intermediates TECHNICAL FIELD

The invention relates to processes for the production of compounds of the general formula (I),

(I)

wherein

R ¹ is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group; and

R ² is, independently of R ¹ , a linear or branched alkyl group having 1 to 4 carbon atoms; or a -Z-CH ₂ -T group, wherein

Z is a linear or branched alkylene group having 1 to 4 carbon atoms; and T is -OH or -NR ¹⁰ R ¹¹ group, wherein

R ¹⁰ and R ¹ are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

The invention also encompasses the compound of the formula (Id), which is a novel compound.

(Id). By certain processes according to the invention the compounds of the general formula (I) are produced via novel intermediates, the invention therefore also encompasses these novel compounds and the production processes thereof.

The compounds of the general formula (I), produced by the novel processes are preferably used as chelators for forming suitable, widely usable complexes (in other words, chelates) with transition metals and rare earth metals. BACKGROUND OF THE INVENTION

The compounds of the general formula (I) are N-substituted derivatives of 1 ,4,7 triazacyclononane, or by its generally accepted short name, TACN.

TACN (Qx) The free electron pairs of the nitrogen atoms can form coordinate bonds with cations of d- and f- elements having vacant electron orbitals. Thereby, chelate ions of the general formula (Q _x ) are formed, wherein the central "core" of atoms M ^z+ acting as electron pair acceptor is fixed inside the molecular ring by the electron pair donor groups - in this particular case, the nitrogen atoms of the TACN-ring. In the formula, M represents the d- or f- element, while z denotes the charge number of the core.

The ligands which are capable of forming at least two coordinate bonds, and thus of forming cyclic complexes that also comprise a core, and the complexes formed this way, are termed in the literature "chelators" and "chelates", respectively. TACN-derivative chelates are highly significant from a scientific aspect and have a wide range of practical applications. The simplest and most widely used TACN- based chelator is 1 ,4,7-trimethyl-1 ,4,7-triazacyclononane of formula (la), or, to use the abbreviations used in international literature, Me3-TACN or tmtacn:

H ₃ C CH ₃

(la), i.e. Me ₃ -TACN

(la) corresponds to a particular compound of the compounds of the general formula (I) wherein R is hydrogen atom, and R ² is methyl group.

A great number of simple and more complex TACN derivative chelates are described in literature, see for instance: Inorg. Chem. 24, 1230-5 (1985); Inorg.

Chem. 32, 4300-5 (1993); Inorg. Chem. 35, 1974-9 (1996); Inorg. Chem. 36, 3125-

3132 (1997); Inorg. Chem. 37, 3705-13 (1998); Inorg. Chem. 46(1 ), 238-50 (2007);

Inorg. Chem. 46(4), 1315-31 (2007); Inorg. Chem. 47(7), 2280-93 (2008); J. Am.

Chem. Soc, 120, 13104-20 (1998); J. Chem. Soc. Dalton Trans. 1994, 457-64; J. Chem. Soc. Dalton Trans. 2000, 3034-40].

US 4,639,365 discloses gadolinium chelates used as contrast agents in MRI medical diagnostic technology for improving image quality.

US2010/0256331 discloses NODAGA-BP ¹ peptide conjugates (e.g. NODAGE- TATE) comprising a ⁶⁸ Ga(lll) core, which open up new possibilities in PET diagnostics because ⁶⁸ Ga is a favourably short half-life (T _/2 = 68 min) β ⁺ emitting radioisotope that can be easily produced and is easy to handle.

NODAGA (Q i.e. NODAGA-BP

EP 2,708,547 discloses chelates of ^99m Tc, ¹⁸⁶ Re and ¹⁸⁸ Re isotopes complexed by TACN derivate compounds, which can also be applied in the fields of therapeutics and diagnostics.

The publication J. Chem. Soc. Dalton Trans., 1996, 353-62 concerns the possibilities for synthesising of bridgehead Mn(lll)- and/or Mn(IV) coordinated O ^2" - containing, double-core 1 R ³ -4R -7R ⁵ -TACN chelates, and the analysis of the substances produced.

2+

[Mn(lll) ₂ (p-O)(M-OAc) ₂ (R ³ R ⁴ R ⁵ -TACN)2]

(Q ₂ )

[Mn(IV) ₂ (M-O) ₃ (R ³ R ⁴ R ⁵ -TACN) ₂ ] ²⁺

(Q ₃ ) The Q ₂ and Q ₃ chelates function as oxygen-transferring catalysts in aqueous oxidation processes. The oxygen source can be a peroxide or even oxygen from the air, because they can activate both hydroperoxyl radicals and molecular oxygen. Thus, they can be advantageously applied in the modelling of biochemical oxidation processes [New J. Chem., 26, 1238-45 (2002)].

The practical application of Q ₂ and Q3 chelates is the most significant in bleaching fibres, textiles, and papers, as well as in cleaning textiles and clothing. Transition metal chelates had been applied for a longer time as activators in peroxide bleaching processes. The use of TACN chelates is preferred because the amount of organic and inorganic peroxide compounds contained in cleaning/bleaching materials containing such activators can be greatly reduced, using oxygen from the air as an oxidizing reagent. Thereby the environmental load of bleaching plants, laundrettes and households can be reduced by a great extent.

For these purposes usually such (Q ₂ )- and (ChHype chelates are used which comprise the 1 ,4,7-trimethyl-1 ,4,7-triazacyclononane ligand (R ³ =R ⁴ =R ⁵ =methyl).

Production of manganese complexes of the (Q ₂ ) and (Q ₃ ) type, or state-of-the-art, environmentally friendly bleaching materials comprising such compounds are disclosed in a number of patent descriptions, e.g. in US 5,244,594, US 5,246,621 and W095/27775. According to US 5,246,612 the same chelates are used as activators in state-of-the-art automatic dishwasher powders. The production of one of the most widespread Mn-containing, oxygen -transfer complex catalysts, [Mn ^(IV) ₂ (MO) ₃ (Me3-TACN) ₂ ](PF ₆ ) ₂ ^* H ₂ 0, is disclosed in US 5,153,161 ; US 5,274,147; and US 5,256,779.

