EP1590331A1

EP1590331A1 - Method of preparing an acylimidazolium-type reagent

Info

Publication number: EP1590331A1
Application number: EP04701979A
Authority: EP
Inventors: Thierry Schlama; Franco Manfre
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 2003-01-15
Filing date: 2004-01-14
Publication date: 2005-11-02
Also published as: FR2849851A1; WO2004069807A1; FR2849851B1; US20060149051A1

Abstract

The invention relates to a method of preparing an acylimidazolium-type reagent. More specifically, the invention relates to a salt of N-(benzyloxycarbonyl)-N'-methylimidazolium. The inventive method of preparing an acylimidazolium-type reagent is characterised in that it is obtained by: (i) reacting a reagent comprising a -COX group having formula (II) and an imidazole reagent having formula (III); and (ii) subsequently, adding a strong acid HY to the product thus obtained, said acid having a pKa of less than 1, which produces the desired reagent.

Description

PROCESS FOR THE PREPARATION OF AN ACYLIMIDAZOLIUM REAGENT.

The present invention relates to a process for preparing a reagent of the acylimidazolium type.

The invention relates more particularly to an N- (benzyloxycarbonyl) -N'-methylimidazolium salt.

In a multi-step synthesis process developed in the field of organic synthesis, it is frequent to protect certain functional groups, and in particular amino groups.

Mention may in particular be made of the case where the exo amino group is protected from nucleic bases such as, for example, adenine. A reagent which is particularly used because it applies to weakly reactive amino groups consists of the Rapoport reagent which can be represented by the following formula:

in said formula, Y is an anion and represents, for example, a tetrafluoroborate or trifluoromethanesulfonate anion.

Bruce E. Watkins and Henry Rapoport have described (J. Org. Chem. 1982, 47, 4471-4477) a process for obtaining N- (benzyloxycarbonyl) -N'-ethylimidazolium tetrafluoroborate which comprises two steps. The first consists in reacting imidazole and benzyl chloroformate leading to an imidazolide which is separated by crystallization and then reacted with triethyloxonium tetrafluoroborate making it possible to obtain, after crystallization, N- (benzyloxycarbonyl) -N tetrafluoroborate '- ethylimidazolium which is then used as a reagent to protect an amino group. The drawbacks of the process described reside in the fact that it comprises two stages with separation of the intermediate product. Said method involves an alkylation step which uses triethyloxonium tetrafluoroborate which is an expensive reagent, commercially available in solution diluted in dichloromethane and which moreover has a high toxicity. The objective of the present invention is to provide a process which is more easily implemented on an industrial scale and which does not have the abovementioned drawbacks.

It has now been found, and this is what is the subject of the present invention, a process for the preparation of an acylimidazolium type reagent of formula (I):

in said formula: - Ri represent an alkyl or phenyl group,

- R represents an alkyl, alkenyl, cycloalkyl, aryl, arylalkyl group,

- Z represents a valential bond, an oxygen atom or an NR ₂ group; R ₂ having the same meaning as R,

- Y is an anion from an acid whose pKa is less than 1, characterized in that it is obtained by reacting:

- a reagent comprising a -COX group and corresponding to formula (II):

in said formula:

- R and Z have the meaning given above, - X represents a bromine or chlorine atom.

- and an imidazole reagent of formula (III):

(III) in said formula:

- Ri has the meaning given above, - then, by adding to the product obtained, a strong acid HY having a pKa of less than 1, which leads to the reagent of formula (I) which is recovered.

In the context of the invention, the term "alkyl" means a linear or branched hydrocarbon chain having from 1 to 12 carbon atoms and preferably from 1 to 4 carbon atoms.

Examples of preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl. By "alkenyl" is meant a hydrocarbon group, linear or branched having from 2 to 12 carbon atoms, comprising one or more double bonds, preferably 1 to 2 double bonds. The allyl group is a preferred example. By "cycloalkyl" is meant a cyclic, monocyclic hydrocarbon group comprising from 3 to 8 carbon atoms, preferably a cyclopentyl or cyclohexyl group.

