Method for producing 2,4,6-triiodophenol derivatives

Abstract

The present invention relates to a compound of formula (II): The present invention relates to a method for producing a 2,4,6-triiodo-phenol derivative represented by TIFF2025514326000011.tif4237, which comprises triiodinating a phenol derivative corresponding to the 2,4,6-triiodo-phenol derivative using an iodination system comprising I2 and an oxide or salt of an element of Group 11 of the periodic table.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of 2,4,6-triiodo-phenol derivatives, which are intermediates for the synthesis of conventional X-ray contrast agents such as iomeprol, comprising the triiodination of a phenol derivative. [Background technology]

[0002] Non-ionic X-ray contrast agents are well known as a type of contrast agent characterized by triiodized aromatic structures.Suitable examples thereof include monomers such as diatrizoate, iothalamate, ioxythalamate, metrizoate, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iosalkol, iogluamide, acetolyzoate, and iodamide; and dimers such as ioxaglate, iodixanol, iotrolan, iotasur, iodipamide, iocalmate, iodoxamate, iotroxate, and iotrolan.Other examples of triiodized aromatic compounds useful as non-ionic X-ray contrast agents are described, for example, in WO94 / 14478.

[0003] Currently, several multi-step synthetic methods are used to prepare the above triiodinated aromatic compounds. Among these multi-step syntheses, a particularly important step is the iodination of 3,5-disubstituted phenol derivatives to give 2,4,6-triiodo-3,5-disubstituted phenol derivatives. In practice, the latter can be reacted with amides and finally subjected to a Smiles rearrangement (disclosed, for example, in WO88 / 09328 and WO97 / 05097) to give the final triiodinated aromatic compounds useful for X-ray diagnosis. This general process is well known and is disclosed, for example, in WO00 / 32561.

[0004] The iodination process of phenol derivatives to produce 2,4,6-triiodo-phenol derivatives is conventionally carried out using ICl in concentrated hydrochloric acid (HCl) or similar salts of ICl in aqueous solution, such as KICl2 or NaICl2, as disclosed, for example, in WO 00 / 32561 and US 3,914,294.

[0005] However, ICl and its analogues are highly corrosive acids with limited shelf life and stability, and they generate iodine vapor even at room temperature. ICl can generally be stabilized with large amounts of hydrochloric acid, but it must be neutralized before disposal, which increases work time, waste, and costs. Furthermore, the use of ICl and its analogues can reduce the quality (yield and purity) of the final product, as the generated chlorine gas undergoes electrophilic aromatic substitution reactions with phenolic substrates, leading to the undesirable formation of chlorinated by-products.

[0006] Therefore, attempts have been made to perform the iodination step without using ICl or its analogues, such as by using iodine (I2) as the iodination reagent.

[0007] WO2009 / 103666 discloses the synthesis of triiodinated aromatic compounds by electrochemical triiodination of 3,5-disubstituted phenol derivatives. The triiodination reaction carried out in WO2009 / 103666 requires stepwise addition of substrate, reaction times in excess of 2 hours, and heating of the reaction mixture at reflux.

[0008] WO2011 / 154500 discloses the preparation of iodized phenols by in-situ generation of iodized species from iodine, I2, and a suitable oxidizing agent (typically HIO3) by heating the reaction mixture to 60° C. It should be noted that heating above 60° C. during the iodination reaction can result in partial hydrolysis of such moieties, resulting in a lower overall yield and the generation of by-products, particularly when the substrate contains hydrolyzable moieties (e.g., the amide moiety present in the yomeprol intermediate).

[0009] Joshi SN et al. (Tetrahedron (2011), 67, 7461-7469) reported that AgX / I2 (where X is -SO4 and BF4 - or PF6 - disclose the iodination of dichlorinated phenols using I2, a non-coordinating anion selected from the group consisting of iodine, ...

[0010] Yusubov M. et al. (Synthetic Communications (2007), 37, 1259-1265) disclose the solvent-free mono-iodination of nitrophenols and other aromatic compounds with I2 / AgNO3 obtained after grinding in an agate mortar for 10-30 minutes, with yields of 54-90%. This iodination is carried out either for a short time in the solid state or as a slurry formed by the addition of a few drops of acetic acid. However, the reaction is not complete, since the yields do not exceed 90%. Moreover, carrying out the reaction in the solid state or in a slurry is not advantageous from the point of view of industrial development. Summary of the Invention [Problem to be solved by the invention]

[0011] Applicants have discovered a new iodination process that allows the iodination of a substrate to be carried out with good reaction times and yields, and advantageously under mild reaction conditions. [Means for solving the problem]

[0012] Summary of the Invention As claimed, the present invention relates to a process for triiodination of a phenol of formula (I) or a salt thereof to obtain 2,4,6-triiodophenol of formula (II) or a salt thereof. [ka]