According to US 8,735,613 the above mentioned double-core Mn(IV) complexes are used as catalysts in propylene oxidation.

Tosyl derivatives of those homologues of the TACN base compound which have higher numbers of ring members were first produced by H. Stetter and E.E. Roos by the cyclization of the sodium salts of α,ω-disulphonamides with α',ω'- dihaloalkanes, with high dilution and poor yield [Chem. Ber., 87, 566-71 (1954)]. Later a process based on a similar principle but being significantly more effective was published by J. E. Richman and T. J. Atkins [J. Am. Chem. Soc. 96, 2268-70 (1974)], which process is often referenced even nowadays.

US 5,284,944 is also based on the Richmann-Atkins synthesis but includes a number of improvements which make it suitable for industrial-scale production.

(Ao) (Ai)

Ts

N I

TsO OTs NaOH / toluene / water / PTC ^{~ N}

+

Ts Ts Ts \— / i s

PTC: phase transfer catalyst

TACN can be produced from the tritosyl derivative (Ci) by boiling in 90% sulfuric acid followed by liberation by a strong base.

(Ci) TACN Me ₃ -TACN (la), the most gererally used derivative of TACN, is produced without isolating TACN, by the well-known reductive methylation using formic acid and formaldehyde, since that is the only way to prevent the formation of overmethylated quaternary derivatives.

H CH _;

TACN Me ₃ -TACN (la)

The common disadvantages of the above processes lie in the harsh reaction conditions (high temperature, corrosive reagents) and, first and foremost, high starting material specifics. For example, to build up the relatively small TACN molecule (Mr: 129,20), 5 moles of tosyl chloride (Mr: 190,65) are used, of which not a single atom is built into the molecule, but is rather discharged into the environment as waste. Also, a significant environmental load is posed by the use of high amounts of sulfuric acid. In Example 1 of US 5,284,944 a cumulative yield of -60 % is specified for Me ₃ -TACN. US2014/0142298 discloses a process based on a completely novel chemical principle. In the first example of the description (Example A) the starting compound diethylenetriamine (A ₀ ) is cyclized with chloroacetaldehyde (D), and then octahydro-1 H-imidazo[1 ,2-a]pyrazine compound thus produced (formula (E) in the present description and compound (1 ) in the cited patent description) is reacted with 3 moles of benzyl bromide [(F) = Bn-Br] and thereby the quaternary salt 1 ,4,7- tribenzyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium bromide of the formula (Gi) is obtained. Then, by cleaving the 4N-9C bond with sodium borohydride, 1 ,4,7- tribenzyl-TACN of formula (Iw) is produced. A cumulative yield of 37% is specified for the entire process.

(Ao) (D) (E) (Fi) (GO (Iw)

The TACN base compound - compound (3) of the cited patent description - is produced by catalytic debenzylation of the compound (Iw), in a manner known from prior art.

(Iw) TACN

No example related to the production of TACN derivatives from TACN is presented.

In a similar manner, from the compound (E) (i.e. compound of the formula (E)) 1 ,4,7-tris(pyridin-2-ylmethyl)-TACN is produced with 2-(bromomethyl)pyridine hydrobromide (Example G), with a yield of 31 %.

It is no accident that the process is not illustrated with the introduction of smaller alkyl groups, because in such a case the quaternization of the two secondary nitrogen atoms ( N, 7N) is inevitable, and thus the monoalkylation of 1 N and 7N is not feasible.

This is a serious drawback of this process, because, by way of example, a key Me ₃ -TACN intermediate that is analogous with the above compounds and is very important from the aspect of practical application, the compound of the general formula (G ₂ ) - wherein X ^" is a halogenide ion or a suitable complementer base, e.g. H ₃ COS0 ₃ ^~ , i.e. a 1 ,4,7-trimethyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium salt cannot be produced by the process.

(G ₂ )

Also, the process is not suitable for producing directly with acceptable selectivity the compounds of the type 1 R ⁶ -4R ⁷ -7R ⁶ -TACN, of the general formula (Ix) that are especially important as chelators. In the formula, R ⁶ and R ⁷ are primary non-bulky alkyl groups, e.g. methyl, ethyl or normal propyl (n-propyl) group.

(Ix)

As an alternative to the direct 1 ,4,7 trisubstitution of the compound (E), diacylation with the anhydride of the formula (llz), i.e. Boc ₂ 0, is also presented (Example J), wherein the suitable 1 ,7-diBoc derivative of the formula (lllz) is produced, and by quaternizing same with benzyl bromide (Example K) 1 ,7-diBoc-4-benzyloctahydro- 1 /-/-imidazo[1 ,2-a]pyrazin-4-ium bromide, and then, after removing the Boc protective groups, 4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium bromide is produced [Example L). No example is given for producing TACN derivatives from the bicyclic quaternary salts thus produced. The compound 1 ,7-diBoc-octahydro- 1H-imidazo[1 ,2-a]pyrazine produced on the basis of Example J is quaternized with methyl iodide (IVa) to further produce the compound of the formula (Vz), i.e. 1 ,7- di-Boc-4-methyloctahydro-1H-imidazo[1 ,2-a]pyrazin-4-ium iodide (Example M).

(E) (llz) (lllz) (IVa) (Vz)

However, using the process disclosed in US2014/0142298 it is not possible to convert this quaternary compound (Vz) into a TACN derivative, because sodium borohydride used in the process is not capable of cleaving the 4N-9C bond. On page 80 of her dissertation Synthesis and studies of new optimized chelating agents, (Universite de Bourgogne, 2012) Pauline Desorgere makes a reference to an attempt for reducing the compound (Vz) with lithium aluminium hydride where it was possible to detect by means of mass spectrometry the Me ₃ -TACN produced, but it was produced in such a low amount that it was impossible to isolate.

In addition to the four above cited ones, no further example - neither alkylation nor acylation - is presented in US2014/0142298 for the direct 1 ,4,7-trisubstitution of the compound (E).

