Patent Description:
Cyclen (<NUM>,<NUM>,<NUM>,<NUM>-tetraazacyclododecane) is a known compound largely used in the manufacturing of macrocyclic gadolinium complexes, which are widely employed as contrast agents in magnetic resonance imaging (MRI).

Several chemical processes are described in the literature for the preparation of Cyclen. Most of the reported synthetic routes are based on precursors of lower molecular weight that are suitably coupled to afford the macrocyclic ring and that differ on the methods used for the cyclization process.

Among them is the Richman-Atkins method (<NPL>) that starts from diethylene triamine and diethanolamine. The two starting materials, where the amino and hydroxyl groups are suitably protected, are first coupled to yield the tetraazacyclododecane ring then deprotected to obtain free Cyclen.

As an additional example, the Schering <CIT> patent discloses the tetramerization of protected ethanolamine via the corresponding protected aziridine which, after cyclization, is deprotected to yield Cyclen.

Alternative preparation methods are also known as employing triethylene tetramine (TETA) as starting material, first reacted with suitable dicarbonyl derivatives. The main synthetic steps include a first reaction with a dicarbonyl reagent to protect the amino groups other than the terminal ones that are then alkylated by an ethylene substituted reagent, for instance <NUM>,<NUM>-dibromoethane. The cyclization reaction thus affords a tetracyclic intermediate which is finally deprotected to give Cyclen; see, as an example, the patents or patent applications <CIT>, <CIT>, <CIT> and <CIT>.

All of these routes are usually characterized by low atomic efficiencies and cumbersome synthetic steps. In addition, the use and/or formation of hazardous compounds, i.e. aziridines, represents a major drawback for large scale industrial production.

A simpler approach was described by <NPL> and <NPL>); Vol. <NUM> (<NUM>)], starting from dithiooxamide and triethylene tetramine. Dithiooxamide acts as a templating agent for the additional ethylene bridging moiety that is needed to properly close the tetrameric ring. Then, Cyclen is finally obtained by reduction of the corresponding tricyclic bis-amidino derivative with diisobutyl aluminium hydride (DIBAL-H).

This route includes only two synthetic steps with high atomic efficiency. However, it presents the major drawback of using dithiooxamide, a quite expensive raw material further leading to the formation of ammonia and also of hydrogen sulfide as highly toxic by-product. This procedure, therefore, is not or hardly to be intended for the industrial production of Cyclen.

More recent attempts for Cyclen preparation are also reported where dicarbonyl derivatives alternative to dithiooxamide were used. To this extent, following the aforementioned synthetic scheme proposed by Reed, the patent application <CIT> discloses a method for the preparation of Cyclen comprising the use of oxamide in place of dithiooxamide, so as to obtain the tricyclic bis-amidino derivative finally reduced to Cyclen in the presence of lithium aluminium hydride. Nevertheless, the above method implies the release of gaseous ammonia as a byproduct and, remarkably, is further characterized by very poor yields in the final product.

The known drawbacks associated to the former manufacturing methods for Cyclen preparation are overcome by the process object of the present invention.

The present invention thus refers to a process for the preparation of Cyclen which process comprises:.

wherein the above alkyl groups, the same or different in each occurrence, are selected from straight or branched C<NUM>-C<NUM> alkyl groups.

For a better understanding of the reaction steps within the process of the invention see Scheme <NUM> below:
<CHM>
wherein R<NUM>, R<NUM> and R<NUM>, within the dialkyl alluminium hydride or trialkylamine alane complex, have the above reported meanings.

The process of the invention is particularly advantageous as it avoids the use and/or release of hazardous materials during the whole course of the reactions and further provides for the synthesis of Cyclen in high yields and purity, by efficiently operating under mild conditions.

The starting materials and all of the selected reagents are known and easily commercially available. Glyoxal, in particular, is much cheaper and certainly safer than dithiooxamide being used according to the aforementioned prior art processes.

Overall, and as better set forth below, the process of the invention appears to be particularly attractive for large scale industrial production.

