ITMI20071722A1 - PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC - Google Patents

Description

"PROCEDURE FOR THE PREPARATION OF (S) (+) - 3- (AMMINOMETHYL) -5-METHYLESANOIC ACID"

FIELD OF THE INVENTION

The present invention relates to a new process for the preparation of pregabaline, or (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid, of formula (I)

STATE OF THE TECHNIQUE

Pregabaline is known from US 6,197,819 and is used in the treatment of peripheral neuropathic pain, epilepsy and generalized anxiety disorders. US 5,637,767 describes its preparation by resolution of the 3-aminomethyl-5-methylhexanoic acid raceme for the formation of diastereomeric salts with homochiral acids or bases, separation of the pair of diastereoisomers by fractional crystallization or by chromatography, followed by hydrolysis of the salt. US 6,359,169 describes its preparation through an enantioselective reaction, using a chiral auxiliary, for example the Evans oxazolidone (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone, which allows to carry out an asymmetric alkylation to introduce the desired stereocenter. After the asymmetric alkylation, normally carried out at cryogenic temperatures, it is necessary to remove the relatively expensive chiral auxiliary, with a consequent further increase in costs and production times. US 2005/0283023 reports the preparation of pregabaline by means of an enzymatic kinetic resolution of a cyano-diester according to the following scheme

The above process is commercially viable, but has obvious disadvantages. In particular, the non-hydrolyzed enantiomer must be recycled in a chemical racemization step, in addition, the use of hydrogen under pressure is required for the reduction of nitrile and the use of Nickel Raney, which is toxic and difficult to use.

Organic Process Research & Development 1997; 1: 26-38, reports the synthesis of pregabaline, according to the scheme below, starting from a non-chiral diester by enzymatic hydrolysis with PLE (Porcine Liver Esterase) in water and DMSO at pH = 8, obtaining the chiral monoester with a yield of 98% and an enantiomeric purity of 85% (the prevailing enantiomer is that S). The monoester is then converted in the presence of lithium methoxide and formamide into the corresponding monoamide from which, by Hofmann rearrangement, pregabaline is obtained

The enzymatic resolution appears to be drastically conditioned by the concentration of the reagents, as it is selective only at low concentrations; this fact considerably limits its application on a large scale.

An alternative process for the preparation of pregabaline has been found here which overcomes the disadvantages of the previous methods. The new process makes use of an enantiomeric enrichment procedure which allows to obtain a product of high enantiomeric purity by precipitation and crystallization of diastereomeric salts. The new process also uses inexpensive reagents and does not require special equipment such as cryogenic reactors or high pressure hydrogenators.

DETAILED DESCRIPTION OF THE INVENTION

The subject of the invention is a process for the preparation of (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid of formula (I), or a salt thereof,

comprising:

a) the reaction of a compound of formula (II)

with an alcohol of formula ROH, where R is C1-C10alkyl or aryl-C1-C6alkyl; optionally in the presence of an organic base, and, if desired, in the presence of a solvent, to obtain an ester of 3-isobutyl glutaric acid of formula (III), or a salt thereof,

where R is as defined above;

b) the conversion of a compound of formula (III), or a salt thereof, by rearrangement via formation of nitrene / isocyanate, into a solvent of formula RrOH, where R1 is C1-C6alkyl, aryl or aryl-C1-C6alkyl, to obtain a compound of formula (IV), or a salt thereof,

where R and Ri are as defined above;

c) the hydrolysis of a compound of formula (IV), or a salt thereof, to obtain an acid of formula (V), or a salt thereof,

OH

HN N r OR,

o (V)

where Ri is defined as above;

d) the enantiomeric enrichment of a compound of formula (V) in its enantiomer (S);

e) the acid hydrolysis of the enatiomer (S) of a compound of formula (V) to form the acid (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid; and, if desired, its conversion into one of its salt.