By "aryl" is meant an aromatic mono- or polycyclic group, preferably mono- or bicyclic comprising from 6 to 12 carbon atoms, preferably phenyl or naphthyl.

The phenyl group is preferred.

By "arylalkyl" is meant a hydrocarbon group, linear or branched carrying a monocyclic aromatic ring and comprising from 7 to 12 carbon atoms, preferably benzyl.

The starting reagent of formula (II) comprises a group -CO-X.

It is found in a certain number of compounds capable of being used in the process of the invention.

A first class are those of the chloride or bromide type of carboxylic acids of formula (II) in which Z represents a valential bond.

The preferred compounds are those of formula (II) in which R represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl or ethyl group.

As preferred reagent, acetyl chloride is cited. A second family of compounds are the chloro- or bromoformate type compounds.

Preferably, those of formula (II) are chosen in which Z represents an oxygen atom and R preferably represents a linear or branched alkyl group having from 1 to 4 carbon atoms or a benzyl group.

The preferred compounds are the chloroformate or alkyl or benzyl bromoformate.

Another class of compounds are those of formula (II) in which Z represents an NR ₂ group. The envisaged compounds are of the carbamoyl chloride or bromide type. Preferably, those of formula (II) are chosen in which R and R ₂ are identical and preferably represent a linear or branched alkyl group having from 1 to 4 carbon atoms.

As preferred reagent, dimethylcarbamoyl chloride is mentioned.

As regards the imidazole reagent, it is a nitrogen heterocyclic compound which corresponds to formula (III) and which carries on the ring a group Ri which is a linear or branched alkyl group having from 1 to 12 carbon atoms or a phenyl group. It should be noted that these preferred meanings are indicated but not limiting. However, since this group is considered to be a leaving group when the reagent of formula (I) is used as a protecting group, in particular for protecting the amino groups, it is advantageous from an economic point of view to be a simple nature, and more particularly represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl group.

The compounds corresponding to formula (III) are known products. Some are commercially available and others can be easily prepared by those skilled in the art. Thus, those of formula (III) in which R 1 represents an alkyl group can be prepared by alkylation of the imidazole with a bromoalkane (Journal of Organic Chemistry 1999, 64 (3), p. 807-818). By coupling reaction between imidazole and a halobenzene compound in the presence of a catalyst based on copper, palladium or nickel (Journal of American Chemical Society 2001, 123 (31), p. 7727-7729), one obtains a compound of formula (III) in which R 1 represents a phenyl group.

A preferred reagent is N-methylimidazole.

The third reagent involved in the process of the invention is a strong acid HY whose characteristic is to have a pKa in water of less than 1.0.

PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent.

The anion Y ^″ must be non-nucleophilic. More precisely, it must not react in solution with the compound obtained, namely Pacylimidazolium. As more specific examples, we can mention: BF ₄ ^" , PF ₆ ^" ,

Preferably, trifluoromethanesulfonic acid is commonly known as “triflic acid”. A strong concentrated acid, preferably pure, is used to minimize the introduction of water.

In accordance with the process of the invention, the three reactants are reacted without carrying out isolation of the intermediate product.

In addition, reagents are used which are in liquid form and can therefore be transported by pumps. Consequently, they are more easily implemented industrially compared to a solid form. We start by reacting the reagent comprising a -COX group of formula (II) and the imidazole type reagent of formula (III).

The amount of reagents involved is such that the ratio between the number of moles of the reagent of formula (III) over the number of moles of reagent of formula (II) is advantageously chosen between 1 and 1, 2 and preferably around of 1. A preferred embodiment of the invention consists in carrying out the reaction in an organic solvent.

Several imperatives govern the choice of solvent. It must be inert under the conditions of the invention, in particular with respect to the strong acid. Preferably, an organic solvent, aprotic and not very polar, is used.