The reaction of triethylene tetramine with glyoxal is known in the art as reported, for instance, by <NPL>] and leads to the formation of a mixture of four isomers which structures are reported below:
<CHM>.

The percentage of the said isomers, namely the composition of the resulting mixture, strongly depends on the adopted reaction conditions that may lead to the two couples of tricyclic derivatives having geminal (GEM) conformation, known to be thermodynamically favored, or vicinal (VIC) conformation, known to be kinetically preferred, each one in cis and trans configuration.

To this extent, however, it is worth pointing out that the VIC isomers are the sole useful compounds that, by reduction according to the process of the invention, allow for the preparation of Cyclen.

Conversely, and as further detailed in the experimental section, the corresponding reduction of the GEM isomers may only lead to the formation of a piperazine by-product (see structure below)
<CHM>.

As such, especially if the GEM isomers are preponderant or even present in significant amounts in the VIC/GEM mixture undergoing the subsequent reductive step, the obtained piperazine derivative may render much more difficult the final recovery and purification of Cyclen.

For all of the above reasons it is of paramount importance to rely on a process for Cyclen manufacturing that maximizes the yields in the VIC isomers.

To this extent, some efforts to obtain VIC rich mixtures are reported in the art.

As an example, <NPL>) disclosed the formation of the VIC isomers exclusively by operating in anhydrous conditions, that is by using ethanolic solutions of both glyoxal and triethylene tetramine as starting materials, at -<NUM> for <NUM> hours. However, this methodology is not applicable to the industrial scale, at least once starting from commercial glyoxal that is indeed available as an aqueous solution (maximum concentration of <NUM>% in water), so that the presence of water cannot be avoided.

In the alternative, the treatment of aqueous glyoxal with triethylene tetramine in ethanol, at room temperature and under overnight stirring, afforded the VIC isomers in about <NUM>-<NUM>%, as reported in the patent application <CIT>, even if no information are provided on the actual composition of the mixture.

Similar operating conditions for glyoxal and triethylene tetramine coupling but even requiring a prolonged reaction time of <NUM> hours, are also disclosed in the patent application <CIT>, though data on the composition of the isomers mixture are still missing.

Along these lines however, <NPL>] disclosed that by operating under the conditions reported in the prior art, more specifically according to the methodology disclosed in <CIT>, the initial reaction mixture containing an excess of VIC isomers changed its composition during the workup, so as to lead to a mixture of GEM and VIC isomers.

In particular, by analyzing the reaction mixture after only <NUM> hours through a micellar electrokinetic chromatographic method (MEKC), a mixture of VIC isomers was formed with no detection of the GEM ones, hence confirming that the former are the kinetically preferred reaction products.

Then, during workup and collection of the isolated product, a partial isomerization to GEM isomers was observed, hence leading to the aforementioned drawbacks that may be encountered during the subsequent reduction step on the undesired GEM isomers precursors.

Therefore, it is not only of paramount importance to rely on a process for Cyclen manufacturing being highly selective towards the VIC isomers but, also, on a process that minimizes the rate of conversion of the VIC isomers to the more stable GEM ones, during the workup phase.

All of the above is best accomplished by the present invention that provides for a very efficient process to obtain a convenient feed of VIC isomers for the subsequent chemical step of reduction, by starting from commercially available aqueous solutions of glyoxal. The said process allows for a selectivity high as <NUM>% or more in the VIC isomers, without any significant conversion of these latter to the GEM ones during the workup phase.

For the avoidance of doubts, the herewith referred VIC isomers are the cis and trans isomers of the bis-aminals referred to as decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine being obtained at the end of step (a) of the process.

Therefore, unless otherwise provided, the above terms/terminologies may be used interchangeably in the present description.

In practical terms, and to avoid as much as possible the above prior art drawbacks, the commercially available aqueous solution of glyoxal, more specifically the <NUM>% aqueous solution of glyoxal, is slowly added to the anhydrous ethanolic solution of the amine, for instance continuously or portionwise, by operating according to conventional means.

Preferably, the said glyoxal addition is carried out in a time period ranging from at least <NUM> minutes to at least <NUM> minutes. Even more preferably, the addition is carried out in a time period ranging from at least <NUM> minutes to at least <NUM> minutes.