A salt of a compound of formula (I), (III), (IV) or (V) is for example a pharmaceutically acceptable salt, preferably an addition salt with an acid, for example hydrochloride, sulfate, acetate, alkylsulfonate; or a salt with a base salt, for example a salt of lithium, sodium, potassium, magnesium or aluminum.

A C1-C10alkyl group, which can be linear or branched, is for example a C1-C8alkyl group, preferably a

the C1-C6alkyl group or a C1-C6alkyl residue, which can be linear or branched, is preferably a C1-C4alkyl group or residue, more preferably methyl, ethyl, propyl, butyl or isobutyl, in particular methyl or ethyl.

An aryl-C1C6alkyl group is for example phenyl-C1C6alkyl or naphthyl-C1-C6alkyl; in particular phenyl-C1-C4alkyl. Said group can be substituted by 1 to 5 substituents independently selected from halogen, nitro, cyano and C1-C6dyalkyl-amino, for example dimethyl-, diethyl-, or diisopropylamino.

An aryl group is for example phenyl or naphthyl, in particular phenyl. Said group can be substituted substituted by 1 to 5 substituents independently selected from C1-C6dyalkyl-amino, nitro, cyano and halogen.

A halogen is for example chlorine, fluorine, bromine or iodine; in particular chlorine or bromine.

An alcohol of formula ROH is for example a primary alcohol, where R is preferably C1-C8alkyl or phenyl C1-C4alkyl, in particular methanol, ethanol, propanol, isopropanol, isobutanol, octanol, benzyl alcohol; more preferably methanol.

The reaction between a compound of formula (II) and an alcohol of formula ROH can be carried out at a temperature comprised between approximately 15 ° C and the reflux temperature of the reaction mixture, preferably between about 20 and about 50 ° C. Reaction times can vary from about 1 to 24 hours.

The reaction can optionally be carried out in the presence of an organic base, for example a C1-C4tryalkylamine, typically methyl-diethylamine, triethylamine, tributylamine or ethyl-diisopropylamine, in particular triethylamine.

The reaction can optionally be carried out in a solvent, selected for example from an aprotic dipolar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide; a ketone, typically acetone or methyl isobutyl ketone; an ether, typically tetrahydro furan, methyl-tert-butylether or dioxane; a chlorinated solvent, typically dichloromethane trichloroethane and tetrachlorethylene or chloroform; a tertiary alcohol such as, for example, terbutyl alcohol, teramyl alcohol; or a non-polar solvent, typically toluene or hexane; or a mixture of two to four, preferably two or three, of said solvents with each other.

When the reaction is carried out in the presence of a solvent, the quantity of alcohol of formula ROH used can be approximately equal to or greater than 1 mole per mole of substrate of formula (II); preferably it is comprised between about 1.1 and 2.1.

Preferably the reaction is carried out using only the same alcohol of formula ROH as solvent.

The following compounds of formula (III):

Propyl 3-isobutyl-glutarate,

Isobutyl 3-isobutyl-glutarate,

Octyl 3-isobutyl glutarate;

and their salts are new and are an object of the invention.

The rearrangement of a compound of formula (III), or a salt thereof, to obtain respectively a compound of formula (IV) or a salt thereof, via the formation of nitrene / isocyanate, can be carried out for example according to the Schmidt reactions, Lossen, Hofmann or Curtius.

A solvent of formula R1-OH is preferably a C1-C4alkanol, for example methanol, ethanol or i-propanol; more preferably methanol or i-propanol.

The compounds of formula (IV) and their salts are new and are an object of the invention.

