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WO2019034569A1 - Procédé de génération de bromure de cyanogène (brcn), générateur de brcn, générateur de brome et procédé de synthèse d'un composé contenant de l'azote - Google Patents

Procédé de génération de bromure de cyanogène (brcn), générateur de brcn, générateur de brome et procédé de synthèse d'un composé contenant de l'azote Download PDF

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Publication number
WO2019034569A1
WO2019034569A1 PCT/EP2018/071820 EP2018071820W WO2019034569A1 WO 2019034569 A1 WO2019034569 A1 WO 2019034569A1 EP 2018071820 W EP2018071820 W EP 2018071820W WO 2019034569 A1 WO2019034569 A1 WO 2019034569A1
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Prior art keywords
cyanogen bromide
bromine
unit
fluid
bromide
Prior art date
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Ceased
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PCT/EP2018/071820
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English (en)
Inventor
Gabriel GLOTZ
Christian Oliver KAPPE
Doris DALLINGER
Rene LEBL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Karl Franzens Universitaet Graz
RESEARCH CENTER PHARMACEUTICAL ENGR GmbH
Original Assignee
Karl Franzens Universitaet Graz
RESEARCH CENTER PHARMACEUTICAL ENGR GmbH
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Publication of WO2019034569A1 publication Critical patent/WO2019034569A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01C—AMMONIA; CYANOGEN; COMPOUNDS THEREOF
    • C01C3/00—Cyanogen; Compounds thereof
    • C01C3/004—Halogenides of cyanogen
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B7/00—Halogens; Halogen acids
    • C01B7/09—Bromine; Hydrogen bromide
    • C01B7/096—Bromine

