WO2006097594A1 - Method for preparing n-alkyl substituted aliphatic tertiary amides - Google Patents

Abstract

The invention concerns a novel method for preparing N-alkyl substituted aliphatic tertiary amides. More particularly the invention concerns preparation of a 2-isopropyl-2,3-dimethyl-N-alkylbutanamide. Preferably, it concerns preparation of 2-isopropyl-N-2,3-trimethylbutanamide. The inventive method for preparing N-alkyl substituted aliphatic tertiary amines is characterized in that it includes: (i) reacting a carboxamide of formula (II), wherein: R<SUB>1</SUB>, R<SUB>2</SUB> and R<SUB>3</SUB>, identical or different, represent a C<SUB>1</SUB>-C<SUB>4</SUB> alkyl group and the sum of the number of carbon atoms of R<SUB>1</SUB>, R<SUB>2</SUB> and R<SUB>3</SUB> is not less than 4; with an aldehyde of formula (III) R<SUB>5</SUB> - CHO, wherein: R<SUB>5</SUB> represents a hydrogen atom or a C<SUB>1</SUB>-C<SUB>3</SUB> alkyl group; (ii) followed by catalytic hydrogenolysis of the resulting compound leading to the production of an N-alkyl substituted aliphatic tertiary amide.

Description

 PROCESS FOR THE PREPARATION OF ALIPHATIC TERTIARY AMIDES

N-ALKYL SUBSTITUES.

The present invention relates to a new process for the preparation of N-alkyl substituted aliphatic tertiary amides.

The invention relates more particularly to the preparation of a 2-isopropyl-2,3-dimethyl-N-alkylbutanamide.

It relates preferentially to the preparation of 2-isopropyl-N-2,3-trimethylbutanamide.

Carboxamides in particular, 2-isopropyl-N-2,3-trimethylbutanamide are used in many fields of applications such as the food industry, cosmetics and in pharmaceutical formulations. 2-Isopropyl-N-2,3-trimethylbutanamide is used as a cooling agent for cooling agents. The cold effect is based on a chemical action on the nerve endings that are associated with the feeling of cold.

Thus, by virtue of said property, the market for 2-isopropyl-N-2,3-trimethylbutanamide is developing.

Because of its interest, different methods of preparation have been proposed.

Thus, GB 1 421 744 describes its preparation including the following succession of steps: reaction of n-propionitrile with isopropyl bromide in liquid ammonia, in the presence of sodium to obtain 2,3-dimethyl Isopropylbutyronitrile,

hydrolysis of the nitrile function in amide function by the action of an aqueous solution of sulfuric acid; diazotation of the primary amide using sodium nitrite, in the presence of an aqueous sulfuric acid solution leading to 2,3-dimethyl-2-isopropylbutyric acid,

- Obtaining the corresponding acid chloride by reaction of the previously obtained acid with thionyl chloride, - Finally, reaction of the acid chloride obtained with methylamine to access 2-isopropyl-N-2,3- trimethylbutanamide. It is clear that the process is complicated because of the multiplicity of steps. Moreover, the diazotization step is not desired from an industrial point of view.

Another method is described in WO 2004/031128. The process involves alkylating 2,3-dimethyl-2-isopropylbutyronitrile with an alkylating agent, for example methanol, trimethylborate, dimethylcarbonate, trimethylphosphate. The reaction is conducted in an alcohol in the presence of a polyphosphoric acid.

Said method is much simpler because it comprises only two steps. However, it has the disadvantage of generating a very large amount of phosphates as by-products, during the neutralization of the acidic medium. There is production of phosphate in an amount representing 5 times that of the product amide.

The Applicant proposes a completely different method for overcoming the aforementioned drawbacks and involving a completely different intermediate.