Specific examples of compounds of formula (IV) are:

{4-methyl-2- [(1 -methoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2 - [(1-propoxycarbonyl) -methyl -] - pentyl} -methyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-isobutyloxycarbonyl) -methyl-] -pentii} -methyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -methyl carbamate, { 4-methyl-2- [(1-methoxycarbonyl) -methyl -] - pentyl} -ethylcarbamate, {4-methyl-2- [(1 -ethoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4 -methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl -2- [(1-isobutyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2 - [(1-methoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [ (1-ethoxycarbonyl) -methyl] -pentii} -isopropyl carbamate, {4-methyl-2 - [(1-propoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1 -butoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [(1-isobutyloxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, and

{4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -carbamate of isopropyl. The Schmidt reaction can be carried out according to known methods, for example by treating a compound of formula (III) with hydrazoic acid in the presence of sulfuric acid. Alternatively, the rearrangement can take place according to the Lossen reaction, by reacting a compound of formula (III) with a halogenating agent, preferably thionyl chloride or oxalyl chloride. Subsequently, by reaction with an acyl-hydroxylamine, preferably acetyl-hydroxylamine, the corresponding acylated hydroxamic acid is obtained. The treatment of the latter with an alkaline hydroxide leads to the formation of isocyanate, which spontaneously converts into a compound of formula (IV).

In accordance with the Hofmann reaction, the carboxylic acid of formula (III) is transformed into the corresponding amide according to known methods, and then treating the latter with an alkaline hypohalite, preferably sodium hypochlorite, isocyanate is obtained, which spontaneously converts into a compound of formula (IV).

Finally, according to the Curtius reaction, a compound of formula (III) can be reacted with a halogenating agent, preferably thionyl chloride or oxalyl chloride, and subsequently by treatment with sodium azide or directly with diphenylphosphorylazide, in the presence of a base organic, in particular triethylamine, diisopropylethylamine or pyridine, to form the corresponding acyl-azide. The acyl-azide by heating is converted into the corresponding isocyanate, which spontaneously converts into a compound of formula (IV).

The rearrangement reactions reported above can be carried out according to known methods, for example at a temperature between about 10 and 100 ° C, preferably between 50 and 90 ° C, for a time between 2 and 15 h, preferably between 5 and 10 h.

The hydrolysis of a compound of formula (IV), or a salt thereof, is preferably a basic hydrolysis and can be carried out according to known methods, for example by reaction in water in the presence of an alkaline or alkaline-earth base, typically sodium or potassium hydroxide.

The enantiomeric enrichment of a compound of formula (V), or a salt thereof, in its enantiomer (S) can be obtained through the formation of its diastereomeric salt with a chiral base, followed by the separation of the pair of diastereomers, and subsequent hydrolysis of the diastereomeric salt of the (S) enantiomer of the compound of formula (V).

A chiral base can be a chiral amine, for example chosen from those reported in “S.H. Wilen - Tables of Resolving Agents and Optical Resolutions Un. of Notre Dame Press ”, for example S - (-) - phenylethylamine, S - (-) - naphthylethylamine, brucine and quinine, preferably S - (-) - phenylethylamine.

The reaction of a compound of formula (V) with a chiral base to obtain a diastereomeric salt thereof can be carried out in a solvent, for example in water; in a chlorinated solvent such as chloroform, dichloroethane, trichloroethane and tetrachlorethylene; in a non-polar solvent such as benzene, chlorobenzene, toluene and cyclohexane; in an ester, such as ethyl acetate or methyl acetate; in an aprotic dipolar solvent, for example acetonitrile, dimethylacetamide, dimethyl sulfoxide, dimethyl formamide and N-methylpyrrolidone; a ketone, for example acetone, ethyl ketone and methyl isobutyl ketone; an ether, for example dioxane, tetrahydrofuran, methyl-tert-butylether; in an alcohol such as methanol, ethanol or i-propanol; or in a mixture of two to four, preferably two or three, of said solvents; in particular mixtures of water and alcohol or water and acetone; preferably in water or water and alcohol mixtures.

The separation of the pair of diastereomers can be obtained, for example, by fractional crystallization from the reaction solvent itself or by chromatography.

The optical purity of the mixture of diastereomeric salts thus obtained is typically around 98%; preferably around 99%. This purity can optionally be increased up to about 99.5% or more, by known techniques. For example, the diastereoisomeric salt can be dissolved again in the same previous solvent, and then recrystallized, thus obtaining a further enantiomeric enrichment thereof.