After the addition of the aqueous solution of glyoxal is ended, the reaction is then brought to completion in a short period of time, for instance of from about <NUM> to about <NUM> minutes.

Overall, the reaction according to step (a) of the process is best accomplished in a time period of about <NUM> hour or less, for instance in a time period of from about <NUM> minutes to about <NUM> minutes, being this period comprehensive of both glyoxal addition and reaction completion.

It is thus a further object of the invention a process for the preparation of Cyclen wherein step (a) is carried out by adding an aqueous solution of glyoxal to a solution of the amine in anhydrous ethanol, and by carrying out the reaction in a time period of about <NUM> hour or less.

According to an additional embodiment of the invention, the reaction of step (a) is carried out below room temperature. The above conditions may suitably apply during the addition of glyoxal to the ethanolic solution of the amine and also during the course of the reaction up to completion.

It is therefore a further object of the invention a process for the preparation of Cyclen wherein step (a) is carried out by adding an aqueous solution of glyoxal to a solution of the amine in anhydrous ethanol, kept below room temperature, and by carrying out the reaction below room temperature.

Preferably, the temperature is in the range of from about <NUM> to about <NUM> and, even more preferably, from about <NUM> to about <NUM>.

From all of the above, it is clear to the skilled person that any of the preferred operative conditions of temperature and reaction time may be properly combined.

Therefore, it is a further preferred embodiment of the invention a process for the preparation of Cyclen wherein step (a) is carried out by adding an aqueous solution of glyoxal to a solution of the amine in anhydrous ethanol, kept below room temperature, and by carrying out the reaction below room temperature and in a time period of about <NUM> hour or less.

Unlike what it is reported in the prior art, the process of the invention enables for the preparation of the VIC isomers with high yields and selectivity by operating under mild operative conditions and in a relatively short period of time. As such, by taking advantage of the short residence time that is required for the coupling reaction according to step (a), the process of the invention can be conveniently operated either in semi-batch or even in a continuous mode.

From the above it is clear to the skilled person that as per step (a), the addition of glyoxal to triethylene tetramine, when each of them is properly dissolved in a solvent medium, may be also achieved through the contact or by contacting the former component with the second, as per the terminology typically adopted in continuous mode or flow chemistry techniques where streams of reactants are suitably contacted so as to carry out the desired reactions.

Therefore, unless otherwise provided in the present description, the terms "adding" or "addition" or even "additions", once used in the context of adding a reactant to another, may be conveniently replaced by the terms "contacting" or "contact" or "contacts", as the case may be, eventually more appropriate in continuous mode processes.

Examples of reactors and techniques that could be employed according to the invention, once step (a) of the process is operated under continuous mode, are the known reactors and techniques that may comprise the continuous feeding of the reactants to any suitable reactor with continuous formation and exiting of the reaction product stream. Non limiting examples among them are, for instance, tubular reactors otherwise referred to as pipe reactors, plug flow reactors, microreactors, continuous stirred tank reactors (CSTRs), and the like.

Any parameter of the process for instance including streams flow rate, residence time and temperature, may be then properly selected according to conventional means so as to fit with the desired reaction conditions to be met.

As an example, step (a) of the process of the invention may be easily carried out in a continuous mode by operating through a CSTRs cascade properly fed with suitable solutions of triethylene tetramine in anhydrous ethanol and aqueous glyoxal. Feeding of both streams of reactants may be separately operated by means of conventional syringe pumps or through any suitable pumping system.

Preferably, the ethanolic solution of the amine is fed to a first CSTR, while the proper amount of aqueous glyoxal solution may be then distributed along the CSTRs cascade.

Likewise, by operating in any tubular reactor, the aqueous glyoxal stream may be conveniently distributed among a plurality of inlets positioned along the length of the reactor itself previously fed with the ethanolic solution of the amine.

From the above, it is thus clear to the skilled person that a proper geometry of the reactor together with any selected feeding rate for each of the flow streams may thus provide for an optimal admixing of the reactants for any selected residence time. Temperature, like any other parameter of the process, may be then suitably controlled according to conventional means so as to fit with the desired conversion of the starting materials and the subsequent collection of the VIC isomers.

