ITMI972299A1 - PROCEDURE FOR THE PREPARATION OF AMINOCARBONYL DERIVATIVES OF GENESEROLINE - Google Patents

Description

The present invention relates to a process for the preparation of structural analogues of geneserine, in particular of aminocarbonyl derivatives of geneseroline of formula (I):

where: R is linear or branched C2-C20 alkyl, C3-C7 cycloalkyl, phenyl, benzyl optionally substituted by C ^ -C4 alkyl groups, halogen, C ^ -C4 alkoxy groups.

Background of the invention

In the Italian patent application n. IT MI91A002237 and in the corresponding European patent application n. 599890, both in the name of Chiesi, have been described derivatives of geneseroline with anticholinesterase activity, usable in the treatment of disorders of the central nervous system, of general formula (I) defined above.

The examples of preparation of the cited patent applications involve the following steps:

a) hydrolysis of hexerine to eseroline:

b) O-acylation of eseroline with reagents capable of introducing the desired function-CO-NHR, in which R is as above defined; c) oxidation of the amino carbonyl derivatives of hexeroline thus obtained from the corresponding amino carbonyl derivatives of geneseroline;

More specifically, the preparation of N-heptylaminocarbonylgeneseroline is described in the examples of the application.

For the acylation reaction, substituted imidazoleureas or isocyanates are used.

The oxidation of the derivatives of eseroline to the corresponding derivatives of geneseroline is carried out using organic peracids or peroxides such as m-chloroperbenzoic acid, monoperphthalic acid, peracetic acid, hydrogen peroxide, in inert solvents such as halogenated hydrocarbons, hydrocarbons, dimethylformamide, dimethylsulfoxide.

Alternatively, compounds (I) were prepared starting from geneserine for hydrolyses of the methylaminocarbonyloxy group, and subsequent acylation, carried out always using N-alkylimidazolurea.

The procedures described are not suitable for industrial quantities, due to problems of cost of the starting alkaloid, of reaction rate, of yield and final hardness of the product, due to secondary reactions.

A simple, economical and safe procedure for the preparation of compounds (I) has now been found and constitutes the subject of the invention, applicable on an industrial scale with good quantitative yields. Description of the invention

In a first embodiment of the invention the compounds of formula (I) can be prepared starting from hexerine, according to the following reaction scheme 1, with good yields, a good degree of purity of the final product and improvement of the reaction times.

Scheme 1

This procedure includes:

a) oxidation of hexerine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline without isolation of the geneserine intermediate;

b) acylation of geneseroline with an isocyanate of formula R-N = C = 0, in which R is as defined in formula (I), in the presence of a basic catalyst;

c) possibly obtaining a pharmaceutically acceptable salt.

The process described above, which provides for the oxidation of hexerine followed by hydrolysis to geneseroline without the isolation of the intermediate geneserine, allows a significant increase in yields while maintaining a good purity of the final product.

Furthermore, the adoption of less expensive and less hazardous reagents makes the procedure more suitable for the industrial scale.

The acylation reaction is carried out with the use of isocyanates according to the classical methods using an appropriate basic catalyst selected from alkaline alcoholates, carbonates or hydroxides, such as potassium tert-butylate or potassium carbonate, the latter particularly preferred for application. to industrial productions.

To speed up the process, the reaction can be carried out in the presence of small amounts of a phase transfer catalyst, such as tetrabutylammonium bromide, or using an ultrasonic source.

In a second embodiment of the invention the synthesis was carried out using ethers of formula (II) as starting compounds,

where: 3⁄4 is a protective group of phenolic hydroxyl stable in basic and energetic reducing conditions and removable in acidic conditions without reducing the N-geneserine-like group, such as ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl , npropyl, isopropyl, tetrahydropyranyl according to the following scheme 2, which allows to obtain compounds (I) in three steps:

Scheme 2

This procedure includes:

a) oxidation with peracids or peroxides, preferably hydrogen peroxide of a compound of formula (II)

in an alcoholic solvent or in an alcohol-water mixture to give a compound of formula (III)

b) hydrolysis of the compound of formula (III) to geneseroline by means of a mineral or organic acid which does not reduce the N-oxide group;

c) acylation of geneseroline with an isocyanate of formula R-N = C = 0, where R is as defined above and under the same conditions as the procedure of scheme 1;

d) possibly obtaining a pharmaceutically acceptable salt.