The compounds of formula (V), in particular as enantiomer (S), and their salts, in particular with a chiral base, preferably with S - (-) - phenylethylamine, are new and are a further object of the invention.

Specific examples of compounds of formula (V) in particular as enantiomer (S), and their salts, in particular with a chiral base, preferably with S - (-) - phenylethylamine, are:

Methyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate,

Ethyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, and

{4-methyl-2- [(1 -carboxy) -methyl] -pentii} -carbamate of isopropyl.

The hydrolysis of the diastereomeric salt of the enantiomer (S) of a compound of formula (V) to obtain the enantiomer (S) of the compound of formula (V), can be carried out by treatment with an amount approximately equal to or greater than 1 mole per mole of substrate, preferably comprised between about 1.1 and 2.1, of a mineral acid, for example hydrochloric or sulfuric acid, as known.

The hydrolysis of the enantiomer (S) of a compound of formula (V) to obtain a compound of formula (I), i.e. the (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid is typically a acid hydrolysis, and can be carried out for example by treatment with a mineral acid, typically with hydrochloric acid as known.

If desired, the (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid can be converted into one of its salt, for example a pharmaceutically acceptable salt, according to known methods. Similarly, a compound of formula (III), (IV) or (V) can be converted into a salt thereof, or vice versa, according to known methods.

The (5X +) - 3- (aminomethyl) -5-methylhexanoic acid, or one of its salt, thus obtained, has an enantiomeric purity of around 98%; preferably around 99%, more preferably around 99.8% or more, which satisfies the regulatory requirements for drugs well.

The enantiomeric purity is defined as S / (S + R) x100, where S and R are the quantities of the enantiomers (S) and (R) respectively. According to the invention, the term single enantiomer (S) or (R) means that the enantiomeric purity is at least equal to about 96% or greater, preferably at least equal to about 99%.

The compound of formula (II) is known and can be prepared for example as described in WO 96/38405.

The following examples illustrate the invention.

Example 1 - SYNTHESIS OF METHYL (III) 3-ISOBUTYL-GLUTARATE

3-isobutylglutaric anhydride (50.0 g; 0.290 mol), methanol (500 ml) and triethylamine (29.3 g; 0.290 mol) are added to a 1 1 three-necked flask under a nitrogen atmosphere; the solution thus obtained is kept under stirring at room temperature for about 16-18 h. At the end of the reaction the solvent is evaporated, the mixture is taken up with water (200 ml), acidified to pH 3-4 with hydrochloric acid 37% and extracted with toluene (3 x 150 ml). The combined organic phases are evaporated under reduced pressure, a light yellow oil is obtained (58.6 g; yield: 95%).

1H-NMR (300 MHz, CDC13, 28 ° C): δ 3.65 (s, 3H); 2.40 (m, 5H); 1.60 (m, 1H); 1.20 (m, 2H); 0.90 (d, 6H).

Proceeding in the same way we obtain:

Propyl 3-isobutyl-glutarate,

Isobutyl 3-isobutyl-glutarate, e

Octyl 3-isobutyl-glutarate.

Example 2 - SYNTHESIS OF {4-METHYL-2 - [(1-METHOXYCARBONIL) -METHYL -] - PENTYL -} - ISOPROPYL (IV) CARBAMATE

Methyl 3-isobutylglutarate (60.0 g; 0.297 mol) and a solution of triethylamine (33.0 g; 0.327 mol) in iso-propanol (500 ml) are added to a 50 ml three-necked flask under nitrogen atmosphere. ). The solution is heated to reflux temperature and diphenylphosphorylazide (85.9 g; 0.312 mol) is added in about 2 h; at the end of the addition it is left to boil for about 1 h. It is cooled to room temperature and the reaction mixture is poured into a 5% w / w sodium hydroxide solution (500 ml), extracted with toluene (3 x 500 ml), and the combined organic phases are washed with water (250 ml). The organic phase is concentrated under reduced pressure to obtain 62.0 g of a light yellow oil; yield 80%.