It is thus a further object of the invention a process for the preparation of Cyclen wherein step (a) is carried out in a continuous mode by contacting an aqueous solution of glyoxal to an ethanolic solution of the amine.

Preferably, the addition of the aqueous solution of glyoxal is carried out portionwise, along the reactor length of any given tubular reactor or anyhow distributed among a plurality of continuous reactors, for instance within a CSTRs cascade.

The subsequent step (b) of the process of the invention implies the reduction of the VIC bis-aminals, that is of decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine.

The reaction is carried out in homogeneous phase by treatment of the above VIC bis-aminals with the selected reducing agent, in the presence of hydrocarbon solvents at refluxing conditions.

As such, at the end of step (a) a solvent change is carried out.

This operation can be accomplished according to conventional means, either in batch, semi-batch or preferably in a continuous mode, by feeding the reaction crude coming from step (a) and the selected water immiscible hydrocarbon solvent to a distillation column.

Ethanol and water may be thus collected as top products whilst the VIC bis-aminals in the anhydrous hydrocarbon solvent are recovered at the bottom.

The distillation is preferably carried out under vacuum and typically occurs in few minutes only so as to provide for a VIC-isomers rich hydrocarbon stream, either directly intended for the subsequent reduction step or to be eventually worked-up for products collection. In both cases, however, no or minimal conversion to the GEM isomers could be observed.

Suitable hydrocarbon solvents are all of the solvents that may enable for the collection of ethanol and water as top products whilst remaining at the bottom of the distillation column.

Typical examples may thus include aromatic or aliphatic hydrocarbons such as toluene, xylene, ethylbenzene, mesitylene, hexane, heptane, octane, isooctane, nonane, decane and the like, or even mixtures thereof.

Preferably, the hydrocarbon solvent is selected from toluene, xylene, ethylbenzene, mesitylene or mixtures thereof. Even more preferably the hydrocarbon solvent is toluene.

As far as the reducing agent is concerned, any of R<NUM>, R<NUM> and R<NUM> within the above dialkyl aluminium hydrides AlHR<NUM>R<NUM> or trialkylamine alane AlH<NUM>·NR<NUM>R<NUM>R<NUM> complexes represent, each independently, a straight or branched C<NUM>-C<NUM> alkyl group. Non limiting examples may thus include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

More preferably, the said R<NUM>, R<NUM> and R<NUM> are, each independently, straight or branched C<NUM>-C<NUM> alkyl groups.

According to a preferred embodiment of the invention, the reducing agent is selected from the group consisting of diisobutyl aluminium hydride (DIBAL-H), dimethylethylamine alane complex, or mixtures thereof.

Even more preferably the reducing agent is diisobutyl aluminium hydride.

The said reducing agents are either commercially available, for instance in toluene solution, or anyhow preparable according to known methods.

For a general reference to the preparation of the dialkyl aluminium hydrides see, as an example, <NPL>), <NPL>), and <NPL>).

For a general reference to the preparation of the alane complexes see, as an example, <NPL>), <NPL>), and <NPL>).

The reduction reaction requires <NUM> equivalents of reducing agent and occurs in two stages: a first portion of reducing agent is in fact needed to substitute each of the hydrogen atoms of the secondary amino groups within the decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine, whilst a second portion of reducing agent provides for ring reduction, thus affording the macrocylic tetraazacyclododecane structure wherein the nitrogen atoms are still bound to the aluminium groups (i.e. >N-AlR<NUM>R<NUM>). Then, as set forth below, subsequent workup according to known methods finally provides for Cyclen recovery.

The said portions of any selected reducing agent according to the invention may be either combined or alternatively separated over the time, so as to comprise a first portion of reducing agent then followed by a second portion of the same or even different reducing agent, in both cases added to the substrate undergoing the reductive step.

At the end of the addition, reaction completion is typically carried out under refluxing conditions at atmospheric pressure.

Therefore, it represents a further object of the invention a process for the preparation of Cyclen wherein step (b) comprises:.

Preferably, the addition of the reducing agent in step (b') is carried out according to conventional means, for instance dropwise or portionwise, at a temperature in the range of from about <NUM> to about <NUM> and, even more preferably, at room temperature.

On the other side, refluxing under step (b") is carried out at a temperature of about <NUM> to about <NUM>, depending on the selected hydrocarbon solvent to be used, for a time varying from a few hours to few days, for instance from about <NUM> hours to about <NUM> hours, depending on the selected operative conditions and choice of reducing agent being employed.

As an example, in fact, the use of DIBAL-H enabled for the quantitative formation of the macrocyclic derivative (i.e. Cyclen precursor) by refluxing the reaction mixture in the presence of toluene, that is at about <NUM> at atmospheric pressure, in a period of from about <NUM> hours to about <NUM> hours, more preferably from about <NUM> hours to about <NUM> hours.

Surprisingly, we have now found that the reaction time in step (b") can be dramatically shortened, being for instance comprised from about <NUM> to about <NUM> hours and even more preferably from about <NUM> to about <NUM> hours, whilst maintaining proper selectivity and high yields. The above was in fact achieved by refluxing the reaction mixture under pressure. Therefore, it represents a further object of the invention a process for the preparation of Cyclen wherein step (b) comprises:.

In this latter occurrence, step (b") may be easily accomplished according to conventional means in any suitable reactor intended to be operated under pressure, for instance of from about <NUM> to about <NUM> atmospheres. Proper pressure conditions can be easily achieved depending on the selected hydrocarbon solvent and the refluxing temperature being adopted, for instance comprised from about <NUM> to about <NUM>.

Preferably, as said, step (b") is carried out in toluene by operating under pressure, at a temperature of from about <NUM> to about <NUM>, for instance at about <NUM>, for a time period of from about <NUM> to about <NUM> hours, for instance in a time period of about <NUM> hours.

Finally, the isolation of Cyclen may be carried out according to known procedures, for instance as described by <NPL> and <NPL>) based on the workup procedure for reactions involving DIBAL-H as reducing agent (<NPL>). To this extent, hydrolysis of the Al-isobutyl species within the macrocyclic derivative obtained at the end of step (b) of the process with water and treatment with NaF or NaOH affords the precipitation of aluminium as fluoride or hydroxide species. Final extraction with a suitable solvent, for instance toluene-chloroform mixtures, and subsequent purification of the resulting product gives Cyclen in <NUM>-<NUM> % isolated yield referred to the VIC isomers present in the bis-aminals feed.

From all of the above it is clear to the skilled person that any of the preferred embodiments of the invention and that may either refer to steps (a) or (b) of the process may be suitably combined to each other. As an example, any of the parameters of the process for instance including the time of addition of the aqueous solution of glyoxal to the ethanolic solution of the amine and the time to reaction completion, as per step (a), together with the selected reaction temperature may be suitably combined. Likewise, the above may also apply to the choice of the hydrocarbon solvent, the selected reducing agent, and any of the parameters referring to step (b) of the process, for instance including temperature and/or pressure conditions being applied.

Additional embodiments of the inventions are also represented by each of the above steps (a) and (b) of the process per se, together with any of the aforementioned preferred operative conditions.

In particular, it is a further object of the invention a process for the preparation of decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine which process comprises adding an aqueous solution of glyoxal to a solution of triethylene tetramine in anhydrous ethanol, and by carrying out the reaction in a time period of about <NUM> hour or less.

It is a further object of the invention a process for the preparation of Cyclen which process comprises adding a reducing agent selected from the group consisting of dialkyl aluminium hydride or trialkylamine alane complex, or mixtures thereof, to a solution of decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine in a hydrocarbon solvent, so as to obtain the <NUM>,<NUM>,<NUM>,<NUM>-tetraazacyclododecane derivative wherein the nitrogen atoms are still bound to the dialkyl aluminium groups, then converted to Cyclen according to known methods; wherein the above alkyl groups, the same or different in each occurrence, are selected from straight or branched C<NUM>-C<NUM> alkyl groups.

Finally, as the aforementioned N-(<NUM>-piperazin-<NUM>-ylethyl)ethane-<NUM>,<NUM>-diamine is a known compound that finds a variety of applications, for instance in the field of resins and polymers as curing additive, the process for its preparation through the reduction of the above GEM derivative with trialkyl aluminium hydrides or trialkylamine alane complexes, represents a further object of the invention.

Further details concerning the process of the invention are reported in the following experimental section, with the sole aim to better illustrate it without posing any limitation.

Di-hydrated triethylene tetramine (<NUM> grams, <NUM> mmoles) and <NUM> of anhydrous ethanol were charged to a three necks <NUM> liter round bottom flask with a stirrer. The solution was cooled to <NUM> and glyoxal <NUM>% in water (<NUM> grams, <NUM> mmoles) was slowly added over <NUM> minutes. The solution was aged for <NUM> minutes and fed to the bottom of a <NUM> trays distillation column containing <NUM> grams of toluene. Distillation was operated under vacuum, with a bottom temperature equal to <NUM>-<NUM>, withdrawing the aqueous/ethanolic phase at the top of the column using a Dean-Stark separator. After residual solvent removal <NUM> grams of a cereous solid were obtained, having a VIC/GEM ratio <NUM>/<NUM> (<NUM> % VIC selectivity, <NUM>% chromatographic yield).

Di-hydrated triethylene tetramine (<NUM> grams, <NUM> mmoles) and <NUM> of anhydrous ethanol were charged to a three necks <NUM> liter round bottom flask with a stirrer. The solution was cooled to <NUM> and glyoxal <NUM>% in water (<NUM> grams, <NUM> mmoles) was slowly added in <NUM> minutes. The solution was aged for <NUM> minutes and then concentrated under vacuum to a volume of <NUM>. The concentrated solution was fed to the bottom of a <NUM> trays distillation column containing <NUM> grams of toluene. Distillation was operated under vacuum, with a bottom temperature equal to <NUM>-<NUM>, withdrawing the aqueous/ethanolic phase at the top of the column using a Dean-Stark separator. After residual solvent removal <NUM> grams of a cereous solid were obtained, having a VIC/GEM ratio <NUM>/<NUM> (<NUM> % VIC selectivity, <NUM>% chromatographic yield).

When step (a) of the process is carried out in a continuous mode and each of the two streams of reactants, namely the <NUM>% aqueous solution of glyoxal and triethylene tetramine in anhydrous ethanol, are fed through an inlet of a tubular reactor, the reaction kinetics may simulate the one occurring in a pure batch reactor. However, as this approach gave poor results affording a VIC selectivity as low as <NUM>%, a simulation model was carried out for the continuous synthesis of the title compound through a CSTRs cascade.

More in particular, this simulation model represents the continuous reactor as a CSTRs cascade where the triethylene tetramine ethanolic solution is fed to a first cell, while the <NUM>% aqueous glyoxal solution is fed distributing the total quantity in a number of parts equal to the number of CSTR stages, and feeding each part sequentially to each stage. The VIC bisaminals synthesis was thus simulated in a CSTRs cascade including <NUM> stages, each one having a volume of <NUM> for a total volume of <NUM>. A solution of triethylene tetramine with a concentration of <NUM> moles/L in anhydrous ethanol is fed to the first stage at a rate of <NUM>/min. A <NUM>% aqueous solution of glyoxal is fed to each stage at a rate of <NUM>/min per stage. Temperature is of <NUM> and overall residence time is of <NUM> minutes.

From the simulation model analysis it can be observed that by distributing the aqueous glyoxal solution stream along the reactor length the selectivity towards the VIC isomers can be surprisingly increased up to <NUM>% and higher, with a final triethylene tetramine conversion of <NUM>%. The model predicts that the VIC selectivity in the stream exiting the last CSTR increases with the number of CSTRs forming the reactor, as per the following table:.

The bisaminal mixture (<NUM>, <NUM> mmol, VIC/GEM =<NUM>, VIC = <NUM>%) was placed in a <NUM> Schlenk tube and subjected to <NUM> vacuum-argon cycles and placed in a cold water bath (~<NUM>). Then, <NUM> equivalents of a <NUM> solution of DIBAL-H in toluene (<NUM>, <NUM> mmol) were added dropwise under argon flow. After formation of a clear light yellow solution the Schlenk was placed in an oil bath and stirred at reflux temperature for <NUM> hours. The solution was allowed to cool down to room temperature and NaF (<NUM>, <NUM> mmol, <NUM> equiv. ) was added, obtaining a suspension which was stirred for <NUM> minutes in an ice bath. Water <NUM> (<NUM> mmol, <NUM> equiv. ) was added dropwise over <NUM> minutes time. The slurry was heated up to <NUM> and stirred for <NUM> minutes and filtered through celite pad. The cake was washed with hot toluene (3x20 mL) and EtOH (2x10 mL) which were removed in vacuum, affording <NUM> of a white product (<NUM> % yield). The <NUM>C{<NUM>H} NMR analysis of the crude product gave <NUM>% of Cyclen (δC = <NUM> ppm) and <NUM>% of N-(<NUM>-piperazin-<NUM>-ylethyl)ethane-<NUM>,<NUM>-diamine.

A bisaminals mixture (<NUM>, <NUM> mmol, VIC/GEM = <NUM>, VIC = <NUM>%) was placed in a <NUM> round bottle flask and subjected to <NUM> vacuum-argon cycles. Then <NUM> equivalents of a <NUM> solution of DIBAL-H in toluene (<NUM>, <NUM> mmol) were added portionwise under argon flow. After complete dissolution of the mixture the flask was placed in an oil bath removing the overpressure generated during the heating up and mechanically stirred at reflux for <NUM> hours. The solution was allowed to cool down at room temperature, NaF (<NUM>, <NUM> mmol. <NUM> equiv. ) added and the stirred for <NUM> minutes. The flask was placed in an ice bath and water <NUM> (<NUM> mmol, <NUM> equiv. ) was added dropwise over <NUM> hour. The slurry was stirred for <NUM> minutes at <NUM> and filtered with a glass funnel filter. The cake was washed with hot toluene (3x50 mL), EtOH (2x50 mL) and the solvents were removed in vacuum, affording <NUM> of a white product (<NUM> %). The <NUM>C{<NUM>H} NMR analysis of the crude product gave <NUM>% of Cyclen and <NUM>% of N-(<NUM>-piperazin-<NUM>-ylethyl)ethane-<NUM>,<NUM>-diamine.

A bisaminals mixture (<NUM>, <NUM> mmol, VIC/GEM = <NUM>, VIC = <NUM>%) was placed in a <NUM> Schlenk tube and subjected to <NUM> vacuum-argon cycles. Then <NUM> equivalents of a <NUM> solution of DIBAL-H in toluene ((<NUM>, <NUM> mmol) were added dropwise under argon flow. After complete dissolution, the mixture was transferred under argon with a canula into a sealed glass reactor, placed in an oil bath and stirred at <NUM> for <NUM> hours. The solution was allowed to cool down at room temperature and NaF (<NUM>, <NUM> mmol, <NUM> equiv. ) was added. The suspension was placed in a cold water bath (~<NUM>) and water <NUM>µL (<NUM> mmol, <NUM> equiv. ) was carefully added dropwise. The slurry was stirred for <NUM> minutes at <NUM> and filtered with a glass funnel filter. The cake was washed with hot toluene (3x10 mL), EtOH (2x5 mL) and the solvents were removed in vacuum, affording <NUM> of a white product (<NUM> % yield). The <NUM>C{<NUM>H} NMR analysis of the crude product gave <NUM>% of Cyclen and <NUM>% of N-(<NUM>-piperazin-<NUM>-ylethyl)ethane-<NUM>,<NUM>-diamine.

A bisaminals mixture (<NUM>, <NUM> mmol, GEM/VIC = <NUM>, GEM = <NUM> %) was placed in a <NUM> Schlenk tube and subjected to <NUM> vacuum-argon cycles. Then <NUM> equivalents of a <NUM> solution of DIBAL-H in toluene (<NUM>, <NUM> mmol) were added dropwise. After complete dissolution of the mixture the Schlenk was placed in oil bath removing the overpressure generated during the heating up and stirred at reflux. After <NUM> hours the solution was allowed to cool down at room temperature and NaF (<NUM>, <NUM> mmol, <NUM> equiv. ) was added and the suspension was stirred for <NUM> minutes. The Schlenk was placed in a cold water bath (~<NUM>) and water <NUM>µL (<NUM> mmol, <NUM> equiv. ) was carefully added dropwise. The slurry was stirred for <NUM> minutes at <NUM> and filtered with a glass funnel filter. The cake was washed with hot toluene (3x5 mL), EtOH (2x5 mL) and the solvents were removed in vacuum, affording <NUM> of a white product, (<NUM> % Yield). The <NUM>C{<NUM>H} NMR analysis of crude product gave <NUM>% of N-(<NUM>-piperazin-<NUM>-ylethyl)ethane-<NUM>,<NUM>-diamine (δC = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> ppm) and <NUM>% of Cyclen.

<NUM> of triethylene tetramine dihydrate (<NUM> mmol) and <NUM> of ethanol were introduced into a <NUM> flask to obtain a clear colourless solution. The solution was cooled with an ice bath up to <NUM>, then <NUM> of <NUM>% solution of glyoxal in water (<NUM> mmol) were added in <NUM> minutes. The reaction solution was kept at <NUM> for <NUM> minutes. The clear yellowish solution was concentrated under reduced pressure at <NUM> to remove the solvent, affording <NUM> of clear orange liquid were obtained.

Toluene (<NUM>) was added and the mixture was poured into a <NUM> three-necked flask equipped with a <NUM>-plate column, heavy phase collection head and condenser. The system was connected to vacuum and heated to <NUM>-<NUM> in an oil bath (plate set <NUM>, Tout <NUM>, Tin <NUM>) and the distillate was taken and discarded. At the end of the distillation the solvent was completely roto-evaporated, obtaining a waxy yellowish solid (<NUM>) containing <NUM>% of the VIC isomers (chromatographic analysis).

<NUM> of the obtained bisaminals (<NUM> mmol) and <NUM> of toluene were introduced into a <NUM> three-necked flask equipped with a magnetic stir bar and dropping funnel, obtaining a clear yellow solution. Internal temperature was <NUM>. By means of a cannula, under nitrogen pressure, <NUM> of DIBAL-H <NUM>% in toluene (<NUM> mmol) were poured into the dropping funnel, then at room temperature the toluene solution of DIBAL-H was slowly added (<NUM> hours) while maintaining the nitrogen atmosphere (inlet nitrogen above the dripping funnel). Initially an exothermy was noted: the temperature rose to <NUM> and the system was cooled with an ice bath. The exothermy ended after the addition of the first <NUM> of the solution. At the end of the addition, the dropping funnel was removed and replaced with a reflux refrigerant. The system was kept at reflux (set <NUM>) for <NUM>. A <NUM> analytical sample treated with NaF and ethanol afforded by chromatography a conversion of bisaminals of <NUM>% and a reduction yield to Cyclen equal to <NUM>%. The overall yield of Cyclen on triethylene tetramine resulted <NUM>%.

Claim 1:
A process for the preparation of Cyclen which process comprises:
a) reacting glyoxal with triethylene tetramine so as to obtain decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine; and
b) reducing the thus obtained decahydrodiimidazo[<NUM>,<NUM>-a:<NUM>',<NUM>'-c]pyrazine with a reducing agent selected from the group consisting of dialkyl aluminium hydride, trialkylamine alane complex, or mixtures thereof;
wherein the above alkyl groups, the same or different in each occurrence, are selected from straight or branched C<NUM>-C<NUM> alkyl groups, and
wherein step (a) is carried out by adding an aqueous solution of glyoxal to a solution of the amine in anhydrous ethanol, and by carrying out the reaction in a time period of <NUM> hour or less.