[0013] The process of the invention offers several advantages, since it allows carrying out a triiodination reaction that does not produce, at least to a significant extent, by-products originating either from partial iodination of the aromatic ring or from other impurities, particularly when the iodination system comprises silver and copper. Moreover, the process of the invention operates at room temperature and with short reaction times, resulting in a high yield and essentially complete conversion of phenol to 2,4,6-triiodophenol. Furthermore, the process of the invention is advantageously carried out in an aqueous medium, thereby improving safety and cost-effectiveness compared to prior art triiodination processes. Embodiments of the invention are described in the dependent claims. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the time course of the amount of compound 2 ("Tri-I") formed during the following reactions: Example 1 (comparative example) ([Compound 1]=0.3 mM, [I2]=1.1 mM, pH=7.5, 25° C.) (◇); Example 2 ([Compound 1]=0.3 mM, [I2]=1.1 mM, [Ag2O]=0.55 mM, pH=7.5, 25° C.) (△); and Example 3 ([Compound 1]=0.3 mM, [I2]=1.1 mM, [Cu2+]=1.1 mM, [NaHCO3]=0.2 mM, pH=7.5, 25° C.) (●). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention According to a first aspect, the present invention provides a compound of formula (II): [ka] [In the formula, R and R', independently of each other, represent a moiety selected from the group consisting of hydrogen, -COOR1, and -CONR1R2; R1 and R2, independently of each other, represent hydrogen or a C1-C6 alkyl group, preferably a C1-C4 alkyl group, optionally substituted by one or more groups selected from hydroxyl (-OH), C1-C6 alkoxy and C1-C6 hydroxyalkoxy. A method for producing 2,4,6-triiodophenol represented by the following formula (I) or a salt thereof, comprising the steps of: a) Formula (I) [ka] [In the formula, R and R′ are as defined above.] or a salt thereof; b) providing an iodination system comprising I2 and at least an oxide or salt of an element of group 11 of the periodic table, preferably silver or copper, with the proviso that when the element of group 11 is copper, the iodination system further comprises at least phosphate, carbonate and / or ions thereof; and c) reacting said phenol of step a) with said iodination system of step b) in an aqueous medium having a pH in the range of 7.0 to 9.0 to obtain 2,4,6-triiodophenol of formula (II). The present invention relates to a manufacturing method comprising the steps of:

[0016] Unless otherwise specified, the term "group 11 element" refers to any chemical element in group 11 of the periodic table according to the IUPAC numbering (and thus a transition metal), i.e., a group 11 element is selected from the group consisting of copper (Cu), silver (Ag), gold (Au) and roentgenium (Rg), with silver and copper being particularly preferred.

[0017] Unless otherwise specified, the term "oxide of an element of Group 11" means oxygen, O2 -and an element of group 11 as defined above, preferably such element is silver or copper. Preferred oxides are therefore Ag2O, Cu2O, and CuO, with Ag2O being particularly preferred.

[0018] Unless otherwise specified, the term "salt of an element of group 11" refers to a compound comprising an ionic association of a cation of an element of group 11, preferably a silver or copper cation, with an anion as a counterion. Preferably, the anion of the salt of an element of group 11 is not a halide (i.e., iodide, bromide, chloride, fluoride). Preferred anions are phosphate, sulfate, carbonate and nitrate, optionally hydrogenated, e.g., phosphate (PO4 3- ), monohydrogen phosphate ion (HPO4 2- ), dihydrogen phosphate ion (H2PO4 - ), sulfate ion (SO4 2- ), hydrogen sulfate ion (HSO4 - ), carbonate ion (CO3 2- ), hydrogen carbonate ion (HCO3 - ) and nitrate ion (NO3 - ) Particularly preferred salts are therefore silver or copper salts with anions selected from the above list.

[0019] Unless otherwise specified, the term "phosphate, carbonate and / or their ions" refers to phosphoric acid (H3PO4), carbonate (H2CO3), and their optionally hydrogenated anions, i.e., phosphate ion (PO4 3- ), monohydrogen phosphate ion (HPO4 2- ), dihydrogen phosphate ion (H2PO4 - ), carbonate ion (CO3 2- ), and bicarbonate ion (HCO3 - ) is particularly preferred. The phosphate ion and carbonate ion are as described above, and the hydrogen carbonate ion (HCO3 - ).

[0020] Unless otherwise specified, the term "alkyl" refers to a straight or branched hydrocarbon chain. Thus, "C1-C6 alkyl" means a straight or branched chain containing 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.

[0021] Unless otherwise specified, the term "alkoxy" includes within its meaning an alkyl chain as defined above further comprising one or more oxygen atoms; examples include alkyl-oxy (or -Oalkyl) groups such as methoxy, ethoxy, n-propoxy, isopropoxy, and alkyl-(poly)oxy in which the alkyl chain is interrupted by more than two oxygen atoms.

[0022] Unless otherwise specified, the term "hydroxyalkoxy" refers to any of the above alkyloxy residues further containing one or more hydroxyl (-OH) moieties in the alkyl chain.

