Electrochemical iodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide

Abstract

The present invention relates to a method for producing an iodized X-ray contrast agent. More specifically, the present invention relates to a method for producing an iodized X-ray contrast agent by converting N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) into iodide ions (I - The present invention relates to a method for producing N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) by electrochemical iodination with molecular iodine (I2) that is electrochemically generated in situ from a source of iodide ion (I - ) is obtained by dissolving hydrogen iodide (HI) or an alkali metal iodide in the reaction medium or is generated during the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide with I2. The present invention also relates to the use of the intermediate compound of formula (I), obtained by the above-mentioned electrochemical iodination of compound (II), in the preparation of N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (iomeprol).

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of iodized X-ray contrast agents, more specifically to a process for the preparation of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) by electrochemical iodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) and the use of the product thus obtained as an intermediate in the synthesis of iomeprol. [Background technology]

[0002] 2. Background of the Invention Contrast agents and their use in diagnostics have been widely described in the literature. In particular, iodized aromatic derivatives are a group of compounds used as contrast agents in diagnostic techniques (radiography, tomography, etc.) that depend on the absorption of X-rays by tissues and organs. Among these iodized aromatic derivatives, one of the best-known and widely used X-ray contrast agents in routine diagnostics is iomeprol (N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide) (A. Gallotti et al., Eur. J. Radiol.1994, 18(S1), S1-S12).

[0003] Like many iodinated X-ray contrast agents, the chemical structure of iomeprol consists of a triiodinated aromatic nucleus that provides enhanced contrast, typically derived from a derivative of 5-hydroxy-1,3-benzenedicarboxylic acid that undergoes triiodination at the 2-, 4-, and 6-positions of the aromatic ring. For general references regarding the synthetic routes for the industrial manufacture of iomeprol, see, for example, WO00 / 32561.

[0004] The triiodination reaction on the aromatic nucleus can be carried out according to various procedures known in the art. In the industrial process currently used to produce iomeprol and other iodinated X-ray contrast agents, iodination of the aromatic substrate is usually carried out using a solution of iodine monochloride (ICl) in concentrated hydrochloric acid (HCl). However, this method has several drawbacks, the main ones being the extremely acidic working conditions which are made increasingly harsh due to the generation of hydrochloric acid during the reaction, the toxicity and corrosiveness of the iodinating agents used, and the limited shelf life.

[0005] Iodine monochloride (ICl), for example, is produced by the reaction of elemental iodine with chlorine; however, iodine is a highly toxic gas, and strict precautions and safety measures are required due to its toxicity and danger. Iodine monochloride (ICl) reacts with pure water to produce HCl, iodine, and oxygen. For this reason, stable aqueous solutions of ICl can only be obtained in the presence of large amounts of chloride anions (NaCl, KCl, HCl, etc.).

[0006] Alternatively, as described in WO2011 / 003894, 3 moles of ICl can be produced by electrochemically oxidizing 1 mole of starting ICl to produce an iodine derivative with the oxidation state of iodine equal to (III) by reacting it with molecular iodine (I2). However, to carry out the iodination reaction, the iodized species needs to be transferred to a separate compartment, which can lead to difficult handling and poor solution stability.

[0007] In any case, the iodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide with ICl needs to be carried out at controlled pH and temperature (25 °C) to achieve good yield and purity. This means that a large amount of base (such as NaOH) must be added to the reaction, not only to neutralize the acid generated by the reaction, but also to neutralize the hydrochloric acid in which ICl has dissolved. The neutralization reaction is highly exothermic, so the base needs to be added slowly to keep the temperature below 25 °C and to avoid the formation of by-products.

[0008] Instead of using ICl, the iodination reaction can also be carried out in an aqueous medium using molecular iodine (I2), but the drawback of this method is that half of the added iodine is lost in the form of iodide ions during the reaction, in particular hydroiodic acid (HI). Furthermore, when an aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide is iodized with molecular iodine alone, some of the molecular iodine combines with the iodide ions in the solution during the reaction to form, for example, triiodide ions (I3 - ), resulting in low yields of the corresponding triiodinated compounds.

[0009] To utilize all of the iodine available in the reaction and overcome the above problems, an oxidizing agent such as iodic acid (HIO3) is usually added to the mixture (see, for example, WO2011 / 154500).

[0010] As yet another method, WO2009 / 103666 describes the use of electrochemically generated iodine cations (I + According to this disclosure, a platinum sheet anode is inserted into a stock solution of iodine in a solvent such as methanol and electrolysis is performed in galvanostatic mode to prepare I before iodination in a separate compartment. + A solution is obtained. Next, the thus obtained I + The substrate to be iodized is added portionwise to the solution and iodination is carried out by refluxing to achieve conversion.