Definitions

  • 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.
  • Cyanogen bromide (BrCN) is an interesting target molecule: it is an
  • 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
  • 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.
  • cyanogen bromide 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.
  • 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 invention relates to a process for generating cyanogen bromide (BrCN) comprising the steps of:
  • the present invention further relates to an apparatus configured for
  • 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
  • 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.
  • 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
  • reaction unit configured for reacting the bromate and the bromide with each other under acidic condition to give bromine
  • discharge unit configured for discharging the bromine
  • 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.
  • a connecting unit or interface unit
  • the present invention relates to a process for synthesizing a nitrogen-containing compound comprising the steps of
  • 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.
  • 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
  • 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,
  • the fluid containing a bromine source may be a liquid, in particular an aqueous liquid.
  • the fluid containing a cyanide source may be a liquid, in particular an aqueous liquid.
  • cyanide source 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.
  • the cyanide source may comprise or consist of a cyanide compound, in particular potassium cyanide (KCN) and/or sodium cyanide (NaCN).
  • KCN potassium cyanide
  • NaCN sodium cyanide
  • 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.
  • the bromine source may comprise or consist of bromine (Br 2 ).
  • the fluid containing a bromine source comprises bromine (Br 2 ).
  • 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).
  • KBr potassium bromide
  • NaBr sodium bromide
  • the fluid containing a bromine source comprises bromine (Br 2 )
  • 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.
  • 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).
  • a bromate such as sodium bromate, NaBrC , or potassium bromate, KBr
  • a bromide such as sodium bromide, NaBr, or potassium bromide, KBr
  • an acid such as hydrobromic acid, HBr, or sulfuric acid, H2SO4
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a (crude) reaction mixture containing cyanogen bromide is obtained.
  • this reaction mixture contains water which is detrimental to the stability of the cyanogen bromide.
  • 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.
  • the obtained cyanogen bromide might not be
  • 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)) .
  • a membrane-based separation to give (purified, such as substantially pure) cyanogen bromide (in an organic solvent, such as dichloromethane (DCM)) .
  • DCM dichloromethane
  • 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.
  • the step of purifying the reaction mixture comprises passing of cyanogen bromide through a membrane.
  • 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.
  • 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.
  • 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
  • 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.
  • a microreactor chip such as a glass microreactor chip
  • the membrane has a hydrophobic surface.
  • 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.
  • the membrane has a pore size of less than 1.0 ⁇ , in particular of from 0.2 to 0.8 ⁇ , in particular of about 0.5 ⁇ .
  • it may be possible to substantially suppress that water enters into the organic phase and/or that organic solvent enters into the aqueous phase.
  • the process for generating cyanogen bromide further comprises a step of monitoring the purity of the cyanogen bromide after the purifying step.
  • 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).
  • the step of monitoring comprises determining a
  • concentration of the 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
  • the step of monitoring comprises a spectroscopic method, in particular by means of Fourier transform infrared (FTIR) spectroscopy.
  • FTIR Fourier transform infrared
  • cyanogen bromide can be determined on the basis of the
  • 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.
  • 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.
  • 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).
  • T mixer or Y mixer 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).
  • 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.
  • fluid transport means include for instance one or more pumps.
  • the reaction unit is a tubular reaction unit, such as a reaction coil .
  • a tubular reaction unit such as a reaction coil .
  • the reaction time may be easily adjusted by adjusting the flow rate of the fluid passing the reaction zone.
  • an efficient and simple temperature control, such as cooling, of the reaction unit may be realized.
  • the BrCN generator may further comprise a third temperature control unit configured for controlling (in particular lowering) the temperature of the reaction unit.
  • 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.
  • the microreactor chip is located upstream of a liquid-liquid membrane separator.
  • 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.
  • the liquid-liquid membrane separator is located downstream of a microreactor chip.
  • the membrane of the purification unit may be configured such that cyanogen bromide may pass through (permeate) the membrane.
  • the membrane has a hydrophobic surface.
  • 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.
  • the membrane has a pore size of less than 1.0 ⁇ , in particular of from 0.2 to 0.8 ⁇ , in particular of about 0.5 ⁇ .
  • a pore size of less than 1.0 ⁇ , in particular of from 0.2 to 0.8 ⁇ , in particular of about 0.5 ⁇ .
  • 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.
  • the aqueous reaction mixture may be combined with the organic solvent in a (glass) microreactor chip.
  • the BrCN generator further comprises a monitoring unit located downstream of the purification unit and configured for monitoring the purity of the cyanogen bromide.
  • the monitoring unit comprises a spectrometer, in particular a Fourier transform infrared (FTIR) spectrometer.
  • FTIR Fourier transform infrared
  • the BrCN generator further comprises a bromine
  • 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
  • reaction unit configured for reacting the bromate and the bromide with each other under acidic condition to give bromine
  • a discharge unit configured for discharging the bromine.
  • 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.
  • the bromine generator may be coupled (or connected) to the BrCN generator by means of the connecting unit.
  • both generators i.e. the bromine generator and the BrCN generator
  • the bromine generator may be arranged in series with the bromine generator arranged upstream of the BrCN generator.
  • 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.
  • the present invention relates to a (continuous or semi- batch) process for synthesizing a nitrogen-containing compound comprising the steps of
  • Cyanogen bromide obtained by the process for generating cyanogen bromide as described herein may be versatilely used for synthesizing nitrogen- containing compounds.
  • nitrogen-containing compounds that may be synthesized include those shown in the following scheme together with respective educts:
  • 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).
  • verubecestat 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 .
  • 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 .
  • a diamine compound which may be dissolved in an alcohol, such as methanol
  • 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.
  • a vessel such as a flask
  • the diamine compound (educt) typically dissolved in a solvent, in particular an organic solvent
  • 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.
  • the vessel may be replaced by another vessel containing (fresh) educt.
  • the nitrogen-containing compound may comprise an organic cyanamide and the educt may comprise a tertiary amine compound.
  • 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.
  • 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.
  • a bromine source such as 1 M (mol/l) Br 2 in 13 wt.% aqueous KBr.
  • 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 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 .
  • 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 ⁇ 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.
  • 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
  • the two fluids 14, 18 are mixed by a mixing unit 20 having a T-shape. Subsequently, the mixed fluids are
  • 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 ⁇ min
  • the bromine source and the cyanide source react with each other to give a crude reaction mixture containing cyanogen bromide.
  • 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.
  • 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.
  • P3 a pump
  • 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.
  • 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.
  • a monitoring unit 32 comprising an FTIR spectrometer 34 in this embodiment and located downstream of the purification unit 24.
  • 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.
  • a fluid 44 containing a bromate such as 0.66 M aqueous NaBrC
  • a bromide such as 3.34 M aqueous NaBr.
  • 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 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 ⁇ 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.
  • the two fluids 44, 48 are mixed by a mixing unit 50 having a T-shape. Subsequently, the mixed fluids are
  • 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
  • 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.
  • 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.
  • a BrCN generator for instance a BrCN generator 10 as discussed above with reference to Figure 1
  • upstream thereof a bromine generator for instance a bromine generator 40 as discussed above with reference to Figure 2.
  • 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 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 substrate educt
  • an organic solvent for instance DCM
  • 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.
  • the vessel 60 may be replaced by another vessel (not shown) containing (fresh) educt.
  • bromine generator configured for continuously generating bromine