As examples of solvents suitable for the present invention, there may be mentioned in particular aliphatic, cycloaliphatic or aromatic hydrocarbons, halogenated or not. As examples of aliphatic hydrocarbons, ΌΠ may more particularly cite paraffins such as, in particular, hexane, cyclohexane, methylcyclohexane, petroleum ether type petroleum fractions; aromatic hydrocarbons such as in particular benzene, toluene, xylenes, cumene, petroleum fractions consisting of a mixture of alkylbenzenes, in particular cuts of the Solvesso® type.

As more specific examples of organic solvents, mention may be made of halogenated aliphatic hydrocarbons and more particularly, n-chlorobutane, dichloromethane, 1, 2-dichloroethane; halogenated aromatic hydrocarbons, and more particularly, mono- or dichlorobenzene. It is also possible to use a mixture of organic solvents.

The preferred solvents are: dichloromethane or toluene. The amount of organic solvent used is such that the concentration of the reagents of formula (II) and (III) in the solvent is between 5% and 30% by weight.

The reaction is carried out at a temperature which is advantageously between 0 ° C and 30 ° C, preferably at room temperature. By "ambient temperature", most often means a temperature between 15 ° C and 25 ° C.

Generally, the reaction is carried out at atmospheric pressure, but lower or higher pressures may also be suitable. According to a preferred variant of the process of the invention, the process of the invention is carried out under a controlled atmosphere of inert gases. An atmosphere of rare gases, preferably argon, can be established, but it is more economical to use nitrogen.

According to another preferred variant of the process of the invention, the reaction is carried out with stirring and protected from moisture.

From a practical point of view, the process can be carried out batchwise or continuously.

According to a preferred embodiment of the process of the invention, one begins by introducing the solvent then the reagent of formula (II). Then, the reagent of formula (III) is added, preferably in a gradual manner (continuously or in fractions).

A suspended product is formed which corresponds to formula (IV):

in said formula, R, Ri, X and Z have the meanings given for formulas (II) and (III).

This product is not isolated and is kept in suspension by stirring. The strong acid is preferably added triflic acid. The amount of acid added is such that the ratio between the number of H ⁺ ions and the number of moles of product of formula (IV), product obtained following the reaction of the reactants (II) and (III), varies between 0.9 and 1.5, preferably between 1 and 1.1.

According to a preferred mode, the acid is gradually added to the reaction medium.

A perfectly clear homogeneous solution is obtained comprising the reagent of formula (I). This reagent providing a protective group of RZ-CO- type capable of being used to block functional groups, preferably amino groups can therefore be used in the form of the solution previously obtained. It is also possible to use it in solid form obtained after elimination of the reaction solvent by evaporation.

Said reagent is advantageously used to protect the amino or substituted amino groups present in any type of molecule.

It is particularly suitable for protecting the functional groups present in primary and secondary amines. By way of illustration, there may be mentioned the primary and secondary amines which can be represented by the following formula:

(la) in said formula (la):

- R _a and R independently of one another represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups, - R _a and R _b can be linked so as to constitute with the carbon atoms which carry them a heterocyclic group having from 3 to 20 atoms, saturated, unsaturated, or aromatic, monocyclic or polycyclic

- At most one of the groups R _a and R _b represents a hydrogen atom. In the formula (la), the different symbols can take more particularly the meaning given below.

Thus, R _a and R can represent, independently of one another, an acyclic aliphatic group, saturated or unsaturated, linear or branched.

More specifically, R _a and Rb preferably represent an acyclic saturated linear or branched aliphatic group, preferably in Ci to Cι ₂ , and even more preferably in Ci to C ₄ .

The invention does not exclude the presence of an unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.

The hydrocarbon chain can optionally be interrupted by a heteroatom (for example, oxygen, sulfur, nitrogen or phosphorus) or by a functional group insofar as the latter does not react and a group such as in particular -CO- can be mentioned in particular.

The hydrocarbon chain may optionally carry one or more substituents (for example, halogen, carboxylic, ester, amino or alkyl and / or arylphosphine) insofar as they do not interfere.

The acyclic, saturated or unsaturated, linear or branched aliphatic group may optionally carry a cyclic substituent. By cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle.

The acyclic aliphatic group can be linked to the ring by a valential bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulfonyl etc.

As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents themselves being optionally carriers of any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. Mention may in particular be made of alkyl and C1 to C alkoxy groups.

Among the aliphatic groups carrying a cyclic substituent, more particularly is aimed at cycloalkylalkyl groups, for example, cyclohexylalkyl or arylkyl groups preferably C ₇ to C ₂ , in particular benzyl or phenylethyl.

In the general formula (la), the groups R _a and R _b can also represent, independently of one another, a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally C ₃ to C ₈ , preferably to 6 carbon atoms in the ring; said cycle can be substituted. As preferred examples of this type of group, mention may be made of cyclohexyl groups optionally substituted by linear or branched alkyl groups having from 1 to 4 carbon atoms. The groups R _a and Rb may represent, independently of one another, an aromatic, and in particular benzene, hydrocarbon group corresponding to the general formula

in which : - q represents an integer from 0 to 5,

- Q represents a group selected from a linear or branched alkyl, Ci -C ₆ alkoxy linear or branched Ci to C ₆ alkylthio group linear or branched Ci -C ₆₎ -NO ₂ , a -CN group, a halogen atom, a CF ₃ group.

R _a and Rb can also represent, independently of one another, a polycyclic aromatic hydrocarbon group with the cycles being able to form between them ortho-condensed, ortho- and pericondensed systems. Mention may more particularly be made of a naphthyl group; said cycle can be substituted. R _a and R _b can also represent, independently of one another, a polycyclic hydrocarbon group constituted by at least 2 saturated and / or unsaturated carbocycles or by at least 2 carbocycles of which only one of them is aromatic and forming between them ortho- or ortho- and pericondensed systems. Generally, the cycles are in C ₃ to C ₈ , preferably in C ₆ . As more specific examples, mention may be made of the bornyl group or the tetrahydronaphthalene group.

As more specific examples of amines corresponding to formula (la), there may be mentioned aniline, N-methylaniline, diphenylamine, benzylamine, dibenzylamine. R _a and Rb can also represent, independently of one another, a heterocyclic group, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen atoms (not substituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle can also be substituted. R _a and R can also represent a polycyclic heterocyclic group defined as being either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems , or either a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems; the carbon atoms of said rings possibly being substituted.

By way of examples of groups R _a and Rb of heterocyclic type, there may be mentioned, among others, the furyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl, phosphino and quinolyl, naphthyridinyl, benzopyrannyl groups. , benzofurannyl.

R _a and R can be linked so as to constitute, with the carbon atoms which carry them, a heterocyclic group having 3 to 20 atoms, saturated, unsaturated, or aromatic, monocyclic or polycyclic as defined above. It can include two or three ortho-condensed rings which means that at least two rings have two carbon atoms in common. In the case of polycyclic compounds, the number of atoms in each cycle preferably varies between 3 and 6. R _a and R preferentially form a pyrimidine or purine type cycle.

The number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art. It is possible that for example, an alkyl or alkoxy group of Ci to C _4, amino or oxy group (= O).

The reagent of the invention can be used to protect the amino groups present in amino acids. Examples of amino acids that may be mentioned include glycine, cysteine, aspartic acid, glutamic acid, histidine. The reagent of the invention is very particularly suitable for protecting weakly nucleophilic nitrogen atoms (deactivated). Thus, it is very advantageous to use it during the synthesis of the nucleic acid monomers to protect the amino groups which are present in natural bases such as those derived from pyrimidine (C ₄ N ₂ H ₄ ), thymine (C ₅ N ₂ O ₂ H ₆ ), cytosine

(C ₄ N3OH5) and those derived from purine (C5N4H4), adenine (C ₅ N ₅ H ₅ ), guanine

(C ₅ N ₅ OH ₅ ).

To this end, reference may be made to what is described in the state of the art, in particular in the Journal of Organic Chemistry 59, 19, (1994), p. 5767-5773. According to a practical embodiment, the compound comprising the amino or substituted amino group to be protected can be reacted with the reagent of the invention, in a suitable solvent.

The solvent is chosen so that it completely or partially dissolves the reagents and the product obtained. The molar ratio between the reagent and the compound comprising the group to be protected can vary widely, for example between 1 and 10, preferably between 1 and 3.