It has now been found, and this is the subject of the present invention, a process for the preparation of tertiary N-alkyl substituted aliphatic amides corresponding to formula (I):

Ri

R ₂ - C -CO - NH - R ₄

R ₃

(I) in said formula:

R 1, R ₂ , R ₃ and R ₄ , which may be identical or different, represent an alkyl group

Ci - C ₄ , - the sum of the number of carbon atoms of R ₁ , R ₂ and R ₃ is at least equal to 4, characterized in that it comprises: - (i) the reaction of a carboxamide responding to the following formula:

Ri

R ₂ - C -CO - NH ₂

R ₃

(H) in said formula, R 1, R ₂ , R ₃ , which are identical or different, represent a C 1 - C ₄ alkyl group and the sum of the number of carbon atoms of R 1, R ₂ and R ₃ is at least equal to 4, with an aldehyde corresponding to the following formula: R ₅ - CHO ( _| , _| ) in said formula, R ₅ represents a hydrogen atom or a Ci - C ₃ alkyl group.

- (ii) followed by a catalytic hydrogenolysis of the compound obtained, thus leading to the production of an N-alkyl substituted aliphatic tertiary amide.

In the context of the invention, the term "alkyl", a linear or branched hydrocarbon chain having 1 to 4 carbon atoms and preferably having 1, 2 or 3 carbon atoms. Thus, the alkyl groups concerned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl.

In the process of the invention, a carboxamide comprising a tertiary carbon atom is involved.

Thus, in formula (II), the sum of the number of carbon atoms of R 1, R ₂ and R ₃ is at least 4 and preferably between 5 and 9 and preferably equal to 6 or 7.

The process of the invention preferably involves compounds of formula (II) in which R 1 and R ₃ represent a methyl, ethyl or isopropyl group, R ₂ a methyl group. Advantageously, the process of the invention relates more particularly to the compounds of formula (II) in which R 1 is isopropyl and R ₃ is isopropyl or ethyl and R _{2 is} methyl.

Thus, according to a preferred embodiment of the process of the invention, the invention more particularly relates to a process for preparing a 2-isopropyl-2,3-dimethyl-N-alkylbutanamide corresponding to formula (I '):

dans ladite formule :

in said formula:

- R ₄ represents a C ₁ -C ₄ alkyl group, characterized in that it comprises: - (i) the reaction of 2-isopropyl-2,3-dimethylbutanamide corresponding to the following formula:

. with an aldehyde having the following formula: R ₄ - CHO (III) in said formula, R ₄ represents a hydrogen atom or a Ci - C ₃ alkyl group.

- (ii) followed by the catalytic hydrogenolysis of the compound obtained thus leading to the production of a 2-isopropyl-2,3-dimethyl-N-alkylbutanamide. Thus, in this preferred embodiment of the invention, the carboxamide used is 2-isopropyl-2,3-dimethylbutanamide.

According to the process of the invention, a first step is carried out in an aqueous medium by reacting the compound of formula (II), preferably of formula (M ') and an aldehyde of formula (III), optionally in the presence of based.

The preferred compounds of formula (III) are those which correspond to formula (III) in which Rs is a hydrogen atom or a methyl group and preferably a hydrogen atom.

As examples of aldehydes of formula (III), mention may be made of: formaldehyde or a formaldehyde generator such as, for example, trioxane or paraformaldehyde used in the form of linear polyformaldehydes of indifferent degree of polymerization, preferably having a number of units (CH ₂ O) of between 8 and 100 units or hexamethylenetetramine, acetaldehyde,

- propionaldehyde.

Of the above-mentioned aldehydes, formaldehyde is preferred.

The reagent is generally used in the form of an aqueous solution having a concentration of less than 50% by weight, preferably of between 20 and 50% by weight. It may contain a few percentages of an alcohol, usually methanol.

Preferred is formaldehyde in aqueous solution, commercial form (37% by weight). The amount of aldehyde of formula (III) expressed in moles of aldehyde per mole of carboxamide of formula (II) or (H ') is preferably at least equal to the stoichiometric amount.

The aldehyde / carboxamide molar ratio may vary between 1 and 1, 2, and is preferably around 1.

One can implement a base but its presence is not mandatory. However, it is advantageous to implement it because it increases the reactivity of the amine function of the compound of formula (II) or (H ').

