) expected.

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 temperature and the base used during the first step make it possible to obtain a compound of formula (IV), in a secure manner. In addition, the compounds of formula (I) are obtained with an overall yield greater than 28%, 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 process 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 ^ preferably represents a methyl radical; R ₅ preferably represents a methyl, ethyl or 2-hydroxyethyl radical and R ₂ , R ₃ , R ₄ and R ₆ , independently of each other, 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-alkyl-1 H-indol-5-ylmethyl) -1-alkyl-pyridiniums of formula (I) which can be obtained by implementing the process of the invention, include: - 3- (4-hydroxy-1-methyl-1 H-indol-5-ylmethyl) -1-methylpyridinium methylsulfate;

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

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

Advantageously, the solvent (s) used in the various stages of the process according to the invention are inert solvents such as, for example, a lower C ₄ -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 and their mixtures; 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 C _r C ₄ alcohol such as methanol, ethanol, isobutanol; tetrahydrofuran; ethyl acetate and mixtures thereof.

The solvent used during the first step is preferably chosen from tetrahydrofuran and ethyl ether.

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 lithium diisopropylamide and sodium methylate. A particularly preferred base is lithium diisopropylamide. The amount of base used is preferably of the order of one molar equivalent 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 three 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 dimethylsulfate and chloromethane.

According to an advantageous embodiment of the process of the invention, the temperature of the reaction during the first stage is between -70 and 25 ° C approximately and preferably between -30 and 0 ° C approximately. A particularly preferred temperature is around -15 ° C.

Of course, during the first step, and depending on the nature of the different radicals present on the compounds of formulas (II) and (III) starting, the skilled person will take care to protect certain substituents so that these- these do not intervene in the following reactions. Thus, and by way of example, when a compound of formula (III) 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 benzyl ether.

When the reaction is complete, the expected products, such as for example 3- (4-hydroxy-1-methyl-1 H-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 derivatives formula (IV) and (V) formed respectively at the end of the first step and of the second step of the synthesis process according to the invention are new compounds, and as such, constitute another object of the invention.

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

- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -pyridin-3-yl-methyl acetate;

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -methyl] -1-methyl-pyridinium methyl sulfate;

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -methyl] -1-methyl-pyridinium chloride; and

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) chloride - methyl] -1- (2-hydroxyethyl) -pyridinium chloride .

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

a) Step 1: Preparation of (1-methyl-4-oxo-1, 5,6,7-tetrahvdro-1 H-indol-5-yl) -pyridin-3-yl-methyl acetate

In a 250 ml three-necked flask, 8.95 g of 1-methyl-1,5,6,7-tetrahydro-indol-4-one (0.06 mol) and 6.56 g of pyridine were dissolved under nitrogen. 3-carboxaldehyde (0.06 mole) in 100 ml of tetrahydrofuran. The mixture was then cooled to -15 ° C and 33 ml of a 2 molar solution of lithium diisopropylamide in a tetrahydrofuran / heptane mixture (0.066 mol) were added dropwise over 30 minutes. The reaction mixture was stirred at -15 ° C for 1 hour and then added 6.9 ml of acetic anhydride (0.072 mole), maintaining the temperature at -15 ° C. The reaction medium was then heated at 20 ° C for 1 hour and then treated with 650 ml of a saturated solution of ammonium chloride. The mixture thus obtained was extracted with ethyl acetate (twice per 450 ml). The combined organic phases were washed with water and dried over Na ₂ SO ₄ . The solvent was evaporated to give 19.34 g of a light brown oil which was used directly in the next step. The 1 H NMR analysis (CDCI ₃ , 400 MHz), in accordance with the expected product in the form of a mixture of two diastereoisomers, was as follows: 8.51-8.69 (m, 2H); 7.62-7.83 (m, 1H); 7.23-7.35 (m, 2H); 6.52 to 6.70

(m, 3H); 3.55 and 3.59 (2s, 3H); 2.60-3.51 (m, 3H); 2.03 and 2.13 (2S, 3H); 1.45-2.21 (m, 2H). b) Step 2: Preparation of 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahvdro-1 H-indol-5-yl) -methyl] -1- methyl sulfate methyl-pyridinium