DESCRIPTION OF THE INVENTION

Based on the above, the object of the invention is to provide a process that is suitable for producing the above defined TACN derivatives of the general formula (I) with good yield, using inexpensive reagents, and in a direct manner, i.e. without the preparation of the unsubstituted TACN. This object was accomplished by providing the processes according to the invention. The invention is based on the recognition that the different reactivity of the individual nitrogen atoms of the key compound (E) can be preferably exploited and thereby such compounds of the general formula (V) can be produced, from which the TACN derivatives of the general formula (I), among them 1-alkyl-4,7-dimethyl- TACN and the most important one, ,4,7-trimethyl-TACN, i.e. the compound of the formula (la) can be produced.

Furthermore, our experiments led to the unexpected recognition that complex aluminium hydrides - such as e.g. lithium aluminium hydride, sodium bis(2- methoxyethoxy) aluminium hydride known as RedAI, LiAIH(O e) ₃ , LiAIH(OtBu) ₃ or DIBALH) - being more reactive than sodium borohydride used in US2014/0142298 are capable of cleaving the 4N-9C bond of the above defined compound of the formula (Vz), and also of simultaneously reducing the Boc groups into methyl groups. Thereby, it was possible to produce Me3-TACN of the formula (la) from the compound (Vz) that hitherto had been considered as useless.

The invention relates to a process for the production of compounds of the general formula (I),

I

N-

N

R ² V J CH.

(I)

wherein

R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group; and

R ² is, independently of R ¹ , a linear or branched alkyl group having 1 to 4 carbon atoms; or -Z-CH ₂ -T group, wherein

Z is a linear or branched alkylene group having 1 to 4 carbon atoms; and T is -OH or -NR ¹⁰ R ¹¹ group, wherein

R ¹⁰ and R ¹¹ are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

characterised in that

a)

compound of the formula (E):

(E)

is reacted with an acid derivative of the general formula (II):

wherein

R ⁸ is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group; and

W is halogen atom, a linear or branched alkoxy group having 1 to 4 carbon atoms, or an -0-C(0)-R ⁸ group;

thereby acylating the compound of the formula (E) at the 1- and 7-positions (wherein the term acylation is understood as extending also to formylation), a bicyclic intermediate compound of the general formula (III) thus obtained is optionally isolated:

(III),

wherein R ⁸ is as defined above for formula (II),

and the product of the general formula (III) is reacted with an alkylating agent of the general formula (IV):

Y-X wherein :

Y is R ² , a -Z-COOR ⁹ , -ZCN or -Z-CONR ¹⁰ R ^{1 1} group, wherein

R ² is as defined above for formula (I),

Z is as defined above for formula (I),

R ⁹ is a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

R ¹⁰ and R ¹ are, independently of each other, hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

and X is halogen or an R ² OS0 ₃ group, wherein R ² is as defined above;

thereby the compound of the general formula (III) is alkylated at the 4-position

(quaternized),

and a bicyclic quaternary compound of the general formula (V) thus obtained:

(V),

wherein R , Y and X are as defined above for formulas (II) and (IV),

is reacted with a complex aluminium hydride, and thereby the compound of the general formula (I) is obtained, which is optionally isolated and is optionally purified; or compound of the general formula (III):

(I"), wherein R is as defined above for formula (II),

is reacted with an alkylating agent of the general formula (IV):

Y-X

(iv), wherein Y and X are as defined above,

and is thus alkylated at the 4-position,

and a bicyclic quaternary compound of the general formula (V) thus obtained

(V),

wherein R ⁸ , Y and X are as defined above for formulas (II) and (IV),

is reacted with a complex aluminium hydride, and thereby the compound of the general formula (I) is obtained, which is optionally isolated and is optionally purified; or c) a bicyclic quaternary compound of the general formula (V):

(V),

wherein R ⁸ , Y and X are as defined above for formulas (II) and (IV), is reacted with a complex aluminium hydride, and the compound of the general formula (I) obtained is optionally isolated and is optionally purified.

Accordingly, any of the above described processes a), b), or c) can be used according to the invention for producing a compound of the general formula (I).

By the new processes, among others a novel compound of the formula (Id) was produced, which compound is also a subject matter of our invention. This -OH terminated derivative is especially significant because it is capable of binding 2- (TACN)-ethyl groups to other molecules ("mother molecules") - including macromolecules, and more particularly, biopolymers - and thereby allows for producing chelators for various purposes.

The invention further extends to the compounds of the general formulas (III) and (V) produced in the above described process, which are intermediates of the process a) as described below:

In the novel compounds of the general formula (III) according to the invention

(Hi).

R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group; with the proviso that R ⁸ is a group other than a te/f-butoxy group.

In the novel compounds of the general formula (V) according to the invention

(V),

R is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, phenyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, or phenoxy group;

Y is R ² , a -Z-COOR ⁹ , -ZCN or -Z-CONR ¹⁰ R ¹¹ group, wherein

R ² is a linear or branched alkyl group having 1 to 4 carbon atoms, or a -Z-CH ₂ -T group, wherein

Z is a linear or branched alkylene group having 1 to 4 carbon atoms; and

T is -OH or -NR ¹⁰ R ¹¹ group, wherein R ¹⁰ and R ¹¹ are the same or different, and are hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

R ⁹ is a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group;

R ⁰ and R ¹ are, independently of each other, hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or benzyl group; and X ^" is a halogen or an R ² OSO ₃ ^~ ion,

with the proviso that the compound is other than 1 ,7 bis[(ferf-butoxy)carbonyl]-4- methyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium-iodide.

DETAILED DISCLOSURE OF THE INVENTION

Preferred compounds according to the invention are 1 ,7-diformyl-octahydro-1 /-/- imidazo[1 ,2-a]pyrazine (formula Ilia, see below) and 1 ,7-diacetyl-4-methyl- octahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium iodide (formula Vc, see below).

