FIELD OF THE INVENTION The present invention relates to a process for generating cyanogen bromide (BrCN). The present invention further relates to an apparatus configured for continuously generating cyanogen bromide and an apparatus configured for continuously generating bromine, which both apparatuses may be combined, as well as a process for synthesizing a nitrogen-containing compound.

BACKGROUND

Cyanogen bromide (BrCN) is an interesting target molecule: it is an

exceptionally versatile reagent in organic synthesis which most frequently participates as an electrophilic cyanide source and reacts with N, O, S, C and P nucleophiles to generate e.g. cyanamides, guanidines, cyanates or nitriles. In addition, it can be used in the von Braun reaction for the dealkylation of tertiary amines which often results in ring-opening of the respective N- heterocycles. Along similar lines, BrCN can also act as a cleavage agent for dialkyl thioethers. This reaction represents an important technique in peptide mapping and amino acid sequence analysis, due to the regioselective demethylation of methionine-containing peptides. Notably, bromocyanation of alkynes provides the most atom-efficient method for the synthesis of bromoacrylonitriles.

However, BrCN can be considered as a very hazardous chemical . It is acutely toxic, it sublimes at room temperature and can be absorbed into the body by inhalation of its vapor and through the skin. Exposure to even small amounts may cause convulsions or death (permissible exposure limit: 5 mg m ³ ). Pure BrCN is stable for longer periods if stored under dry conditions at 2-8 °C, but impurities catalyze its exothermic and explosive trimerization to cyanuric bromide. Furthermore, it is gradually decomposed by water/moisture and rapidly by acids to highly toxic HCN and corrosive HBr. Although BrCN is commercially available, it would clearly be desirable to avoid its

transportation, storage and handling. In addition, BrCN is conventionally purified by means of distillation which involves a potential exposure risk. To eliminate the need of handling, storage and transportation of toxic, reactive, or explosive reagents these materials are best produced when needed from benign (or at least less hazardous) precursors directly at the site of use. The in-situ synthesized reagent is then directly converted into the desired final product. Continuous flow processing specifically addresses the needs for this so-called "on-site on-demand" generation of hazardous species with safety being one of the most significant advantages over a traditional batch set-up. Inside a low volume tube- or plate reactor, the accumulation of dangerous amounts of hazardous materials is avoided since only small quantities are present at any time. In addition, ultrafast exothermic reactions can safely be performed due to the high mass- and heat transfer rates. Setups for the continuous production of synthetically useful reagents are commonly termed "generators" of the reagent. In an ideal scenario the complete operation including generation of the reagent, separation from its byproducts and downstream consumption is performed in a fully contained fashion ensuring zero exposure to the hazardous material throughout operation.

Thus, there might be a demand for the generation of cyanogen bromide on- site and on-demand in a manner that reduces or even eliminates the risk of exposure with this hazardous chemical substance or potentially hazardous precursors thereof. OBJECTS OF THE INVENTION

An object of the present invention is to provide a process for generating cyanogen bromide with reduced risk of exposure and other potential health implications and which allows for generating cyanogen bromide on-site and on-demand. Another object of the present invention is to provide an apparatus configured for generating cyanogen bromide (in the following also referred to as "BrCN generator") in such manner. Another object of the present invention is to provide an apparatus configured for generating bromine (in the following also referred to as "bromine generator") with reduced risk of exposure and which may be coupled with such BrCN generator. Another object of the present invention is to provide a process for synthesizing a nitrogen-containing compound utilizing thus obtained cyanogen bromide. SUMMARY OF THE INVENTION