19.34 g of (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -pyridin-3-yl-methyl acetate obtained above at the previous step were dissolved in 150 ml of ethyl acetate, under nitrogen. 7.1 ml of dimethyl sulphate (0.075 mole) were then added over 5 minutes and at a temperature of 20 ° C. The mixture was stirred at room temperature for 3 hours. The solid obtained, hygroscopic, was filtered and then rinsed with ethyl acetate. After drying, 17.01 g of an orange solid were obtained, ie a yield of 67% in two stages from 1-methyl-1, 5,6,7-tetrahydro-indol-4-one. ¹ H NMR analysis (D ₂ O, 200 MHz), in accordance with the expected product in the form of a mixture of two diastereoisomers, was as follows:

8.65 (m, 1H); 8.54 (m, 1H); 8.32 (m, 1H); 7.83 (m, 1H); 6.52 (m, 1H); 6.29 (m, 1H); 6.18 (m, 1H); 4.18 (s, 3H); 3.31 and 3.33 (2S, 3H); 2,40-

3.05 (m, 3H); 1.87 and 1.95 (2S, 3H); 1.48-2.30 (m, 2H).

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

2.23 g of 3- [acetoxy- (1-methyl-4-oxo-1,5,6,7-tetrahydro-1 H-indol-5-yl methyl sulfate) were mixed in a 50 ml flask. ) -methyl] - 1 -methyl- pyridinium obtained above in the previous step (5.3 mmol) and 17 ml of absolute ethanol. The reaction mixture was heated under nitrogen at reflux to obtain a homogeneous solution. 2.6 ml (18.4 mmol) of triethylamine with a density d = 0.726 were then added. The reaction mixture was continued to reflux for 38 hours. The reaction medium was then cooled to room temperature and then to 4 ° C. The solid obtained was filtered, then rinsed twice with absolute ethanol. 0.81 g of the expected product was obtained with a yield of 42% in the form of a dark yellow solid which melted 215 ° C (Kofler). The NMR-H analysis (D ₂ 0, 200 MHz), in accordance with the expected product, was as follows: , 46 (m, 2H); 8.28 (d, J = 6Hz, 1H); 7.80 (dd, J = 7.2 and 7.3 Hz, 1H); , 15 (d, J = 3Hz, 1H); 7.08 (d, J = 7 Hz, 1 H); 7.03 (d, J = 7Hz, 1H); , 51 (d, J = 3Hz, 1H); 4.21 (s, 3H); 3.70 (s, 2H); 3.67 (s, 3H).

Claims

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

in which :

- R _T represents a hydrogen atom; an alkyl radical in

; a C ₇ -C ₁₂ aralkyl radical; a CC ₆ alkoxy (C _r C ₆ ) alkyl radical; an alkyl (C ₁ -C ₆₎ thioalkyl, C, -C ₆ alkyl; a CC ₆ alkoxy (O, -C ₆ ) carbonylalkyl radical; an O, -Cg cyanoalkyl radical; an O, -Cg trifluoroalkyl radical; a CC 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; a CC ₆ alkyl radical; a C ₇ -C ₁₂ aralkyl radical or a CC ₆ alkoxy radical;

- R ₄ represents a hydrogen or halogen atom; a hydroxyl radical; a C _r C ₆ alkyl radical; a C ₇ -C ₁₂ aralkyl radical; a CC ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a nitro radical; a cyano radical; a C 1 -C ₆ cyanoalkyl radical; a C 1 -C 6 alkoxy radical; a trialkyl (CC ₆ ) silanealkyl radical in CC ₆ ; an alkylcarbonyl radical in