By way of examples of such solvents, mention may be made of nitriles such as acetonitrile, benzonitrile; amides such as dimethylformamide, dimethylacetamide; aliphatic or aromatic halogenated hydrocarbons, and mention may be made of partially chlorinated hydrocarbons such as dichloromethane, dichloroethane, aromatic halogenated hydrocarbons such as monochlorobenzene. The reaction temperature is advantageously between 0 and 100 ° C, preferably between 20 and 60 ° C.

It should be noted that a higher chosen temperature makes it possible to reduce the reaction time. The product obtained comprising the protected group is recovered in a conventional manner. It will be specified for example that in the case of the use of the dimethylformamide solvent, at the end of the reaction, water is added and the product formed precipitates so that it can be separated, for example by filtration.

If necessary, the group can be deprotected, for example by treatment with a strong acid.

By strong acid is meant in the present invention, an acid having a pKa in water of less than - 1.0.

PKa is defined as the ionic dissociation constant of the acid / base couple, when water is used as a solvent. As preferred examples of strong acids, mention may in particular be made of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methane sulfonic acid, trifluoromethanesulfonic acid.

Preferably a concentrated acid solution is used. Commercial solutions are used in particular, especially hydrochloric acid (37%), sulfuric acid (95 - 98%), trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid (100%).

The amount of acid expressed by the ratio of the number of proton equivalents to the number of moles of substrate to be deprotected can vary between approximately 2 and 10, preferably between approximately 2 and 5. The temperature of the deprotection reaction is advantageously situated between room temperature and 60 ° C.

It is optionally possible to carry out deprotection under hydrogen pressure, for example between 1 and 20 Bar, in the presence of a noble metal preferably deposited on a support. Mention may in particular be made of palladium deposited on carbon black, at a rate for example between 3 and 5% by weight.

The temperature of the deprotection reaction is within the same temperature range specified above.

Examples of the invention are given below. They are given by way of illustration and without limitation. Example 1

Preparation of N- (benzyloxycarbonyl) -N'-methylimidazolium triflate.

20 g of benzyl chloroformate in 265 g of dichloromethane are loaded into a 1 liter double-jacketed reactor equipped with central mechanical stirring and maintained under an inert nitrogen atmosphere.

9.5 g of N-methylimidazole are added at ambient temperature (20 ° C.), with stirring and under an inert atmosphere (nitrogen).

A white suspension is then formed in the solvent.

Then 17.5 g of triflic acid (100%) is added to this suspension. At the end of the addition, the suspension has disappeared to make way for a homogeneous and clear solution.

The solvent is evaporated under reduced pressure of 12 mm of mercury.

41.7 g of a white solid are obtained, which corresponds to a yield of 100%. It can be used as it is without further purification.

The characteristics of the reagent obtained are as follows:

- Melting point: 77-80 ° C.

- ¹ H NMR / CDCI ₃ (ppm): H _(a ro atic): 7.4-7.5; H _{CH 2): 5.53; H (i _m idazoie) 7.76, 7.50; 9.52; H ₍ mesia): 4.05.

Example 2

Protection of ethyl- (adenin-9-yl) acetate.

To a solution of 10 g of ethyl- (adenin-9-yl) acetate in 82 g of anhydrous dimethylformamide under an inert atmosphere and at room temperature (20 ° C), 41.5 g of the reagent are added all at once. prepared in Example 1.

The medium is left under stirring for 6 days.

Then 300 g of water are added to the reaction medium, causing a pale yellow solid to precipitate. This solid is recovered by filtration, washed with water and then dried under reduced pressure of 12 mm of mercury.

Thus, 12 g of ethyl- (N ⁶ - (benzyloxycarbonyl) adenine-9-yl) acetate are obtained with a purity determined by high performance liquid chromatography greater than 98% (melting point: 140-145 ° C).