[0023] Suitable examples of the alkoxy group or hydroxyalkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-pentoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 1,3-dihydroxyisopropoxy, and the like.

[0024] Surprisingly, it has been found that the process of the present invention allows the triiodination reaction to be carried out without producing, at least to a significant extent, by-products originating from either partial iodination of the aromatic ring or other impurities; i.e., after completion of step c) of the process of the present invention (especially when the salt of the group 11 element does not contain chloride as an anion), there are substantially no chlorinated by-products, and the yield of the triiodination product is relatively high, typically higher than 90%, and in most cases higher than 95%. Thus, unlike some iodination methods of the prior art, the 2,4,6-triiodophenol obtained by the process of the present invention can avoid purification. In fact, such 2,4,6-triiodophenol already meets the analytical specifications of the industrially produced intermediate in crude solution, and can therefore be used as is (i.e. without isolation and / or purification) in the next reaction step.

[0025] Moreover, the process of the present invention provides high yields and substantially complete conversion of phenol to 2,4,6-triiodophenol by operating at room temperature and in a relatively short reaction time, and is therefore a very convenient process for industrial use. In fact, as shown in the experimental section below, it has been found that by operating at around room temperature, complete reaction can be achieved in a reaction time of about 80 minutes (by about 100 minutes, depending on the iodination system selected), and substantially complete triiodination (>90% yield) can be achieved in a reaction time of about 45 minutes (by about 80 minutes, depending on the iodination system selected). Since operating at temperatures higher than 40° C. usually results in some degree of hydrolysis of the -COOR1 and -CONR1R2 moieties preferably present in the phenol of formula (I), operating at room temperature is highly advantageous in substantially avoiding such hydrolysis. Thus, reaction step c) can be carried out by adjusting and / or maintaining the temperature at or below 40°C, for example in the range of 15°C to 35°C, for example at 25°C (room temperature), for example for a time period of less than 2 hours, preferably less than 1 hour and 30 minutes, for example in the range of 30 minutes to 2 hours, preferably 45 minutes to 1 hour and 30 minutes.

[0026] In contrast, triiodination reactions carried out without the use of the iodination system disclosed herein, when using the same reaction conditions, result in low yields and incomplete reactions, as demonstrated by the comparative examples and shown in FIG. 1.

[0027] Furthermore, the process of the invention is advantageously carried out in an aqueous medium. According to the invention, the term "aqueous medium" refers to a solution or suspension comprising water as a solvent or as the external phase of the suspension. Preferably, the aqueous medium is substantially free of organic solvents miscible with water, and thus the aqueous medium is a solution or suspension comprising water as the only solvent or as the only external phase of the suspension. The process of the invention therefore makes it possible to use a solvent that is cheap and safe for both the user and the environment, namely water.

[0028] According to a preferred embodiment of the method of the present invention, the iodination system comprises silver oxide and / or a copper salt and I2. However, when the iodination system comprises such a copper salt, the iodination system further comprises at least phosphate, carbonate, and / or ions thereof. According to a particularly preferred embodiment, the iodination system is selected from the group consisting of Ag2O / I2, I2 / CuSO4 / NaHCO3, and mixtures thereof.

[0029] According to a preferred embodiment of the process of the present invention, for both formulas (I) and (II), R and R', independently of one another, represent a -COOR1 or -CONR1R2 moiety, preferably -CONR1R2, where R1 and R2, independently of one another, represent hydrogen or a C1-C4 alkyl group optionally substituted with 1 to 3 hydroxyls (-OH), such as 1,3-dihydroxyisopropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-methylisopropyl, or 2,3,4-trihydroxybutyl.

[0030] Even more preferably, for both formulas (I) and (II), R and R', independently of each other, represent a moiety selected from -CONHCH, -CONHCH-CH(OH)-CHOH, -CONHCH(CHOH), and -CON(CH)-CH-CH(OH)-CHOH.

[0031] According to the most preferred embodiment, the phenol of formula (I) is N,N'-bis[2,3-dihydroxypropyl]-5-hydroxybenzene-1,3-dicarboxamide (compound 1) and the 2,4,6-triiodophenol of formula (II) is N,N'-bis[2,3-dihydroxypropyl]-5-hydroxy-2,4,6-triiodobenzene-1,3-dicarboxamide (compound 2). [ka]

[0032] Since neither R nor R' groups are directly involved in the iodination step, the groups R and R' that may undergo undesirable side reactions can be appropriately protected prior to carrying out the iodination step. The protection and subsequent deprotection of these groups can be carried out by a variety of methods well known in the art and conventionally used in organic synthesis techniques, such as those disclosed in TW Greene, Protective Groups in Organic Synthesis (Wiley, NY 1981).

[0033] If necessary, the pH of the aqueous medium in step c) of the process of the invention is preferably adjusted and / or maintained in the ranges described above, for example by adding a catalytic amount of a suitable base, such as NaOH or NH3, particularly preferably NH3, and / or a catalytic amount of a suitable acid. According to the invention, the terms "suitable base" and "suitable acid" refer to bases and acids, respectively, that are not involved in the triiodination of the phenol of formula (I), and can be easily recognized by the skilled person. Suitable bases are, for example, NaOH or NH3, with NH3 being particularly preferred, and suitable acids are, for example, HClO4. For example, when the iodination system comprises Ag2O / I2, it is preferred to add a base (e.g. NaOH or NH3) during step c) (e.g. continuously or stepwise) to improve the solubilization of Ag2O.

[0034] According to a preferred embodiment, the pH of the aqueous medium of step c) of the process of the invention is constituted in the range of 7.5 to 8.0, optionally by adding a catalytic amount of a suitable base, such as the above-mentioned bases, and / or, if necessary, a catalytic amount of a suitable acid. According to one embodiment, a base (such as NaOH or NH3) is added continuously during step c) to maintain the pH within the above-mentioned ranges.

[0035] Some of the components of the iodination system, e.g. Ag2O and I2, may be only sparingly soluble under the reaction conditions of step c) so that the reaction mixture of step c) may form a suspension.

[0036] According to a preferred embodiment, at least step c) is carried out in the dark and / or using a non-transparent reactor, i.e. a reactor that limits the visible light reaching the reaction mixture, such as a stainless steel reactor or a reactor covered with tin or aluminum foil. Indeed, at least step c) is preferably carried out without exposing the reaction mixture to direct sunlight or possibly artificial light.

[0037] According to a preferred embodiment, in step c) of the present invention, phenol is reacted with the iodination system in a molar ratio of at least 3 moles of I2 per mole of phenol, for example according to the conditions disclosed above. More preferably, the molar ratio of I2 to phenol in the reaction of step c) ranges from 3:1 to 4:1, even more preferably from 3:1 to 3.5:1.

[0038] According to a preferred embodiment, when the iodination system comprises silver, the molar ratio between I2 and silver (e.g., present as Ag2O) is at least 4:1, preferably in the range of 4:1 to 1:1, more preferably in the range of 3:1 to 1:1, even more preferably in the range of 2:1. Indeed, it has been found that these ratios allow the complete conversion of phenol to 2,4,6-triiodophenol to be achieved in a short time, typically about 1 hour or less.

[0039] According to another preferred embodiment, when the iodination system contains copper, the molar ratio of I2 to copper (eg, present as CuSO4) ranges from 1:0.8 to 1:3, more preferably 1:1.

[0040] It has been found that when copper salts or oxides are included in the iodination system, the reaction of step c) is more effective if at least phosphates, carbonates and / or their ions are also present. The phosphates and carbonates can advantageously be provided according to step b) as salts, for example as sodium or potassium salts, for example Na3PO4, K3PO4, Na2HPO4, K2HPO4, NaH2PO4, KH2PO4, Na2CO3, K2CO3, NaHCO3, KHCO3.

[0041] According to a further preferred embodiment, when the iodination system comprises copper and thereby at least phosphate, carbonate and / or ions thereof, the phosphate, carbonate or ions thereof (e.g. when such component of the iodination system is NaHCO3) is present in the reaction mixture of step c) in an amount of at least 0.01 M, more preferably at least 0.1 M.

[0042] The components of the iodine system are commercially available and can be obtained as such. Alternatively, the components of the iodine system can be prepared according to known methods. For example, Ag2O can be obtained according to the method disclosed in Example 2 below.

[0043] Step c) of the inventive process provides 2,4,6-triiodophenol and the precipitation of iodide ions with group 11 elements, e.g. AgI and / or CuI (based on the iodination system selected). In fact, part of the iodine derived from I2 is used to triiodinate the phenol and part is used to oxidize the free Ag + and / or with free group 11 elements such as free copper ions to form AgI and / or CuI, respectively. This is particularly useful for two reasons: (i) there is no need to finally dispose of excess iodized species in a conventional manner, for example by addition of a suitable amount of an alkali iodide, e.g., KI, to form a KI complex, or by addition of sodium sulfite or sodium bisulfite to remove such iodized species from the mixture; and (ii) the components of the iodination system which did not participate in the triiodination reaction can be recovered from the precipitate of iodide ions with group 11 elements, e.g. AgI and / or CuI salts, and can be reused for further iodination, e.g. according to step c) of the inventive process; That is why.

[0044] In view of the above, according to a preferred embodiment, when the iodination system comprises silver, the method further comprises the steps of: d) converting at least a portion of the AgI formed during and / or after step c) into I2 and an oxide or salt of silver different from AgI.

[0045] According to the embodiment comprising step d), the inventive method has the additional advantage of recovering the unreacted components of the iodination system, such as silver oxide or salt and I2, thus making the method itself more cost-effective. The recovered iodination system can indeed be used for further reactions according to step c) of the inventive method.

[0046] In particular, when the iodination system comprises silver, step d) can be carried out, for example, by: d1) separating, e.g., by filtering, the AgI formed during and / or after step c) from the reaction mixture of step c); d2) Mixing the separated AgI with water or an aqueous solution to form a suspension; d3) treating the suspension with a reducing agent, preferably hydrazine or NaBH4, and optionally treating the suspension with sunlight, e.g. by exposing the suspension to sunlight, preferably for 1 to 3 hours, to obtain I - to obtain silver particles (Ag) suspended in a solution containing; d4) I - Separating silver particles from a solution containing; d5) treating silver particles with an oxidizing agent such as HNO3 to obtain AgNO3; and d6) I - A solution containing I is treated with an oxidizing agent. - Oxidize to I2 (wherein steps d5) and d6) can be carried out in any order).

[0047] In step d5), for example, the separated silver particles Ag are dissolved in NO3 - This can be achieved by mixing with an acidic solution containing, for example, a concentrated HNO3 solution (at least 50% w / w, preferably 65% ​​w / w concentration).

[0048] Step d6) may, for example, be - A solution containing KIO3 (preferably I -This can be achieved by mixing, preferably under acidic conditions, with a solution of HCl (in a ratio of 5:1 to KIO3) or with a solution of HIO3 as disclosed, for example, in WO2011 / 154500.

[0049] According to a preferred embodiment, when the iodination system comprises copper, the method further comprises the steps of: e) converting at least a portion of the CuI formed during and / or after step c) into I2 and an oxide or salt of copper different from CuI.

[0050] According to the embodiment including step e), the inventive method has the additional advantage of recovering the unreacted components of the iodination system, such as copper oxide or salt and I2, thus making the method itself more cost-effective. The recovered iodination system can be used for further reactions according to step c) of the inventive method.

[0051] In particular, when the iodination system contains copper, step e) can be carried out, for example, by: e1) separating, e.g. by filtering, CuI formed during and / or after step c) from the reaction mixture of step c); e2) Mix the separated CuI with a basic aqueous solution, e.g., NaOH aqueous solution, to obtain I - and obtain a solution containing precipitate Cu(OH)2; e3)I - Separating Cu(OH)2 from the solution containing, for example by filtering; e4) The filtered Cu(OH)2 is dissolved in SO4 2- to form CuSO4; and e5)I - A solution containing I is treated with an oxidizing agent. - Oxidize to I2 (wherein steps e4) and e5) can be carried out in any order).

[0052] Step e5) may, for example, be - A solution containing KIO3 (preferably I- This can be achieved by mixing, preferably under acidic conditions, with a solution of HIO3 (in a ratio of 5:1 to KIO3) or as disclosed, for example, in WO2011 / 154500.

[0053] Experimental Section material and method Compound 1 used herein as the starting material of the preparation method of the present invention is known and can be prepared according to known methods. For general references regarding compound 1, see, for example, WO88 / 09328, WO97 / 05097 and WO00 / 32561.

[0054] Other reaction reagents and / or solvents used in the present preparation methods are known and readily available, or if not commercially available, can be prepared according to known methods described in the literature. Setting up the HPLC-ESI-MS measurement experiment - HPLC system: Agilent 1260 Infinity II HPLC instrument equipped with quaternary pump, degasser, autosampler, PDA and MS detector (LCQ Deca XP-Plus - Thermo Finnigan); - Stationary phase: Zorbax SB C18 (4.5 mm × 150 mm - 3.5μm) Zorbax - art. 863953-902; - Mobile phase: 99%NH4OAc (10mM, pH=4.6) / 1% MeOH; - Elution: Isocratic; - Flow rate: 1.5mL / min; - Temperature: 35℃; - Detection: DAD (210, 254, 300, 320 and 340 nm); - Injection volume: 10μL - Sample concentration: 0.3 mM compound 1 / compound 1 monoiodinated / compound 1 diiodinated / compound 2; - Stop time: 32 minutes; - Holding time: about 2 to 10 minutes

[0055] 1 H NMR measurement experimental setup 1 H NMR measurements were performed on a Bruker DRX 400 (9.4T) spectrometer equipped with a Bruker VT-1000 thermocontroller (298K) and a BB inverse z-gradient probe (5mm). 1 1 H NMR spectra were recorded using a standard Bruker excitation sculpting pulse sequence. 1 H NMR spectra were analyzed using TOPSPIN version 3.5 (Bruker) software. EXAMPLES

[0056] Example 1 (Comparative) - Iodination of Compound 1 with I2 (pH 7.5, 25°C) (No Iodination System) [ka] A 0.3 mM solution (25 mL) of compound 1 (Bracco Imaging) was prepared by dissolving 2.5 mg of compound 1 (7.6 μmol) in 25 mL of air-free distilled water. The reaction was initiated by adding 5.6 mg of I2 (Sigma, 22 μmol) to a 0.3 mM solution (20 mL) of compound 1. The pH of the reaction was adjusted to 7.5 by stepwise addition of NaOH solution. The reaction was kept at 25 °C and stirred at 120 rpm. To monitor the reaction, 1 mL solution samples were withdrawn at regular intervals and analyzed by HPLC-ESI-MS and HPLC-ESI-MS according to the experimental setup disclosed above. 1 The solution was analyzed by H NMR spectroscopy. A 1 mL sample of the solution was filtered through a 0.45 μm syringe filter to remove unreacted I2 and I - To reduce it to the anion and quench the reaction, it was mixed with 1.4 mg of Na2SO3 (Sigma, 11 μmol). The HPLC chromatogram of the sample obtained according to this example with a reaction time of 120 min shows the presence of compound 1, as well as the mono- and di-iodinated derivatives.1 The H NMR spectrum confirms this, as the signals for compound 1, as well as the mono- and di-iodized derivatives, are still clearly visible at 114.3 min of reaction time. Thus, the HPLC measurements and the NMR experimental results show that Example 1 (comparative) shows only partial and therefore incomplete triiodination of compound 1 within 2 h, even in the presence of a 3.7-fold excess of I2. 1 By considering the integrals of aromatic protons of compound 1, mono-iodized compound 1 and di-iodized compound 1 in HNMR spectrum, the amount of compound 2 formed in the iodination reaction of Example 1 (Comparative Example) was calculated taking into account the total concentration of compound 1 ([Comparative Example 1]t=[Comparative Example 1]+[Comparative Example 1 mono-I]+[Comparative Example 1 di-I]+[Comparative Example 2]=0.3 mM). The amount of compound 1 versus reaction time in Example 1 (Comparative Example) is shown in FIG. 1 by diamonds (◇). According to these data included in FIG. 1, the iodination in Example 1 (Comparative Example) converted about 70% of compound 1 to compound 2 in 2 hours.

[0057] Example 2 - Iodination of compound 1 with Ag2O / I2 (pH 7.5, 25°C) The reaction of Scheme 1 above was carried out as follows. Solid Ag2O was prepared by adding 40 mg of NaOH (Sigma, 1 mmol) to 10 mL of 0.1 M AgNO3 solution (Sigma, 1 mmol). The brown Ag2O precipitate was filtered through a Büchner funnel and washed four times with distilled water. The brown Ag2O precipitate was dried overnight under reduced pressure to obtain 100 mg of Ag2O (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 μmol) in 25 mL of air-free distilled water. To 20 mL of the 0.3 mM solution of compound 1, 5.6 mg of I2 (Sigma, 22 μmol) and 2.5 mg of Ag2O (11 μmol) were added to initiate the iodination reaction. 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. To monitor the reaction, 1 mL solution samples were withdrawn at regular intervals and analyzed by HPLC-ESI-MS and HPLC-ESI-MS according to the experimental setup disclosed above. 1 The solution was analyzed by H NMR spectroscopy. A 1 mL sample of the solution was filtered through a 0.45 μm syringe filter to remove unreacted I2 and I - To reduce it to the anion and quench the reaction, it was mixed with 1.4 mg of Na2SO3 (Sigma, 11 μmol). The HPLC chromatogram of the sample obtained at a reaction time of 45 min for iodination in this example showed a substantial absence of signals for compound 1, as well as the mono- and di-iodized derivatives, confirming the substantial complete formation (>90% yield) of compound 2 within 45 min at pH=7.5 and 25° C. This substantial complete formation (>90% yield) was confirmed by ESI-MS and 1 This was confirmed by H NMR spectroscopy. 1 1 H NMR spectroscopy confirmed final completion (yield approx. 99%) after approximately 80 minutes reaction time. As in Example 1 (Comparative Example), the amount of compound 2 produced in the iodination reaction of Example 2 was calculated taking into account the total concentration of compound 1, and is shown in FIG. 1 by a triangle (△).

[0058] Example 3 - Iodination of compound 1 with CuSO4 / NaHCO3 / I2 (pH 7.5, 25°C). The reaction of Scheme 1 above was carried out as follows: 2.5 mg of compound 1 (7.6 μmol) was dissolved in 25 mL of air-free distilled water to prepare a 0.3 mM solution of compound 1. The triiodination reaction was initiated by adding 5.6 mg of I2 (Sigma, 22 μmol), 5.5 mg of CuSO4+5H2O (Sigma, 22 μmol) and 336 mg of NaHCO3 (Sigma, 4 mmol) to 20 mL of the 0.3 mM solution of compound 1. 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. To monitor the reaction, 1 mL solution samples were withdrawn at regular intervals and analyzed by HPLC-ESI-MS and HPLC-ESI-MS according to the experimental setup disclosed above. 1The solution was analyzed by H NMR spectroscopy. A 1 mL sample of the solution was filtered through a 0.45 μm syringe filter to remove unreacted I2 and I - To reduce it to the anion and quench the reaction, it was mixed with 1.4 mg of Na2SO3 (Sigma, 11 μmol). In this example 1 1 H NMR spectrum confirmed that the triiodination of compound 1 was at least substantially complete at 86 min. Similar to Example 1 (Comparative Example), the amount of compound 2 produced in the iodination reaction of Example 3 was calculated taking into account the total concentration of compound 1, and is shown by a circle (●) in FIG.

[0059] Example 4 - Direct Comparison of Example 1 (Comparative), Example 2 and Example 3 The results obtained for Example 1 (Comparative Example), Example 2 and Example 3 1 By considering the integrals of the aromatic protons of compound 1, monoiodized compound 1, and diiodized compound 1 in the H NMR spectra, the amount of compound 2 ("tri-I" in Figure 1) formed in the iodination reactions of these examples was calculated taking into account the total concentration of compound 1 ([compound 1]t = [compound 1] + [compound 1 mono-I] + [compound 1 di-I] + [compound 2] = 0.3 mM, i.e., 3 × 10 in Figure 1). -4 mol / dm 3 These amounts are shown in FIG. 1 (Example 1 (Comparative Example): diamond ◇, Example 2: triangle △, Example 3: circle ●). FIG. 1 clearly shows the improvement in reaction time and completeness of the process of the present invention compared to non-inventive processes.

[0060] Example 5 - Recovery of silver-containing iodination systems from AgI 46.95 mg (0.2 mmol) of AgI obtained as a by-product in the iodination method of the present invention, e.g., Example 2, was filtered off from the reaction mixture after the iodination was substantially complete. The AgI precipitate was then washed three times with 5 mL of double distilled water and centrifuged (6000 rpm, 10 min). 80 mg of NaBH4 (80 mg, 2.1 mmol) (Sigma) was added to the AgI precipitate suspended in 3 mL of double distilled water. The suspension was stirred in air for 20 min. The Ag element formed by reduction of the AgI precipitate was washed three times with 5 mL of double distilled water and centrifuged (6000 rpm, 10 min). After centrifugation, the I released from the AgI precipitate was - The supernatant containing ions (especially NaI) was collected and made up to 50 mL of stock solution with double distilled water. After a washing procedure, the retained Ag element was dissolved in 3 mL of a 65% solution of high purity HNO3 (Sigma). The acid excess of the resulting AgNO3 solution was evaporated in air. After evaporation of the acid excess, AgNO3 was dissolved in 0.1 M HNO3 to prepare 20 mL of stock solution. For example, as described in step d6) or e5) of the present invention, I can be obtained by treating with an oxidizing agent such as HIO3 or KIO3. - I2 can be obtained from the supernatant containing ions. The concentrations of AgNO3 and NaI solutions were determined by potentiometric titration with a standardized 0.015 M KI solution. A Metrohm-6.0502.160 I was used for the potential measurements and titrations. -A Metrohm 888 Titrando titration workstation equipped with a selective electrode and a Metrohm-6.0750.100 double junction reference electrode was used. Potentiometric measurements were performed in 10 mL samples at 25 °C at constant pH (a: pH = 7.4, 0.01 M HEPES, b: pH = 1.7, 0.02 M HNO3) and constant ionic strength (0.15 M NaNO3). The solutions were stirred and continuously purged with N2. To calculate the [NaI] recovered from AgI, the potentiometric system was calibrated with a standardized 0.015 M KI solution in a 0.01 M HPES solution (pH = 7.4, 25 °C). In this experiment, a 10 mL aqueous solution (pH = 7.4, 25 °C) prepared with 0.01 M HEPES and 0.15 M NaNO3 was titrated with a standardized 0.015 M KI solution. The slope (102.3%) and pI0 (6.40) calculated from the E (mV) vs pI data pair were used to calculate the [I - ] was calculated. To measure the concentration of AgNO3 recovered from AgI, a potentiometric system was used. + The calibration was also performed with a standardized 0.015 M KI solution under acidic conditions to avoid ions precipitating in the form of Ag2O. In this experiment, 10 mL of aqueous solution (25 °C) prepared with 0.02 M HNO3 and 0.15 M NaNO3 was titrated with 0.015 M KI solution. The slope (101.8%) and pI0 (6.43) values ​​calculated from the calibration E (mV) vs pI data pair were used to calculate the pI value in the titration experiment. To calculate the concentration of AgNO3 recovered from AgI, a AgNO3 solution (10 mL, 0.02 M HNO3, 0.15 M NaNO3, 25 °C) was titrated with a standardized 0.015 M KI solution. V KI The pI values ​​calculated from the measured E (mV) as a function of (mL) were used to calculate the concentration of AgNO3 recovered from AgI. Based on the potentiometric experiment, the concentrations of 50 mL NaI and 20 mL AgNO3 stock solutions obtained from the recovery of the AgI precipitate were 0.00361 and 0.009773 mol / dm, respectively. 3 (I - : 0.181mmol, Ag +Considering the amount of AgI precipitate (0.2 mmol), - and Ag + The recoveries were found to be 91% and 98%, respectively.