[0011] The above method has some problems. For example, the iodinating agent (I + ) solution must be transferred to a separate compartment for iodination, and I + The stability and shelf life of the compound is limited, which can affect the yield of the manufacturing process. Summary of the Invention [Problem to be solved by the invention]

[0012] Since iodine is a very expensive reagent, in order to realize an efficient and economical production method, it is desirable to minimize loss as much as possible by recovering and reusing the iodine used in the iodination reaction. Furthermore, the above synthesis requires an additional step of removing the solvent by evaporation. [Means for solving the problem]

[0013] To overcome the above problems, we have found that N,N'-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide can be efficiently prepared by using molecular iodine (I2) as the iodination species, which is electrochemically regenerated in situ upon reaction or generation by reduction of iodide ions present in the reaction medium. Advantageously, the synthesis of the present invention achieves conversion yields of over 90% while minimizing loss of iodine.

[0014] Summary of the Invention The present invention relates to a method for the preparation of a compound comprising the steps of: - The present invention relates to a method for producing N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide by reacting it with molecular iodine (I2) that is electrochemically generated in situ from a source of iodide ions (I3). Such iodide ions can be obtained by dissolution of HI or an alkali metal iodide (e.g., NaI, KI) in the reaction medium or can be obtained directly from the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide with molecular iodine (I2). [Brief description of the drawings]

[0015] [Figure 1]FIG. 1 shows a reaction scheme of one embodiment of the present invention for the production of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) by reacting N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) electrochemically generated in situ from iodide ions (I-) obtained by dissolving sodium iodide (NaI) in water. The electrochemical cell is an undivided cell (25x25mm) with a graphite cathode and a platinum anode, and the electrochemical reaction is carried out under galvanostatic control. [Diagram 2] 2 shows a reaction scheme according to another embodiment for producing N,N'-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) by reacting N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) electrochemically regenerated in situ from iodide ions (I-) obtained by reaction of compound (II) with I2. The electrochemical cell is an undivided cell (25x25mm) with a graphite cathode and a platinum anode, and the electrochemical reaction is carried out under galvanostatic control. [Diagram 3] 3 represents a two-compartment electrochemical cell used according to another preferred embodiment of the invention for the preparation of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) by reacting N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) electrochemically regenerated in situ from iodide ions (I-) obtained by reaction of compound (II) with I2. The two compartments are separated by a cationic membrane (one compartment is equipped with a working electrode WE and a reference electrode RE, the other compartment with a counter electrode CE), and electrolysis is performed in potentiostatic mode. [Figure 4] Figure 4 shows a representative example of a flow electrochemical cell according to one embodiment of the present invention: (a) the cell alone, and (b) the cell integrated into a flow system in which the anolyte and catholyte solutions are recirculated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The first aspect of the present invention is a method for producing N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I), comprising the steps of: a) N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is dissolved in a reaction medium in the presence of molecular iodine (I2), and b) iodinating said compound (II) with molecular iodine (I2) to obtain said compound (I); The reaction medium is an aqueous solution, and molecular iodine (I2) is converted into iodide ions (I - ) is electrochemically generated in situ from a source of

[0017] Preferably, the aqueous solution is water. The electrochemical step b) of the present invention can be carried out in galvanostatic or potentiostatic mode. According to a preferred embodiment, iodide ions (I - ) is provided by the addition and dissolution of hydrogen iodide (HI) or an alkali metal iodide in the reaction medium or is generated during the reaction of I2 with the compound of formula (II) according to step b).

[0018] Process step b) can also be represented in Scheme 1 below. [ka]

[0019] This reaction is an electrophilic substitution, where one atom of iodine (I2) replaces a hydrogen atom in the aromatic ring, while the other atom of iodine forms an iodide ion (I - ) The stoichiometry of the iodination reaction of the present invention requires at least 3 moles of I2 as reactive species per mole of aromatic substrate of formula (II) for triiodination to the corresponding compound of formula (I). Preferably, the molar ratio of molecular iodine (I2) to N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) may be in the range of 3:1 to 1.5:1, preferably 2:1 to 1.5:1. In some preferred embodiments, both steps a) and b) of the manufacturing method are carried out in the same single compartment of an undivided electrolytic cell consisting of two electrodes selected from both the anode and the cathode conventionally employed in industrial applications.