Claims

1. Process for the preparation of an acylimidazolium type reagent of formula

in said formula:

- Ri represent an alkyl or phenyl group,

- R represents an alkyl, alkenyl, cycloalkyl, aryl, arylalkyl group,

- a reagent comprising a -COX group and corresponding to formula (II):

in said formula:

- R and Z have the meaning given above,

- X represents a bromine or chlorine atom. - and an imidazole reagent of formula (III):

in said formula:

2 - Process according to claim 1 characterized in that the reagent of formula (II) is of the chloride or bromide type of carboxylic acid, chloroformate or bromoformate, chloride or bromide of carbamoyl.

3 - Process according to claim 2 characterized in that the reagent corresponds to formula (II) in which Z represents a valence bond and R represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a group methyl or ethyl. 4 - Process according to claim 3 characterized in that the reagent is acetyl chloride.

5 - Process according to claim 2 characterized in that the reagent corresponds to formula (II) in which Z represents an oxygen atom and R represents a linear or branched alkyl group having from 1 to 4 carbon atoms or a group benzyl.

6 - Process according to claim 5 characterized in that the reagent is a chloroformate or an alkyl or benzyl bromoformate.

7 - Process according to claim 2 characterized in that the reagent corresponds to formula (II) in which Z represents a group NR ₂ and in which R and R ₂ are identical and represent a linear or branched alkyl group having from 1 to 4 carbon atoms.

8 - Process according to claim 7 characterized in that the reagent is dimethylcarbamoyl chloride.

9 - Process according to claim 1 characterized in that the imidazole reagent corresponds to formula (III) in which the group Ri represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl group.

10 - Process according to claim 9 characterized in that the preferred reagent is N-methylimidazole.

11 - Process according to claim 1 characterized in that the strong acid is an acid of formula HY in which Y represents the anions BF ₄ ^" , PF ₆ ^" ,

12 - Process according to claim 11 characterized in that the strong acid is trifluoromethanesulfonic acid.

13 - Method according to one of claims 1 to 12 characterized in that the amount of reactants involved is such that the ratio between the number of moles of the reagent of formula (III) out of the number of moles of reagent of formula (II) is chosen between 1 and 1, 2 and preferably around 1.

14 - Method according to one of claims 1 to 13 characterized in that the amount of acid added is such that the ratio between the number of H ⁺ ions and the number of moles of product obtained following the reaction of the reactants (II) and (III) varies between 0.9 and 1.5, preferably between 1 and 1.1.

15 - Method according to one of claims 1 to 14 characterized in that the reaction is carried out in an organic solvent, preferably an aliphatic, cycloaliphatic or aromatic hydrocarbon, halogenated or not.

16 - Process according to claim 15 characterized in that the solvent is dichloromethane or toluene.

17 - Method according to one of claims 1 to 16 characterized in that the reaction is carried out at a temperature which is between 0 ° C and 30 ° C, preferably at room temperature.

18 - Method according to one of claims 1 to 17 characterized in that the reaction is carried out at atmospheric pressure but under a controlled atmosphere of inert gases.

19 - Method according to one of claims 1 to 18 characterized in that the reaction is carried out with stirring and protected from moisture.

20 - Method according to one of claims 1 to 19 characterized in that one begins by introducing the solvent and then the reagent of formula (II), then adding the reagent of formula (III), preferably d 'in a progressive manner and then the strong acid, preferably in a progressive manner which leads to a homogeneous solution comprising the reagent of formula (I).

21 - Process according to claim 20 characterized in that the reagent of formula (I) is recovered in solid form after removal of the organic solvent.

22 - Use of the reagent of formula (I) obtained according to the process described in one of claims 1 to 21 as reagent providing a protective group of functional groups, preferably amino or substituted amino groups of primary or secondary amines.

23 - Use of the solution comprising the reagent of formula (I) obtained according to the process described in one of claims 1 to 20 as reagent providing a protective group of functional groups, preferably amino or substituted amino groups of primary amines or secondary.

24 - Use according to one of claims 22 and 23 characterized in that the functional groups are amino or substituted amino groups present in the nucleic bases.

25 - Use according to claim 24 characterized in that the nucleic bases are thymine, cytosine, adenine or guanine.