EP3429999A1 - Method for preparing alkylamines - Google Patents

Abstract

The present invention relates to a method for preparing alkylamines using carbon monoxide, and to the use of said method in the production of vitamins, pharmaceutical products, adhesives, acrylic fibres, synthetic leathers, pesticides, surfactants, detergents and fertilisers. The invention also relates to a method for producing vitamins, pharmaceutical products, adhesives, acrylic fibres, synthetic leathers, pesticides, surfactants, detergents and fertilisers, which includes a step of preparing alkylamines using the method according to the invention. The present invention further relates to a method for preparing labelled alkylamines and to their uses.

Description

 PROCESS FOR THE PREPARATION OF ALKYL AMINES

The present invention relates to a process for the preparation of alkylamines using carbon monoxide and the use of this process in the manufacture of vitamins, pharmaceuticals, glues, acrylic fibers and synthetic leathers, pesticides, surface, detergents and fertilizers.

 It also relates to a process for producing vitamins, pharmaceuticals, glues, acrylic fibers, synthetic leathers, pesticides, surfactants, detergents and fertilizers, comprising a step of preparing alkylamines by the process according to the invention.

 The present invention further relates to a process for the preparation of labeled alkylamines and their uses.

Amines are commodities of chemistry. They are especially used as dyes or drugs. Today, methylamines can be synthesized "sustainably" from C0 ₂ , while alkylamines are synthesized from petrochemical derivatives.

One of the main routes of synthesis of alkylamines is the alkylation of amines using alcohols or haloalkanes (Figure 1) which are themselves produced in several stages from petroleum or from carbon monoxide (CO) and hydrogen (H ₂ ) via the Fischer-Tropsch process. The major disadvantage of this synthetic route is the presence of multiple steps that result in low yields and significant costs of treatment and separation.

One of the other main routes of synthesis of alkylamines is the reduction of amides. This can be done by hydrogenation of the amides, with, however, limited efficacy and sensitivity to the nature of the amide. The hydrogenation can be carried out by hydrosilylation as shown in FIG. 2, or by hydroboration, two techniques which have good yields but a low atomic economy. For example, hydrosilylation of amides in the presence of Co ₂ CO ₈ as a catalyst (Dombray, T., Helleu, C., Darcel, J., Sortais, Adv Synth, Catal, 2013, 355, 3358) can have quantitative yields but will be effective only with aromatic amides. In addition, the number of substituents on the nitrogen atom of the amides and the resulting steric hindrance can influence the reactivity and rate of reduction of the amide. Moreover, the synthetic processes described above involve several steps that require intermediate purifications.

The use of recoverable CO as a source of carbon for the production of chemical consumables is a major challenge in reducing our dependence on fossil fuels. In addition, CO can be considered as a source of renewable carbon because it can be produced today from biomass or C0 ₂ . The technical difficulty lies in the development of chemical reactions that make it possible to functionalize CO while reducing the carbon center (ie, by replacing the CO bond of CO with CH or CC bonds).

 The conversion of CO into chemical consumables such as alkylamines is therefore of particular interest.

 In the context of the synthesis of alkylamines using carbon monoxide, the technical challenge is to couple the functionalization of carbon monoxide (formation of a CN bond) to a chemical reduction step (formation of two CH bonds) in order to arrive at alkylamines having variable chain lengths. To maximize the energy efficiency of such a transformation, it is necessary to develop reactions with a limited number of steps (ideally only one) and catalysed, to avoid energy losses of kinetic order.

 There is therefore a real need for a process for sustainably preparing alkylamines with different chain lengths.

 In particular, there is a real need for a process for preparing alkylamines using carbon monoxide (CO) as a renewable molecular brick leading to the formation of alkyl chains whose length may vary, said method for coupling the functionalization of the carbon monoxide at a chemical reduction stage.

 More particularly, there is a real need for a process which makes it possible to obtain, in a limited number of steps or even a single step, alkylamines whose length of the alkyl chains can vary in a controlled manner from a renewable carbon source. .

Moreover, the labeled alkylamines, incorporating radioisotopes and / or stable isotopes, are of particular interest in many fields, for example in the life sciences (study / elucidation of enzymatic mechanisms, biosynthetic mechanisms, biochemistry, etc. .), environmental sciences (tracing waste, etc.), research (study / elucidation of reaction mechanisms) or research and development of new pharmaceutical and therapeutic products. Thus, developing a process as described above for the preparation of labeled alkyl amines meeting the requirements indicated above, meets a real need. The present invention is specifically intended to meet these needs by providing a process for the preparation of alkylamines of formula (I):

in which

⁸ R ^5, R ² and R ³ represent, independently of one another, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups being optionally substituted; or

 1 2

^" R ¹ and R 1 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, and

R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

s m, m 'and m "are integers chosen from 0 and 1

"¾ <i _'> <¾" ^{t n} integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

R ¹ , R ² , R ³ and -CH ₂ - optionally include H, C, N, O, F, Si and / or S as defined below:

 H represents a hydrogen atom (H), deuterium (H) or tritium (H); C represents a carbon atom (C), a C, C or C isotope;

N represents a nitrogen atom ( ¹⁴ N), an isotope ^{, 5} N;

O represents an oxygen atom ( ¹⁶ 0), an isotope ⁱ⁷ 0 or ^, 80;

F represents a fluorine atom ( ^I9 F), an ¹⁸ F isotope;

o S represents a sulfur atom (S), an isotope S, S or ^~ S; characterized in that an amine of formula

in which

R, R, R, -CH ₂ -, m, m 'and m "are as defined above;

 - R represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

 X represents a halogen atom, trifluoromethylsulphonate (triflate),

methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate);

n is an integer selected from 0 and 1; with CO in which C and O are as defined above and a reducing agent selected from H ₂ , LiAlH ₄ , NaBH ₄ , Zn, LiBH ₄ ,

a silane of formula (III)

a borane of formula (IV)

in which

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a group aryl, a heteroaryl group, a heterocycle, a silyl group, a siloxy group, an amino group, said alkyl, alkenyl or alkynyl groups, aryl, heteroaryl, endocycle, silyl, siloxy and amino being optionally substituted, or

 • R and R taken together with the boron atom to which they are attached form an optionally substituted heterocycle; in the presence of a metal catalyst selected from salts and metal complexes, and optionally a promoter.

Thus, the process of the invention makes it possible to prepare both unmarked and marked alkylamines of formula (I).

 The process of the invention has the advantage of enabling CO to be converted to alkylamines with a large choice of amines of formula (II) (primary, secondary, aromatic, aliphatic amines, etc.). This process makes it possible to create one or more alkyl chains on the amines of formula (II) and / or to lengthen the alkyl chain (s) already present on the amines of formula (II). ), which, to date, has never been described. In this process, CO, through the presence of reducing agents which provide the reduction of CO under catalytic conditions, is used to alkylate said amines of formula (II).

 Another advantage of the process of the invention is that it allows, when desired, to promote the production of certain types of alkylamines of formula (I) from the amine of formula (II).

 As already indicated, the process of the invention makes it possible to obtain the alkylamines of formula (I) in a limited number of stages (one or two stages) without separation of the intermediate products.

 Thus, the preparation of the alkylamines by the process of the invention, whether in one or two stages, is monotope ("one-pot" in English), that is to say that the amines of formula (II) ) are converted into alkylamines of formula (I) by undergoing several successive and / or simultaneous reactions in a single reaction mixture (a single reactor for example), thus avoiding the long processes of separation and purification of the intermediate compounds. Thus, industrially the method of the invention is of great interest because it saves time, cost of production and overall performance.

In order for the process of the invention to lead to the production of alkylamines of formula (I), a judicious and adequate combination of amines of formula (II), reducing agent, catalysts and possibly promoters is essential. . he is in In particular, it is necessary for the amine of formula (II) and the catalyst to be chosen, in particular taking into account their respective steric hindrance, the reducing nature of the reducing agent, the nucleophilic nature of the catalyst and their solubility in the reaction medium.