[0020] Preferably, said electrolytic cell comprising an aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) comprises a carbon-based cathode (e.g. made of graphite) and an anode consisting of a metal selected from those typically used in similar electrochemical systems (e.g. platinum or other elements of group VIIIB of the periodic table). Such metals can be, for example, in the form of a grid, foil or net. The anode can also be made of a material suitably coated with a sufficiently thick film of the abovementioned metals. Alternatively, for pulsating or alternating current experiments, it is possible to use cathodes made of platinum or other layers commonly employed in industrial electrochemical anodes, such as Ta2O2, IrO2, RuO2, or SnO2.

[0021] Advantageously, in such an embodiment, the electrolytic generation of I2 according to the invention can be carried out by operating in galvanostatic mode, i.e. by applying a constant current density during the process while the aqueous solution is stirred with a magnetic stirrer, preferably between 5 and 100 mA / cm. 2A constant current comprised in the range of 5 to 20 mA / cm is passed through the solution during the process. More preferably, the constant current is comprised in the range of 5 to 20 mA / cm 2 The range is.

[0022] Alternatively, in another preferred embodiment, steps a) and b) of the process can be carried out in a two-compartment electrolysis cell. One advantage of using this type of cell is that it reduces the risk of cathodic deiodination of the final product (I) after it has reached its maximum concentration.

[0023] The compartments may be separated by a permeable separator, for example a porous barrier or diaphragm, or a permeable membrane such as an ion exchange membrane.

[0024] In one embodiment, the presence of a porous partition reduces the separation between the compartments, thereby allowing OH - Ions and H + / Na + The pH can be kept constant while allowing both diffusion and / or movement of ions.

[0025] Alternatively, the membrane ensures a stronger separation. An example of a suitable membrane is the OH 2 Catalyst from the cathode to the anode. - An anionic membrane that allows automatic flow of ions to balance the pH drop at the anode, or H + and Na + (An example of such a configuration is shown in FIG. 3.) More conveniently, the cationic membrane is used in the production method of the present invention, especially in the case of industrial scale-up. Preferred anionic membranes are made with a polymeric core such as polyamide, polyester, polystyrene, polyvinylbenzene, and the like. The preferred cationic membrane is, for example, a polymeric fluorocarbon membrane selected from the group consisting of polytetrafluoroethylene (PTFE), tetrafluoroethylene-perfluoropropylene copolymer (FEP), tetrafluoroethylene-perfluoroalkoxy copolymer (PFA), ethylene-tetrafluoroethylene copolymer (ETFE), polyvinylidene fluoride (PVDF) membranes and their derivatives. More preferably, the cationic membrane is tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-7-octene sulfonic acid copolymer (Nafion® 117).

[0026] Suitable anodes in the present case are graphite anodes or glassy carbon anodes. Preferably, the anodes can be made of graphite, carbon paper or carbon cloth, the latter optionally combined with carbon felt.

[0027] The cathode may be any of the conventional metals, preferably made of platinum, nickel, inox steel, etc., and may be made of electronically conductive materials with various structures, such as fully solid materials or materials that form a three-dimensional network of electronically conductive pathways. Preferably, the two-compartment cell is a filter press cell, which is also suitable for industrial-scale flow electrolysis reactions.

[0028] In a first embodiment of the present invention, molecular iodine (I2) is added to the reaction medium as iodide ions (I - According to this embodiment, the method of manufacture comprises the steps of: a') Iodide ion source (I - dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium to which is added b') iodinating the compound (II) with molecular iodine (I2) to obtain the compound (I); where the reaction medium is an aqueous solution and molecular iodine (I2) reacts with added iodide ions (I - ) source electrochemically generated in situ. Preferably, the aqueous solution is water. Preferably, the electrochemical reaction according to this embodiment is carried out in a galvanostatic mode. Iodide ion (I - The source of iodide (IOD) can be obtained by dissolution of hydrogen iodide (HI) or an alkali metal iodide added to the reaction medium.

[0029] Typically, the alkali metal iodide is selected from sodium iodide (NaI), potassium iodide (KI), lithium iodide (LiI) and cesium iodide (CsI), preferably selected from NaI and KI. Hydroiodic acid (HI) or a suitable metal iodide (e.g., NaI or KI) is added to N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) to form the iodide (I - ) in a molar ratio of 6:1 to 3:1, preferably 4:1 to 3:1, in the reaction medium. Usually, a slight excess of iodide is used. Preferably, during the iodination reaction of step b'), the solution is maintained at a constant temperature in the range of 20° C. to 75° C., more preferably 50° C. to 60° C., by operating according to a conventional method. More preferably, the reaction of step b') is carried out at a temperature of 50° C.