The definition of R ^, for the purposes of the present invention, is well understood by the average person skilled in the art, making use of general knowledge, as for example described in Greene T. W., Wuts P. G. M. "Protective groups in organic synthesis", 3, 145, Wiley , 2nd Edition 1990; Kocienski P.J. "Protecting groups" 2, 21, Thieme 1994 Ed.

This procedure can be applied to both enantiomers of ethers of formula (II), allowing to obtain both the products with structure (I) and the corresponding enantiomers.

In a further embodiment of the invention the compounds (I)

can be prepared

Scheme 3

This procedure includes:

a) hydrolysis by means of a mineral or organic acid of a compound of formula (II)

where: R ^ is a protective group of the phenolic hydroxyl stable in basic and energetic reducing conditions and removable in acidic conditions, such as for example ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl.

to give eserolina (Ila)

b) acylation of eseroline (IIa) with an isocyanate of formula R-N = C = 0 where R is as defined above and under the same conditions as

procedure referred to in scheme 1;

c) oxidation of the so obtained aminocarbonyl derivative of eseroline to the corresponding aminocarbonyl derivative of geneseroline;

d) possibly obtaining a pharmaceutically acceptable salt.

One of the ethers that can be used in the synthesis, eseretol, is commercially available at low cost and in adequate quantities.

Other ethers which have proved particularly suitable as starting compounds for the preparation of compounds (I) are for example:

wherein R] _ is t-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl.

These ethers can be prepared according to methods known from the literature.

The ethers of hexeroline of formula (II) in which it is isopropyl, tbutyl, methoxymethyl, and the ethers of geneseroline of formula (III) in which R1 is alkyl or alkoxyalkyl, including tetrahydropyranyl, are in themselves new, as they are never been described above.

The embodiments of the invention according to the reaction schemes 2 and 3 are characterized by the passage which involves the hydrolysis of ethers of eseroline of formula II or of geneseroline of formula III respectively to eseroline or geneseroline.

In the literature there are many examples of hydrolysis of this type of alkaloids, in particular of esermetol and eseretolo: Polonovski M, Nitzberg C, Bull. Soc. Chim. Br., 19, 33-37 (1916); Julian P. L., Pikl J., J. Am. Chem. Soc. 57, 755-757 (1935); Yu Q.S., Brossi A., Heterocycles, 27, 745-750 (1988).

In all previous documents, literature or patents, however, the hydrolysis of these ethers is carried out using classic dealkylating agents such as BBr3, BCI3, AICI3 (Lewis acids), HBr or other halogenhydric acids.

For example, US patent 5310935 describes the preparation of (3aS-cis) -eseroline by hydrolysis of methyl ether (or analogous ethers) by means of AICI3 or BB ^; in the international patent application WO 9427963, the hexeretol is converted to physostigmine or its derivatives following the teaching contained in Julian P. L., Pikl J., J. Am.Chem. Soc. 57, 755-757 (1935); in the European patent application EP 253372 the hydrolysis of eseroline ethers is carried out by using AICI3 or BBr3.

However, the application of the methods reported in the literature to the hydrolysis of ethers of formula (III) to geneseroline has not given good results, as other reduction side reactions also occur, with the formation of unwanted by-products and consequently difficulties in purification of the obtained geneseroline and low yields. The method described in the present invention, on the other hand, allows to obtain, with good yields, high purity geneseroline. The application of this method offers considerable advantages also in the presence of compounds of formula (II) in terms of operation and costs compared to the use of Lewis acids.

A particular aspect of the invention therefore relates to the use of a mineral or organic acid for the hydrolysis of alkyl ethers of indole derivatives such as for example eseroline, geneseroline or fisovenol.

Acids suitable for the hydrolysis of compounds of formula (II) or (III) are those which do not have reducing properties, in particular towards compounds of formula (III), where the N-0 group is sensitive to reducing agents. In the process according to the present invention, the acid is preferably selected from the group consisting of: sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, strong acid ion exchange resin such as Amberlyst (<R>).

Depending on the group present, the hydrolysis conditions will be suitably chosen, in particular the type of acid, its concentration and the hydrolysis temperature.

Sulfuric acid can be used at concentrations ranging from 10 to 85% and preferably hot at a temperature between 50 and 90 "C.

Phosphoric acid is generally used at a concentration of 85% hot and preferably at temperatures around 90'C.

The methanesulfonic acid used as such is reacted when hot and preferably at temperatures around 90 ° C.