As examples of bases, it is possible to use strong bases such as alkali metal and / or alkaline earth metal hydroxides, preferably sodium hydroxide of potassium, magnesium, calcium, barium or salts. alkali metals, in particular alkali metal carbonates, hydrogencarbonates, phosphates, hydrogenphosphates, sulphates, acetates and trifluoroacetates. Among the abovementioned inorganic bases, sodium or potassium hydroxide is preferably chosen.

It is also possible to use a tertiary amine. Examples of such amines include diisopropylethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, N, N-diethylcyclohexylamine, Ia pyridine, 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, Nn-butylpiperidine, N-methylpyrrolidine.

The base can be put in a solid form but it is preferred to use it in the form of an aqueous solution having a concentration for example ranging between 5 and 30% by weight.

The amount of base implemented can vary widely. It is such that the ratio between the number of moles of base and the number of moles of the compound of formula (II) or (H ') varies between 0.1 and 5, preferably around 0.3.

As mentioned previously, the reaction takes place in an aqueous medium. There may also be addition of an alcohol solvent.

Indeed, it is possible to add a solvent of alcohol type chosen, preferably of the same nature as the R ₄ group present in the compound of formula (I) or (I '). Thus, it is possible to use a C ₁ -C ₄ aliphatic alcohol and, more particularly, methanol, ethanol, propanol and isopropanol may be mentioned.

It is specified, as an indication, that the amount of water and / or solvent used, expressed as the ratio between the weight of water and / or solvent and the weight of the compound of formula (II) or (N '): said ratio being generally from 1 to 10, preferably from 1 to 5.

As regards more precisely the amount of solvent, it is in a weight ratio of 1 to 5, expressed relative to the weight of the compound of formula (II) or (II ¹ ).

Formaldehyde, when used, usually provides the water needed for the reaction.

According to one embodiment of the invention, the compound of formula (II) or (N ') is mixed with the aldehyde and then the base is added in solid form or in solution.

This first reaction is carried out at a temperature ranging between 15 ° C. and 40 ^° C., preferably between 20 ^° C. and 35 ° C.

The process of the invention is carried out under atmospheric pressure.

A preferred mode is to work under a controlled atmosphere of inert gases such as nitrogen or rare gases, for example argon.

Once the addition of the base is complete, the reaction medium is kept under stirring, for a period of time for example between 30 minutes and 1 hour 30 minutes.

The compound of formula (IV) which can be represented by the following formula is obtained in the reaction medium:

R ₂ - C -CO - NH - CH - OH

R ₃ (IV) in said formula,

- R ₁ , R ₂ , R ₃ , R ₅ have the meaning given above.

According to the preferred embodiment of the process of the invention, there is obtained from the compound of formula (II ¹ ), the compound of formula (IV) which can be represented by the following formula:

dans ladite formule,

in said formula,

- R ₅ has the meaning given above.

The compound of formula (IVa) is claimed as new products.

According to the process of the invention, the obtained compound of formula (IV), preferably of formula (IV) or (IVa) is subjected to a reduction operation, preferably a hydrogenolysis conducted in the presence of a strong acid.

According to a first variant of the process of the invention, it is possible to carry out the hydrogenolysis of the obtained compound of formula (IV), preferably of formula (IV) or (IVa), without separating it from the reaction mixture. According to another preferred variant of the process of the invention, the compound of formula (IV), preferably of formula (IV) or (IVa), is separated from the reaction medium before subjecting it to a hydrogenolysis operation.

For this purpose, at the end of the reaction, the water is first evaporated (for example under 100 mm of mercury at 40 ^° C.). A solid residue is obtained which is extracted with the aid of an organic solvent which solubilizes it.

Examples of solvents that may be mentioned are aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiobutyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane), dioxane, tetrahydrofuran.

It is also possible to use aliphatic or aromatic halogenated hydrocarbons, more particularly mention may be made of perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane; partially chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, trichlorethylene, 1-chlorobutane, 1,2-dichlorobutane; monochlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene or mixtures of different chlorobenzenes. Dichloromethane or chloroform is preferably chosen. The amount of solvent is generally at least equal to the volume of the reaction medium The organic solvent is evaporated under reduced pressure generally between 5 and 200 mm of mercury.