; a C _r C ₆ thioalkyl radical; a (C _r C ₆ ) thio alkyl radical; - R ₅ represents a CC ₆ alkyl radical; a CC ₆ monohydroxyalkyl radical; a C ₂ -C ₆ polyhydroxyalkyl radical; a C ₇ -C ₁₂ aralkyl radical; an aryl radical; an aminoalkyl radical into an aminoalkyl radical in which the amine is protected by an alkyl (CC ₆ ) carbonyl, carbamyl or (C ₁ -C ₆ ) alkyl sulfonyl radical; a C 1 -C 6 carboxyalkyl radical; a C 1 -C ₆ cyanoalkyl radical; a C _r C ₆ carbamylalkyl radical; a C ₆ -C ₆ trifluoroalkyl radical; a tri (C ₁ -C ₆₎ alkylsilane C, -C ₆ alkyl; a sulfonamidoalkyl radical in

; an alkyl radical (CC ₆₎ carboxyalkyl CC _6; a (C ₁ -C ₆ ) alkyl sulfinylalkyl radical in

; an alkyl (C _{r C6)} sulfonylalkyl, C, -C ₆ alkyl; an alkyl (C, -C ₆₎ alkylketo C _r C _6; an N-alkyl (CC ₆ ) carbamylalkyl C ₁ -C ₆ radical; an N-alkyl (C _r C ₆ ) sulfonamidoalkyl radical CC ₆ ;

- R ₆ represents a hydrogen or halogen atom; a CC ₆ alkyl radical; an alkoxy radical in

; alkoxy (C _{r C6)} alkyl, C _r C _6; a thiophene radical; a furan radical; a phenyl radical; or a C _r C ₆ aralkyl radical;

- X represents a monovalent or divalent anion;

consisting in a first step, to carry out in a solvent containing at least one base, an aloioiisation reaction between a 1,5,6,7-tetrahydro-indol-4- one of formula (II) below:

in which R _{1 τ} R ₂ , R ₃ and R ₆ have the same meanings as those indicated above for the compounds of formula (I), and 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), while trapping the alcoholate resulting from said alkalization reaction with an anhydride or an acid chloride, for obtain a 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) and R ₇ represents a radical R ' ₇ CO or R " ₇ SO ₂ in which R ' ₇ represents a linear or branched, saturated or unsaturated CC ₆ alkyl radical, an aryl radical or a C ₇ -C ₁₂ aralkyl radical, and R " ₇ represents a linear C ₆ -C ₆ alkyl radical or branched, saturated or unsaturated, an aryl radical or a C ₇ -C ₁₂ aralkyl radical, then in a second step, reacting, in solvent medium, said derivative 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 compound of the following formula (V):

in which the radicals R., at R ₆ and X ^" have the same meanings as those indicated above for the compounds of formula (I) and in which the radical R ₇ has the same meanings as those indicated above for the compounds of formula (IV), then in a third step, transforming the compound of formula (V) thus obtained, in a solvent medium and in the presence of a base, to obtain the expected compound of formula (I).

2. Method according to claim 1, characterized in that R ^ represents a methyl radical; R ₅ represents a methyl, ethyl or 2-hydroxyethyl radical and R ₂ , R ₃ , R ₄ and R ₆ , independently of each other, 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-ylmethyl) -1-methyl-pyridinium 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-ylmethyl) -1- (2-hydroxyethyl) -pyridinium chloride.

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; dichioromethane or acetonitrile and their mixtures; 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 tetrahydrofuran and ethyl ether.

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 lithium diisopropylamide and sodium methylate.

10. Method according to any one of the preceding claims, characterized in that the base used during the third step is 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 -70 and 25 ° C.

13. The method of claim 12, characterized in that the reaction temperature during the first step is between -30 and 0 ° C.

14. The method of claim 13, characterized in that the reaction temperature during the first step is -15 ° C.

15. 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-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -pyridin-3-yl-methyl acetate;

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -methyl] -1-methyl-pyridinium methyl sulfate;

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) -methyl] -1-methyl-pyridinium chloride; and

- 3- [acetoxy- (1-methyl-4-oxo-1, 5,6,7-tetrahydro-1 H-indol-5-yl) chloride - methyl] -1- (2-hydroxyethyl) -pyridinium chloride .

17. Use of the 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 the claims 1 to 4.