 Without wishing to be bound by theory, in the process of the invention, the technical challenge to be taken is to couple the functionalization of carbon monoxide (formation of a CN bond) to a chemical reduction step (formation of two CH bonds). ), which is not, a priori, obvious or easy. Indeed, it is not enough that the carbonylation followed by the reduction is done independently but that the carbonylation can take place in the presence of a reducing agent and that the reduction can take place in the presence of CO, and this at the appropriate time and under the same conditions. However, for example, silanes (reducing agent) are known to form methane in the presence of iodomethane (promoter) which would deactivate the system, or to form a silylated amine in the presence of an amine as shown in FIG. The inventors have found, quite unexpectedly, that a judicious choice of reagents and operating conditions makes it possible to eliminate the undesirable reactions. Moreover, a judicious choice of reagents and operating conditions makes it possible to perform either a single or a multiple carbonylation and reduction cascade thus leading to the formation of several C-C bonds.

 Within the meaning of the invention, a "promoter" designates a compound which increases the catalytic power of a catalyst, without itself having intrinsic catalytic power. The promoters are themselves inactive.

 The promoters can be of formula RX in which

 R represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, the said alkyl, alkenyl, alkynyl, heteroaryl or heterocycle groups being optionally substituted, with the groups alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle as defined within the scope of the present invention; and

 X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms; trifluoromethylsulfonate (triflate), methanesulfonate (mesylate) and p-toluenesulfonic acid (tosylate).

The promoters may also be a quaternary ammonium salt of the formula RgRioRnR ^ NX in which - R _9> Rio, Ru, R12 represent, independently of one another, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups being optionally substituted, with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups as defined within the scope of the present invention; and

X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms; trifluoromethylsulfonate (triflate); methanesulfonate (mesylate) and p-toluenesul acid mildew (tosyiate).

 For the purposes of the invention, the term "catalyst" means a compound capable of modifying, in particular by increasing, the speed of the chemical reaction in which it participates, and which is regenerated at the end of the reaction. This definition encompasses both catalysts, that is, compounds that exert their catalytic activity without the need for any modification or conversion, and compounds (also called pre-catalysts) that are introduced into the medium. and converted therein to a catalyst.

In the context of the invention, "additive" denotes a compound capable of improving and increasing the yield and / or the rate of conversion of the amines of formula (II) into alkylamines of formula (I), but which, alone, can not catalyze this conversion. The additives may be chosen from amides, preferably aromatic or derived, in particular acetanilide, benzanilide, and N-methylacetanilide; and Lewis acids include AlCl _3, LiCl, LiBF _4j FeCl _3, InCl _3, BiCl _3.

 For the purposes of the present invention, an "alkyl" group denotes a linear, branched or cyclic, saturated, optionally substituted carbon radical comprising 1 to 12 carbon atoms. As saturated, linear or branched alkyl, there may be mentioned, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, undecyl, dodecanyl and their branched isomers. As cyclic alkyl, there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloalkyl, bicyclo [2,1,1] hexyl, bicyclo [2,2,1] heptyl radicals. The alkyl group may comprise for example 1 to 8 carbon atoms.

By "alkenyl" or "alkynyl" is meant a linear, branched or cyclic unsaturated carbon radical, optionally substituted, said unsaturated carbon radical comprising 2 to 12 carbon atoms comprising at least one double (alkenyl) or a triple bond (alkynyl) . As such, there may be mentioned, for example, ethylenyl, propylenyl, butenyl, pentenyl, hexenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl and their branched isomers. Cyclic alkenyls include, for example, cyclopentenyl, cyclohexenyl. The alkenyl and alkynyl groups may comprise for example 2 to 8 carbon atoms.

The alkyl, alkenyl, alkynyl groups may be optionally substituted by one or more hydroxyl groups; one or more alkoxy groups; one or more halogen atoms selected from fluorine, chlorine, bromine or iodine atoms; one or more nitro groups (~ N0 ₂ ); one or more nitrile groups (-CN); one or more aryl groups, with the alkoxy and aryl groups as defined in the context of the present invention.

The term "aryl" generally refers to a cyclic aromatic substituent having from 6 to 20 carbon atoms. In the context of the invention, the aryl group may be mono- or polycyclic. The aryl group may be optionally substituted by one or more hydroxyl groups, one or more alkoxy groups, one or more "siloxy" groups, one or more halogen atoms selected from fluorine, chlorine, bromine and iodine atoms, one or more several nitro groups (-NO ₂ ), one or more nitrile groups (-CN), one or more alkyl groups, with the alkoxy, alkyl and siloxy groups as defined in the third scope of the present invention. The aryl group may comprise, for example, 6 to 10 carbon atoms. As an indication, mention may be made of phenyl, benzyl, naphthyl, o-toluyl, m-toluyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl, o-methoxybenzyl, p-nitrophenyl, methoxybenzyl, m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl.

The term "heteroaryl" generally denotes a mono- or polycyclic aromatic substituent having from 5 to 12 members of which at least 2 carbon atoms, and at least one heteroatom selected from nitrogen, oxygen or sulfur. As an indication, mention may be made of furyl, benzofuranyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, thiophenyl, benzothiophenyl, pyridyl, quinolinyl, isoquinolinyl, imidazolyl, benzimidazolyl, triazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl groups. pyridazinyl, pyrimidilyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,1-diphenylhydrazinyl, 1,2-diphenylhydrazinyl, carbazolyl. The heteroaryl group may be optionally substituted by one or more hydroxyl groups, one or more alkoxy groups, one or more halogen atoms selected from fluorine atoms, chlorine, bromine and iodine, one or more nitro groups (-N <¾), one or more nitrile groups (-CN), one or more aryl groups, one or more alkyl groups, with the alkyl, alkoxy and aryl groups such as defined in the context of the present invention. It is obvious that the term "heteroaryl" also encompasses mono- or polycyclic aromatic compounds having from 5 to 12 members, of which at least 2 are carbon atoms, and at least one heteroatom chosen from nitrogen, oxygen or sulfur. whose radicals / groups are derived from it.

 The term "alkoxy" means an alkyl group, as defined above, bonded through an oxygen atom (-O-alkyl).

The term "heterocycle or heterocyclic" generally refers to a saturated or unsaturated mono- or polycyclic 5 to 12-membered substituent containing from 1 to 4 heteroatoms selected independently of one another from nitrogen, oxygen, boron and sulfur. As an indication, mention may be made of borolane, borole, borinane, 9-borabicyclo [3.3.1] nonane (9-BBN), 1,3,2-benzodioxaborole (catecholborane or catBH), pinacholborane (pinBH) ; morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrimidinyl, tetrahydroisoquinolinyl, benzazepinyl, triazolyl, pyrazolyl, thianyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl substituents. The heterocycle may be optionally substituted by one or more hydroxyl groups, one or more alkoxy groups, one or more aryl groups, one or more halogen atoms selected from fluorine, chlorine, bromine and iodine atoms, one or more groups. nitro (-NO ₂ ), one or more nitrile groups (-CN), one or more alkyl groups, with the alkyl, alkoxy and aryl groups as defined within the scope of the present invention. It is obvious that the term "heterocycle or heterocyclic" also encompasses saturated or unsaturated 5 to 12 membered mono- or polycyclic compounds containing from 1 to 4 heteroatoms chosen independently of each other, from 1 nitrogen, oxygen, boron and sulfur, from which the above-mentioned radicals / groups derive therefrom.

 By atom of "halogen" is meant an atom chosen from fluorine, chlorine, bromine and iodine atoms.

By group "silyl" means a group of the formula [-Si (Y) _3] wherein each Y, independently of one another, is selected from hydrogen; one or more halogen atoms selected from fluorine, chlorine, bromine or iodine atoms; a or more alkyl groups; one or more alkoxy groups; one or more siloxy groups; one or more aryl groups; with the alkyl, alkoxy and aryl groups as defined in the context of the present invention, for example, trimethylsilyl (TMS), triethylsilyl ((CH ₃ CH ₂ ) ₃ Si- or TES) may be mentioned; ,? -? - butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), dimethylhydrosilyl, triisopropylsilyl (trif), tri (trimethylsilyl) silyl or ((CH ₃ ) ₃ Si) ₃ Si- (TTMS) , at {tert-butyl) silyl or ((CH ₃ ) ₃ C) ₃ Si ~, (C ₆ H ₅ ) H ₂ Si-, diphenylhydrosilyl ((C ₆ H ₅ ) ₂ HS-), triphenylsilyl (( C ₆ H ₅ ) ₃ Si-), trietoxoxysilyl ((EtO) ₃ Si-). It is obvious that the term "silyl" also encompasses compounds whose radicals / groups derive from it.