The scheme of the reactions related to the processes according to the invention is the following:

(E) (M) (III)

(IV) (V) (I) ln the formula (II) R preferably is hydrogen atom, methyl, phenyl, or tert-butoxy group, and the leaving group W preferably is

an alkoxy group having 1 to 4 carbon atoms, more preferably methoxy or ethoxy group, or an -0-C(0)-R ⁸ group wherein R ⁸ is tert-butoxy group (i.e. the -0-C(0)-R ⁸ group is preferably a pivaloyl group).

If W is a halogen atom, it is preferably a chlorine atom. The compound of the general formula (II), used as a diacylating agent, may therefore be e.g. an acid halide, e.g. acetyl chloride, benzoyl chloride, or preferably an ester, preferably a methyl ester, e.g. methyl formate, or an anhydride, e.g. di-ferf-butyl dicarbonate (Boc ₂ 0).

In our experiments it was found that the compound (E) is highly acid-sensitive, it decomposes quickly under the effect of traces of organic or inorganic acids. As a result, in case the acylation processes are performed with acid chlorides or anhydrides (e.g. with acetic acid anhydride or mixed acetic acid-formic acid anhydride) in the presence of a base (organic or inorganic), the corresponding amides can be produced with much lower yield compared to acylations with esters, several decomposition products can be detected. Furthermore, our experiments have led to the unexpected recognition that in case the starting compound (E) is reacted with an ester without a base, in addition to the production of a compound of the general formula (III) the decomposition of the starting compound (E) was also observed, but using an ester for the production in the presence of an organic or inorganic base (such as, e.g. alkaline or alkaline earth metal carbonates and hydrogencarbonates and alcoholates, e.g. Na ₂ CO ₃ , K ₂ C0 ₃ , Cs ₂ C03, NaHC03, sodium methoxide) the required amide (compounds of the general formula III) can be produced with a favourable yield and purity.

To prevent adverse side reactions, in the case of using esters the acylation reaction is preferably performed in the presence of 0.3 - 3 equivalent of an alkaline or alkaline earth metal carbonate or bicarbonate, said amount is relative to the compound (E), more preferably of 0.5 - 1 equivalent of sodium, potassium or cesium carbonate or sodium alcoholate, preferably sodium methylate or sodium ethylate. In the case of using acid halides or acid anhydrides, for binding the hydrogen halogenide forming in the reaction preferably an amount of 2 - 5 equivalent of non-reactive organic base (relative to the compound (E)), preferably an amount of 2 - 3 equivalent of triethylamine or ethyl diisopropylamine is used. The diacylation reaction performed to produce a compound of the general formula (III) is typically performed at a temperature of -10 °C - 100 °C, preferably at a temperature of 0 - 60 °C.

As a solvent, preferably an excess of the compound of the general formula (II), or an indifferent aprotic solvent - preferably acetonitrile, a halogenated hydrocarbon, such as dichloromethane, chloroform, or an ether or aromatic hydrocarbon, most preferably toluene - is used.

In the diacylation reaction the relative molar ratio of the compounds (E) and (II) is preferably 1 : 2 - 1 : 50, more preferably 1 : 2 - 1 : 33. In the process a) the product of the general formula (III) is optionally isolated.

To produce a compound of the general formula (V) the 4N nitrogen atom of the respective compound of the general formula (III) is alkylated using an alkylating agent of the general formula (IV). In the general formula (IV) Y is preferably methyl group, ethyl group, or ethoxycarbonylmethyl group.

X is preferably CI, Br, I, or CH ₃ OS0 ₃ .

The alkylation reaction is preferably carried out in a polar organic solvent, e.g. in acetonitrile. In the alkylation reaction the relative molar ratio of the compounds (III) and (IV) is preferably 1 :1 - 1 :5 and/or the reaction temperature is 10-140 °C, preferably 20-120 °C depending on the reactivity of the compound (IV). If the produced quaternary compound of the general formula (V) crystallizes well, it is typically isolated by filtration after crystallization, and in the opposite case chromatographic purification may be applied or most simply isolation and purification can be skipped and the concentrate of the compound of the general formula (V) produced in the reaction can be directly utilized in the subsequent synthesis step. ln the process a) or b) the 1 ,7-diacyl-4-alkyl-ammonium salt of the general formula (V) obtained in the alkylation reaction is used after isolation or without isolation in the reaction performed with a complex aluminium hydride. The complex aluminium hydride used in the reaction with a complex aluminium hydride is preferably RedAI ^® , LiAIH ₄ , LiAIH(OMe) ₃ , LiAIH(OtBu) ₃ or DIBALH. In the reaction, typically an aprotic, halogen-free, anhydrous organic solvent not reacting with the complex aluminium hydride, preferably a solvent identical with the diluent of the applied complex aluminium hydride reagent, e.g. toluene or tetrahydrofuran is used, and expediently an inert, protective gas, preferably nitrogen or argon atmosphere capable of oxygen exclusion is applied. The reaction temperature is typically chosen - depending on the reactivity of the particular compound of type (V) - to fall in the range of 0 °C - 140 °C, preferably in the range of 20 °C - 120 °C. Reaction time is typically determined on the basis of monitoring the reaction by chromatography, preferably TLC or HPLC. To convert the compound of the general formula (V) into the compound of the general formula (I), i.e. to reduce the two C=0 groups and cleave the 4N-9C bond, in principle an amount of 10 hydride equivalent of complex aluminium hydride reagent is required, but in case also the Y group contains reducible substituents, e.g. C=0 or nitrile, the simultaneous reduction thereof requires a further amount of the complex aluminium hydride. Thus the molar ratio of the complex aluminium hydride relative to the compound of the general formula (V) may typically be 2.5 - 14, preferably, with RedAI ^® , 4 - 12. The reaction mixture is typically quenched by applying a dilute aqueous solution, preferably a basic solution, e.g. 10% NaOH solution. The product of the formula (I) is typically isolated by extraction with an organic solvent, preferably with the inexpensive toluene.

The product of the formula (I) can be isolated and purified in a known manner, preferably by vacuum fractioning.

When there is a possibility for producing a salt derivative that crystallizes well, then typically a suitable salt of the compound (I) is produced, which can be isolated by filtration and thereby can be purified. In the opposite case the organic extract can be evaporated, and then the pure TACN derivative of the general formula (I) can be obtained by vacuum distillation from the concentrate thus produced.