[0030] The reaction medium is maintained at a neutral pH, ie in the range of 5 to 7.5, preferably 6 to 7, by continuous addition of a protic acid, such as H2SO4.

[0031] According to the present invention, iodide ions (I - ) is oxidized at the anode surface, resulting in the following reaction: [ka] This results in molecular iodine (I2).

[0032] In step b'), the molecular iodine produced is reacted with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in solution. This reaction is an electrophilic substitution in which one atom of the iodine molecule (I2) replaces a hydrogen atom in the aromatic ring of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) and the other atom of iodine is converted to an iodide ion (I - )

[0033] Released iodide ions (I - ) are electrochemically reoxidized to molecular iodine (I2) and recycled in situ. In this way, all iodine atoms admitted to the cell compartment are fully utilized for the iodination reaction. + ) is also produced in the process and is reduced to gaseous hydrogen (H2) at the cathode surface.

[0034] The reaction when an alkali metal iodide, NaI, is used is shown in Figure 1. The stoichiometric equations of the reactions involved in this process are shown below. [Table 1]

[0035] The reaction time depends on the reaction conditions, mainly on the combination of the applied current density and the electrode surface employed, but also on the ratio between the reactants, their purity, temperature, etc. A person skilled in the art can find the optimal conditions by relying on his personal knowledge and experience. The completion of the reaction can be detected by the usual analytical means used in organic chemistry, for example by spectrometric devices such as HPLC. The reaction is usually completed within 3 to 48 hours, typically within 6 to 12 hours.

[0036] Generally, the generation of I2 occurs at a faster rate than the consumption rate in the reaction with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide(II), so the electrochemically generated I2 tends to deposit on the anode, which becomes purple, and slowly dissolve by the reaction with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide(II). The constant current can be periodically turned off to completely dissolve the iodine deposited on the anode. In a preferred embodiment, it is convenient to turn off the current for intervals of 30 to 60 seconds every 2 to 5 minutes. As a further option, a pulsating current can be passed between the electrodes to achieve the same result.

[0037] In a second embodiment of the present invention, I2 is an iodide ion (I2) generated by the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) by applying a constant current. - ) is electrochemically regenerated in situ.

[0038] According to this embodiment, the method comprises the steps of: a") dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I2); b″1) partially iodinating said compound (II) with molecular iodine (I2) in the absence of electric current; and b"2) passing an electric current through the reactant obtained in step b"1) to complete the iodination and obtain said compound (I); wherein the reaction medium is an aqueous solution and molecular iodine (I2) is reacted in step b"2) with the iodide ions (I - ) is electrochemically regenerated in situ. Preferably, the aqueous solution is water. Preferably, the electrochemical reaction according to this embodiment is carried out in a galvanostatic mode.

[0039] In one embodiment, an aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is placed in a non-divided electrochemical cell equipped with a graphite cathode and a platinum anode. Step a") is carried out by adjusting the pH of the aqueous solution after dissolution of compound (II) to a value of >6, preferably >10, using a base such as NaOH or KOH, or alternatively by using a pre-prepared aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) having a pH >6, preferably >10. Step b″1) is carried out without applying electric current. In this way, partial iodination of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is achieved. Compound (I) is obtained together with the corresponding mono- and di-iodized intermediates, and iodide ions (I - Preferably, the molar ratio of I2 to N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is in the range of 3:1 to 1.5:1, preferably 2:1 to 1.5:1. The reaction is preferably carried out at a temperature of from 40° C. to 60° C., more conveniently at about 55° C., for a period of from 1 hour to 6 hours, typically from 2 hours to 3 hours. Step b"2) is carried out by passing an electric current, preferably a constant current (galvanostatic mode), through the magnetically stirred solution obtained in step b"1). In this way, the iodide ions obtained in step b"1) after the iodination reaction are reoxidized to molecular iodine (I2), which reacts with the remaining N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) or with the corresponding mono- and di-iodized intermediates present in the reaction mixture. The temperature of the solution is maintained at 40° C. to 60° C., preferably 55° C. For example, the applied current is 5 to 100 mA / cm 2 It may be configured in the range of 5 to 20 mA / cm 2 A constant current is applied for 3 to 48 hours, typically 6 to 12 hours. The reaction solution is maintained at a neutral pH, ie, in the range of 5 to 7.5, preferably 6 to 7, by the continuous addition of a protic acid such as H2SO4.