1H-NMR (300 MHz, CDC13, 28 ° C): δ 5.00-4.75 (m, 2H of which one exchangeable with D2O); 3.60 (s, 3H); 3.20 (m, 1H); 3.00 (m, 1H); 2.20 (d, 2H); 2.05 (m, 1H); 1.60 (m, 1H); 1.20-1.00 (m, 8H); 0.80 (dd, 6H).

Example 3 - SYNTHESIS OF {4-METHYL-2 - [(1-METHOXYCARBONIL) -METHYL -] - PENTYL -} - METHYL (IV) CARBAMATE

Methyl 3-isobutylglutarate (3.4 g; 17 mmol) and a solution of triethylamine (1.9 g; 19 mmol) in methanol (25 ml) are added to a 50 ml three-necked flask under nitrogen atmosphere. The solution is heated to reflux temperature and diphenylphosphorylazide (2.2 g; 18 mmol) is added in about 2-3 h; at the end of the addition it is left to boil for about 1 h. It is cooled to room temperature and the reaction mixture is poured into a 10% w / w sodium hydroxide solution (30 ml), extracted with toluene (3 x 25 ml) and the combined organic phases are washed with water ( 2 x 25 mi). The washed organic phase is concentrated under reduced pressure, obtaining 3.5 g of a light yellow oil; yield 80%.

1H-NMR (300 MHz, CDC13, 28 ° C): δ 3.6 (s, 6H); 3.2 (m, 1H); 3.0 (m, 1H); 2.3 (m, 2H); 2.1 (m, 1H); 1.6 (m, 1H); 1.2 (m, 2H); 0.9 (m, 6H). GC-MS (M +): 231

Example 4 - SYNTHESIS OF {4-METHYL-2 - [(1-CARBOSS) -METHYL -] - PENTYL -} - ISOPROPYL CARBAMATE (V)

{4-methyl-2- [(1-methoxycarbonyl -) - methyl-] -pentii-} -carbamate of isopropyl (62.0 g; 0.237 mmol) is added to a 50 ml three-necked flask under nitrogen atmosphere. to a solution of sodium hydroxide (16.0 g; 0.400 mol) in water (300 ml) and kept under stirring at room temperature for 18 h. A 37% w / w hydrochloric acid solution is added up to an acid pH (60 ml); the aqueous phase is extracted with toluene (3 x 300 ml). The organic phase is concentrated to a small volume, a light yellow oil is obtained (56.9 g; yield: 97%).

1H-NMR (300 MHz, CDC13, 28 ° C): δ 7.00 (broad, 1H exchangeable with D2O); 4.70 (m, 1H); 3.00 (m, 1H); 2.80 (m, 1H); 2.10 (m, 2H); 1.95 (m, 1H); 1.60 (m, 1H); 1.20-1.00 (m, 8H); 0.80 (d, 6H).

Proceeding in the same way we obtain:

{4-methyl-2- [(1-methoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4 -methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl -] - pentyl} -methylcarbamate, {4- methyl-2 - [(1-isobutyloxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2 - [(1-octyloxycarbonyl) -methyl] -pentyl} -methylcarbamate, {4-methyl- 2- [(1-methoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4-methyl-2- [(1 -butoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4-methyl-2- [( 1-isobutyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1 - ethoxycarbonyl) -methyl] -pentii} -isopropyl carbamate, {4-methyl-2 - [(1-propo ssicarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2 - [(1-isobutyloxycarbonyl) -methyl] -pentyl} -carbamate of isopropyl, e

{4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -carbamate of isopropyl.