When R ⁸ is hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group, the R ⁸ group is not converted in the reaction with the complex aluminium hydride, i.e. R ⁸ and R ¹ are identical. However, in case R ⁸ is a linear or branched alkoxy group having 1 to 4 carbon atoms or phenoxy group, the R ⁸ group is converted into hydrogen in the reaction with the complex aluminium hydride.

When Y is a linear or branched alkyl group having 1 to 4 carbon atoms, or phenyl group, the Y group is not converted in the reaction with the complex aluminium hydride, i.e. Y and R ² are identical. In case, however, Y is -Z-T'-, wherein Z is as defined above, and T' is a terminal group capable of reduction, e.g. -CN, -COOR ⁹ or -CONR ¹⁰ R ¹¹ , wherein R ⁹ , R ¹⁰ , R ¹¹ are as defined above, the -Y group is converted into an -R ² group of the -Z-CH ₂ -T type.

For converting the compounds of the general formula (V) into the compounds of the general formula (I) it has been found to be particularly preferable to apply sodium bis(2-methoxyethoxy)-aluminium hydride, commonly known as an industrial reducing agent under the trade names Vitrid ^® and RedAI ^® .

According to certain embodiments of the invention the produced compound of the formula (I) is trimethyl-TACN or the compound of the formula (Id).

According to certain embodiments of the invention the compound (E) is reacted with methyl formate of the formula (Ma), also functioning as a solvent, followed by methylation at the 4-position, without isolation, of the obtained intermediate product (Ilia) presented in the reaction scheme below. As a methylating agent, methyl iodide of the formula (IVai) or dimethyl sulfate of the formula (IVa ₂ ) or methyl chloride of the formula (IVa ₃ ) is applied in a molar ratio of 1-5 : 1 to the compound of the formula (Ilia), in the presence of a halogenide catalyst - preferably sodium iodide - which is used in a molar ratio of 0 - 0.05 calculated for the compound (Ilia) in a polar organic solvent, preferably acetonitrile. By cleaving the 4N-9C bond of the thus produced bicyclic quaternary compound of the formula (Va-i) or (Va ₂ ) or (Va ₃ ) with a complex aluminium hydride - preferably with 70% RedAI ^® in toluene - Me3-TACN of the formula (la) is obtained, which is extracted from the reaction mixture by extraction with an organic solvent - preferably toluene -, and is optionally purified by distillation.

(E) (Ma) (Mia)

UB-14878

It can easily be seen that the production of the (Ilia) diformyl derivative has significantly better atom efficiency compared to the case of the (lllz) diBoc compound, which in itself promises economic and environmental advantages.

UB-14878 (IVa^ (Va (la)

UB-14879 UB- 14054

la) + H ₃ C-OSO ₃ CH ₃

UB-14878 (IVa ₂ (Va ₂ ) (la)

UB-15056

UB- 14054 -CH ₃

UB- 14878 (IVa ₃ ) (Va ₃ ) (la)

UB-15190 UB- 14054

The processes according to the present invention can equally be applied for producing complexly substituted TACN derivative chelators, and simpler derivatives to be produced in high volume, e.g. Me ₃ -TACN (UB-14054).

Notable is the production of TACN derivatives that comprise an R ² terminal linker group which can be characterised by the general formula -Z-CH2-T. Z and T are as defined above.

By way of example, according to a preferred embodiment of the invention the compound of the formula (Ilia) is quaternized at the 4-position with the bromoacetic acid ethyl ester of the formula (IVd) in acetonitrile solution at room temperature, and, by reacting the thus produced quaternary ammonium bromide compound of the formula (Vd) with 10- equiv. RedAI ^® in a toluene solution at reflux temperature, including reducing the carbethoxy group into hydroxymethyl group, and by quenching the reaction mixture with dilute sodium hydroxide solution, and subsequently evaporating the organic phase the compound of the formula (Id) is obtained.

The invention is illustrated without limiting the scope thereof by way of the following examples.

EXAMPLES

Example 1 - Reference Example Octahydro-1 H-imidazo[1 ,2-a]pyrazine (E)

According to Example A of US2014/0142298 A1

A 10-litre double glass reactor equipped with a stirrer is filled with 6000 ml of acetonitrile, 260 g (2.52 mol, 1.00 eq.) of diethylenetriamine and 696 g (5.040 mol, 2.00 eq.) of anhydrous potassium carbonate, and then 435 g (2.77 mol, 1.10 eq) of 50% aqueous chloroacetaldehyde solution is added under stirring at 10 - 20 °C over a period of 2½ hours. Stirring is continued at 25 °C with gas chromatographic monitoring until the diethylenetriamine content of a sample taken from the reaction mixture drops below 5 area percent. Reaction time: 16 hours.

The inorganic salt mixture is filtered from the reaction mixture, and the filtrate is evaporated in a rotary evaporator in vacuum.

264.4 g of yellowish oil is obtained as crude product which is fractionated in 1 - 1.5 mbar vacuum. The pure compound (E) is obtained at 50 °C and a pressure of 1.3 mbar as 136 g (1.07 mol) of colourless oil with a purity of 97.2% (GC), which corresponds to a yield of 42.4%.

¹ H-NMR (500 MHz, CDCI ₃ , T=300K) δ 3.24 (dd, 1 H), 3.17-3.07 (m, 2H), 3.02-2.90 (m, 3H), 2.87-2.78 (m, 2H), 2.58 (dd, 1 H), 2.37-2.27 (m, 2H), 1 .61 (s, br, 2H).