The present inventors have made diligent studies and have found that cyanogen bromide (BrCN) may be generated on-site and on-demand in a safe manner with little (or even no) risk of exposure by means of a continuous flow processing set-up wherein two fluids containing a bromine source and a cyanide source, respectively, are mixed and reacted with each other, followed by purifying the obtained reaction mixture by means of a membrane-based separation. In order to further reduce potential health implications, the bromine source, which may be in particular bromine, may also be generated on-site and on-demand by a respective bromine generator, which may be coupled to a BrCN generator. The present inventors have further found that BrCN thus obtained may be (immediately) utilized in the syntheses of various nitrogen-containing compounds which further reduces the risk of exposure by (immediately) consuming this hazardous reagent without the need of considerable storage and transportation thereof. Accordingly, the present invention relates to a process for generating cyanogen bromide (BrCN) comprising the steps of:

mixing a fluid containing a bromine source with a fluid containing a cyanide source,

reacting the bromine source and the cyanide source with each other to give a reaction mixture containing cyanogen bromide,

purifying the reaction mixture by means of a membrane-based separation to give cyanogen bromide. The present invention further relates to an apparatus configured for

continuously generating cyanogen bromide (BrCN), the apparatus comprising a first supply unit configured for supplying a fluid containing a bromine source,

a second supply unit configured for supplying a fluid containing a cyanide source,

a mixing unit configured for mixing the fluid containing the bromine source and the fluid containing the cyanide source,

a reaction unit configured for reacting the bromine source and the cyanide source with each other to give a reaction mixture containing cyanogen bromide,

a purification unit comprising a membrane.

Moreover, the present invention relates to an apparatus configured for continuously generating bromine, the apparatus comprising

a first feeding unit configured for supplying a fluid containing a bromate and a bromide,

a second feeding unit configured for supplying a fluid containing an acid, in particular hydrobromic acid (HBr),

a mixing unit configured for mixing the fluid containing the bromate and the bromide and the fluid containing the hydrogen bromide,

a reaction unit configured for reacting the bromate and the bromide with each other under acidic condition to give bromine, and a discharge unit configured for discharging the bromine.

As mentioned above, the bromine generator may be coupled to the BrCN generator, for instance by means of a connecting unit (or interface unit) configured for providing a fluidic communication between the discharge unit of the bromine generator and the first supply unit of the BrCN generator.

In addition, the present invention relates to a process for synthesizing a nitrogen-containing compound comprising the steps of

performing a process for generating cyanogen bromide as described herein,

mixing and reacting the thus obtained cyanogen bromide with an educt to give the nitrogen-containing compound. Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following detailed description of embodiments and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an illustrative embodiment of a process for generating cyanogen bromide (BrCN) and an apparatus configured for continuously generating cyanogen bromide according to the present invention.

Figure 2 shows an illustrative embodiment of an apparatus configured for continuously generating bromine according to the present invention.

Figure 3 shows an illustrative embodiment of a combination of a bromine generator and a BrCN generator connected in series according to the present invention. In addition, Figure 3 shows an illustrative embodiment of a process for synthesizing a nitrogen-containing compound in a semi-batch set-up. DETAILLED DESCRIPTION OF THE INVENTION

Hereinafter, details of the present invention and other features and

advantages thereof will be described. However, the present invention is not limited to the following specific descriptions, but they are rather for illustrative purposes only.

It should be noted that features described in connection with one exemplary embodiment or exemplary aspect may be combined with any other exemplary embodiment or exemplary aspect, in particular features described with any exemplary embodiment of a process for generating BrCN may be combined with any further exemplary embodiment of a process for generating BrCN as well as with any exemplary embodiment of a BrCN generator, a bromine generator, a process for synthesizing a nitrogen-containing compound and vice versa, unless specifically stated otherwise.

Where an indefinite or definite article is used when referring to a singular term, such as "a", "an" or "the", a plural of that term is also included and vice versa, unless specifically stated otherwise, whereas the word "one" or the number "1", as used herein, typically means "just one" or "exactly one".

The expression "comprising", as used herein, includes not only the meaning of "comprising", "including" or "containing", but also encompasses "consisting essentially of" and "consisting of".

In a first aspect, the present invention relates to a (continuous and/or in-line) process for generating cyanogen bromide (BrCN) comprising the steps of: mixing a fluid containing a bromine source with a fluid containing a cyanide source,

reacting the bromine source and the cyanide source with each other to give a (crude) reaction mixture containing cyanogen bromide, purifying the reaction mixture by means of a membrane-based separation to give (purified) cyanogen bromide.

In an embodiment, the fluid containing a bromine source may be a liquid, in particular an aqueous liquid. Similarly, the fluid containing a cyanide source may be a liquid, in particular an aqueous liquid.

The term "cyanide source", as used herein, may in particular denote a cyanide-containing compound or mixture of cyanide containing compounds which may react with an appropriate bromine source, such as bromine (Br ₂ ), to cyanogen bromide. In an embodiment, the cyanide source may comprise or consist of a cyanide compound, in particular potassium cyanide (KCN) and/or sodium cyanide (NaCN). The term "bromine source", as used herein, may in particular denote a bromine-containing compound or mixture of bromine-containing compounds which may react with an appropriate cyanide source, such as a cyanide, to cyanogen bromide. In an embodiment, the bromine source may comprise or consist of bromine (Br ₂ ). In an embodiment, the fluid containing a bromine source comprises bromine (Br ₂ ). In an embodiment, the fluid containing a bromine source further (for instance in addition to bromine) comprises a bromide compound, in particular potassium bromide (KBr) and/or sodium bromide (NaBr). Hereby, it may be possible to increase the solubility of Br ₂ , in particular in an aqueous liquid, such as water.

In an embodiment where the fluid containing a bromine source comprises bromine (Br ₂ ), it might be advantageous to generate the bromine (in situ and/or immediately prior to use), for instance by means of a bromate-bromide synproportionation, which may be carried under acidic conditions.

In an embodiment where the fluid containing a bromine source comprises bromine (Br ₂ ), the process may further comprise mixing a fluid containing a bromate (such as sodium bromate, NaBrC , or potassium bromate, KBrC ) and a bromide (such as sodium bromide, NaBr, or potassium bromide, KBr) with a fluid containing an acid (such as hydrobromic acid, HBr, or sulfuric acid, H2SO4), and reacting the bromate and the bromide with each other under acidic condition (bromate-bromide synproportionation). Such additional process steps may be in particular carried out by means of a bromine generator described in further detail below. When coupling such bromine generator with a BrCN generator described in further detail below, it has turned out advantageous for ensuring homogenous operation to conduct such bromate-bromide synproportionation by using NaBrC and NaBr as well as HBr. The molar ratio of bromate to bromide in the fluid containing a bromate and a bromide may be in particular in the range of from 1 :4 to 1 : 6, for instance about 1 : 5. In an embodiment, the fluid containing a bromine source and/or the fluid containing a cyanide source are cooled (precooled) before the mixing step. Since the reaction between the bromine source and cyanide source is typically highly exothermic, the reaction may be better controlled and/or the formation of side-products may be suppressed by precooling one or both fluids of the reaction educts.

In an embodiment, the step of mixing the fluid containing a bromine source with the fluid containing a cyanide source is performed by means of a T shaped or Y shaped mixing unit, such as T mixer or Y mixer, respectively, which may in particular comprise two influents (or supply channels) for the two fluids to be mixed and one effluent (or discharge channel) for the mixture. Such set-up might be advantageous for providing an efficient and simple continuous flow processing. In an embodiment, the step of reacting the bromine source and the cyanide source with each other is performed in a tubular reaction unit, such as a reaction coil . Such set-up might be advantageous for providing an efficient and simple continuous flow processing. For instance, at a given length of the tubular reaction unit or reaction coil, the reaction time may be easily adjusted by adjusting the flow rate of the fluid passing the reaction zone. In addition, an efficient and simple temperature control, such as cooling, of the reaction unit may be realized .

In an embodiment, the step of reacting the bromine source and the cyanide source with each other is performed for a time period of from 2 to 10 min, in particular of from 4 to 6 min, such as about 5 min.

In an embodiment, the step of reacting the bromine source and the cyanide source with each other is performed while cooling the (tubular) reaction unit. Since the reaction between the bromine source and cyanide source is typically highly exothermic, the reaction can be better controlled and/or the formation of side-products can be suppressed by cooling the (tubular) reaction unit, such as reaction coil.

As a result of the step of reacting the bromine source and the cyanide source with each other a (crude) reaction mixture containing cyanogen bromide is obtained. Typically, this reaction mixture contains water which is detrimental to the stability of the cyanogen bromide. In other words, the obtained cyanogen bromide needs to be separated and substantially freed from water so as to render it stable. The reaction mixture may also contain impurities, side-products or unreacted educts which might impair the intended use of the cyanogen bromide, for instance in a subsequent reaction, such as in a process for synthesizing a nitrogen-containing compound described in further detail below. In other words, the obtained cyanogen bromide might not be

sufficiently pure for the intended subsequent use thereof. Therefore, the process for generating cyanogen bromide according to the present invention comprises a step of purifying the reaction mixture by means of a membrane-based separation to give (purified, such as substantially pure) cyanogen bromide (in an organic solvent, such as dichloromethane (DCM)) . In contrast to conventional purification of cyanogen bromide by means of distillation which involves a potential exposure risk, the present inventors have found that purifying the reaction mixture containing cyanogen bromide by means of a membrane-based separation can be appropriately integrated in a continuous flow processing set-up so that the potential exposure risk can be further reduced or even avoided.

In an embodiment, the step of purifying the reaction mixture comprises passing of cyanogen bromide through a membrane.

In an embodiment, the step of purifying the reaction mixture comprises a (continuous in-line) liquid-liquid extraction of cyanogen bromide from the (crude) reaction mixture via a membrane.

In an embodiment, the step of purifying the reaction mixture comprises a liquid-liquid extraction of cyanogen bromide from an aqueous (polar) phase of the (crude) reaction mixture into an organic (apolar) phase of an organic solvent. The aqueous (polar) phase and the organic (apolar) phase may be separated by a membrane which may be permeable for cyanogen bromide. Appropriate examples of the organic solvent include a hydrocarbon, in particular a halogenated hydrocarbon and/or an aromatic hydrocarbon (such as toluene), in particular a chlorinated hydrocarbon, in particular

dichloromethane (DCM). In an embodiment, the aqueous reaction mixture may be combined with the organic solvent in a microreactor chip, such as a glass microreactor chip, prior to liquid-liquid extraction.

In an embodiment, the membrane has a hydrophobic surface. Hereby, the permeability of the membrane for cyanogen bromide may be improved and/or the permeability of the membrane for other compounds, in particular hydrophilic compounds, such as water, may be reduced. In an embodiment, the membrane has a pore size of less than 1.0 μηη, in particular of from 0.2 to 0.8 μιτι, in particular of about 0.5 μιτι. Hereby, it may be possible to substantially suppress that water enters into the organic phase and/or that organic solvent enters into the aqueous phase.

In an embodiment, the process for generating cyanogen bromide further comprises a step of monitoring the purity of the cyanogen bromide after the purifying step. By such quality control step, it may be ensured that cyanogen bromide obtained after the purification will only be utilized in a subsequent chemical reaction if the cyanogen bromide possesses a certain, predetermined purity (typically depending on the subsequent chemical reaction) or if impurities, such as water, are below a certain, predetermined threshold (typically depending on the subsequent chemical reaction). In an embodiment, the step of monitoring comprises determining a

concentration of the cyanogen bromide. A too low concentration of cyanogen bromide may indicate that the subsequent chemical reaction may not be carried as intended and/or that failures in the process for generating cyanogen bromide occurred, for instance in the purification step, that are to be remedied. The step of monitoring may also comprise determining a

concentration of water. A too high concentration of water or of any other impurity may in particular indicate that conditions of the purification step have to be modified. In an embodiment, the step of monitoring comprises a spectroscopic method, in particular by means of Fourier transform infrared (FTIR) spectroscopy. For instance, cyanogen bromide can be determined on the basis of the

characteristic CN stretch at 2188 cm ¹ , whereas water can be determined on the basis of the characteristic OH stretch at around 3500 cm ¹ . The process for generating cyanogen bromide according to the present invention may be in particular carried out by means of a BrCN generator, as will be described hereinafter. In a second aspect, the present invention relates to an apparatus configured for continuously generating cyanogen bromide (BrCN), the apparatus comprising

a first supply unit configured for supplying a fluid containing a bromine source,

a second supply unit configured for supplying a fluid containing a cyanide source,

a mixing unit configured for mixing the fluid containing the bromine source and the fluid containing the cyanide source,

a (tubular) reaction unit configured for reacting the bromine source and the cyanide source with each other to give a (crude) reaction mixture containing cyanogen bromide,

a purification unit comprising a membrane.

In an embodiment, the first supply unit comprises a first temperature control unit configured for controlling (in particular lowering) the temperature of the fluid containing a bromine source and/or the second supply unit comprises a second temperature control unit configured for controlling (in particular lowering) the temperature of the fluid containing a cyanide source. Since the reaction between the bromine source and cyanide source is typically highly exothermic, the reaction may be better controlled and/or the formation of side-products may be suppressed by precooling one or both fluids of the reaction educts by such temperature control units.

In an embodiment, the mixing unit comprises or consists of a T shaped or Y shaped mixing unit, such as T mixer or Y mixer, respectively, which may in particular comprise two influents (in fluid communication with the first and the second supply unit) and one effluent (in fluid communication with the reaction unit). Such set-up might be advantageous for providing an efficient and simple continuous flow processing.

In an embodiment, the BrCN generator may further comprise fluid transport means configured for moving one or more fluids into, within and/or out of the BrCN generator. Suitable fluid transport means include for instance one or more pumps.

In an embodiment, the reaction unit is a tubular reaction unit, such as a reaction coil . Such set-up might be advantageous for providing an efficient and simple continuous flow processing. For instance, at a given length of the tubular reaction unit or reaction coil, the reaction time may be easily adjusted by adjusting the flow rate of the fluid passing the reaction zone. In addition, an efficient and simple temperature control, such as cooling, of the reaction unit may be realized. In an embodiment, the BrCN generator may further comprise a third temperature control unit configured for controlling (in particular lowering) the temperature of the reaction unit.

In an embodiment, the purification unit comprises a microreactor chip, such as a glass microreactor chip. The microreactor chip may be configured for mixing and/or combining the aqueous reaction mixture exiting the reaction unit and an organic solvent which may be supplied by a separate (third) supply unit. In an embodiment, the microreactor chip is located upstream of a liquid-liquid membrane separator.

In an embodiment, the purification unit comprises a liquid-liquid membrane separator (a liquid-liquid extraction unit). The liquid-liquid membrane separator may be configured for extracting cyanogen bromide from a (crude aqueous) reaction mixture via a membrane into an organic solvent. In an embodiment, the liquid-liquid membrane separator is located downstream of a microreactor chip. In an embodiment, the membrane of the purification unit may be configured such that cyanogen bromide may pass through (permeate) the membrane.

In an embodiment, the membrane has a hydrophobic surface. Hereby, the permeability of the membrane for cyanogen bromide may be increased and/or the permeability of the membrane for other compounds, in particular hydrophilic compounds, such as water, may be reduced.

In an embodiment, the membrane has a pore size of less than 1.0 μηη, in particular of from 0.2 to 0.8 μηη, in particular of about 0.5 μιτι. Hereby, it may be possible to substantially suppress that water enters into the organic phase and/or that organic solvent enters into the aqueous phase.

In an embodiment, the purification unit comprises a third supply unit configured for supplying an organic solvent, which solvent may be used in a liquid-liquid extraction with an aqueous phase. In an embodiment, the aqueous reaction mixture may be combined with the organic solvent in a (glass) microreactor chip. In an embodiment, the BrCN generator further comprises a monitoring unit located downstream of the purification unit and configured for monitoring the purity of the cyanogen bromide.

In an embodiment, the monitoring unit comprises a spectrometer, in particular a Fourier transform infrared (FTIR) spectrometer.