Example 5 - OPTICAL RESOLUTION OF (S) - {4-METHYL-2 - [(1-CARBOSS) -METHYL -] - PENTYL -} - ISOPROPYL CARBAMATE (V) In a 100 ml three-necked flask under the atmosphere of nitrogen are added {4-methyl-2 - [(1-carboxy -) - methyl -] - pentyl -} - isopropyl carbamate (13.0 g, 53.0 mmol), triethylamine (2.70 g; 26, 5 mmol) and (S) - (-) - Phenylethylamine (3.2 g, 26.5 mmol) in a 95: 5 water / isopropanol mixture (50 ml). The solution is heated to a temperature of about 60-65 ° C and slowly cooled to about 35 ° C, then it is heated to 50 ° C and allowed to cool spontaneously to room temperature. It is cooled to 0-5 ° C for at least 1 h and the solid is filtered by washing with cold water (2 x 10 ml), then with toluene (3 x 10 ml). The product is dried in an oven at 50 ° C under vacuum for 18 hours, giving 8.9 g of product having an enantiomeric ratio 98 (S): 2 (R) and a yield of 92%.

Proceeding in the same way we obtain:

Methyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, and

{4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate of ethyl.

Example 6 - SYNTHESIS OF THE ACID (S) - (+) - 3-AMINOMETHYL-5-METHYLESANOIC (I)

(S) - {4-methyl-2 - [(1-carboxy -) - methyl -] - pentyl -} - carbamate of isopropyl salt of (S) are added to a 50 ml three-necked flask under nitrogen atmosphere - (-) - phenylethylamine (60.0 g, 164 mmol) having an enantiomeric ratio 98 (S): 2 (R) and a 37% w / w hydrochloric acid solution (17.8 g, 180.4 mmol ) in water (200 ml), and extracted with toluene (2 x 200 ml). The organic phase is concentrated to a small volume, taken up with hydrochloric acid 30% w / w (59.6 g, 490 mmol) and the mixture is heated at 90-95 ° C for 24 h. The solution is cooled to 0-5 ° C, sodium hydroxide (18.0 g, 450 mmol) is added and it is kept under cold stirring for at least 1 h. The solid is filtered by washing with an 8: 2 water / isopropanol solution cooled to 0-5 ° C (2 x 15 ml) and dried in an oven. A white solid is obtained, 21.1 g, with an enantiomeric ratio 99.96 (S): 0.04 (R); yield 82%.

1H-NMR (300 MHz, CDC13, 28 ° C): δ 2.95 (m, 2H); 2.30-2.05 (m, 3H); 1.60 (m, 1H); 1.2 (m, 2H); 0.80 (dd, 6H).

Claims (21)