Example 2

1, 7-di-tert-butyloctahydro-1 H-imidazo[1 ,2-a]pyrazine-1 , 7-dicarboxylate (UB-14833, lllz)

A solution of 13.7 g (63 mmol) of Boc ₂ 0 (llz) in 70 ml of dichloromethane is added dropwise at room temperature to 4.0 g (31.4 mmol) of octahydro-1H-imidazo[1 ,2- a]pyrazine (E) dissolved in 70 ml of dichloromethane. After stirring for 3 hours the reaction mixture is evaporated, the evaporation residue is dissolved in 100 ml of diethyl ether, and the insoluble inorganic contaminants are filtered out. The filtrate is evaporated. The resulting reddish-brown oil (10.5 g) (lllz, UB-14833) is used without purification. 1 , 7-bis[(tert-butoxy)carbonyl]-4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium iodide (UB-14834, Vz)

10.5 g (32 mmol) of the above compound (lllz) is dissolved in 50 ml of acetonitrile, followed by adding dropwise, at 0°C, 2 ml (32 mmol) of methyl iodide (IVa) dissolved in 13 ml of acetonitrile. Thereafter, the mixture is stirred for 12 hours at room temperature. The reaction mixture is evaporated, the obtained oily residue is triturated with 100 ml of diethyl ether, is filtered, washed with ether and dried.

Product: 12.5 g of a yellow solid (Vz, UB-14834). ¹ H-N R (500 MHz, DMSO-d ₆ , T=333K) 5 5.12 (t, 1 H), 4.15-3.55 m, 10H), 3.27 (s, 3H), 1 .47 (s, 9H), 1.44 (s, 9H). Me3-TACN, (UB-14054, la)

12.5 of the above compound (Vz) is added to 88 ml (266 mmol) of 60% Red-AI in toluene at 65 °C portionwise. After the addition the mixture is stirred for 3-4 hours at 65°C. The reaction is monitored by GC and HPLC. After the reaction has completed, the reaction mixture is added dropwise to 60 ml of 10% NaOH solution under intensive cooling, followed by extraction with 3x150 ml of heptane. The organic phase is evaporated to dryness.

Product: 4.3 g of yellow oil. Me ₃ -TACN (la, UB-14054) content is 60% by GC and HPLC.

1H-NMR (500 MHz, DMSO-d ₆ , T=300K) δ 2.61 (s, 12H), 2.27(s, 9H). Example 3

1, 7-diformyloctahydro-1 H-imidazo[1 ,2-a]pyrazine (UB-14878, Ilia)

28.4 g (223 mmol, 1.00 eq.) of starting compound (E) is dissolved in 450 ml of methyl formate (7344 mmol, 32.93 eq.) (Ha), which also functions as solvent. 62.6 g of anhydrous potassium carbonate (466 mmol, 2.09 eq.) is added, and the suspension is stirred at 35 °C with reaction progress being monitored by TLC. Reaction time: 24 hours. After filtering out the inorganic salt mixture the solution is evaporated. 42.7 g of a yellowish oil is obtained as the crude (Ilia) (UB-14878). The substance can be used in the subsequent steps of the synthesis without purification.

¹ H-NMR (500 MHz, DMSO-d ₆ , T=300K) δ 8.24, 8.23, 8.22, 8.20, 8.09, 8.07, 8.04, 8.03 (s, 2H, 4 rotamers), 4.77, 4.35, 4.19, 4.09 (dd, dd, dd, dd, 1 H), 4.00-2.30 (m, 10H).

Example 4

1, 7-diformyl-4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium iodide (UB-14879, 41 .3 g (225 mmol, 1 .00 eq.) of crude UB-14878 (Ilia) is dissolved in 470 ml of acetonitrile and14.3 ml (229 mmol, 1 .02 eq.) of methyl iodide (IVa-i) is added. The mixture is stirred at 25 °C. After 2-3 hours the (Va^ quaternary product begins to precipitate in a white crystalline form. Reaction progress is monitored by TLC. After 10 hours of stirring the product is filtered out from the reaction mixture, it is washed with 2 x 50 ml of acetonitrile, and is dried in vacuum at 60 °C.

48.9 g of dry, white powder-like product is obtained (Vai , UB-14879), which corresponds to a chemical yield of 67%.

¹ H-NMR (500 MHz, DMSO-d ₆ , T=353K) δ 8.41 , 8.30, 8.14 (s, br, s, s, 2H, rotamers), 5.36, 5.20 (s, br, s, br, 1 H, rotamers), 4.45-3.55 (m, br, 10H), 3.33 (s, 3H).

Example 5

1, 7-diformyl-4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium methyl sulfate (UB-15056, Va ₂ )

519 mg (2.8 mmol, 1 eq.) of crude UB-14878 (Ilia) is dissolved in 10 ml of acetonitrile and 630 mg (5 mmol, 1 .78 eq.) of dimethyl sulfate (IVa ₂ ) is added. The mixture is stirred at 25 °C, with reaction progress being monitored by TLC.

After 10 hours of stirring no starting compound can be detected. The reaction mixture is evaporated in a rotary evaporator in vacuum. 1600 mg of dark brown oily crude product is obtained, which is identified as 1 ,7-diformyl-4-methyl- octahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium methyl sulfate (Va ₂ ) by ¹ H-NMR, and used in the next step without isolation and further purification similarly to the product produced according to Example 4.

1H-NMR (500 MHz, DMSO-d ₆ , T=353K) δ 8.41 , 8.29, 8.12 (s, br, s, br, s, br, 2H, rotamers), 5.38, 5.30, 5.14 (s, br, s, br, s, br, 1 H, rotamers), 4.45-3.55 (m, br, 10H), 3.39 (s, 3H)

Example 6

1 -diformyl-4-methyloctahydro-1H-imidazo[1,2-a]pyrazin-4-ium chloride (UB- 15190, Va ₃ )

10 ml of acetonitrile, 1 .0 g (20 mmol, 3.64 eq.) of methyl chloride (IVa ₃ ), 50 mg (0.3 mmol, 0.05 eq.) of sodium iodide and 1000 mg (5.5 mmol, 1 .0 eq.) of crude UB-14878 (Ilia) are fed to a pressure-resistant reaction vessel cooled to -30 °C. After closing the reactor the substance, while stirred intensively, is left to warm up to room temperature, and is then slowly heated to 80 °C under continued stirring. Reaction progress is monitored by TLC analysis of samples taken every 4-6 hours. After 30 hours of stirring the starting compound (Ilia) cannot be detected.. The reactor is cooled to a temperature below 10 °C carefully open, and the precipitated white crystalline substance is filtered, washed with acetonitrile, and dried. The product obtained is 840 mg (3.6 mmol) of 1 ,7-diformyl-4-methyloctahydro-1 H- imidazo[1 ,2-a]pyrazin-4-ium chloride (Va3, UB-15190), which corresponds to a chemical yield of 65%, and can be used in the subsequent reaction similarly to the product produced according to Example 4.