By "siloxy" group is meant a silyl group, as defined above, linked by an oxygen atom (-O-Si (Y) ₃ ) with Y as defined above. As such, there may be mentioned, for example, trimethylsiloxy-OSi (CH ₃ ) ₃ , triethylsilyoxy-OSi (CH ₂ CH ₃ ) ₃ , tert-butyldiphenylsiloxy-OSi (iBuPh ₂ ) ₃ , methylsiloxy (-OSi ( H) ₂ (CH ₃ ), dimethylsiloxy (- OSi (H) (CH ₃ ) ₂ ), ethylsiloxy (-OSi (H) ₂ (C ₂ ¾), diethylsiloxy (-OSi (H) (C ₂ H) ₅ ) _z ), tetramethyldisiloxane (TMDS or O (Si (Me) ₂ H) ₂ ) In the context of the invention, the siloxy group also includes polymeric siloxides. polymethylhydrosiloxane (PMHS), polydimethylsiloxane, poly (dimethylsiloxane-C0-diphenylsiloxane). It is quite obvious that the term "siloxy" also encompasses the compounds of which the above-mentioned radicals / groups derive therefrom.

By "amino" group is meant a group of formula -NR ¹³ R ¹⁴ , in which: R ^B and R ¹⁴ represent, independently of one another, a hydrogen atom, an alkyl group, an alkenyl group , an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, a silyl group, a siloxy group, with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, silyl, siloxy, as defined in the context of the present invention; or

R ¹³ and R ¹⁴ taken together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more hydroxyl groups; one or more alkyl groups; one or more alkoxy groups; one or more halogen atoms selected from fluorine, chlorine, bromine and iodine atoms; one or more nitro groups (-NO ₂ ); one or more nitrile groups (-CN); one or more aryl groups; with the alkyl, alkoxy and aryl groups as defined in the context of the present invention. It is obvious that the term "amino" also encompasses compounds whose radicals / groups above derive from it. For example, we can cite, for example, the diethylamino (-NET ₂ ), diphenylamino (-NPh ₂ ), methylethylamino (-NMeEt), bis (trimethylsilyl) amino (-N (SiCH ₃ ) ₂ ), N-methylaniline (-N (Me) (Ph)) .

 In general, the definitions of the different radicals / groups produced in the context of the present invention extend and also include the compounds of which said radicals / groups derive therefrom.

The substituents, radicals and groups defined above may optionally contain deuterium ( ² H), tritium ( ³ H), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, the ^{i &} F, ³ S, ³⁴ S and / or ³⁶ S.

 When the compounds of formula (I), (II) contain at least one radiolabel / radiotracer or an isotope, they may also be designated by the formulas (F), (ΙΓ) and (ΙΙΓ).

 According to a first embodiment of the invention,

a R ¹ , R ² and R ³ represent, independently of one another, a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups; being optionally substituted;

m, m 'and m "are integers selected from 0 and 1

■ q, q _'5 q "are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

"n = 0.

 In this embodiment, preferably,

BR ¹ , R ² and R ³ represent, independently of one another, a hydrogen atom; an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof; an optionally substituted aryl group selected from benzyl, phenyl, o-toluyl, m-toluyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl, o-methoxybenzyl, p-methoxybenzyl, m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl.

 In this first embodiment, the presence of a promoter and / or an additive may be advantageous.

 According to a second embodiment of the invention,

R ¹ and R ² taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, and R ³ represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

 B m, m 'and m "are integers selected from 0 and 1

^■ q, q _'s q "is are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; * n = 0.

 In this embodiment, preferably,

^{B R]} and R ² taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from morpholine, piperidine, piperazine, pyrrolidine and tetrahydroisoquinoline, indoline and isoindoline, and

 R represents a hydrogen atom; an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof; an optionally substituted aryl group selected from benzyl, phenyl, o-toluyl, m-toluyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl, o-methoxybenzyl, p-methoxybenzyl, m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl.

 In this second embodiment, the presence of a promoter and / or an additive may be advantageous.

 According to a third embodiment of the invention,

m R, R and R represent, independently of one another, a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted; ;

^■ R is a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle being optionally substituted;

m m, m 'and m "are integers selected from 0 and 1;

^B l _> l " ^{are es} * integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; ^β X represents a halogen atom, trifluoromethylsulfonate (triflate) , methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate).

 In this embodiment, preferably,

^■ R ^1, R ² and R ³ represent, independently of one another, a hydrogen atom; an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof; optionally substituted aryl selected from benzyl, phenyl, o-toluyl, m-toluyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl, o-methoxybenzyl, p-methoxybenzyl, m-tolyl methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl;

 R represents a hydrogen atom; an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof, an optionally substituted aryl group selected from o-methoxybenzyl, p-methoxybenzyl, m-methoxybenzyl, o- methylbenzyl, p-methylbenzyl and m-methylbenzyl. In this third embodiment, the method of the invention does not require the presence of a promoter. However, the use of an additive can be advantageous.

 According to a fourth embodiment of the invention,

BR ¹ and R ² taken together with the nitrogen atom to which they are bonded form an optionally substituted heterocycl, and

 R represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

R represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

^■ m, m 'and m "are are integers chosen from 0 and 1

^■ q q \ q "is are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

^B X represents a halogen atom, trifluoromethylsulfonate (triflate), methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate).

 In this embodiment, preferably,

^■ R ^! and R ² taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle selected from morpholine, piperidine, piperazine, pyrrolidine and tetrahydroisoquinoline, indoline and isoindoline, and

R ³ represents a hydrogen atom; an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof; an optionally substituted aryl group selected from benzyl, phenyl, o- toluyl, m-toluyl, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl, o-methoxybenzyl, p-methoxybenzyl, m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and the like. m-methylbenzyl;

f ⁱ R represents a hydrogen atom, an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, optionally substituted aryl group selected from benzyl, o-methoxybenzyl, p-methoxybenzyl , m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl, and their branched isomers.

 In this embodiment, preferably X represents a halogen atom selected from fluorine, chlorine, bromine and iodine.

 In this fourth embodiment, the method of the invention does not require the presence of a promoter. However, the use of an additive can be advantageous.

 In all the variants and embodiments of the invention, the values of m, m ', m ", q, q' and q" in the alkylamines of formula (I) are preferably chosen in such a way that :

 - 0 <m + q <10; and or

 - 0 <m '+ q' <10; and or

 - 0 <m "+ q" <10.

In all the variants and all the embodiments of the invention, the reducing agent is, in particular, chosen from H ₂ , a silane of formula (III)

a borane of formula (IV)

β R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a group aryl, a heteroaryl group, a heterocycle, a silyl group, a siloxy group, an amino group, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, siiyl, siloxy and amino groups being optionally substituted, or

R ⁷ and R ⁸ taken together with the boron atom to which they are attached form an optionally substituted heterocycle.

More particularly, the reducing agent is chosen from H ₂ , a silane of formula (III) and a borane of formula (IV) in which

® R ^4, R ^s, R ^6, R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom; an alkyl group selected, for example, from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and their branched isomers, cyclohexyl; an alkoxy group selected, for example, from methoxy and ethoxy; an optionally substituted aryl group selected, for example, from benzyl and phenyl; a siloxy group chosen, for example, trimethyl siloxy-OSi (CH ₃ ) 3, triethylsiloxy-OSi (CH ₂ CH ₃ ) ₃ , tert-butyldiphenylsiloxy-OSi (fBuPh ₂ ) ₃ , methylsiloxy (-OSi ( H) ₂ (CH ₃ ), dimethyl siloxy (-OSi (H) (CH ₃ ) ₂ ), ethylsiloxy (- OSi (H) ₂ (C ₂ H ₅ ), diethylsiloxy (-OSi (H) C ₂ H ₅ ) ₂ ), tetramethyldisiloxane (TMDS or O (Si (Me) ₂ H) ₂ ) and polymethylhydrosiloxane (PMHS);

"R ⁷ and R ⁸ taken together with the boron atom to which they are attached form a heterocycle, said heterocycle being selected from catecholborane (catBH), pinacolborane (pinBH) or 9-borabicyclo [3.3.1] nonane (9-BBN).

 Even more particularly, the reducing agent is chosen from ¾ and a silane of formula (III) in which

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom; an alkyl group selected, for example, from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and their branched isomers, cyclohexyl; an alkoxy group selected, for example, from methoxy and ethoxy, an optionally substituted aryl group selected, for example, from benzyl and phenyl, a siloxy group selected from dimethyl siloxy (-OSi (H) (CH ₃ ) ₂ ), ethylsiloxy (-OSi (H) ₂ (C ₂ H ₅ ), polymethylhydrosiloxane (PMHS).

By way of example of a reducing agent, mention may be made of H ₂ (C ₆ H ₅ ) SiH ₃ , (C ₆ H ₅ ) ₂ SiH ₂ , (CH ₃ CH ₂ ) ₃ SiH, (EtO) ₃ SiH , dimethylsiloxane, polymethylhydrosiloxane (PMHS), tetramethyldisiloxane (TMDS or O (Si (Me) ₂ H) ₂ ). As already indicated, the presence of a promoter may be advantageous in the first and second embodiments where n = 0.

 The promoter may be of formula RX, with R representing a hydrogen atom, an alkyl group, a heteroaryl group, an aryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted; and X representing a halogen atom, trifluoromethylsulfonate (triflate), methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate).

The promoter may also be a quaternary ammonium salt of formula R9R10R. _Î 1R12 wherein

- ^ RJ _{O. J} ^ ^ independently of one another, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocycle being optionally substituted, with alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle groups as defined within the scope of the present invention; and

X represents a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms; trifluoromethylsulfonate (triflate); methanesulfonate (mesylate) and p-toluenesulfonic acid (tosylate).

 The promoter is advantageously of formula RX.

 More preferably, the promoter is of the formula RX with R representing an alkyl group selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and branched isomers thereof; an optionally substituted aryl group selected from benzyl, o-methoxybenzyl, p-methoxybenzyl, m-methoxybenzyl, o-methylbenzyl, p-methylbenzyl and m-methylbenzyl; and X represents a halogen atom selected from fluorine, chlorine, bromine and iodine.

 As an example of a promoter, mention may be made of iodomethane, iodoethane, iodopropane and iodomethane.

 In all the variants and all the embodiments of the invention, the catalyst may be a metal catalyst chosen from salts and metal complexes.

The metal can then be a transition metal selected from chromium, tungsten, manganese, rhenium, silver, ruthenium, rhodium, cobalt, iron, nickel, copper, iridium, nickel, osmium, molybdenum, gold, platinum and palladium. When the metal catalyst is a metal salt, the anions which can form salts with the aforementioned transition metals are chloride (Cl ^- ), sulphate (SO _{4 -} ² ),

 2 2

sulfide (S ^" ), nitrate (NO 3 ^" ), oxide (O ^" ) and hydroxide (OH ^" ). As such, there may be mentioned for example, CuCl, PtCl _2, PdCl _2, MnS0 _4, CoCl _2> FeCl _2, FeCl _3.

 The catalyst may also be a metal complex.

 By metal complex is meant an organometallic or inorganic coordination compound in which a metal ion is bonded to an organic or inorganic ligand. An organometallic or inorganic complex may be obtained by mixing a metal salt with a ligand, which ligand binds to the metal by phosphorus, carbon, nitrogen, oxygen, hydrogen or silicon atoms, for example.

 When the metal catalyst is a metal complex, the ligands that can be bonded to the aforementioned transition metals can be chosen from:

 nitrogenous bases such as, for example, secondary or tertiary amines chosen from trimethylamine, triethylamine, piperidine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), proline, phenylalanine, thiazolium salt, N-diisopropylethylamine (DIPEA or DIEA), bipyridyl (bipy), terpyridine (terpy); phenantroline (phen), ethylenediamine, N, N, N ', N'-tetramethyl-ethylenediamine (TMEDA), quinoline and pyridine;

phosphorus bases such as, for example, alkyls and aryl phosphines chosen from triphenylphosphine, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (ΒΓ ΑΡ), triisopropylphosphine, tris [2-diphenylphosphino); ethyl] phosphine (PP ₃ ), tricyclohexylphosphine, 1,2-bis-diphenylphosphinoethane (dppe), 1,2-bis (diphenylphosphino) ethane (dppb); alkyl and aryl phosphonates selected from diphenylphosphate, triphenylphosphate (TPP), tri (isopropylphenyl) phosphate (TIPP), cresyldiphenyl phosphate (CDP), tricresylphosphate (TCP); alkyl and aryl phosphates selected from di-n-butyl phosphate (DBP), tris- (2-ethylhexyl) phosphate and triethyl phosphate;

oxygenated bases such as, for example, acetate (OAc), acetylacetonate, methanolate, ethanolate, benzoyl peroxide;

silylated ligands, for example alkylsilyls or arylsilyls chosen from triphenylsilyl, diphenylhydrosilyl, trimethylsilyl, dimethylhydrosilyl, triethylsilyl and triethoxysilyl; carbon-containing ligands chosen from, for example, CO, CN ^" , and N-heterocyclic carbenes derived from an imidazolium salt chosen from 1,3-bis (2,6-diisopropylphenyl) -1H-imidazol salts; 3-ium (IPr), 1,3-bis (2,6-diisopropylphenyl) -4,5-dihydro-1H-imidazol-3-ium, 1,3-bis (2,4,6-trimethylphenyl) 1H-imidazol-3-ium (IMes), 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydro-1H-imidazol-3-ium, 4,5-dichloro-1 , 3-bis (2,6-diisopropylphenyl) -1H-imidazol-3-fum, 1,3-di-tert-butyl-1H-imidazol-3-ium (also referred to as "ItBu" or "ItBu carbene" ), 1,3-di-tert-butyl-4,5-dihydro-1H-imidazol-3-ium, said salts being in the form of chloride salts.

 -heterocyclic are shown below;

The metal complex may optionally comprise a counterion chosen from, for example, sodium (Na ⁺ ), potassium (K ⁺ ), ammonium (H ₄ ⁺ ).

The metal complex may be bimetallic. In the bimetallic complexes, certain ligands may be "in bridging", that is to say, simultaneously bonded to two metal centers, for example CChCOg, Fe ₂ C09 or Fe ₃ C0 ₁₂ .

Examples of metal complexes include, Co ₂ CO _g, [Fe (CO) _5], [Ir (CO) (Cl) (PPh _{3) 2]} [Cr (CO) ₃ ^ ⁶ -C ₆ ¾)], Fe (acac) ₃ , Cu (OAc) ₂ (¾O), NaCoC0 ₄ , MoCo ₆ , FeC0 ₅ , and Co ₂ COs optionally in the presence of bipyndyl (bipy), terpyridine (terpy) or phenantroline (phen).

 Preferably, the ligands used are

carbon-containing ligands selected from, for example, CO, CN ^" , 1,3-bis (2,4,6-trimethylphenyl) -1H-imidazol-3-ium (IMes) and 1,3-bis (2,6-bis); diisopropylphenyl) -1H-imidazol-3-ium (IPr); nitrogenous bases such as, for example, secondary or tertiary amines selected from bipyridyl (bipy), phenantroline (phen), terpiridine (terpy), quinoline.

Preferably, the metal is selected from cobalt, iron and molybdenum. The metal complexes preferentially used are NaCoCO, *, MoC0 ₆ , FeCOs, Fe ₃ COi ₂ and Co ₂ CO ₈ optionally in the presence of bipyridyl (bipy), terpyridine (terpy) or phenantroline (phen) to form [(bipy) ₃ Co ] ²⁺ ([CoCC4] ^~ ) ₂ , [(terpy) ₂ Co] ²⁺ [CoCO4] - ^J (phen) ₃ Co] ²⁺ [CoCO4] -.