Trifluoroacetic acid as such and hydrochloric acid at a concentration of 10% can be reacted by heat at temperatures around 40 "C.

Compounds (I) can be suitably transformed into their salts with pharmaceutically acceptable acids.

The derivatives of formula (I), in analogy to their parent geneserine, in the free base form have a 1,2-oxazine structure while in the respective salified forms they have the N-oxide structure (see Scheme 4).

Scheme i

The following examples further illustrate the invention.

Example 1

Synthesis of ceneseroline

Eserine (40 g, 0.1455 mol) was dissolved in 80 ml of methanol in a flask cooled to 10 <*> C with an ice bath. Potassium bicarbonate (14.5 g, 0.1455 mol) was added under vigorous stirring, then a 35% w / v hydrogen peroxide solution (21.2 ml, 0.2182 mol) was dropped in the 10 minutes.

The cooling bath was removed and stirring continued for 2.5 hours.

An HPLC analysis showed an hexerine content of less than 1%. The solution was cooled again in an ice bath and 150 ml of a 25% w / v NaCl solution was added.

The methanol was evaporated under reduced pressure, heating at a maximum of 35 ° C for 10 minutes.

The aqueous phase was extracted three times with 150 ml of chloroform and the organic phases were evaporated under reduced pressure giving a crude geneseroline as a foaming oily residue.

The crude residue was redissolved in 100 ml of 62% w / w sulfuric acid and the solution was quickly heated to 85 ° C under a weak nitrogen stream.

Heating was continued for 2 hours and HPLC analysis showed a geneserin content of less than 1%.

The mixture was cooled to rt and poured into 100 g of ice. 30% v / v ammonium hydroxide in water (120 ml) was added drop by drop, under stirring, maintaining the temperature within 20-25 ° C with a water bath. Once pH = 4 was reached, 250 ml of ethyl acetate was added. When the aqueous phase was approximately neutral, a pitchy residue began to separate.

The neutral aqueous phase was again extracted with two 200 ml aliquots of ethyl acetate, the organic phases were combined, washed with 20% w / v sodium chloride solution in water (200 ml), dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was triturated in hexane (200 ml), about 100 ml of solvent were evaporated under reduced pressure and the suspension thus obtained was cooled to 5eC and filtered.

The product was dried at 50 ”C and under reduced pressure giving 26.53 g (78%) of geneseroline.

m.p. (Holes) = 142.5-146'C

content (titration on anhydrous)> 98%

purity (HPLC)> 98%

IR, Mass and NMR conform to the expected product

Example 2

Synthesis of geneseroline

aJ_ Synthesis of geneseretol

Eseretol (92.5 g, 0.377 mol) was dissolved in 185 ml of methanol then potassium bicarbonate (37.7 g, 0.377 mol) was added and the mixture was stirred for 10 minutes. Subsequently, in 10 minutes, a 40% w / v hydrogen peroxide solution (48 ml, 0.566 moles) was dropped and 5 ml of water were added, cooling the flask in a water bath.

The mixture was stirred for 3 hours during which time the temperature rose from 20 to 26 "C. The conversion of the hexeretol was checked regularly with HPLC and the reaction was stopped when the residual content of eseretol was less than 2%.

The mixture was poured under stirring into 750 ml of 25% w / v NaCl solution, then extracted with petroleum ether (1000 + 500 + 500 ml).

The yellow organic phase was washed with 20% w / v sodium chloride solution in water (200 ml), dried over sodium sulphate, filtered and concentrated in a rotary evaporator. Evaporation was stopped at a residual volume of about 150ml. The suspension thus obtained was cooled under stirring in an ice bath for 30 minutes and filtered. The product was dried at 30’C under vacuum, giving 72.04 g (73.2%) of geneseretol.

m.p. (Holes) = 78-80 "C

content (titration on anhydrous) = 96%

purity (HPLC)> 98%

[α] β ^ (0.5% ethanol) = -177 "

11) _ Synthesis of aeneseroline

Geneserethol (71.9 g, 0.274 mol) was dissolved in 87.5% w / w sulfuric acid (250 mL) and the reddish solution was stirred and heated to 90 ° C.

The conversion of geneseretol was checked by HPLC analysis and the reaction was stopped after 3 hours, when the residual content of geneseretol was about 3%.

The mixture was cooled in an ice bath and poured into ice (800 g) under stirring.