CLAIMS 1. Process for the preparation of the (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid of formula (I), or one of its salt, comprising: a) the reaction of a compound of formula (II) with an alcohol of formula ROH, where R is C1-C10alkyl or aryl-C1-C6alkyl; optionally in the presence of an organic base, and, if desired, in the presence of a solvent, to obtain an ester of 3-isobutyl glutaric acid of formula (III), or a salt thereof, where R is as defined above; b) the conversion of a compound of formula (III), or a salt thereof, by rearrangement via formation of nitrene / isocyanate, into a solvent of formula RrOH, where R1 is C1-C6alkyl, aryl or aryl-C1-C6alkyl, to obtain a compound of formula (IV), or a salt thereof, where R and R1 are as defined above; c) the hydrolysis of a compound of formula (IV), or a salt thereof, to obtain an acid of formula (V), or a salt thereof, where R1 is as defined above; d) the enantiomeric enrichment of a compound of formula (V) in its enatiomer (S); e) the acid hydrolysis of the enatiomer (S) of a compound of formula (V) to form the acid (S) (+) - 3- (aminomethyl) -5-methylhexanoic acid; and, if desired, its conversion into one of its salt. 2. Process according to claim 1, where in the alcohol of formula ROH R is C1C8 alkyl or phenyl C1C4alkyl. 3. Process according to claim 1, where the organic base is a C1-C4trialkylamine. 4. Process according to claim 1, where in step a) the solvent is selected from an aprotic dipolar solvent, a ketone, an ether, a chlorinated solvent, a tertiary alcohol or an apolar solvent; or a mixture of two to four of said solvents with each other. 5. Process according to claim 1, where, when a solvent is used in the reaction in step a), the quantity of alcohol of formula ROH used is approximately equal to or greater than 1 mole per mole of substrate of formula (II) . 6. Process according to claim 1, where the reaction in step a) is carried out using the same alcohol of formula ROH as solvent. 7. Process according to claim 1, where the rearrangement via formation of nitrene / isocyanate is carried out according to the reactions of Schmidt, Lossen, Hofmann or Curtius. 8. Process according to claim 1, wherein the solvent of formula R1-OH is a C1-C4alkanol. 9. Process according to claim 1, where the enantiomeric enrichment of a compound of formula (V), or a salt thereof, in its enantiomer (S) is obtained through the formation of a diastereomeric salt thereof with a chiral base, followed from the separation of the pair of diastereomers, and subsequent hydrolysis of the diastereomeric salt of the (S) enantiomer of the compound of formula (V). 10. Process according to claim 9, where the chiral base is a chiral amine. 11. Process according to claim 10, wherein the chiral amine is selected from S - (-) - phenylethylamine, S - (-) - naphthylethylamine, brucine and quinine. 12. Process according to claim 9, where the reaction of formation of a diastereomeric salt of a compound of formula (V) with a chiral base is carried out in water, a chlorinated solvent, an apolar solvent, an ester, an aprotic dipolar solvent , a ketone, an ether, an alcohol, or in a mixture of two to four of said solvents. 13. Process according to claim 12, where the solvent is water; a mixture of water and alcohol; or a mixture of water and acetone. 14. Process according to claim 9, where the separation of the pair of diastereomers is obtained by fractional crystallization from the reaction solvent itself or by chromatography. 15. A compound, chosen from: Propyl 3-isobutyl-glutarate, Isobutyl 3-isobutyl-glutarate, e Octyl 3-isobutyl glutarate; or one of its salt. 16. A compound of formula (IV), or a salt thereof, where R is C1-C10alkyl or aryl-C1C6 alkyl; and R 1 is C1-C6alkyl, aryl or aryl-C1-C6 alkyl. 17. A compound according to claim 16, chosen from: {4-methyl-2- [(1-methoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4 -methyl-2- [(1-propoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2- [(1 -butoxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl -2 - [(1-isobutyloxycarbonyl) -methyl] -pentii} -methyl carbamate, {4-methyl-2 - [(1-octyloxycarbonyl) -methyl] -pentyl} -methylcarbamate, {4-methyl-2 - [(1 -methoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-ethoxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [ (1-propoxycarbonyl) -methyl] -pentii} -ethylcarbamate, {4-methyl-2 - [(1-butoxycarbonyl) -methyl] -pentyl} -ethylcarbamate, {4-methyl-2- [(1 -isobutyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1-octyloxycarbonyl) -methyl] -pentii} -ethyl carbamate, {4-methyl-2- [(1 -methoxycarbonyl ) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [(1 -et oxycarbonyl) -methyl -] - pentyl} -isopropyl carbamate, {4-methyl-2 - [(1-propoxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, {4-methyl-2- [(1 -butoxycarbonyl ) -methyl] -pentii} -isopropyl carbamate, {4-methyl-2- [(1-isobutyloxycarbonyl) -methyl] -pentyl} -isopropyl carbamate, and {4-methyl-2 - [(1-octyloxycarbonyl) -methyl] -pentyl} -carbamate of isopropyl; or one of its salt. 18. A compound of formula (V), or a salt thereof, where R1 is C1-C6alkyl, aryl or aryl-C1-C6 alkyl. 19. A compound according to claim 18, selected from Methyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, Ethyl {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate, and {4-methyl-2 - [(1-carboxy) -methyl] -pentyl} -carbamate of isopropyl; or one of its salt. 20. Enantiomer (S) of a compound of formula (V), or a salt thereof, as defined in claim 18 or 19. 21. The S - (-) - phenylethylamine salt of a compound of formula (V), as defined in claim 18, 19 or 20.