In an embodiment, the BrCN generator further comprises a bromine

generator, wherein a discharge unit of the bromine generator is in fluid communication with the first supply unit of the BrCN generator by means of a connecting unit (or interface unit). In a third aspect, the present invention relates to an apparatus configured for continuously generating bromine, the apparatus comprising

a first feeding unit configured for supplying a fluid containing a bromate and a bromide,

a second feeding unit configured for supplying a fluid containing an acid, in particular hydrobromic acid (HBr),

a mixing unit configured for mixing the fluid containing the bromate and the bromide and the fluid containing the hydrogen bromide,

a reaction unit configured for reacting the bromate and the bromide with each other under acidic condition to give bromine, and

a discharge unit configured for discharging the bromine.

In an embodiment, the bromine generator further comprises a connecting unit (or interface unit) configured for providing a fluidic communication between the discharge unit and the first supply unit of the BrCN generator. Thus, the bromine generator may be coupled (or connected) to the BrCN generator by means of the connecting unit.

Thus, both generators, i.e. the bromine generator and the BrCN generator, may be arranged in series with the bromine generator arranged upstream of the BrCN generator. Hereby, the bromine generator may provide on-site and on-demand for the bromine source which may be used (immediately) in the downstream BrCN generator so that no substantial amounts of the potentially hazardous bromine source needs to be stored or kept available, thereby further reducing potential health risks.

In a fourth aspect, the present invention relates to a (continuous or semi- batch) process for synthesizing a nitrogen-containing compound comprising the steps of

performing a process for generating cyanogen bromide as described herein, mixing and reacting the thus obtained cyanogen bromide with an educt (substrate) to give the nitrogen-containing compound.

Cyanogen bromide obtained by the process for generating cyanogen bromide as described herein may be versatilely used for synthesizing nitrogen- containing compounds. Examples of nitrogen-containing compounds that may be synthesized include those shown in the following scheme together with respective educts:

In an embodiment, the nitrogen-containing compound comprises a cyclic guanidine compound and the educt comprises a diamine compound, as shown in the above scheme at the bottom on the right-hand side (the framed nitrogen-containing compound being a cyclic guanidine compound).

As an example for a commercially very interesting nitrogen-containing compound that may be synthesized by means of cyanogen bromide generated as described herein, verubecestat may be mentioned, which is a promising drug candidate for the treatment of Alheimer ^' s Disease. The synthesis of verubecestat typically includes a guanidinylation as described by Thaisrivongs et al ., Org. Lett. 2016, 18, 5780-5783 (see in particular Scheme 5). The cyanogen bromide required for the synthesis of verubecestat may be generated as described herein .

In an embodiment, the cyclic guanidine compound is formed in a (completely) continuous process, for instance by continuously mixing a fluid containing a diamine compound (which may be dissolved in an alcohol, such as methanol) with a stream of the obtained cyanogen bromide and causing a chemical reaction of the cyanogen bromide with the diamine compound, such as by heating the mixture to a temperature in a range of between 40 to 60 °C, in particular at about 50 °C, in a (tubular) reaction unit, such as a reaction coil, for e.g. 15 to 40 min, in particular for about 25 min .

In an embodiment, the cyclic guanidine compound is formed in a semi-batch process, in particular wherein the cyanogen bromide is continuously generated and the reaction of the cyanogen bromide with the diamine compound is carried out batchwise, for instance by adding (feeding) cyanogen bromide to a vessel (such as a flask) containing the diamine compound (educt) typically dissolved in a solvent, in particular an organic solvent, wherein the formed cyclic guanidine compound (reaction product) precipitates and/or crystallizes (also referred to as "reactive crystallization") because of its lower solubility in the (organic) solvent. After a certain period of time, the precipitated cyclic guanidine compound may then be removed from the vessel in a batchwise manner and finally recovered and the vessel may then be provided again with further educt. Alternatively, upon completion of the formation of the cyclic guanidine compound, the vessel may be replaced by another vessel containing (fresh) educt. In an embodiment, the nitrogen-containing compound may comprise an organic cyanamide and the educt may comprise a tertiary amine compound. Thus, the cyanogen bromide obtained by the process for generating cyanogen bromide as described herein may be used in a dealkylation reaction of tertiary amines, such as a von Braun reaction, as shown for instance in the above scheme on the left-hand side in the middle.

The present invention is further described by reference to the accompanying figures, which are solely for the purpose of illustrating specific embodiments, and shall not be construed as limiting the scope of the invention in any way.

Figure 1 shows an illustrative embodiment of a process for generating cyanogen bromide (BrCN) and an apparatus 10 configured for continuously generating cyanogen bromide according to the present invention.

The apparatus 10 configured for continuously generating cyanogen bromide, i.e. the BrCN generator 10, as shown in Figure 1, includes a first supply unit 12 configured for supplying a fluid 14 containing a bromine source, such as 1 M (mol/l) Br ₂ in 13 wt.% aqueous KBr. More specifically, the first supply unit 12 comprises the fluid 14 containing a bromine source, which fluid may be stored in a reservoir for instance or provided directly by a bromine generator (not shown in Figure 1, see Figure 3), a pump (PI) and a first temperature control unit 15 configured for controlling the temperature of the fluid 14. The apparatus 10 further comprises a second supply unit 16 configured for supplying a fluid 18 containing a cyanide source, such as 1.15 M aqueous KCN . More specifically, the second supply unit 16 comprises the fluid 18 containing a cyanide source, which fluid may be stored in a reservoir for instance, a pump (P2) and a second temperature control unit 19 configured for controlling the temperature of the fluid 18. Both pumps may be set so as to provide for the same flow rate of both fluids 14, 18, such as 250 μΙ min ¹ . Both pumps may however also be set so as to provide for different flow rates of both fluids 14, 18, basically depending on the concentrations of the reactants in the fluids 14, 18. In the embodiment shown in Figure 1, both fluids 14, 18 are cooled by the first and the second temperature control unit 15, 19, respectively, embodied as (precooling) coils in this embodiment, to a

temperature within the range of 0 to 5 °C.

In the embodiment shown in Figure 1, the two fluids 14, 18 are mixed by a mixing unit 20 having a T-shape. Subsequently, the mixed fluids are

forwarded to a tubular reaction unit 22 embodied as a reaction coil in this embodiment. The reaction coil is also kept at a temperature within the range of 0 to 5 °C. The reaction coil in this embodiment has a volume of 2.6 ml corresponding to a reaction time of 5.2 min at the flow rates as set (2 x 250 μΙ min In the reaction unit 22, the bromine source and the cyanide source react with each other to give a crude reaction mixture containing cyanogen bromide.

In the embodiment shown in Figure 1, the crude reaction mixture is fed into a purification unit 24 comprising a glass microreactor chip 27 and a liquid-liquid membrane separator 25 including a membrane 26, for instance a Zaiput liquid-liquid separator. In addition, an organic solvent 30, such as DCM, is fed my means of a third supply unit 28 comprising a pump (P3) to the purification unit 24, more specifically to the glass microreactor chip 27. In the purification unit 24, the crude reaction mixture is subjected to a liquid-liquid extraction such that cyanogen bromide is transferred from an aqueous phase of the crude reaction mixture via the membrane 26 into an organic phase of the organic solvent 30. After the liquid-liquid extraction, the aqueous phase is disposed and the organic phase comprising BrCN in purified form is further transferred to a monitoring unit 32 comprising an FTIR spectrometer 34 in this embodiment and located downstream of the purification unit 24. In the monitoring unit 32, the purity of the cyanogen bromide 36 in the organic solvent, for instance DCM, is monitored. Figure 2 shows an illustrative embodiment of an apparatus 40 configured for continuously generating bromine according to the present invention.

The apparatus 40 configured for continuously generating bromine, i.e. the bromine generator 40, as shown in Figure 2, includes a first feeding unit 42 configured for supplying a fluid 44 containing a bromate, such as 0.66 M aqueous NaBrC , and a bromide, such as 3.34 M aqueous NaBr. More specifically, the first feeding unit 42 comprises the fluid 44 containing a bromate and a bromide, which fluid may be stored in a reservoir for instance, and a pump (PI). The apparatus 40 further comprises a second feeding unit 46 configured for supplying a fluid 48 containing an acid, such as 4 M aqueous HBr. More specifically, the second feeding unit 46 comprises the fluid 48 containing an acid, which fluid may be stored in a reservoir for instance, and a pump (P2). Both pumps may be set so as to provide for the same flow rate of both fluids 44, 48, such as 125 μΙ min ^_1 . Both pumps may however also be set so as to provide for different flow rates of both fluids 44, 48, basically depending on the concentrations of the reactants in the fluids 44, 48.

In the embodiment shown in Figure 2, the two fluids 44, 48 are mixed by a mixing unit 50 having a T-shape. Subsequently, the mixed fluids are

forwarded to a tubular reaction unit 52 embodied as a reaction coil in this embodiment. The reaction coil is kept at a temperature within the range of 20 to 30 °C. The reaction coil in this embodiment has a volume of 1 ml

corresponding to a reaction time of 4 min at the flow rates as set (2 x 125 μΙ min ^_1 ). In the reaction unit 52, the bromate and the bromide react with each other (synproportionation reaction) under acidic conditions to give bromine 56, more specifically a fluid containing 1 M bromine (Br ₂ ) and 2 M bromide (Br). The thus obtained bromine 56 is discharged from the bromine generator 40 by means of a discharge unit 54.

Figure 3 shows an illustrative embodiment of a combination of a bromine generator and a BrCN generator connected in series according to the present invention. In addition, Figure 3 shows an illustrative embodiment of a process for synthesizing a nitrogen-containing compound, such as a cyclic guanidine compound, in a semi-batch set-up. The illustrative embodiment of a combination of a bromine generator and a BrCN generator connected in series is in particular shown in the upper part of Figure 3 and includes a BrCN generator, for instance a BrCN generator 10 as discussed above with reference to Figure 1, and upstream thereof a bromine generator, for instance a bromine generator 40 as discussed above with reference to Figure 2. Elements which have been described above with reference to Figure 1 or Figure 2 will not be described again .

As shown in Figure 3, the discharge unit 54 of the bromine generator 40 is connected to (more specifically, in fluid communication with) the first supply unit 12 of the BrCN generator 10 by means of a connecting unit 58.

The illustrative embodiment of a process for synthesizing a nitrogen- containing compound in a semi-batch set-up is in particular shown in the lower part on the right-hand side of Figure 3.

In this illustrative embodiment, the cyanogen bromide (BrCN) 36 is generated by a process and apparatus as described with reference to Figure 1. After quality control of the generated BrCN by means of a monitoring unit 32 comprising for instance FTIR 34, the cyanogen bromide 36 is added to a vessel 60 wherein a substrate (educt), such as a diamine compound, has been placed and dissolved in an organic solvent (for instance DCM) in advance. Within the vessel 60 which may be equipped with a stirring means 62, BrCN reacts with the substrate (e.g. the diamine compound) to give a nitrogen-containing compound (e.g. a cyclic guanidine compound, which may be less soluble in the organic solvent and therefore begins to precipitate, for instance in crystalline form. The thus precipitated nitrogen-containing compound may then be removed from the vessel 60 from time to time and may thus be recovered in a batchwise manner. Alternatively, upon completion of the formation of the nitrogen-containing compound, the vessel 60 may be replaced by another vessel (not shown) containing (fresh) educt. While the present invention has been described in detail by way of specific embodiments and examples, the invention is not limited thereto and various alterations and modifications are possible, without departing from the scope of the invention.

List of reference signs:

10 apparatus configured for continuously generating cyanogen bromide ("BrCN generator")

12 first supply unit

14 fluid containing a bromine source

15 first temperature control unit

16 second supply unit

18 fluid containing a cyanide source

19 second temperature control unit

20 mixing unit

22 reaction unit

24 purification unit

25 liquid-liquid membrane separator

26 membrane

27 microreactor chip

28 third supply unit

30 organic solvent

32 monitoring unit

34 spectrometer

36 cyanogen bromide (BrCN)

40 apparatus configured for continuously generating bromine ("bromine generator")

42 first feeding unit

44 fluid containing a bromate and a bromide

46 second feeding unit

48 fluid containing an acid

50 mixing unit

52 reaction unit

54 discharge unit

56 bromine

58 connecting unit vessel stirring means