Then 30% w / v (500 ml) ammonium hydroxide was dropped slowly bringing the pH to 7.5, keeping the temperature below 30 ° C with the addition of ice. When the pH was about 5-6, acetate was added. ethyl (1000 ml to dissolve the geneseroline that had separated).

The neutral aqueous phase was extracted with other ethyl acetate (500 + 500 ml) and the organic phases were collected, washed with sodium chloride solution at 20% w / v in water (500 ml), dried over sodium sulphate and filter.

The solution was concentrated in a rotary evaporator and, when the solid product began to precipitate, 600 ml of neptane were added in two successive portions and the evaporation was continued up to a residual volume of solvent of about 200 ml.

The suspension thus obtained was cooled under stirring at 5'C for 30 minutes, filtered and washed with petroleum ether.

After drying at 50 ° C under vacuum, 54.5 g (84.7%) of geneseroline were obtained.

m.p. (Holes) = 143.5-145.5 * C

purity (HPLC)> 98%

[a] p2® (0.5% ethanol) = -180 *

Example 3

Hydrolysis of geneseroline ethers

With a procedure similar to that of example 2b, ethers of geneseroline of formula (III) were subjected to hydrolysis.

The following Table indicates the acids used, the temperature conditions and the reaction times, together with the yield in geneseroline, evaluated as a percentage area in the HPLC chromatograiran of the crude product obtained.

Table

acid tempe yield time of conc. (w / w) rature geneseroline reaction (min.)

t-butyl H2S0487.5% 90'C 10 99.3% i-propyl H2S0487.5% 90'C 10 73.9% n-propyl H2S0487.5% 90 <*> C 10 76.7% t-butyl H2S0462% 90'C 5 100% i-propyl H2S0462% 90 <e> C 15 96.3% MOM H2S04 16% 90 "C 15 69.8% MEM H2S04 16% 90 <e> C 15 71.7% t -butyl H2S04 16% 90 ° C 15 92.4% THP H2S04 16% 90'C 5 77.9% MOM H3P04 85% 90 <*> C 15 79.4% MEM H3P04 85% 90 "C 15 75.4 % t-butyl H3P04 85% 90 "C 15 100% i-propyl H3P04 85% 90 ° C 150 99.4% THP H3P04 85% 90'C 5 84.5% t-butyl MES 90 ° C 15 100% i -propyl MES 90 "C 15 92.7% t-butyl TFA 40'C 15 95.5% MOM TFA 40 <e> C 60 88.7% MEM TFA 40" C 60 96.6% THP TFA 40 <e > C 5 83.0% t-butyl HC1 10% 40 "C 30 94.6% MOM HCl 10% 40 * C 30 91.3% MEM HCl 10% 40" C 30 89.5% THP HCl 10% 40 * C 81.2% THP AcOH 90% 40'C 120 80.0% Where: MOM: Methoxymethyl, MEM: methoxyethoxymethyl, MES: methanesulfonic acid, TFA: trifluoroacetic acid, THP: tetrahydropyranyl, AcOH: acetic acid.

EseropÌQ__4

Synthesis of eseroline by hydrolysis of eseretol

Eseretol (5 g, 0.0203 moles) was dissolved in sulfuric acid at 87.5% w / w (25 ml) and the solution was stirred at 90'C until complete conversion (75 minutes). The mixture was cooled and poured into ice. In a nitrogen atmosphere 30% ammonia (55 ml) was slowly added up to pH = 8, maintaining the cooling.

The aqueous phase was saturated with NaCl and extracted with ethyl ether (100 + 75 + 75 ml).

The organic phase was washed with 20% w / v sodium chloride solution in water, dried over sodium sulphate, filtered and evaporated. A yellow oil was obtained which solidified at rest. After drying under vacuum at rt, 3.04 g (70.6%) of hexeroline with 97% purity (HPLC) were obtained.

With similar procedures other eseroline ethers of formula (II) can be subjected to hydrolysis to give eseroline. Once eseroline has been obtained, derivatives of geneseroline of formula (I) can be prepared according to examples 1 and 6 of European patent application n.0 599890.

Example 5

Synthesis of N-heptylaminocarbonylgeneséroline

Geneseroline (73 g, 0.31 mol) was dissolved in ethyl acetate (1100 ml) at 37 ° C.