¹ H-NMR (500 MHz, DMSO-d ₆ , T=353K) δ 8.41 , 8.29, 8.13 (s, br, s, s, 2H, rotamers), 5.35, 5.19 (s, br, s, br, 1 H, rotamers), 4.45-3.55 (m, br, 10H), 3.32 (s, 3H).

Example 7

Me ₃ -TACN (la, UB-14054).

44 ml of 70% toluene solution of RedAI® (155 mmol, 5.00 eq.) is heated to 65 °C under stirring in a nitrogen-inertized flask, followed by slowly - in about 1 hour - adding 10.0 g (31 mmol, 1 .00 eq.) of the compound (Vai , UB-14879). The reaction mixture is heating up intensively and gas evolution also being detected. After adding the reagent the progress of the reaction is monitored by TLC. After a period of 5 hours has elapsed, no starting compound can be detected anymore.

20 ml of 10%) NaOH solution is added for quenching the mixture while applying ice cooling, followed by separating the phases. The inorganic phase is extracted with 2 x 50 ml of toluene, the toluene phases are combined and dried with anhydrous sodium sulfate.

After evaporating the toluene, 3.9 g of a yellowish oil is obtained, which is, on the basis of HPLC, Me ₃ -TACN (la) with a purity of 94%. Yield: 74 %. Thus, the product is directly applicable for most purposes. Further purification is performed by vacuum fractionation. The main fraction is collected in a 21 mbar vacuum at 77 - 85 °C. Example 8

4-ethyl-1 -diformyloctahydro-1H-imidazo[1,2-a]pyrazin-4-ium iodide (Vb, UB- 15111)

4.2 g (23 mmol) of the compound of the formula (Ilia) (UB-14878) is dissolved in 50 ml of acetonitrile at room temperature, followed by adding 3.6 g (23 mmol, 1 .00 eq.) of ethyl iodide (IVb). After stirring for 24 hours the reaction mixture is evaporated and the obtained crude product is purified by reverse phase flash chromatography method, using water as eluent. The obtained solidifying oil is crude 4-ethyl-1 ,7-diformyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium iodide (Vb, UB-15111) with a weight of 3.5 g, which corresponds to a yield of 46%.

¹ H-NMR: (500 MHz, DMSO-d ₆ , T=300 K) δ 8.45, 8.26, 8.25, 8.15, 8.14, 8.13, 8.12, 8.05 (s, 2H, 4 rotamers), 5.44, 5.37, 5.33, 5-15 (t, dd, t, t, 1 H), 4.64-3.39 (m, 12H), 1.41-1.24 (m, 3H). Example 9

1-ethyl-4, 7-dimethyl-TACN (lb, UB-15139)

2.8 g (8 mmol, 1.00 eq.) of the compound (Vb, UB-151 1 1 ) is dissolved in 10 ml of toluene, followed by adding a 70% toluene solution of 10 ml (35 mmol, 4.37 eq.) of RedAI ^® at room temperature under argon atmosphere. After the addition, the reaction mixture is stirred for 6 hours at reflux temperature, followed by quenching the reaction mixture with 15 ml of 10% NaOH solution. After separating the phases the lower, aqueous layer is extracted with 2 x 15 ml of toluene. The toluene phases are combined and are evaporated in a rotary evaporator in vacuum.

640 mg of yellowish oil is obtained, which is identified by GC as 1-ethyl-4,7- dimethyl-TACN (lb, UB-15 39) having a purity of 80%. Yield: 42 %.

¹ H-NMR: (500 MHz, DMSO-d ₆ , T=300K) δ 2.66 (s, 4H), 2.64-2.58 (m, 8H), 2.48 (q, 2H), 2.27 (s, 6H), 0.96 (t, 3H).

Example 10

1 , 7-diacetyl-4-methyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium iodide (Vc, UB- 15156)

5.0 g (39 mmol, 1.00 eq.) of starting compound (E) is dissolved in 50 ml of acetonitrile, followed by adding 15.2 g of ethyl diisopropyl amine (EDIPA) (118 mmol, 3 eq.), and then the mixture is cooled to 10 °C and 6.8 g (87 mmol, 2.23 eq.) of acetyl chloride (lie) is added. After 1 hour stirring at room temperature the starting compound can no longer be detected by TLC in the reaction mixture.

5.6 g (39 mmol, 1.00 eq.) of methyl iodide (IVa) is added to the reaction mixture containing 1 ,7-diacetyl-octahydro-1 H-imidazo[1 ,2-a]pyrazine (lllc, UB-15137)), and stirred for 3 hours at room temperature. The precipitated crystalline product is filtered out, washed with acetonitrile, and dried in vacuum at 40 °C.

2.7 g of white crystalline product, 1 ,7-diacetyl-4-methyl-octahydro-1 H-imidazo[1 ,2- a]pyrazin-4-ium iodide (Vc, UB-15156), is obtained, which corresponds to a yield of 20%.

¹ H-NMR: (500 MHz, DMSO-d ₆ , T=353K) δ 5.38 (s, br, 1 H), 4.65-3.50 (m, 10H), 3.29 (s, 3H), 2.09 (s, 3H), 2.07 (t, 3H).

Example 1

1 ,4-diethyl-7-methyl TACN (lc, UB-15095)

Under argon atmosphere, 2.1 g (6 mmol) of the compound (Vc, UB-15156) is added at 60 °C to 70% toluene solution of 9 ml (32 mmol, 5.33 eq.) RedAI ^® . After the addition the reaction mixture is stirred for 12 hours at 80°C. Reaction progress is monitored by gas chromatography. The reaction mixture is quenched by 15 ml of 10% NaOH solution, and is extracted with 2 x 10 ml of toluene. After evaporating the toluene, 1.0 g of a yellow oil is obtained as 1 ,4-diethyl-7-methly TACN (lc, UB-15095) identified by GC having a purity of 75%. Yield: 89 %.