 In all the variants and embodiments of the invention, the catalyst is preferably a metal complex.

 Some of the abbreviations used for ligands are shown below:

 BDI ligand dppb

The catalysts may, where appropriate, be immobilized on heterogeneous supports, for example, in order to ensure easy separation of said catalyst and / or its recycling. Said heterogeneous supports may be chosen from supports based on silica gel or on plastic polymers such as, for example, polystyrene; carbon supports selected from carbon nanotubes; silica carbide; alumina; or magnesium chloride (MgCl ₂ ).

The process of the invention may furthermore take place in the presence of an additive. The additives may be selected from especially aromatic amides such as, for example, acetanilide, benzanilide, and N-methylacetanilide; Lewis acids such as, for example, AlCl ₃ , LiCl, L ₁ BF ₄ , FeCl ₃ , InCl ₃ , BCl ₃ .

In the process according to the invention, the reaction can take place under CO pressure. The pressure of the CO can then be between 1 and 200 bar, preferably between 1 and 100, more preferably between 1 and 60 bar inclusive. A mixture of CO and H ₂ can also be used. In this case, the pressure of ¾ is independent of that of CO. The CO pressure can then be between 1 and 200 bar, preferably between 1 and 100, more preferably between 1 and 60 bar inclusive, and the pressure of H ₂ can be between 1 and 100 bar, preferably between let 50 bars, more preferably between 5 and 30 bars, limits included.

In the presence of silane of formula (III) or borane of formula (IV) as reducing agent, a pressure of CO is preferred to a mixture of pressures of CO and H ₂ .

 The reaction may be carried out at a temperature of between 25 and 300 ° C., preferably between 50 and 250 ° C., more preferably between 80 and 200 ° C., inclusive.

 The reaction time depends on the conversion rate of the amine of formula (II).

Thus, the optimal reaction time corresponds to the complete conversion of the amine of formula (II). The reaction time is between 1 hour and 72 hours, preferably preferably between 3 and 24 hours, limits included.

 The process of the invention, in particular the reaction between the different reactants, may take place in a mixture of at least two solvents chosen from:

 ethers chosen from diethyl ether, THF, dioxane and diglyme;

 amides chosen from N-methyl-2-pyrrolidone (NMP) and N-dimethylformamide (DMF);

 hydrocarbons chosen from benzene, toluene, pentane and hexane;

the nitrogenous solvents chosen from pyridine and acetonitrile;

 - the water ;

 sulfoxides, such as dimethyl sulphoxide;

 alkyl halides selected from chloroform and methylene chloride;

 the aryl halides chosen from chlorobenzene and dichlorobenzene.

 The concentration of the amine of formula (II) in the reaction medium is between 0.01 and 10 M, preferably between 0.1 and 5 M, more preferably between 0, 1 and 2 M, inclusive limits. .

 The amount of catalyst is from 0.00001 to 1 molar equivalent, preferably from 0.0001 to 0.9 molar equivalents, more preferably from 0.0001 to 0.2 molar equivalents, even more preferentially from 0.001 to 0.1 equivalents. molar, inclusive limits, with respect to Famine of formula (II).

When the process uses a promoter, the amount of promoter is between 0.00001 and 1 molar equivalent, preferably between 0.01 and 0.9 equivalent. molar, more preferably between 0.1 and 0.4 molar equivalents, inclusive limits, relative to the amine of formula (II).

 When the process uses an additive, the amount of additive is between 0.00001 and 0.5 molar equivalents, preferably between 0.01 and 0.9 molar equivalents, more preferably between 0.1 and 0.4. molar equivalent, inclusive limits, with respect to the amine of formula (II).

 The various reagents used in the process of the invention (the amines of formula (II), the reducing agents, the catalysts, the promoters, the additives, etc. are, in general, commercial compounds or compounds which can be prepared by methods known to those skilled in the art.

 The process of the invention also makes it possible to prepare marked alkylamines of formula (I). This is another object of the invention. The labeled alkylamines correspond to the alkylamines of formula (I) comprising at least one radiolabel / radiotracer or a selected isotope.

 Isotopes mean, for the same element, two atoms having the same number of protons (and electrons) but a different number of neutrons. Having the same number of electrons and protons, the chemical properties of the isotopes of the same element are almost identical. There may, however, be slight variations in the rate of a chemical reaction when one of the atoms of a reagent is replaced by one of its isotopes. On the other hand, as the nucleus does not have the same number of neutrons, the mass of the atoms varies which can make the atom unstable: that is why they can be radioactive. These are radioisotopes. In the context of the invention, the term "isotopes" may also include "radioisotopes".

 Radiolabeling is the act of associating with a given molecule or compound an isotope that will make it possible to follow the evolution or / and the fixation of the molecules, for example, in an organ. The radiotracer is the radioactive element (s) present within a molecule to follow the path of this substance, for example, in an organ.

This method can thus provide access to alkylamines marked ⁿ C, ^{13 C,! 4} C, ^{I5 N,! 7} 0, ^¾8 F ² Si ₅ ³⁰ Si, ³³ S, ³⁴ S, ³⁶ S, ² H (D ) and / or ³ H (T).

The conditions of temperature, reaction time, solvent, as well as the amounts of reagents and catalysts used in the preparation process labeled alkylamines are those previously described in the process of preparing alkylamines of formula (I).

The use of molecules for tracing, metabolization, imaging, etc., is detailed in the literature (U, Pleiss, R. Voges, "Synthesis and Applications of Isotopical Label Compounds, Volume 7", Wiley VCH 2001, R. Voges, JR Heys, T. Moenius, "Preparation of Compounds Labeled with Tritium and Carbon-14", Wiley-VCH: Chippenham (UK), 2009). The ability to form the labeled alkylamines can be ensured by the availability of corresponding labeled reagents, e.g., by amino RR NH enriched N are accessed from the ammonium chloride enriched ¹⁵ N: ^[i5 NH _4] [Cl ] (Yong-Joo Kim, Max P. Bernstein, Angela S. Galiano Roth, Floyd E. Romesberg, Paul G. Williard, David J. Fuller, Aidan T. Harrison, and David B. Colum, J. Org, Chem. 1991, 56, pp. 4435-4439);

 the R R NH amines with labeled R and / or R are prepared by the synthetic routes detailed by U. Pleiss, R. Voges, "Synthesis and Applications of Isotopically Labeled Compounds, Volume 7", Wiley-VCH, 2001; and R. Voges, J. R. Heys, T. Moenius, "Preparation of Compounds Labeled with Tritium and Carbon-14", Wiley-VCH: Chippenham (UK), 2009);

- the CO marked ^1! C or C ⁱ⁴ is the main source of ^U C C and ^I4 is obtained by acidification marked barium carbonate Ba ¹⁴ C0 _3. (R. Voges, JR Heys, Moenius T., "Preparation of Labeled Compounds with tritium and Carbon- 14 "Wiley-VCH: Chippenham (UK), 2009).

The iodoalkanes, for example ¹³ CH ₃ I, ¹³ CH ₃ ¹³ CH ₂ I and ¹⁴ CH ₃ I, are respectively commercial and easily synthesizable from Ba ¹⁴ CO ₃ . (R. Voges, JR Heys, T. Moenius, "Preparation of Compounds Labeled with Tritium and Carbon-14", Wiley-VCH: Chippenham (UK), 2009).

Preferably the labeled CO C ^n, C ^{i4 I3} or C is used in the process for preparing marked alkylamines of formula (Γ).

Molecules labeled ¹⁴ C have contributed to many advances in life sciences (enzymatic mechanisms, bio synthetic mechanisms, biochemistry), environmental sciences (tracing of waste), research (elucidation of reaction mechanisms), diagnosis, research and development of new pharmaceutical and therapeutic products. The labeled molecules ^l C indeed, have an advantage for metabolic studies because C is easily detectable and quantifiable in vitro medium as in vivo.

The main source of ¹⁴ C is ¹⁴ CO which is obtained by acidification of barium carbonate Ba ¹⁴ C0 ₃ . The development of methods for synthesizing basic molecules used for the preparation of drugs is essential to produce ¹⁴ C labeled active ingredients whose metabolism can thus be determined (, Voges, J., R. Heys, T. Moenius, "Preparation of Compounds Labeled with Tritium and Carbon-14" Wiley-VCH: Chippenham (UK), 2009).

The major constraint limiting the synthesis of ¹⁴ C labeled molecules is the need to have a high yield of ¹⁴ C product formed relative to the amount of ⁴ CO used and rely on a limited number of steps to minimize the costs associated with the use of Ba ¹⁴ C0 ₃ (U. Pleiss, R. Voges, "Synthesis and Applications of Isotopically Labeled Compounds, Volume 7 Wiley-VCH, 2001, R. Voges, JR Heys, T. Moenius, "Preparation of Compounds Labeled with Tritium and Carbon-14", Wiley-VCH: Chippenham (UK), 2009).

 The subject of the invention is also the use of the process for the preparation of alkylamines of formula (I) according to the invention, in the manufacture of vitamins, pharmaceutical products, glues, acrylic fibers and synthetic leathers, pesticides, surfactants, detergents and fertilizers.

The invention also relates to the use of the method for preparing alkylamines of formula (1) labeled according to the invention, in the manufacture of radiotracers and radiolabel. Examples of radiotracers and radiolabels include 6-bromo-7- [ ⁿ C] methylpurine and 6-bromo-7- [ ¹⁴ C] methylpurine, [N- [ ¹ C] methyl] -2- (4 ^, - (methylammo) phenyl) -6-hydroxybenzothiazole (also called [ ¹ C] PIB), the structures of which are represented below:

Raclopride labeled * C = C or C

6-bromo-7- [ ^* C] methylpurine [ ^* C] PiB

* C = ¹¹ C or ¹⁴ C * C = C or ¹⁴ C

The subject of the invention is also a process for producing vitamins, pharmaceutical products, glues, acrylic fibers, synthetic leathers, pesticides, fertilizers, surfactants and detergents characterized in that it comprises (i) a step of preparing alkylamines of formula (I) by the process according to the invention, and optionally (ii) a hydrolysis step or an acidification step, to form, for example, the corresponding hydrochloride, borohydrate, hydrofluoride or iodohydrate. After the hydrolysis, optionally distillation or concentration in vacuo may be necessary.

 The subject of the invention is also a process for producing tracers and radiotracers, characterized in that it comprises (i) a step for preparing alkylamines of formula (I) labeled by the process according to the invention and optionally (ii) a hydrolysis step or an acidification step, to form, for example, the corresponding hydrochloride, borohydrate, hydrofluoride or iodohydrate. After the hydrolysis, optionally distillation or concentration in vacuo may be necessary.

 As already indicated, the process according to the invention leads to the formation of alkylamines whose length of alkyl chains present may be different. In other words, the process of the invention makes it possible to create and / or extend the alkyl chain (s) already present on the amines of formula (II) independently and in a controlled manner.

 The by-products which may be formed during the process of the invention generally correspond to the amides resulting from the carbonylation of the corresponding alkylamines formed. A simple filtration may make it possible to recover the optionally supported catalyst and to eliminate some of the by-products that may be formed. The amides can be separated by filtration on silica, recycled and reused in the process of the invention.

By acting on the operating conditions, as shown in the examples, the formation of the by-products and the extension of the chain and / or alkyl chains can be controlled. Other advantages and features of the present invention will appear on reading the examples below given for illustrative and non-limiting and the accompanying Figures.

 Figure 1 shows the alkylation of amines using alcohols or haloalkanes via the Fischer-Tropsch process.

Figure 2 shows the reduction of araides to amines by hydrosilylation of amides in the presence of Co ₂ CO ₈ as a catalyst.

 Figure 3 shows the adverse reactions that may occur when the carbonylation reaction occurs in the presence of a reducing agent and a promoter and that the reduction occurs in the presence of CO. For example, silanes (reducing agent) are known to form methane in the presence of iodomethane (promoter) which would deactivate the system, or to form a silylated amine in the presence of an amine.

In all the examples, the reagents used, in particular the amine of formula (II), the catalyst, the promoter and the reducing agent are commercial products or can be synthesized following the procedures described in the literature. In particular, the synthesis of NaCoC04 is described in F. W. Edgell, J. Lyford, Inorg. Chem., 1970, 1932 the synthesis of N-methyl-1,2,3,4-tetrahydrosioquinoline in C. Casagrande, A. Galli, R. Ferrini, G. Miragoli, Farmaco, Edizione Scientifica, 1972, 445. The remaining used products are purchased from Sigma-Aldrich.

EXAMPLE 1 The Preparation of Alkylamines of Formula (I) of Variable Chain Length

 The process for the preparation of alkylamines of formula (I) can be carried out in a single step and in a single reaction mixture and in the same autoclave (one step one-pot) according to the following experimental protocol.

An autoclave is loaded in a glove box with the catalyst (between 0.001 and 0.1 molar equivalents), the amine of formula (II) (1 molar equivalent), the promoter (between 0.1 and 1 molar equivalent), 1 reducing agent (between 1 and 6 molar equivalents), optionally an additive and the solvent. The amine concentration of formula (II) in the reaction medium is between 0.05 M and 0.3 M, the order of addition is not important.

 The autoclave is sealed and then purged several times (4 times) with 10 bar of CO and the temperature is raised to between 50 and 200 ° C. in 35 minutes. The CO pressure is maintained between 1 and 100 bar. The reaction time is 1 to 24 hours.

 Once the reaction is complete, the autoclave is cooled to room temperature (20 ± 5 ° C). The crude reaction product is filtered through Celite. The volatile compounds are removed under reduced pressure and the reaction mixture containing the various alkylamines is purified by chromatography on silica gel using ethyl acetate / n-pentane as eluent to obtain the analytically pure alkylamines.

A set of results is presented below in Table 1, giving examples of conversions of amines of formula (II) to alkylamines (determined by NMR) using phenylsilane PhSiH ₃ (marketed by Aldrich) as a reducing agent, optionally C3¾I (marketed by Aldrich) as promoter, and Co ₂ C0 ₈ and FeCO ₅ (marketed by Aldrich) as catalysts, according to the conditions presented below.

Table 1

PhSiH ₃ Co ₂ CO _s CO 50 bar, 7h, 78% r

 (1.5 eq.) (0.06 eq.) 180 ° C.

 H J 56%

 Solvent: MeCN

 (0.2M)

 Cn

 Yields are determined by GC / MS. The yields of alkylamines have not been optimized but are encouraging. The by-products obtained are the corresponding amides. They can be recycled and serve as starting products.

 The results show that the operating conditions specified above lead to mixtures of alkylamines whose length of each alkyl chain may be different and vary independently. The reaction conditions are therefore very important for the selectivity and the efficiency of the reaction.

EXAMPLE 2 The Preparation of Alkylamines of Formula (I) of Variable Chain Length

 The same procedure as that of Example 1 is followed. In this example, different reducing agents have been tested.

 The results are summarized below in Table 2.

 Table 2

 Amine Reducer Catalyst Converter Conditions Conversion Products

PhSiI ₃ Co ₂ C0 ₈ CO 50 bar, 7h, 99% r

 (2 eq.) (0.06 eq.) 200 ° C,

 10%

(0.2 M) Solvent: MeCN

 (0.2M)

PhSi¾ Co ₂ CO _g CO 50 bar, 7h, 90%

 (3 eq.) (0.06 eq.) 200 ° C (

(0.2 M) Solvent: MeCN

(0.2M)

 The amount of reducer and the type of reducer are crucial factors since the performance depends on it. Yields are determined by GC / MS. The yields of alkylamines have not been optimized but are encouraging. The by-products obtained are the corresponding amides which come from the carbonylation of the corresponding alklyamines. These amides can be recycled and serve as starting products.

EXAMPLE 3 Preparation of alkylamines of formula (I) of controlled chain length

 A) Two-step reaction control in the same autoclave (two steps one-pot)

 The process for the preparation of alkylamines of formula (I) can be carried out in two stages and in a single reaction mixture (two steps one-pot) according to the following experimental protocol.

 An autoclave is loaded glove box with the catalyst (between 0.001 and 0.1 molar equivalent), the amine of formula (II) (1 equivalent), the promoter (between 0.3 and 1 molar equivalent) and the solvent. The concentration of amine of formula (II) in the reaction medium is between 0.01 M and 0.3 M. The order of addition is not important.

The autoclave is sealed and then purged several times (4 times) with 10 bar of CO and the temperature is raised to between 150 and 200 ° C. in 35 minutes. The CO pressure is maintained between 1 and 100 bar. The reaction time is 1 to 24 hours. The autoclave is then purged with 4 times 5 bar of argon and then the reducing agent (between 1 and 6 molar equivalents) is introduced. The autoclave is then heated at 50 to 200 ° C for 1 to 10 hours.

 Once the reaction is complete, the autoclave is cooled to room temperature (20 ± 5 ° C). The crude reaction product is filtered through Celite. The volatile compounds are removed under reduced pressure and the reaction mixture containing the various alkylamines is purified by chromatography on silica gel using ethyl acetate / n-pentane as eluent to obtain the analytically pure alkylamines.

The reaction scheme is as follows:

Table 3

 This result shows that the operating conditions specified above lead to an alkylamine whose alkyl chain is elongated in a controlled manner. All the converted amine gives the corresponding alkylamine. The reaction is therefore particularly clean since no by-product is obtained. In addition, the unreacted amine can be recycled.

B) Pressure control

A Wilmad NMR tube (or an autoclave) is loaded in a glove box with the catalyst (between 0.001 and 0.1 molar equivalent), the amine of formula (II) (1 equivalent), the promoter (between 0.3 and 1 molar equivalent) and the solvent. The concentration of amine is between 0.01 M and 0.3 M. The order of addition is not important. An additive (between 0.05 and 1 molar equivalent) can be added to promote the reaction. This additive can be an amide or a Lewis acid as described above.

 The tube is sealed and then purged several times (2 times) with 10 bar of CO. The tube is then pressurized to a CO pressure between 1 and 30 bar. The tube is then heated to between 50 ° C and 150 ° C.

 Once the reaction is complete, the autoclave is cooled to room temperature (20 ± 5 ° C). The crude reaction product is filtered through Celite. The volatile compounds are removed under reduced pressure and the reaction mixture containing the alkylamines is purified by silica gel chromatography using ethyl acetate / n-pentane as eluent to obtain the analytically pure alkylamines.

A set of results is presented below in Table 4, giving examples of conversions of amines of formula (II) to alkylamines (determined by NMR) using phenylsilane PhSiH ₃ (marketed by Aldrich) as a reducing agent, optionally CH ₃ I and CH ₃ CH ₂ I (marketed by Aldrich) as promoter, N-ethylacetanilide and AlCl ₃ as additives (marketed by Aldrich), and Co ₂ CO _s , and Co ₂ CO ₈ + bpy and FeC0 ₅ (sold by Aldrich), NaCoC04 manufactured according to the procedure described in the reference mentioned above, as catalysts, according to the conditions presented below.

 Table 4

(0.3 eq.)

 Solvent: MeCN

 (0.3)

PnSiH ₃ Co ₂ CO ₈ CO 8 bar, 17h, 46% (2 eq) (0.06 eq) 200 ° C.

CH ₃

Promoter:

CH ₃ I (0.3 eq.)

 (0.3M)

 Additive:

 N-ethylacetanilide 46% (0.3 eq.)

 Solvent: MeCN

 (0.3M)

PhSiH ₃ NaCoC0 ₄ CO 8 bar, 17h, 46% (2 eq.) (0.06 eq.) 200 ° C.

 Promoter:

CH ₃ I (0.3 eq.)

 (0.3M)

 Additive:

 N-46% ethylacetanilide

 (0.3 eq.)

 Solvent: MeCN

 (0.3M)

PhSiHj Co ₂ C0 ₈ CO S bar, 17h, 25%

 (2 eq.) (0.06 eq.) 200 ° C.

 Promoter:

CH ₃ I (0.3 eq.)

 (0.3M)

 Additive: 25% N-Fehylacetanilide

 (0.3 eq.)

 Solvent: toluene

 (0.3M)

PhSiH ₃ Co ₂ CO _g CO 8 bar, 17h, 17%

 (2 eq.) (0.06 eq.) 200 ° C.

 Promoter:

CH ₃ CH ₂ I (0.3

(0.3M) eq.)

Solvent: MeCN

 (0.3M)

PhSi¾ Co ₂ CO _g CO 8 bar, 17h, 17%

 1 (2 eq.) (0.06 eq.) 100 ° C.

 o Additive:

 AlClj (0.3 eq.)

 (0.3M) 17%

 Solvent: MeCN

 (0.3M)

PhSiH ₃ Co ₂ CO ₈ CO 8 bar, 16h, 40%

 (2 eq.) (0.06 eq.) 200 ° C.

 Promoter:

(0.3M) CH ₃ I (0.3 eq.)

 Additive: N-ethylacetanilide

 (0.3 eq.)

 Solvent: toluene

 (0.3M)

Yields are determined by GC / MS. The yields of alkylamines have not been optimized but are encouraging. The possible by-products obtained are the corresponding amides which come from the carbonylation of the corresponding alklyamines. These amides can be recycled and serve as starting products.

 The results show that under the operating conditions indicated in the

Table 4, the conversion of amines of formula (II) to alkylamine of formula (I) is generally in excellent yield. Indeed, all converted amine gives corresponding alkylamine.

All the results obtained in the experimental part show that the preparation of alkylamines by the process of the invention is sufficiently flexible to efficiently convert a large variety of amines into alkylamines.

Claims

Process for the preparation of alkylamines of formula (I)

 in which

 1 2 3

 R, R and R represent, independently of one another, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl groups, alkenyl, alkynyl, aryl, heteroaryl, heterocycle being optionally substituted; or

- R ¹ and R ² taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, and

 R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle being optionally substituted;

n m, m 'and m "are integers selected from 0 and 1;

s q, q \ q "are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

^H R ¹ , R ² , R ³ , and -CH ₂ - optionally include H, C, N, O, F and / or S as defined below:

 H represents a hydrogen atom (H), deuterium (H) or tritium (H); C represents a carbon atom (C), a C, C or C isotope;

N represents a nitrogen atom ( ¹⁴ N), a ⁵ N isotope;

o O represents an oxygen atom ( ^¾6 0), an isotope ¹⁷ 0 or ^ls O;

F represents a fluorine atom ( ¹⁹ F), an ¹⁸ F isotope;

S represents a sulfur atom ( ³² S), a ³³ S, ³⁴ S or ³⁶ S isotope; characterized in that an amine of formula (II) is reacted

 in which

R ¹ , R ² , R ³ , -CH ₂ -, m, m 'and m "are as defined above;

 R represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group or a heterocycle, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocycle groups being optionally substituted,

X represents a halogen atom, trifluoromethylsulfonate (triflate), methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate);

n is an integer selected from 0 and 1; with CO in which C and O are as defined above and a reducing agent selected from H ₂ , LiAlH ₄ , NaBH ₄ , Zn, LiBH ₄ ,

a silane of formula (III)

 (III), and a borane of formula (IV)

in which

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, , a heteroaryl group, a heterocycle, a silyl group, a siloxy group, an amino group, said alkyl, alkenyl or alkynyl groups, aryl, heteroaryl, heterocycle, silyl, siioxy and amino being optionally substituted, or

 • R and R taken together with the boron atom to which they are attached form an optionally substituted heterocycle; in the presence of a metal catalyst selected from salts and metal complexes, and optionally a promoter.

2. Method according to claim 1, characterized in that

^B R ^s , R ² and R ³ represent, independently of one another, a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups; being optionally substituted;

B m, m 'and m "are integers selected from 0 and 1

^■ q, q \ q "are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

^■ n = 0.

3. Method according to claim 1, characterized in that

^■ R and R ² taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, and

R ³ represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

^■ m, m 'and m "are integers selected from 0 and 1

^■ q, q ', q "is are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

^■ n = 0.