Claims

1. Formula (II): 【Chemistry 1】 [In the formula, R and R' are each independently hydrogen, -COOR １ , and -CONR １ R ２ represents a moiety selected from the group consisting of: R １ and R ２ are each independently hydrogen, or optionally hydroxyl (—OH), C １ -C ６ Alkoxy and C １ -C ６ C optionally substituted by one or more groups selected from hydroxyalkoxy １ -C ６ represents an alkyl group] A method for producing 2,4,6-triiodophenol represented by the formula: a) Formula (I) 【Chemistry 2】 wherein R and R′ are as defined above. providing a phenol represented by the formula: b) I ２ and at least an oxide or salt of an element of Group 11 of the periodic table, with the proviso that when the element of Group 11 is copper, the iodination system further comprises phosphate, carbonate and / or ions thereof; and c) reacting the phenol of step a) with the iodination system of step b) in an aqueous medium having a pH in the range of 7.0 to 9.0 to obtain 2,4,6-triiodophenol of formula (II). A manufacturing method comprising:

2. The method of claim 1 , wherein the Group 11 element is silver or copper.

3. The iodination system is composed of silver oxide and / or copper and I ２ 3. The method of claim 2, wherein the iodination system comprises a salt of copper, with the proviso that when the iodination system comprises a salt of copper, the iodination system further comprises at least phosphate, carbonate and / or ions thereof.

4. When the group 11 element is copper, the iodination system contains at least phosphate ions (PO ４ ３－ ), monohydrogen phosphate ion (HPO ４ ２－ ), dihydrogen phosphate ion (H ２ P.O. ４ － ), carbonate ions (CO ３ ２－ ) and bicarbonate ion (HCO ３ － 4. The method according to claim 1, further comprising phosphate or carbonate ions selected from the group consisting of:

5. The iodine system is Ag ２ O / I ２ , I ２ / CuSO ４ / NaHCO ３ The method according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of: and mixtures thereof.

6. In both formulas (I) and (II), R and R′ are each independently —COOR １ Part or -CONR １ R ２ represents the part, and R １ and R ２ are each independently hydrogen or C optionally substituted by 1 to 3 hydroxyl (—OH) groups. １ -C ４ The method according to any one of claims 1 to 3, wherein the alkyl group represents an alkyl group.

7. The phenol is N,N'-bis[2,3-dihydroxypropyl]-5-hydroxybenzene-1,3-dicarboxamide (Compound 1). 【Transformation 3】 and the 2,4,6-triiodophenol is N,N'-bis[2,3-dihydroxypropyl]-5-hydroxy-2,4,6-triiodobenzene-1,3-dicarboxamide (compound 2). 【Chemistry 4】 The method according to claim 6, wherein

8. Step c) is carried out in a proportion of at least 3 moles of I per mole of phenol. ２ Preferably, the ratio is I ２ The method according to any one of claims 1 to 3, wherein the molar ratio of phenol to methyl methyl ketone is in the range of 3:1 to 4:1, more preferably in the range of 3:1 to 3.5:

1.

9. If the iodination system contains silver, I ２ The method of any one of claims 1 to 3, wherein the molar ratio of ZnO to silver is at least 4:1, preferably in the range of 4:1 to 1:1, more preferably 2:

1.

10. If the iodination system contains copper, I ２ The method according to any one of claims 1 to 3, wherein the molar ratio of copper to Zn is in the range of 1:0.8 to 1:3, and more preferably 1:

1.

11. 4. The method according to claim 1, wherein when the iodination system comprises copper, thereby comprising at least phosphate, carbonate and / or ions thereof, the phosphate, carbonate and / or ions thereof are contained in the reaction mixture of step c) in an amount of 0.01 M or more, more preferably 0.1 M or more.

12. The method of any one of claims 1 to 3, when the iodination system contains silver, further comprising the steps of: d) converting at least a portion of the AgI produced during and / or after step c) into I ２ and converts it into a silver oxide or salt different from AgI.

13. The method according to any one of claims 1 to 3, when the iodination system contains copper, further comprising the steps of: e) converting at least a portion of the CuI produced during and / or after step c) into I ２ and converting it into an oxide or salt of copper different from CuI.

14. The process according to any one of claims 1 to 3, wherein the reaction in step c) is carried out by adjusting and / or maintaining the temperature at or below 40°C, preferably in the range of 15°C to 35°C, more preferably at room temperature.

15. The process according to any one of claims 1 to 3, wherein the reaction of step c) is carried out for a time period of less than 2 hours, preferably less than 1 hour and 30 minutes.

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