The product of formula (IV), preferably of formula (IV) or (IVa), is thus recovered in the form of a solid. According to the process of the invention, the compound obtained of formula (IV), preferably of formula (IV) or (IVa), which is separated or not from the reaction medium, is subjected to catalytic hydrogenation in the presence of a strong acid.

Preferred catalysts are metals of Group VIII of the Periodic Table, preferably palladium and / or platinum. Palladium is preferably chosen.

Said metal may be provided in finely divided form or deposited on a support. As examples of carriers, mention may be made of charcoal, activated charcoal, acetylene black, silica, alumina, zirconia, clays or equivalent materials. The metal may be deposited on the support in metallic form or in the form of a compound which will be reduced to metal in the presence of hydrogen. Among other things, it is possible to use an oxide.

Preferred metals are platinum and palladium, preferably deposited on carbon black. Preferably platinum and / or palladium is deposited on a support.

Generally, it is deposited in a proportion of 0.5% to 10% by weight of the catalyst, preferably 3%.

The amount of hydrogenation catalyst used, expressed as weight of catalyst per weight of compound of formula (IV), preferably (IV) or (IVa) may vary, for example, between 1 and 100%, preferably between 20 and 50%.

The hydrogenation reaction is conducted in the presence of a strong acid.

By strong acid is meant in the present invention, an acid having a pKa in water of less than -0.1 and preferably less than -1.0.

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

There may be mentioned more particularly perhalogenated carboxylic acids such as trichloroacetic acid or trifluoroacetic acid; halosulphonic acids such as fluorosulphonic acid, chlorosulphonic acid or trifluoromethanesulphonic acid, methanesulphonic acid, ethanesulphonic acid, ethanedisulphonic acid, benzenesulphonic acid, benzenedisulphonic acids, toluenesulphonic acids, naphthalenesulphonic acids and naphthalenedisulphonic acids. Among these acids, it is preferable to use trifluoromethanesulphonic acid, para-toluenesulphonic acid, chlorosulfonic acid, fluorosulphonic acid, methanesulphonic acid.

In particular, trifluoroacetic acid is chosen. The amount of acid used expressed relative to the compound of formula (IV), preferably (IV) or (IVa) is at least equal to the stoichiometric amount. The acid / compound molar ratio of formula (IV) or (IV) or (IVa) varies between 1 and 10, and is preferably between 1 and 3.

The process of the invention is carried out at a temperature selected from a temperature range of ambient temperature to 45 ^° C.

By "ambient temperature" is meant a temperature most often between 15 and 25 ° C.

It is preferably carried out at room temperature.

The reaction is carried out under atmospheric pressure. The amount of hydrogen introduced during the reaction is at least that required to convert all the compound of formula (IV) or (IV) or (IVa) into a compound of formula (I) or (I ¹ ).

In a preferred manner, the stream of hydrogen is bubbled in the reaction medium. The reaction is continued until the hydrogen consumption ceases.

The process according to the invention is conducted in the heterogeneous liquid phase.

For this purpose, an organic solvent is used.

An organic solvent which is less active than the starting substrate and which preferably solubilizes it is chosen.

It is possible to use an inert solvent under the reaction conditions of the invention. Thus, aliphatic, cycloaliphatic, aromatic, chlorinated hydrocarbons, preferably hexane, cyclohexane chloroform dichloromethane monochlorobenzene can be used; alcohols such as methanol, ethanol, propanol, cyclohexanol.

Preferred solvents are chlorinated aliphatic hydrocarbons and in particular chloroform.

The concentration of the compound of formula (IV) or (IV) or (IVa) used in the solvent may vary within very wide limits, until saturation under the operating conditions. Generally, it is not economically advantageous to use less than 5% by weight of compound of formula (IV) per volume of solvent. In general, the concentration by weight of compound of formula (IV), preferably of formula (IV) or (IVa), per volume of solvent is between 10% and 75%.