4. Method according to claim 1, characterized in that

^■ R, R and R independently of one another, a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle being optionally substituted ;

R represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted; ^■ m, m 'and m "are integers is selected from 0 and 1;

^■ q, q ', q "is are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

^■ X represents a halogen atom, trifluoromethylsulfonate (triflate), methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate).

5. Method according to claim 1, characterized in that

 1 ")

^B R and R, taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycle, and

R ³ represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

B R represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted;

 m, m 'and m "are is integers selected from 0 and 1

aq, q ', q "is are integers selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ^10;" n = l;

^B X represents a halogen atom, trifluoromethylsulfonate (triflate), methanesulfonate (mesylate), p-toluenesulfonic acid (tosylate).

6. Process according to any one of claims 1 to 5, characterized in that the values of m, m ', m ", q, q' and q" in the alkylamines of formula (I) are chosen so that than :

 - 0 <m + q <10; and or

 - 0 <m '+ q' <10; and or

 - 0 <m "+ q" <10.

7. Process according to any one of Claims 1 to 6, characterized in that the reducing agent is chosen from H ₂ , a silane of formula (III) a borane of formula (IV)

 R

B H

R (IV)

in which

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represent, independently of one another, a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a group aryl, a heteroaryl group, a heterocycle, a silyl group, a siloxy group, an amino group, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, silyl, siloxy and amino groups being optionally substituted, or

• R ⁷ and R ⁸ taken together with the boron atom to which they are attached form an optionally substituted heterocycle.

8. Method according to any one of claims 1 to 3, characterized in that the promoter is of formula RX, with R representing a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heterocycle, said alkyl, aryl, heteroaryl, heterocycle groups being optionally substituted; and X represents a halogen atom, trifluoromethylsulfonate (triflate), meshanesulfonate (mesylate) p-toluenesulfonic acid (tosylate).

9. Process according to any one of claims 1 to 8, characterized in that the catalyst is a metal salt which

 the metal is a transition metal selected from chromium, tungsten, manganese, rhenium, silver, ruthenium, rhodium, cobalt, iron, nickel, copper, iridium, osmium, molybdenum, gold, platinum and palladium, and

- anions forming salts with the above transition metals are chloride (Cf), sulfate (S0 ₄ ^{2 "),} sulfide (S ^2"), nitrate (N03 ^~), oxide (O ^{2 "} ) and the hydroxide (OH ^" ).

10. Process according to any one of claims 1 to 8, characterized in that the catalyst is a metal complex of which

 the metal is a transition metal selected from chromium, tungsten, manganese, rhenium, silver, ruthenium, rhodium, cobalt, iron, nickel, copper, iridium, osmium, molybdenum, gold, platinum and palladium, and

 the ligands that are linked to the transition metals are chosen from;

nitrogenous bases such as secondary or tertiary amines chosen from trimethylamine, triethyleamine, piperidine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), proline, phenylalanine a thiazolium salt, N-diisopropylethylamine (DIPEA or DIEA), bipyridyl (bipy), terpyridine (terpy); phenantroline (phen), ethylenediamine, N, N, N ', N' α-methyl-ethylenediamine (TMEDA), quinoline and pyridine; phosphorus bases such as alkyls and aryl phosphines selected from triphenylphosphine, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), triisopropylphosphine, tris [2-diphenylphosphino) ethyl] phosphine (PP ₃ ), tricyclohexylphosphine, 1,2-bis-diphenylphosphoethane (dppe), 1,2-bis (diphenylphosphino) ethane (dppb); alkyl and aryl phosphonates selected from diphenyl phosphate, triphenyl phosphate (TPP), tri (isopropylphenyl) phosphate (TIPP), cresyldiphenyl phosphate (CDP), tricresyl phosphate (TCP); alkyl and aryl phosphates selected from di-n-butyl phosphate (DBP), tris- (2-ethylhexyl) phosphate and triethyl phosphate; oxygenated bases such as acetate (OAc), acetylacetonate, methanolate, ethanolate, benzoyl peroxide;

 silylated ligands such as alkylsilyl or arylsilyl chosen from triphenylsilyl, diphenylhydrosilyl, trimethylsilyl, dimethylhydrosilyl, triethylsilyl and triethoxysilyl;

the carbon-containing ligands chosen from CO, CN ^" and the N-heterocyclic carbenes derived from an imidazolium salt chosen from 1,3-bis (2,6-diisopropylphenyl) -H-imidazol-3-iux salts; 1,3-bis (2,6-diisopropylphenyl) -4,5-dihydro-1H-imidazol-3-ium, 1,3-bis (2,4,6-trimethylphenyl) -1H-imidazol-3- ium, 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydro-1H-imidazol-3-ium, 4,5-dichloro-1,3-bis (2,6-diisopropylphenyl) - 1H-Imidazol-3-ium, 1,3-di-tert-butyl H-imidazol-3- ium, 1,3-di-tert-butyl-4,5-dihydro-1H-imidazol-3-ium, said salts being in the form of chloride salts;

the metal complex optionally comprising a counterion selected from sodium (Na ⁺ ), potassium (K ⁺ ), ammonium (NH ₄ ⁺ ).

A process according to any one of claims 1 to 10, characterized in that the process is further carried out in the presence of an additive selected from aromatic amides such as acetanilide, benzanilide, and N- methylacetanilide; Lewis acids such as AlCl ₃ , LiCl, LiBF ₄ , FeCl ₃ , InCl ₃ , BiCl.

Process according to one of Claims 1 to 11, characterized in that the reaction takes place under a pressure

 - CO between 1 and 200 bars, inclusive, or

 - CO between 1 and 200 bar and ¾ between 1 and 100 bar, limits included.

13. A method according to any one of claims 1 to 12, characterized in that the reaction is carried out at a temperature between 25 and 300 ° C ₅ inclusive.

14. Process according to any one of Claims 1 to 13, characterized in that the reaction time is between 1 hour and 72 hours, limits included.

15. Process according to any one of Claims 1 to 14, characterized in that the reaction takes place in one or a mixture of at least two solvent (s) chosen from:

 ethers chosen from diethyl ether, THF, dioxane and diglyme;

 amides chosen from N-methyl-2-pyrrolidone (NMP) and N, N-dimethylformamide (DMF);

 hydrocarbons chosen from benzene, toluene, pentane and hexane;

 the nitrogenous solvents chosen from pyridine and acetonitrile;

 - the water ;

 sulfoxides, such as dimethyl sulphoxide;

 alkyl halides chosen from chloroform or methylene chloride;

the aryl halides chosen from chlorobenzene and dichlorobenzene.

16. Process according to any one of claims 1 to 15, characterized in that the concentration of the amine of formula (II) in the reaction medium is between 0.01 and 10 M inclusive.

17. Process according to any one of Claims 1 to 16, characterized in that the amount of catalyst is from 0.00001 to 1 molar equivalent, inclusive limits, relative to the 3 'amine of formula (II).

18. Process according to any one of Claims 1 to 3 and 6 to 17, characterized in that the amount of promoter is between 0.00001 and 1 molar equivalent, inclusive limits, relative to the amine of formula (II). ).

19. Process according to any one of claims 1 1 to 18, characterized in that the amount of additive is between 0.00001 and 0.5 molar equivalents, inclusive, with respect to amine of formula (II).

20. Use of a process for the preparation of alkylamines of formula (I) according to any one of claims 1 to 19, in the manufacture of vitamins, pharmaceuticals, glues, acrylic fibers and synthetic leathers, pesticides , surfactants, detergents and fertilizers.

21. Use of a process for the preparation of alkylamines of formula (I) labeled according to any one of claims 1 to 19, in the manufacture of radiotracers and radiolabel.

22. Process for manufacturing vitamins, pharmaceuticals, glues, acrylic fibers, synthetic leathers, pesticides, fertilizers, surfactants and detergents characterized in that it comprises (i) a step method for preparing alkylamines of formula (I) by the process according to any one of claims 1 to 19, and optionally (ii) a hydrolysis step or (ii) an acidification step.

23. A method of manufacturing tracers and radiotracers, characterized in that it comprises (i) a step of preparing alkylamines of formula (I) labeled by the process according to any one of claims 1 to 19, and optionally (ii) a hydrolysis step or (ii) an acidification step.