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Abstract

La présente invention concerne un procédé de génération de bromure de cyanogène (BrCN) comprenant les étapes suivantes : mélange d'un fluide contenant une source de brome avec un fluide contenant une source de cyanure, mise en réaction de la source de brome et la source de cyanure l'une avec l'autre pour donner un mélange réactionnel contenant du bromure de cyanogène, et purification du mélange réactionnel au moyen d'une séparation sur membrane pour donner du bromure de cyanogène (purifié). La présente invention concerne également un appareil conçu pour générer en continu du bromure de cyanogène et un appareil conçu pour générer en continu du brome, lesdits deux appareils pouvant être combinés. La présente invention concerne an outre un procédé de synthèse d'un composé contenant de l'azote.
PCT/EP2018/071820 2017-08-17 2018-08-10 Procédé de génération de bromure de cyanogène (brcn), générateur de brcn, générateur de brome et procédé de synthèse d'un composé contenant de l'azote Ceased WO2019034569A1 (fr)

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GBGB1713208.5A GB201713208D0 (en) 2017-08-17 2017-08-17 Process for generating cyanogen bromide (BrCN, BrCN generator, bromine generator and process for synthesizing a nitrogen-containing compound
GB1713208.5 2017-08-17

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WO2023081255A1 (fr) * 2021-11-05 2023-05-11 The Board of Regents for the Oklahoma Agricultural and Mechanical Colleges Système et procédé de transport sélectif de liquide

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US1779984A (en) * 1927-01-25 1930-10-28 Nat Aniline & Chem Co Inc Process of making cyanogen chlorides
US2500946A (en) * 1946-09-19 1950-03-21 Koppers Co Inc Process for making bromine cyanide
EP0099217A1 (fr) * 1982-07-06 1984-01-25 Eli Lilly And Company Procédé de récupération de bromure de cyanogène
WO2001042138A1 (fr) * 1999-12-09 2001-06-14 Syngenta Limited Elaboration de cyanogene de bromure

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US1779984A (en) * 1927-01-25 1930-10-28 Nat Aniline & Chem Co Inc Process of making cyanogen chlorides
US2500946A (en) * 1946-09-19 1950-03-21 Koppers Co Inc Process for making bromine cyanide
EP0099217A1 (fr) * 1982-07-06 1984-01-25 Eli Lilly And Company Procédé de récupération de bromure de cyanogène
WO2001042138A1 (fr) * 1999-12-09 2001-06-14 Syngenta Limited Elaboration de cyanogene de bromure

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023081255A1 (fr) * 2021-11-05 2023-05-11 The Board of Regents for the Oklahoma Agricultural and Mechanical Colleges Système et procédé de transport sélectif de liquide

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