[0040] Generally, the regeneration of I2 occurs at a rate faster than its consumption in the reaction with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II), so the regenerated I2 tends to deposit on the anode, which becomes purple in color, and slowly dissolves by reaction with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II). The constant current can be periodically switched off to completely dissolve the iodine deposited on the anode. In a preferred embodiment, the current is conveniently switched off for intervals of 30 to 60 seconds every 2 to 5 minutes. As a further option, a pulsating current can be passed between the electrodes to achieve the same result. As a further option, an alternating current can be passed between the electrodes to achieve the same result. The reactions involved in this second embodiment of the manufacturing method are shown in Figure 2. The stoichiometric equations of the reactions involved in this process are shown below. [Table 2]

[0041] The iodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) produces three iodide ions and three protons per molecule of product. Iodide ions are lost in the reaction, resulting in a loss of 50% of the valuable halogen atoms. Advantageously, the electrochemical reaction of step b″2) reoxidizes the iodide ions generated and reintroduces them into the production process until they are completely used and / or until compound (II) is completely converted into compound (I).

[0042] In the third embodiment of the present invention, I2 is converted into iodide ions (I2) generated by the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with molecular iodine (I2) by applying a constant voltage between the electrodes so that the anode potential is 0.5 V to 0.9 V relative to the SCE (saturated calomel electrode as a reference electrode). - ) is electrochemically regenerated in situ.

[0043] According to this embodiment, the method comprises the steps of: a") dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I2); b″1) partially iodinating said compound (II) with molecular iodine (I2) in the absence of an electric potential; and b"2) applying a voltage to the reaction obtained in step b"1) to complete the iodination and obtain said compound (I); wherein the reaction medium is an aqueous solution and molecular iodine (I2) is reacted in step b"2) with the iodide ions (I - ) is electrochemically regenerated in situ.

[0044] The electrochemical reaction according to this embodiment is carried out in a potentiostatic mode. Preferably, the aqueous solution is an electrolyte solution such as an aqueous NaOH solution, more preferably an NaOH solution with a concentration in the range of 0.1M to 0.5M. Preferably, an aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is placed in a two-compartment electrochemical cell equipped with a carbon-based anode and a platinum or stainless steel cathode.

[0045] Step a") is carried out by adjusting the pH of the aqueous solution after dissolution of compound (II) to a value between 8 and 12 with a base such as KOH or NaOH. Step b″1) is the chemical reaction phase, which is carried out without applying voltage. In this way, partial iodination of N,N′-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is achieved. Compound (I) is obtained together with the corresponding mono- and di-iodized intermediates, and iodide ions (I - Preferably, the molar ratio of I2 to N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) is in the range of 2:1 to 1.5:1, preferably 1.5:1. In step b″1, high concentration H + Since the ions inhibit further removal of protons from compound (II) and electrophilic substitution is inhibited, only half of the supplied iodine atoms can react with the substrate. Thus, after this chemical reaction step, the reaction mixture contains not only compound (I), but also residual amounts of unreacted compound (II) and the corresponding mono- or di-iodized intermediates. The reaction is preferably carried out at a temperature of from 50° C. to 70° C., more conveniently at about 60° C., for a period of from 5 minutes to 20 minutes, typically about 10 minutes. Optionally, steps a'' and b''1, which are performed without electrochemical support, can be performed in separate containers and transferred to the electrochemical cell for performing step b''2.

[0046] Step b"2) is carried out by applying a constant voltage (potentiostatic mode) to the magnetically stirred solution obtained in step b"1). In this way, the iodide ions obtained in step b"1) after the iodination reaction are reoxidized to molecular iodine (I2), which reacts with the remaining N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) or the corresponding mono- and di-iodized intermediates present in the reaction mixture to complete the tri-iodination of compound (II). The temperature of the solution is maintained at 50°C to 70°C, preferably 60°C. The reaction is preferably carried out at an anode potential of 0.6V to 0.8V, more preferably 0.65V to 0.7V relative to SCE.

[0047] The reaction medium is maintained at a basic pH, i.e., about 8-12, by the addition of a strong base, such as NaOH pellets, to buffer the gradually increasing acidity. The pH must be controlled, especially when the reaction is carried out in a two compartment cell with a cationic membrane. The amount of base required to neutralize the electrochemical reaction can be added all at once or gradually, before or during step b"2. Preferably, a stoichiometric amount of NaOH is added before carrying out the electrochemical step b"2.

[0048] The stoichiometry of the reactions involved in this preparation process is given below: [Table 3]

[0049] The iodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) produces three iodide ions and three protons per molecule of product. Advantageously, the iodide ions generated by the electrochemical reaction of step b″2) (which are lost during the reaction, resulting in a loss of 50% of the valuable halogen atoms) are reoxidized at the anode and reintroduced into the production process until they are completely used and / or until they are completely converted into compound (II) into compound (I) by converting them in situ directly into the iodinating agent I2. The protons (H + ) is also reduced to gaseous hydrogen (H2) at the cathode surface. Optionally, in all embodiments, the gaseous hydrogen thus produced can then be recovered by methods conventionally used in industrial electrochemical processes, such as by recovery membranes.

[0050] The electrochemical reaction of step b″2, preferably carried out in potentiostatic mode, can also be carried out in a two-compartment filter press cell under flux conditions with recirculation of the electrolyte solution. For example, FIG. 4 shows a representative example of a filter press cell (a) and a flow system (b) consisting of a circuit equipped with two pumps (e.g. centrifugal or peristaltic pumps) for recirculation of the solution and heating means to keep the temperature at 50-70 °C. For example, according to the latter embodiment, the electrolyte solution is an aqueous mixture of compounds (II) and I2 defined in step a″ (anolyte) and a 0.1 M NaOH solution (catholyte).

[0051] Surprisingly, when operated in a flow system, compound (I) was obtained in about 100% yield, demonstrating the potential for the process of the present invention to be used in large-scale plants and integrated into the industrial production of iomeprol or other iodinated contrast agents.

[0052] Therefore, the process of the present invention exemplified in all the above embodiments is a very efficient process that allows the triiodination of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) to be achieved in high yield and without loss of iodine. In fact, all iodine atoms input into the cell are utilized in the iodination reaction.

[0053] Subsequent workup of the reaction mixture can be carried out according to conventional methods known in the art to finally isolate the compound of formula (I).

[0054] Another object of the invention is the process as defined above, further comprising a step c) of isolating the compound of formula (I) obtained by electrochemical iodination of compound (II) according to the process described above. The intermediates of formula (II) are known starting materials and can be prepared according to known methods, see, for example, the aforementioned WO00 / 32561, for a general reference.

[0055] The compounds of formula (I) are useful intermediates in the synthesis of X-ray contrast agents, in particular iomeprol (N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide), as described above. Thus, the use of the intermediate compound of formula (I), obtained by electrochemical iodination of compound (II) according to steps a) and b) of the present process of the invention, in the preparation of N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV, iomeprol) is a further object of the present invention.

[0056] Preferably, the object of the present invention is a process for the preparation of N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV), comprising the following steps: a) dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I2); b) iodinating said compound (II) with molecular iodine (I2) to obtain said compound (I); c) isolating compound (I); d) Reacting compound (I) with ClCH2(CO)NHCH3 to give intermediate (III) [ka] obtaining the above compound; e) subjecting the intermediate (III) to Smiles rearrangement in the presence of a base to give the final compound N,N'-bis[2,3-dihydroxypropyl]-5(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV). [ka] The process of obtaining wherein the reaction medium in step a) is an aqueous solution and the molecular iodine (I2) in step b) converts iodide ions (I - ) source is electrochemically generated in situ.

[0057] Preferably, the reaction medium in step a) is water. For general conditions of steps d) and e) above, see WO00 / 32561.

[0058] The compounds of formula (II) which are the starting materials for this process are known and can be prepared according to known methods, as described above, Similarly, the other reactants and / or solvents used in this process are known and readily available.

[0059] For the purpose of further illustrating the invention, without limiting it, details regarding various embodiments thereof are given in the following examples.

[0060] Experimental Section The following experimental conditions were used in the examples presented below: - A multi-necked round-bottom flask was used as an undivided electrochemical cell by fitting electrodes into the available necks (two-electrode system). A power supply, Supply Lafayette ALP-5A, provided the constant current required to carry out the electrochemical process. Platinum foil (0.1 mm thick) was used as the anode. A graphite rod was used as the cathode, except for the pulsating and alternating current experiments, where platinum foil was used. Electrolysis was carried out in galvanostatic mode. - A two-compartment cell consisting of three electrodes: a working electrode (WE, a carbon-based anode), a counter electrode (CE, made of stainless steel) and a reference electrode (RE, a saturated calomel electrode (SCE). The two compartments are separated by a cationic membrane (e.g., Nafion), and the SCE is contained in a Lugging capillary (polyethylene tubing, 2 mm diameter) and in contact with the anolyte in the anodic compartment. Depending on the experiment, the system was equipped with one or more of the following: a pH meter, a thermostat, a potentiostat, and a hydraulic pump. Electrolysis was performed in potentiostatic mode with chronoamperometry set up at constant potential. EXAMPLES

[0061] Example 1 Electrochemical iodination reaction in galvanostatic mode using iodide ion (NaI) as a starting material An undivided electrochemical cell equipped with a graphite cathode and a platinum anode was charged with NaI (1.34 mmol) and water (50 mL) and a 23.5% w / w aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) (0.34 mmol). Electrolysis was carried out in galvanostatic mode; i.e., the current flowing through the cell was δ = 8 mA / cm. 2The temperature was kept constant at 50°C. The solution was stirred at 50°C and the pH was maintained at 7 by continuous addition of 98% H2SO4. Hydrogen evolution was observed at the cathode surface. Iodine was immediately produced on the anode surface and slowly dissolved by reaction with N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II). The current was periodically switched off to allow complete dissolution of the iodine deposited on the anode. After 3 hours of reaction, HPLC analysis showed the presence of mono- and di-iodo intermediates. After 48 hours of reaction, HPLC showed that the amount of triiodized compound of formula (I) was 90% (HPLC peak area %).

[0062] Example 2 Electrochemical iodination reaction in galvanostatic mode using I2 as starting material An undivided electrochemical cell equipped with a graphite cathode and a platinum anode was charged with molecular iodine (9.8 mmol) and water (7 mL) and a 23.5% w / w solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) (0.34 mmol) in water. The mixture was stirred with a magnetic stirrer at 55°C. After 2 hours, HPLC analysis indicated that the amount of tri-iodinated compound of formula (I) was 54% (peak area %), along with the presence of the corresponding mono- and di-iodinated intermediates. At this point the current was switched on, δ=8 mA / cm. 2 Electrolysis was performed in galvanostatic mode at 55 °C. The solution was stirred and the pH was kept at 7 by continuous addition of 98% H2SO4. Hydrogen evolution was observed at the cathode surface and iodine production was observed at the anode surface. HPLC analysis after 48 h showed that the amount of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) was 90% (HPLC peak area %).

[0063] Example 3 Electrochemical iodination reaction in potentiostatic mode (two-compartment cell) using I2 as starting material An electrochemical cell with two compartments separated by a cationic membrane (Nafion) and equipped with an electrode (cathode) made of stainless steel, nickel or platinum foil, a graphite rod (anode) and a saturated calomel electrode as reference (SCE) was placed in a 23.3% w / w aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) (72 mmol, 100 mL) and I2 (29.46 g). The catholyte was a 0.5 M aqueous NaOH solution. The mixture was stirred with a magnetic stirrer at approximately 65 °C and the pH was maintained at 10-12 by the continuous addition of NaOH pellets. After 10 min, the solution was yellow-orange in color and HPLC analysis indicated that the amount of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) was 55%, along with the presence of the corresponding mono- and di-iodized intermediates. At this point, NaOH (113 mmol) was gradually added and electrolysis was performed in potentiostatic mode, with the chronoamperometry set at a constant potential of 0.7 V vs. SCE, while the temperature was maintained at 65 °C and the pH at 10-12. After 35 hours of reaction, HPLC analysis showed that the amount of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) was 90% (HPLC peak area %).

[0064] Example 4 Scale-up of electrochemical iodination in potentiostatic mode (flow electrochemical cell) A 23.3% w / w aqueous solution of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) (576 mmol, 800 mL) and I2 (220.4 g) were slowly added to a 1 L glass bottle. The solution was stirred while the pH was stabilized at approximately 10 and heated to approximately 55-60 °C until the color of the solution changed from dark red to a clear yellow-orange. After 10 min, HPLC analysis indicated the amount of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) was 55%, along with the presence of the corresponding mono- and di-iodo intermediates. At this point, the solution was transferred to the anolyte chamber of a filter press electrochemical cell for flow electrolysis, as shown in Figure 4. Such a cell was 10 × 30 cm in size and consisted of two compartments separated by a cationic membrane (Nafion® 117), with a stainless steel mesh cathode (CE), a platinum foiled carbon cloth strip as the anode (WE), and a saturated calomel electrode as the reference electrode (SCE) housed in a Luggin capillary (polyethylene, 2 mm diameter). The anode compartment (approximately 180 cm) was 3 The ion exchanger was completely filled with five layers of carbon felt (AvCarb® Style G300A) and the cathode compartment was filled with 1 L of 0.1 M NaOH. The carbon cloth anode was connected to an external electric circuit by a metal (e.g., Pt) foil. Both the Compound (II)+I2 solution in the anode compartment and the 0.1 M NaOH solution in the cathode compartment were recirculated at 0.3 L / min using two membrane pumps. The temperature of the electrolyte was kept at approximately 65 °C by heat exchange with hot water, and electrolysis was performed in potentiostatic mode at a constant potential of 0.65 V vs. SCE. Approximately 35 g of NaOH pellets were continuously added to maintain the pH at 10–12. After 9.3 hours of reaction, the color of the anolyte was orange and HPLC analysis showed that the amount of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I) was 100% (HPLC peak area %). Since the pH of the mixture was strongly basic as a result of the addition of NaOH during the reaction, the product was isolated and characterized in the form of the corresponding sodium phenate. 1 H- and 13C-NMR analysis confirmed the absence of by-products such as hydrolysis products. [Table 4] References 1.Gallotti et al., Eur. J. Radiol., 1994, 18(S1), S1-S2; 2.WO00 / 32561; 3. WO2011 / 003894 4. WO2011 / 154500; 5. WO2009 / 103666.

Claims

1. A process for the preparation of N,N'-bis-(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide (I), comprising the following steps: a) A step of dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I ２ ) and b) iodinating the compound (II) with molecular iodine (I ２ ) to obtain the compound (I); comprising, wherein the reaction medium is an aqueous solution, and molecular iodine (I ２ ), which is electrochemically generated in situ from a source of iodide ions (I － ), a manufacturing method.

2. The process according to claim 1, wherein the aqueous solution is water.

3. The process according to claim 1, wherein steps a) and b) are carried out in galvanostatic mode using an undivided electrolytic cell.

4. Molecular iodine (I ２ ) is electrochemically generated from a source of iodide ions (I － ) selected from alkali metal iodides such as HI and NaI or KI by applying a constant current, the production method according to claim 3.

5. Molecular iodine (I ２ ), which is electrochemically regenerated by applying a constant current switched on 1 to 6 hours after from iodide ions (I ２ ) generated by the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with I － ), the production method according to claim 3.

6. The production method according to claim 4 or 5, wherein the inrush current is in the range of 5 to 100 mA / cm ２ .

7. The process according to claim 4 or 5, wherein the reaction medium is maintained at a pH of 5 to 7.5 by addition of a protonic acid and at a temperature of 40 °C to 60 °C.

8. The process according to claim 1 or 2, wherein steps a) and b) are carried out in potentiostatic mode using an electrolytic cell formed by two compartments separated by a porous partition or an ion-exchange membrane.

9. Molecular iodine (I ２ ) is electrochemically regenerated by applying a constant voltage that generates an anodic potential of 0.5 to 0.9 V, preferably 0.65 to 0.7 V, with respect to the SCE (saturated calomel electrode) from the iodide ion (I ２ ) generated by the reaction of N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) with I － ), the production method according to claim 8.

10. The process according to claim 8, wherein the reaction solution is maintained at a pH of 10 to 12 by addition of a strong base and at a temperature of 50 °C to 70 °C.

11. The process according to claim 8, wherein the two compartments of the cell are separated by a cationic membrane.

12. The electrolytic cell comprises an anodic compartment (anolyte) filled with an aqueous solution of the compounds (II) and I according to step a) of claim 1 ２ and a cathodic compartment (catholyte) filled with a 0.1 to 0.5 M NaOH solution, the production method according to claim 8

13. The process according to claim 12, which is carried out under flux conditions by recycling the anolyte solution and the catholyte solution.

14. The following steps: c) isolating the compound of formula (I) obtained by electrochemical iodination of compound (II) according to the method of claim 1 The process according to claim 1, further comprising the step of

15. A process for the preparation of N,N'-bis[2,3-dihydroxypropyl]-5((hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV), comprising the following steps: a) A step of dissolving N,N'-(2,3-dihydroxypropyl)-5-hydroxy-1,3-benzenedicarboxamide (II) in a reaction medium in the presence of molecular iodine (I ２ ) b) iodinating the compound (II) with molecular iodine (I ２ ) to obtain the compound (I); c) isolating said compound (I); d) Reacting the compound (I) with ClCH ２ (CO)NHCH ３ to obtain the intermediate (III) 【Chemical 1】 to obtain the step; e) subjecting said intermediate (III) to a Smiles rearrangement in the presence of a base to give the final compound N,N'-bis[2,3-dihydroxypropyl]-5((hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarboxamide (IV) [Chemical Formula 2] including a step of obtaining, wherein the reaction medium in step a) is an aqueous solution, and the molecular iodine (I ２ ), which is electrochemically generated in situ from an iodide ion (I － ) source, a production method.

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