According to the process of the invention, the hydrogenation of the compound of formula (IV), preferably of formula (IV) or (IVa), is carried out under atmospheric pressure. A practical embodiment comprises charging the compound of formula (IV), preferably of formula (IV) or (IVa), the solvent, then the strong acid and the catalyst and then bubbling hydrogen directly into the reaction medium. It is possible to introduce the compound of formula (IV), preferably of formula (IV) or (IVa) already in solution in the organic solvent.

The reaction mixture is heated to the chosen hydrogenation temperature.

The duration of the reaction was continued until the hydrogen consumption ceased. The compound of formula (I) or (I ¹ ) is recovered in a conventional manner.

The catalyst can be separated according to conventional solid / liquid separation techniques and then the organic phase is washed for example with a 5% aqueous solution of sodium bicarbonate.

The organic phase can be dried, for example, over magnesium sulphate and the organic solvent is evaporated.

The compound of formula (I) or (I ') is obtained.

The present method is particularly suitable for continuous implementation.

An exemplary embodiment of the invention given for illustrative and non-limiting purposes is given below.

In the examples, the abbreviation "DIPPA" is used to designate 2-isopropyl-2,3-dimethylbutanamide and "DIPPAM", N- (hydroxymethyl) -2-isopropyl-2,3-dimethylbutanamide. The yield defined in the examples corresponds to the ratio between the number of moles of product formed and the number of moles of substrate involved. Examples

Synthesis of methylol DIPPAM:

In a well stirred 25 ml reactor, 0.5 g (3.17 mmol) of DIPPA amide is added to a solution of 0.049 g (0.87 mmol, 0.28 molar equivalents) of potassium hydroxide, 0.258 g ( 3.17 mmol, 1 molar equ) of formaldehyde at 37% by weight in water and 4.4 g of water, and heating for 1 hour at 37 ^° C.

The liquid is evaporated in a dry evaporator and a solid residue is recovered.

From this solid, the methylol is extracted with diethyl ether (3.5 g). 0.18 g of white solid is recovered which is the methylol DIPPAM represented by the following formula:

The purity obtained is 100%. The yield of isolated DIPPAM is 30%. NMR analysis is as follows:

¹ H NMR (DMSO-d 6, 300 MHz, TMS): δ 0.80 (CH ₃ , m, 12H), 0.91 (CH ₃ , s, 3H), 1.92 (CH, heptuplet, 2H) , 4.49 (CH ₂ , t, 2H), 5.34 (OH, t, 1H), 7.83 (NH, t, 1H).

Synthesis of 2-isopropyl-N-2,3-trimethylbutanamide from methylol DIPPAM:

A solution containing 90 mg (0.48 mmol) of methylol, 0.55 g (4.8 mmol, 10 equiv) of trifluoroacetic acid and 92 mg of Pd / C 3% in 7.5 mL of chloroform is hydrogenated at room temperature and under atmospheric pressure with a hydrogen flow rate of 5 mL / min for 1 hour. The catalyst is removed by filtration on celite and the organic phase is washed with 5% w / w aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate and evaporated to give the desired product.

The yield determined by ¹ H NMR in 2-isopropyl-N-2,3-trimethylbutanamide is 50%. The NMR analysis is as follows:

¹ H NMR (DMSO-d 6, 300 MHz, TMS): δ 0.76 (CH ₃ , m, 12H), 0.89 (CH ₃ , s, 3H), 1.90 (CH, heptuplet, 2H) , 2.54 (CH ₃ , d, 3H), 7.12 (NH, broad peak, 1H).

Claims

1 - Process for preparing N-alkyl substituted aliphatic tertiary amides corresponding to formula (I): R ₂ - C -CO - NH - R ₄ R ₃ (I) in said formula: R 1, R ₂ , R ₃ and R ₄ , which may be identical or different, represent a Ci-C ₄ alkyl group, the sum of the number of carbon atoms of R 1, R ₂ and R ₃ is at least equal to 4, characterized in that it comprises: - (i) the reaction of a carboxamide having the following formula: Ri R ₂ - C -CO - NH ₂ R ₃ (H) in said formula, R 1, R ₂ , R ₃ , which are identical or different, represent a C ₁ -C ₄ alkyl group and the sum of the number of carbon atoms of R 1, R ₂ and R ₃ is at least equal to 4, . with an aldehyde corresponding to the following formula: R ₅ - CHO _(m) in said formula, R ₅ represents a hydrogen atom or a Ci - C ₃ alkyl group. - (ii) followed by a catalytic hydrogenolysis of the compound obtained, thus leading to the production of an N-alkyl substituted aliphatic tertiary amide. 2 - Process according to claim 2, characterized in that the carboxamide corresponds to formula (II) in which the sum of the number of carbon atoms of R 1, R ₂ and R ₃ is between 5 and 9, preferably equal to at 6 or 7. 3 - Process according to one of claims 1 and 2, characterized in that the carboxamide meets the formula (II) wherein R 1 and R ₃ represent a methyl group, ethyl or isopropyl, R ₂ a methyl group. 4 - Process according to one of claims 1 to 3, characterized in that the carboxamide meets the formula (II) wherein R1 is isopropyl and R ₃ is isopropyl or ethyl and R _{2 is} methyl. 5 - Process according to one of claims 1 to 4 characterized in that it comprises: - (i) the reaction of 2-isopropyl-2,3-dimethylbutanamide corresponding to the following formula:

. with an aldehyde corresponding to the following formula: R ₄ - CHO (III) in said formula, R ₄ represents a hydrogen atom or a Ci - C ₃ alkyl group. - (ii) followed by the catalytic hydrogenolysis of the compound obtained thus leading to the production of a 2-isopropyl-2,3-dimethyl-N-alkylbutanamide. 6 - Process according to one of claims 1 to 5, characterized in that the aldehyde corresponds to the formula (III) wherein R ₅ is a hydrogen atom or a methyl group, preferably a hydrogen atom . 7 - Process according to claim 1 to 6, characterized in that the aldehyde of formula (III) is formaldehyde or a formaldehyde generator, preferably trioxane or paraformaldehyde used in the form of linear polyformaldehydes degree of polymerization indifferent, preferably having a number of units (CH ₂ O) of between 8 and 100 units or hexamethylenetetramine or acetaldehyde or propionaldehyde. 8 - Process according to claim 7, characterized in that the formaldehyde is in the form of aqueous solution. 9 - Process according to one of claims 1 to 8, characterized in that the amount of aldehyde of formula (III) expressed relative to the carboxamide is such that the molar ratio aldehyde / carboxamide varies between 1 and 1, 2, and is preferably around 1. 10 - Process according to claim 1, characterized in that it implements a base. 11 - Process according to claim 10, characterized in that the base is an alkali metal and / or alkaline earth hydroxide, preferably sodium hydroxide of potassium, magnesium, calcium, barium or at least one alkali metal salt, preferably alkali metal carbonates, hydrogencarbonates, phosphates, hydrogenphosphates, sulfates, acetates and trifluoroacetates. 12 - Process according to claim 11, characterized in that the base is sodium or potassium hydroxide. 13 - Process according to claim 10, characterized in that the base is a tertiary amine, preferably diisopropylethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, N, N-diethylcyclohexylamine, pyridine, 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, Nn-butylpiperidine, N-methylpyrrolidine. 14 - Method according to one of claims 10 to 13, characterized in that the amount of base used is such that the ratio between the number of moles of base and the number of moles of the compound of formula (II) or (N ') varies between 0.1 and 5, preferably around 0.3. 15 - Process according to one of claims 1 to 14, characterized in that one carries out the mixture of the compound of formula (II) or (H ') and aldehyde and then the base is added under solid form or in solution. 16 - Method according to one of claims 1 to 15, characterized in that the temperature of the reaction between the carboxamide and the aldehyde is between 15 ° C and 40 ⁰ C, preferably between 20 ⁰ C and 35 ° vs. 17 - Method according to one of claims 1 to 16, characterized in that the reaction is conducted under atmospheric pressure. 18 - Method according to one of claims 1 to 17, characterized in that the reaction is conducted in the presence of water and / or an alcohol type solvent having 1 to 4 carbon atoms, preferably methanol, ethanol, propanol or isopropanol. 19 - Method according to one of claims 1 to 18, characterized in that the compound obtained corresponds to the following formula: R ₂ - C -CO - NH - CH - OH R ₃ (IV) in said formula, R 1, R ₂ , R ₃ , R ₅ have the meaning given above given in one of claims 1 to 6. 20 - Process according to one of claims 1 to 19, characterized in that the compound obtained corresponds to the following formula:

in said formula, - R ₅ has the meaning given above given in one of claims 1 and 6. 21 - Method according to one of claims 1 to 20 characterized in that one carries out the hydrogenolysis of the compound (IV), preferably (IV) or (IVa) separated or not from the reaction medium. 22 - Process according to claim 21, characterized in that the compound obtained is extracted with the aid of an organic solvent. 23 - Process according to claim 22, characterized in that the organic solvent is an ether-type solvent or a halogenated hydrocarbon. 24 - Process according to one of claims 1 to 23, characterized in that one carries out the hydrogenolysis of the compound (IV), preferably of formula (IV) or (IVa) in the presence of a palladium catalyst and / or platinum, preferably in the presence of a palladium catalyst. 25 - Process according to claim 24, characterized in that said metal is provided in finely divided form or deposited on a support. 26 - Process according to claim 25, characterized in that the support is an inorganic or organic support selected from charcoal, activated charcoal, acetylene black, silica, alumina, zirconia, clays or clays. equivalent materials but preferably activated charcoal. 27 - Method according to one of claims 24 to 26, characterized in that the metal is deposited in a proportion of 0.5% to 10%, preferably 3% of the weight of the catalyst. 28 - Method according to one of claims 24 to 27, characterized in that the amount of hydrogenation catalyst used, expressed by the catalyst / substrate weight ratio varies between 1 and 100%, preferably between 20 and 50 %. 29 - Process according to one of claims 24 to 28, characterized in that the hydrogenation reaction is conducted in the presence of a strong acid. 30 - Process according to claim 29, characterized in that the strong acid is selected from perhalogenated carboxylic acids, preferably trichloroacetic acid or trifluoroacetic acid; halosulphonic acids, preferably fluorosulphonic acid, chlorosulphonic acid or trifluoromethanesulphonic acid, methanesulphonic acid, ethanesulphonic acid, ethanedisulphonic acid, benzenesulphonic acid, benzenedisulphonic acids, toluenesulphonic acids, naphthalenesulphonic acids and naphthalenedisulphonic acids. 31 - Process according to claim 30, characterized in that the strong acid is trifluoroacetic acid. 32 - Process according to one of claims 29 to 31, characterized in that the amount of acid used expressed relative to the compound of formula (IV), preferably of formula (IV) or (IVa) is such that the molar ratio acid / compound of formula (IV) or (IV) or (IVa) varies between 1 and 10, and is preferably between 1 and 3. 33 - Method according to one of claims 24 to 32, characterized in that the temperature at which the hydrogenation reaction is carried out is chosen between room temperature and 45 ° C, preferably at room temperature. 34 - Method according to one of claims 24 to 33, characterized in that the reaction is conducted under atmospheric pressure. 35 - Process according to one of claims 24 to 34, characterized in that the amount of hydrogen introduced during the reaction is at least that required to transform all the compound of formula (IV), preferably of formula ( IV) or (IVa) to a compound of formula (I) or (I '). 36 - Process according to one of claims 24 to 35, characterized in that the hydrogenation is conducted in the liquid phase, in the presence of an organic solvent 37 - Process according to claim 36, characterized in that the organic solvent is chosen from aliphatic hydrocarbons, cycloaliphatic, aromatic, chlorinated or not, preferably hexane, cyclohexane chloroform dichloromethane monochlorobenzene; alcohols such as methanol, ethanol, propanol, cyclohexanol. 38. Process according to claim 37, characterized in that the organic solvent is chloroform. 39 - Process according to one of claims 24 to 38, characterized in that the compound of formula (I) is recovered, preferably of formula (I '). 40 - Process according to claim 1 to 39, characterized in that the compound of formula (I ¹ ) is 2-isopropyl-N-2,3-trimethylbutanamide. - Compound corresponding to the following formula:

(IVa)