1H-NMR: (500 MHz, DMSO-d ₆ , T=300K) δ 2.70-2.62 (m, 8H), 2.60 (s, 4H), 2.48 (q, 2H), 2.27 (s, 3H).

Example 12

4-(2-ethoxy-2-oxoethenyl)-1 , 7-diformyloctahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium bromide (Vd, UB-15160)

2.0 g (1 1 mmol, 1.00 eq.) of the compound UB-14878 (Ilia) is dissolved in 20 ml of acetonitrile, followed by adding 2.2 g (13 mmol, 1.18 eq.) of ethyl bromoacetate (IVd). The reaction mixture is stirred for 24 hours. The reaction mixture is then evaporated, and purified by reverse phase flash chromatography, using water as eluent. 1.2 g of a dense, yellow oil is obtained as 4-(2-ethoxy-2-oxoethenyl)-1 ,7- diformyl-octahydro-1 H-imidazo[1 ,2-a]pyrazin-4-ium bromide (Vd, UB-15160) identified by ¹ H-NMR. Yield: 31 %.

¹ H-NMR (500 MHz, DMSO-d ₆ T=300K) δ 8.43, 8.25, 8.23, 8.22, 8.16, 8.15, 8.1 1 , 8.09 (s, 2H, 4 rotamers), 5.66, 5.50, 5.32 (m, t, t, 1 H), 5.10-4.59 (m, 2H), 4.50-3.54 (m, 12H), 1.30-1.23 (m, 3H).

Example 13

2-(4 -dimethyl-1,4, 7-TACN-1-yl)ethan-1-ol (Id, UB-15187)

1.1 g (3 mmol, 1.00 eq.) of the compound UB-15160 (Vd) is dissolved in 10 ml of toluene, followed by adding a 70% toluene solution of 9 ml (32 mmol, 10.66 eq.) of RedAI ^® at room temperature under argon atmosphere. After the addition the reaction mixture is stirred for 6 hours at reflux temperature, followed by quenching the reaction mixture with 15 ml of 10% NaOH solution. After separating the phases the lower, aqueous layer is extracted with 2 x 10 ml of toluene. The toluene phases are combined and are evaporated in a rotary evaporator in vacuum.

350 mg of colourless oil is obtained as 2-(4,7-dimethyl-1 ,4,7-TACN-1-yl)ethan-1-ol (Id, UB-15187), and has a purity of 81 % by GC. Yield: 56 %.

1H-NMR (500 MHz, DMSO-d ₆ , T=300K) δ 3.43 (t, 2H), 2.69-2.64 (m, 4H), 2.63 (s, 4H), 2.62-2.59 (m, 4H), 2.57 (t, 2H), 2.27 (s, 6H).

Example 14

1 ,7-dibenzoyl-4-methyloctahydro-1 /-/-imidazo[1 ,2-a]pyrazin-4-ium iodide (Ve, UB- 15146)

1.5 g (12 mmol, 1.00 eq.) of starting compound (E) is dissolved in 15 ml of dichloromethane, followed by adding 4.7 g of ethyl diisopropyl amine (EDIPA) (36 mmol, 3 eq.), and then the mixture is cooled to 10 °C and 6.8 g (26 mmol, 2.17 eq.) of benzoyl chloride (lie) is added. After 24 hours stirring at room temperature the starting compound can no longer be detected by TLC in the reaction mixture.

The solvent is removed from the reaction mixture utilizing a rotary evaporator. 6.7 g of a dark brown, oil-like intermediate, 1 ,7-dibenzoyl-octahydro-1H-imidazo[1 ,2- a]pyrazine (llle, UB-15143) is obtained, which can be used in the subsequent synthesis without purification. The obtained crude intermediate UB-15143 (llle) is dissolved in 50 ml of acetonitrile, followed by the dropwise addition of 5.7 g (40 mmol, 3.33 eq.) of methyl iodide (IVa) and the reaction mixture is stirred for 3 hours at room temperature. The precipitated crystalline product is filtered, washed with acetonitrile, and dried in vacuum at 40 °C.

2.6 g of white crystalline product, 1 ,7-dibenzoyl-4-methyloctahydro-1 /-/- imidazo[1 ,2-a]pyrazin-4-ium iodide (Ve, UB-15146), is obtained, which corresponds to a yield of 45% counted for the starting compound (E).

1H-NMR: (500 MHz, DMSO-d ₆ , T=353K) δ 7.67-7.35 (m, 10H), 5.53 (dd, 1 H), 4.34- 3.73 (m, 10H), 3.39 (s, 3H).

Example 15

1 ,4-dibenzyl-7-methyl-TACN (le, UB-15097)

12 ml of 70% toluene solution of RedAI ^® (42 mmol, 5.00 eq.) is heated to 60 °C under stirring in a nitrogen-inertized flask, followed by slowly - in about 2.4 hour - adding 2.4 g (5 mmol, 1.00 eq.) of the compound UB-15146 (Ve). After the addition the mixture is stirred for 4 hours at 80 °C, and reaction progress is monitored by TLC. The reaction mixture is quenched by 15 ml of 10% NaOH solution, followed by separating the phases. The inorganic phase is extracted with 2 x 15 ml of toluene, the toluene phases are combined, and the solvent is removed by applying a rotary evaporator.

1.0 g of a yellowish oil is obtained as 1 ,4-dibenzyl-7-methyl-TACN (le, UB-15097). Yield: 56 %.

¹ H-NMR (500 MHz, DMSO-d ₆ , T=300K) δ 7.34-7.18 (m, 10H), 4.49 (s, br, 1 H), 3.57 (s, 4H), 2.73 (m, 8H), 2.63 (s, 4H), 2.24 (s, 3H).

The codes of the compounds included in the examples are summarized table below: