Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms

Definitions

• the invention relates to a process for the preparation of a 2,4,6-triiodo-phenol derivative comprising the tri-iodination of a phenol derivative.
• the 2,4,6-triiodo-phenol is an intermediate for the synthesis of conventional X-ray contrast agents, such as iomeprol.
• Non-ionic X-ray contrast agents are a well-known class of contrast agents characterized by its triiodinated aromatic structure. Suitable examples of the same include diatrizoate, iothalamate, ioxithalamate, metrizoate, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iosarcol, iogulamide, acetrizoate and iodamide, which are monomeric; and ioxaglate, iodixanol, iotrolan, iotasul, iodipamide, iocarmate, iodoxamate, iotroxate and iotrolan, which are dimeric.
• Other examples of triiodinated aromatic compounds useful as non-ionic X-ray contrast agents are described, for instance, in WO 94/14478.
• the iodination step of a phenol derivative for the preparation of the 2,4,6-triiodo- phenol derivative is conventionally carried out using ICI in concentrated hydrochloric acid (HCI), or the analogues salts of ICI, such as KICI2 and NalCh, in aqueous solution, as disclosed for example in WO 00/32561 and US 3,914,294.
• HCI concentrated hydrochloric acid
• KICI2 and NalCh analogues salts of ICI, such as KICI2 and NalCh
• ICI and analogues thereof are strong corrosive acids with limited storage life and stability, which generate iodine vapours even at room temperature.
• ICI can be generally stabilized with high quantity of HCI, which in turn must be neutralized prior to waste treatment, leading thus to an increase in operation time, waste volumes and costs.
• WO 2009/103666 discloses the synthesis of triiodinated aromatic compounds by electrochemical triioduration of 3,5-disubstituted phenol derivatives.
• the triiodination reaction carried out in WO 2009/103666 requires stepwise addition of the substrate, reaction times higher than 2 hours, and heating the reaction mixture at reflux.
• WO 2011/154500 discloses the in-situ generation of the iodinating species, from iodine h and a suitable oxidant, typically HIO3, to prepare iodinated phenols, by heating the reaction mixture to 60 °C. It should be noted that heating at 60 °C or higher during the iodination reaction, in particular when the substrate contains hydrolysable moieties, such as the amide moieties that are present in iomeprol intermediates, leads to partial hydrolyzation of such moieties, and consequently to a reduction of the overall yield and to the generation of by-products.
• Yusubov M. et al. discloses the solvent-free monoiodination of nitrophenols and other aromatic compounds by h/AgNCh, obtained after grinding for 10-30 min in an agate mortar, with a yield ranging from 54 to 90%.
• This iodination takes place in a short amount of time in the solid-state, or as a slurry formed by the addition of few drops of acetic acid.
• the reaction is not complete as yields do not exceed 90%.
• carrying out the reaction in a solid-state or slurry is not advantageous from an industrial development standpoint.
• Applicant has now found a new iodination process that allows to carry out the iodination of the substrate with good reaction times and good yields, advantageously in mild reaction conditions.
• the present invention relates to a process for the tri-iodination of a phenol of formula (I), or a salt thereof, to obtain the 2,4,6-triiodophenol of formula (II), or a salt thereof
• the process of the invention provides several advantages by virtue of its iodinating system, in particular when the latter comprises silver and copper, as it allows carrying out a tri-iodination reaction that does not generate, at least to a significant extent, sideproducts deriving from either the partial iodination of the aromatic ring or any other impurity. Moreover, the process of the invention provides high yields and substantially complete conversion of the phenol to the 2,4,6-triiodophenol by operating at room temperature and with low reaction times. Furthermore, the process of the invention is advantageously carried out in an aqueous medium, thereby improving the safety and costeffectiveness of the process of the invention compared to some of the prior art tri- iodination processes.
• FIG. 1 shows, as a function of time, the amount of Compound 2 (“Tri-I") formed during the reaction of:
• the present invention relates to a process for the preparation of a 2,4,6-triiodophenol of formula (II), or a salt thereof,
• R and R' represent, independently from one another, a moiety selected from the group consisting of hydrogen, -COORi, and -CONR1R2; wherein Ri and R2 represent, independently from one another, hydrogen or a Ci-Ce alkyl group, preferably a C1-C4 alkyl group, optionally substituted by one or more groups selected from hydroxyl (-OH), Ci-Ce alkoxy, and Ci-Ce hydroxyalkoxy; comprising the following steps: a) providing a phenol of formula (I), or a salt thereof
• element of group 11 refers to any of the chemical elements of group 11 of the periodic table by modern IUPAC numbering (and is thus a transition metal).
• the element of group 11 is thus selected from the group consisting of copper (Cu), silver (Ag), gold (Au), and roentgenium (Rg), with silver and copper being particularly preferred.
• oxide of an element of group 11 refers to a metal oxide between the dianion of oxygen O 2- and the element of group 11 as above defined, preferably such element being silver or copper.
• Preferred oxides are thus AgzO, CU2O, and CuO, with Ag2O being particularly preferred.
• salt of an element of group 11 refers to a compound consisting of an ionic assembly of the cation of the element of group 11, preferably of a cation of silver or copper, with any anion as counter ion.
• the anion of the salt of an element of group 11 is not a halide, namely is not iodide, bromide, chloride nor fluoride.
• the salt of an element of group 11 preferably does not comprise a halide as anion.
• Preferred anions are phosphate, sulphate, carbonate and nitrate ions, possibly hydrogenated, such as phosphate (PO 3- ), monohydrogen phosphate (HPO4 2- ), dihydrogen phosphate (H2PO4-), sulfate (SO 2- ), bisulfate (HSC '), carbonate (CO3 2 -), bicarbonate (HCOa-), and nitrate (NOs-)- Accordingly, particularly preferred salts are the salts of silver or copper with an anion selected from the list mentioned above.
• phosphoric acid, carbonic acid, and/or ions thereof indicates phosphoric acid (H3PO4), carbonic acid (H2CO3), as well as their anions, possibly hydrogenated, namely phosphate (PO4 3 ’), monohydrogen phosphate (HPC 2- ), dihydrogen phosphate (H2PO4-), carbonate (CO3 2- ), and bicarbonate (HCCh')- Particularly preferred are ions of phosphoric acid and carbonic acid, such as the ones listed above, and even more preferred is bicarbonate (HCOs’).
• alkyl refers to a linear or branched hydrocarbon chain.
• Ci-Ce alkyl comprises within its meaning a linear or branched chain comprising from 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
• alkoxy comprises within its meaning an alkyl chain as above defined further comprising one or more oxygen atoms; examples include, for instance, alkyl-oxy (or -Oalkyl) groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, and alkyl-(poly)oxy in which the alkyl chain is interrupted by more than two oxygen atoms.
• hydroxyalkoxy refers to any of the above alkyloxy residues further comprising one or more hydroxyl (-OH) moieties in the alkyl chain.
• alkoxy or hydroxyalkoxy groups comprise methoxy, ethoxy, n- propoxy, isopropoxy, n-pentoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 1,3- dihydroxyisopropoxy, and the like.
• the process of the invention allows carrying out a tri-iodination reaction that does not generate, at least to a significant extent, sideproducts deriving from either the partial iodination of the aromatic ring or any other impurity; that is, substantially no chlorinated by-products are present after the completion of step c) of the process of the invention (in particular when the salt of the element of group 11 does not comprise chloride as anion), and the yield of the triiodinated product is relatively high, typically higher than 90%, even higher than 95% in most cases.
• the purification of the 2,4,6-triiodophenol obtained according to the process of the invention may be avoided. Indeed, such 2,4,6-triiodophenol already fulfils the analytical specifications for the industrially produced intermediate within the crude solution, and may thus be used as such (namely, without isolating and/or purifying it) in the next reaction steps.
• the process of the invention provides high yields and substantially complete conversion of the phenol to the 2,4,6-triiodophenol by operating at room temperature and with relatively short reaction times, thus resulting in a very convenient process for industrial applications.
• substantially complete tri-iodination >90% yield
• substantially complete tri-iodination can be achieved after about 45 minutes of reaction time (up to about 80 minutes of reaction time, depending on the iodinating system selected)
• the complete reaction can be achieved after about 80 minutes of reaction time (or up to about 100 minutes of reaction time, depending on the iodinating system selected) by operating around room temperature.
• reaction step c) can be carried out by adjusting and/or maintaining the temperature to 40 °C or lower, for example in the range of 15 °C to 35 °C, e.g.
• the process of the present invention is advantageously carried out in an aqueous medium.
• aqueous medium refers to a solution or suspension comprising water as solvent or as external phase of the suspension.
• the aqueous medium is substantially free from any organic solvent miscible with water, and thus the aqueous medium is a solution or suspension comprising water as the sole solvent or as the sole external phase of the suspension. Accordingly, the process of the invention allows using a solvent, namely water, which is inexpensive and safe for both the users and the environment.
• the iodinating system comprises a silver oxide and/or a salt of copper and h, provided that when the iodinating system comprises such salt of copper, the iodinating system further comprises at least phosphoric acid, carbonic acid, and/or ions thereof.
• the iodinating system is selected from the group consisting of AgzO/h, h/CuSC /NaHCCh, and mixtures thereof.
• R and R' represent, independently from one another, a -COORi or a -CONR1R2 moiety, preferably a -CONR1R2, wherein Ri and R2, independently from one another, represent hydrogen or a C1-C4 alkyl group optionally substituted by from one to three hydroxyl (-OH), such as, for instance, 1,3-dihydroxyisopropyl, 2,3-dihydroxypropyl, l,3-dihydroxy-2-methyl-isopropyl, or 2,3,4-trihydroxybutyl.
• -OH hydroxyl
• R and R' represent, independently from one another, a moiety selected from: -CONHCH3, -CONHCH2-CH(OH)- CH2OH, -CONHCH(CH 2 OH)2, and -CON(CH 3 )-CH2-CH(OH)-CH 2 OH.
• the phenol of formula (I) is N,N’-bis[2,3- dihydroxypropyl]-5-hydroxybenzene-l,3-dicarboxamide (Compound 1)
• the 2,4,6- triiodophenol of formula (II) is N,N’-bis[2,3-dihydroxypropyl]-5-hydroxy-2,4,6- triiodobenzene-l,3-dicarboxamide (Compound 2)
• R and R' groups do not take direct part to the iodination process, the groups R and R' which may undergo unwanted side reactions could be suitably protected before the iodination step takes place. Protection and subsequent deprotection of the said groups can be accomplished by a variety of methods widely known in the art and conventionally adopted in organic synthesis techniques, for example as disclosed in T. W. Greene, Protective Groups in Organic Synthesis (Wiley, N.Y. 1981).
• the pH of the aqueous medium of step c) of the process of the invention is preferably adjusted and/or maintained to the range provided above, for example by adding a catalytic amount of a suitable base, for instance NaOH or NH3, NH3 being particularly preferred, and/or a catalytic amount of a suitable acid.
• a suitable base for instance NaOH or NH3, NH3 being particularly preferred
• suitable acids can be for example HCIO4.
• a base such as NaOH or NH3 is preferably added (e.g. continuously or step-wise) during step c) to improve the solubilization of AgzO.
• the pH of the aqueous medium of step c) of the process of the invention is comprised in the range of 7.5 to 8.0, possibly by adding a catalytic amount of a suitable base, such as the bases provided above, and/or of a suitable acid if needed.
• a base such as NaOH or NH3 is continuously added during step c) to maintain the pH within the ranges provided above.
• step c) Some of the components of the iodinating systems, e.g. AgzO and I2, might be slightly soluble within the reaction conditions of step c), and accordingly the reaction mixture of step c) might be a suspension.
• step c) is carried out in the dark and/or using non-transparent reactors, i.e. reactors that limit the visible light reaching the reaction mixture, such as stainless steel reactors or reactors covered with tinfoil or with aluminium foil.
• at least step c) is carried out preferably without exposing the reaction mixture to direct sunlight and possibly also to artificial light.
• step c) of the invention provides for reacting the phenol and the iodinating system, e.g. according to the conditions previously disclosed, in a molar ratio of at least three moles of I2 per mole of phenol. More preferably, the molar ratio of I2 to phenol of the reaction of step c) is comprised in the range of 3: 1 to 4: 1, even more preferably of 3: 1 to 3.5: 1.
• the molar ratio between I2 and silver is at least 4: 1, and is preferably comprised in the range of 4: 1 to 1 : 1, more preferably of 3: 1 to 1 : 1, and even more preferably is 2: 1. Indeed, it has been found that these ratios allow obtaining complete conversion of the phenols into the 2,4,6-triiodophenol in a short amount of time, typically around 1 hour or less.
• the molar ratio between I2 and copper is comprised in the range of 1 :0.8 to 1 :3, and more preferably is 1 : 1.
• step c) when copper salt or oxide is comprised in the iodinating system, the reaction of step c) is more effective when at least phosphoric acid, carbonic acid, and/or ions thereof are present as well.
• the ions of phosphoric acid and carbonic acid can be advantageously provided according to step b) as salt, for example as a sodium or potassium salt, such as NasPC , K3PO4, Na2HPC>4, K2HPO4, NaH2PO4, KH2PO4, Na2COs, K2CO3, NaHCO 3 . and KHCO3.
• a sodium or potassium salt such as NasPC , K3PO4, Na2HPC>4, K2HPO4, NaH2PO4, KH2PO4, Na2COs, K2CO3, NaHCO 3 . and KHCO3.
• the iodinating system comprises copper and thereby at least phosphoric acid, carbonic acid, and/or ions thereof
• the phosphoric acid, carbonic acid, or ions thereof is comprised in amount of 0.01 M or higher, more preferably of 0.1 M or higher, within the reaction mixture of step c).
• the components of the iodinating systems are commercially available, and can thus be obtained accordingly.
• the components of the iodinating systems can be prepared according to known methods.
• Ag2O can be obtained according to the method disclosed in Example 2 below.
• Step c) of the process of the invention provides the 2,4,6-triiodophenol, as well as a precipitate of the element of group 11 with iodide ions, such as Agl and/or of Cui (based on the selected iodinating system).
• iodide ions such as Agl and/or of Cui (based on the selected iodinating system).
• part of the iodine deriving from I2 is used to triiodinate the phenol, and part reacts with the free element of group 11, such as free Ag + and/or free copper ions to form Agl and/or Cui, respectively. This is particularly useful i.a.
• the process further comprises the following step: d) converting at least part of Agl that is generated during and/or after step c) to I2 and an oxide or a salt of silver different than Agl.
• the process of the invention has the further advantage of recovering the unreacted components of the iodinating system, such as the oxide or salt of silver and I2, thus improving the cost efficiency of the process itself.
• the recovered iodinating system can indeed be used for further reactions according to step c) of the process of the invention.
• step d) can be carried for example by: dl) separating, e.g. by filtering out, Agl that is generated during and/or after step c) from the reaction mixture of step c); d2) mixing the separated Agl with water or an aqueous solution to form a suspension; d3) treating the suspension with reducing agents, preferably with hydrazine or NaBH 4 , and optionally treating the suspension with sunlight, e.g.
• steps d5) and d6) can be carried out in any order.
• Step d5) can be carried out for example by mixing the separated silver particles Ag with an acidic solution comprising NOs', such as a concentrated HNO3 solution (at least 50% w/w, preferably 65% w/w concentration).
• an acidic solution comprising NOs' such as a concentrated HNO3 solution (at least 50% w/w, preferably 65% w/w concentration).
• Step d6) can be carried out for example by mixing the solution comprising T with a solution of KIO3 (preferably, with the ratio of T to KIO3 being 5: 1), or with a solution of HIO3, for example as disclosed in WO 2011/154500, preferably under acidic conditions.
• the process further comprises the following step: e) converting at least part of Cui that is generated during and/or after step c) to I2 and an oxide or a salt of copper different than Cui.
• the process of the invention has the further advantage of recovering the unreacted components of the iodinating system, such as the oxide or salt of copper and I2, thus improving the cost efficiency of the process itself.
• the recovered iodinating system can thereby be used for further reactions according to step c) of the process of the invention.
• step e) can be carried out for example by: el) separating, e.g. by filtering out, Cui that is generated during and/or after step c) from the reaction mixture of step c); e2) mixing the separated Cui with a basic aqueous solution, for example a solution of NaOH, to obtain a solution comprising T and precipitate Cu(OH)2; e3) separating, e.g. by filtering out, Cu(OH)2 from the solution comprising T; e4) mixing the filtrate Cu(OH)2 to an acidic solution comprising SC 2 ' to form
• a basic aqueous solution for example a solution of NaOH
• Step e5) can be carried out for example by mixing the solution comprising T with a solution of KIO3 (preferably, with the ratio of T to KIO3 being 5: 1), or with a solution of HIO3, for example as disclosed in WO 2011/154500, preferably under acidic conditions.
• Compound 1 used herein as the starting material of the process of the invention, is known and may be prepared according to the known methods.
• a general reference to Compound 1 see, for instance, WO 88/09328, WO 97/05097 and WO 00/32561.
• Any other reactant and/or solvent employed in the instant process is known and readily available. If they are not commercially available per se, they may be prepared according to known methods in literature.
• HPLC system Agilent 1260 Infinity II HPLC instrument equipped with quaternary pump, degasser, autosampler, PDA and MS detector (LCQ Deca XP- Plus - Thermo Finnigan);
• Injection volume 10 pL
• X H NMR measurements were performed with a Bruker DRX 400 (9.4 T) spectrometer equipped with a Bruker VT-1000 thermocontroller (298 K) and a BB inverse z gradient probe (5 mm).
• X H NMR spectra of the samples were recorded by using standard Bruker Excitation Sculpting pulse sequence. Samples were prepared in H2O (a capillary with D2O was used for lock). The X H NMR spectra were analysed with TOPSPIN version 3.5 (Bruker) software.
• Example 1 (Comparative) - Iodination of Compound 1 with I2 at pH 7.5 and 25 °C (without iodinating system)
• a 25 mL 0.3 mM Compound 1 ⁇ Bracco Imaging) solution was prepared by dissolving 2.5 mg of Compound 1 (7.6 pmol) in 25 mL air-free distilled water. The reaction was started by addition of 5.6 mg of I2 (Sigma, 22 pmol) to 20 mL of the 0.3 mM Compound 1 solution. The pH of the reaction was adjusted to 7.5 by stepwise addition of a solution of NaOH. The reaction was kept at 25 °C and stirred at 120 rpm.
• ImL solution samples were withdrawn time by time, and were analyzed by HPLC-ESI-MS and by X H NMR spectroscopy according to the experimental setups disclosed above.
• the 1 mL solution samples were filtered through a 0.45 pm syringe filter and mixed with 1.4 mg Na2SOs ⁇ Sigma, 11 pmol) in order to quench the reaction by the reduction of the unreacted I2 to T anion.
• the HPLC chromatogram of the sample gathered at 120 min reaction time obtained according to the present example shows the presence of Compound 1, and of the mono- and di-iodinated derivatives.
• the X H NMR spectra confirms this, as the signals of Compound 1, and of the mono- and di-iodinated derivatives, are still clearly visible at 114.3 min reaction time. Accordingly, the results of the HPLC measurements and NMR studies show that Example 1 (Comparative) provides partial, and thus incomplete, triiodination of Compound 1 within 2 hours, even in the presence of 3.7-fold excess of I2.
• the amount of Compound 1 as a function of time during the reaction of Example 1 (Comparative) is shown in Figure 1 as diamond ( ⁇ ). According to these data included in Figure 1, the iodination of Example 1 (Comparative) provides a conversion of Compound 1 to Compound 2 of about 70% in 2 hours.
• a reaction according to Scheme 1 above was conducted as follows. Solid AgzO was prepared by the addition of 40 mg NaOH Sigma, 1 mmol) into 10 mL 0.1 M AgNCh solution Sigma, 1 mmol). The brown AgzO precipitate was filtered off by Buchner funnel, and washed four times with distilled water. The brown AgzO precipitate was then dried for a night at reduced pressure to obtain 100 mg of AgzO (0.43 mmol, yield: 86%). A 0.3 mM solution of Compound 1 was prepared by dissolving 2.5 mg of Compound 1 (7.6 pmol) in 25 mL of air-free distilled water.
• the iodinating reaction was started by addition of 5.6 mg h (Sigma, 22 pmol) and 2.5 mg AgzO (11 pmol) to 20 mL of the 0.3 mM Compound 1 solution.
• the pH of the reaction was adjusted to 7.5 by stepwise addition of a solution of NH3.
• the reaction was kept at 25 °C and stirred at 120 rpm.
• This substantially complete formation (yield >90%) was confirmed by the ESI-MS and the X H NMR spectra.
• the X H NMR spectra further confirm the final completion (yield about 99%) after about 80 min reaction time.
• Example 2 Comparative
• the amount of Compound 2 formed in the iodination reaction of Example 2 was calculated by considering the total concentration of Compound 1 and is shown in Figure 1 as triangle (A).
• a reaction according to Scheme 1 above was conducted as follows.
• a 0.3 mM solution of Compound 1 was prepared by dissolving 2.5 mg Compound 1 (7.6 pmol) in 25 mL air- free distilled water.
• the tri-iodination reaction was started by addition of 5.6 mg I2 (Sigma, 22 pmol), 5.5 mg CUSO4+5H2O (Sigma, 22 pmol) and 336 mg NaHCCh (Sigma, 4 mmol) to 20 mL of the 0.3 mM Compound 1 solution.
• the pH of the reaction was adjusted to 7.5 by stepwise addition of a solution of NaOH.
• the reaction was kept at 25 °C and stirred at 120 rpm.
• ImL solution samples were withdrawn time by time and were analyzed by X H NMR spectroscopy according to the experimental setups disclosed above.
• the 1 mL solution samples were filtered through a 0.45 pm syringe filter and mixed with 1.4 mg NazSCh Sigma, 11 pmol) in order to quench the reaction by the reduction of the unreacted h to T anion.
• Example 1 Comparative
• the amount of Compound 2 formed in the iodination reaction of Example 3 was calculated by considering the total concentration of Compound 1 and is shown in Figure 1 as circle (•).
• Example 4 Direct comparison between Example 1 (Comparative), Example 2 and Example 3
• Figure 1 clearly shows the improvement in reaction time and completeness of the process of the invention when compared to a process not according to the invention.
• the supernatant comprising T ions (in particular, Nal) released from Agl precipitate was collected and 50 mL stock solution was prepared with bidistilled water. After the washing procedure the retained elementary Ag was dissolved in 3 mL 65% ultrapure HNO3 (Sigma). The acid excess of the resulting AgNCh solution was evaporated in atmospheric condition. After the evaporation of the acid excess, 20 mL stock solution was prepared by dissolving AgNCh in 0.1 M HNO3. I2 can be obtained from the supernatant comprising T ions for example by treating it with an oxidating agent, such as HIO3 or KIO3, e.g. as disclosed in step d6) or e5) of the invention.
• an oxidating agent such as HIO3 or KIO3, e.g. as disclosed in step d6) or e5 of the invention.
• Concentration of the AgNCh and Nal solution was determined by potentiometric titration with standardized 0.015 M KI solution.
• the slope (102.3 %) and plo (6.40) values calculated from E (mV) vs. pl data pairs of the calibration have been used to calculate the [T] of the Nal solution.
• the potentiometric system was also calibrated with standardized 0.015 M KI solution at acidic condition in order to avoid the precipitation of Ag + ion in the form of Ag2O.
• 10 mL aqueous solution prepared with 0.02 M HNO3 and 0.15 M NaNCh at 25°C was titrated with 0.015 M KI solution.
• the slope (101.8 %) and plo (6.43) values calculated from E (mV) vs. pl data pairs of the calibration have been used to calculate the pl values in the titration experiment.
• AgNCh solution (10 mL, 0.02 M HNO3, 0.15 M NaNCh, 25°C) was titrated with standardized 0.015 M KI solution.
• the pl values calculated from measured E(mV) as a function of VKI (mL) have been used to calculate the concentration of the AgNCh recovered from Agl.
• the concentration of the 50 mL Nal and 20 mL AgNCh stock solutions obtained from the recovery of Agl precipitate was found to be 0.00361 and 0.009773 mol/dm 3 (T: 0.181 mmol; Ag + : 0.196 mmol), respectively.
• the yield of the T and Ag + recovery was found to be 91 and 98%, respectively.

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