Potassium carbonate (11 g) was added to the clear solution and the suspension was stirred for 10 minutes. Then, heptylisocyanate (48 g) was dropped rapidly in 3-5 minutes. A slight development of heat was observed and the temperature rose to 47 ° C. The reaction mixture was stirred for 3 hours, then 1 g of tetrabutylammonium bromide was added; further addition of heptylisocyanate (4.3 g) reduced the geneseroline content to below 2%.

The reaction mixture was cooled, filtered through celite and the clear solution was evaporated under reduced pressure.

Toluene (400 ml) was added twice to the obtained brown oil and the solution was evaporated under reduced pressure. The residue was dissolved in 600 ml of hot hexane and the obtained solution was cooled to 15 ° C under stirring.

The precipitated N-heptylaminocarbonylgeneseroline was filtered, washed with hexane and dried at 50 ° C under vacuum to give 102.7 g of crude product. The crude was suspended in 820 ml of water at rt. for 30 minutes under vigorous stirring, then filtered, washed with hexane and dried at 60'C under reduced pressure to give 98.6 g (84.5%) of N-heptylaminocarbonylgeneseroline.

Example 6

Synthesis of N-eothylaminocarbonylceneseroline hydrochloride

N-heptylaminocarbonylgeneseroline (34.8 g, 0.083 moles) was dissolved in ethyl acetate (100 ml) at 40eC, then a solution of 22.5 ml of HC14.25 M in ethyl acetate was dropped, diluted to 40 ml with the same solvent.

The solution was slowly cooled to 5 ° C, the product precipitated as a white solid, which was filtered and dried at 60 ° C under reduced pressure to give 33.0 g of crude product.

The crude was suspended in 165 ml of toluene at 40 "C and heated for 30 minutes under stirring. The hot suspension was filtered, the solid washed with toluene and diethyl ether, then dried at 60" C under reduced pressure to obtain 31.7 g (84%) of N-heptylaminocarbonylgeneseroline hydrochloride.

m.p. (Holes) = 147-148 ° C

content (titration on anhydrous)> 99%

purity (HPLC)> 99%

The processes of the invention allow to obtain with good yields also compounds of formula (I) in which R is a phenyl or benzyl group, optionally substituted, starting from geneseroline and using a suitably substituted isocyanate as acylating agent.

Example 7

Synthesis of N - (_ 2-ethylphenyl) aminocarbonyleneseroline hydrochloride

To a solution of 2.34 g (10 mmol) of geneseroline in 30 ml of acetone, add 1.61 g (11 mmol) of 2-ethylphenylisocyanate, immerse the vessel in an ultrasonic bath and add 112 mg (1 mmole) of potassium-tert-butylate. After 3 minutes of ultrasonication, 11 mmoles of hydrochloric acid in ethyl acetate are added under magnetic stirring, germinating with a small amount of product and stirring is continued for 2 hours. The crystalline product thus obtained is filtered, washed with ethyl ether and dried s.v. at 40 “C.

3.4 g (81.3%) of white powder are obtained,

m.p. 179-181 'C

[a] D: -135 "(c = 1, H20)

Alternatively, N- (2-ethylphenyl) aminocarbonylgeneseroline hydrochloride can be obtained according to the method reported in the following example.

Example 8

Synthesis of N- (2-ethylphenyl) aminocarbonyleneseroline hydrochloride

75 g (0.3 moles) of geneseroline, dissolved in 750 ml of acetone, and 2 g of anhydrous potassium carbonate was added to the solution.

After 10 minutes of stirring at room temperature, 47.8 g (0.324 moles) of 2-ethylphenylisocyanate dissolved in 100 ml of acetone were added in about 60 minutes, maintaining the temperature at 20'C.

After 30 minutes of stirring it was filtered on celite, washing with a little acetone and the clear solution was concentrated up to about 500 ml. 73 ml of 4.75 M HCl in ethyl acetate were added to the solution by stirring, maintaining the temperature below 25 ° C.

At the end of the addition the temperature was brought to 5 ° C, and after 120 minutes the suspension obtained was filtered by washing with 100 ml of acetone.

The solid obtained was dried at 50 ° C under vacuum to constant weight obtaining 106.04 g of crude product which, crystallized from absolute ethanol, yielded after drying 86.94 g (70.2%) of N- (2-ethylphenyl) aminocarbonylgeneseroline hydrochloride as a white crystalline solid.

Claims (20)

CLAIMS 1. Process for the preparation of compounds of formula (I): where: R is linear or branched C2-C20 alkyl, C3-C7 cycloalkyl, phenyl, benzyl optionally substituted by C1-C4 alkyl groups, halogen, C ^ -C4 alkoxy, which includes: a) oxidation of hexerine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline without isolation of the geneserine intermediate; b) acylation of geneseroline with an isocyanate of formula R-N = C = 0, in which R is as defined above, in the presence of a basic catalyst selected from alcoholates, carbonates or alkaline hydroxides; c) possibly obtaining a pharmaceutically acceptable salt. 2. Process according to claim 1, in which the catalyst of step b) is selected from potassium t-butylate and potassium carbonate. 3. Process according to claim 1, in which, in step b), a phase transfer catalyst is added. 4. Process according to claim 3, wherein the phase transfer catalyst is tetrabutylammonium bromide. 5. Process according to claim 1, in which, in step b), an ultrasound source is used. 6. Process for the preparation of compounds of formula (I): where: R is linear or branched C2-C20 alkyl, C3-C7 cycloalkyl, phenyl, benzyl optionally substituted by halogen alkyl groups, C ^ -C ^ alkoxy, which comprises: a) oxidation with peracids or peroxides of a compound of formula (II) where: it is a protective group of phenolic hydroxyl stable in basic and energetic reducing conditions and removable in acidic conditions without reducing the N-geneserine-like group, in an alcoholic solvent or in an alcohol-water mixture to give a compound of formula (III) b) hydrolysis of the compound of formula (III) to geneseroline by means of a mineral or organic acid which does not reduce the N-oxide group; c) acylation of geneseroline with an isocyanate of formula R-N = C = 0, in which R is as defined above, in the presence of a basic catalyst selected from alkaline alcoholates, carbonates or hydroxides; d) possibly obtaining a pharmaceutically acceptable salt. 7. Process for the preparation of compounds of formula (I): where: R is linear or branched C2-C20 alkyl, C3-C7 cycloalkyl, phenyl, benzyl optionally substituted by halogen alkyl groups, C ^ -C ^ alkoxy, which comprises: a) hydrolysis by a mineral or organic acid of a compound of formula (II) where: Rj is a protective group of phenolic hydroxyl stable in basic and energetic reducing conditions and removable in acidic conditions, to give eserolina (Ila) b) acylation of eseroline (IIa) with an isocyanate of formula R-N = C = 0, in which R is as defined above, in the presence of a basic catalyst selected from alcoholates, carbonates or alkaline hydroxides; c) oxidation of the amino carbonyl derivative of eseroline thus obtained to the corresponding amino carbonyl derivative of geneseroline; d) possibly obtaining a pharmaceutically acceptable salt. 8. Process according to claim 6 or 7, in which the hydrolysis of the compound of formula (II) or (III) is carried out with an acid selected from the group consisting of: sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid and strong acid ion exchange resin. 9. Process according to claim 6 or 7, in which the hydrolysis is carried out with sulfuric acid at a concentration comprised between 10% and 85% by weight. 10. Process according to claim 6 or 7, in which the hydrolysis is carried out under heat with phosphoric acid at 85% by weight. 11. Process according to claim 6 or 7, in which the hydrolysis is carried out with methanesulfonic acid at 90 ° C. 12. Process according to claim 6 or 7, in which the hydrolysis is carried out under heat with trifluoroacetic acid, or 10% hydrochloric acid at 50 ° C. 13. Process according to claim 6 or 7, in which the hydrolysis is carried out with strong acid ion exchange resin. A process according to claim 6 or 7, in which in the acylation step, a phase transfer catalyst is added to the basic catalyst or an ultrasonic source is used. 15. Compounds of formula (II) where: 3⁄4 is a protective group of phenolic hydroxyl stable in basic and energetic reducing conditions and removable in acidic conditions as intermediates in the process of claim 6 or 7. 16. Compounds of formula (II) according to claim 15 wherein R ^ is isopropyl, t-butyl or methoxymethyl. 17. Compounds of formula (III) where: is a protecting group of the phenolic hydroxyl stable under basic and energetic reducing conditions and removable under acidic conditions as intermediates in the process of claim 6. 18. Compounds of formula (III) according to claim 16, wherein R ^ is alkyl, alkoxyalkyl or tetrahydropyranyl. 19. Use of an organic or mineral acid for the hydrolysis of alkyl ethers of an indole derivative. 20. Use according to claim 19, wherein said indole derivative is selected between eseroline and