CN117980287A

CN117980287A - Electrochemical iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide

Info

Publication number: CN117980287A
Application number: CN202280063149.7A
Authority: CN
Inventors: L·拉图阿达; C·卡瓦罗提; G·B·焦文扎纳; F·尤吉里; A·明古齐; A·韦尔托瓦; L·索尔蒂; C·莫莱利
Original assignee: Bracco Imaging SpA
Current assignee: Bracco Imaging SpA
Priority date: 2021-09-24
Filing date: 2022-09-22
Publication date: 2024-05-03

Abstract

The present invention relates to a process for preparing iodinated X-ray contrast agents. More particularly, it relates to a process for the preparation of N, N '-bis- (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) with molecular iodine (I2), which molecular iodine (I2) is electrochemically generated in situ from a source of iodide ions (I ^‑). The 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 invention also relates to the use of an intermediate compound of formula (I) obtained by the above-described electrochemical iodination of compound (II) for the preparation of N, N' -bis [2, 3-dihydroxypropyl ] -5 (hydroxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxamide (iomeprol).

Description

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

The present invention relates to a method for preparing iodinated X-ray contrast agents. More particularly, the present invention relates 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 (Iomeprol).

Background

Contrast agents and their use in the diagnostic field are widely described in the literature. In particular, iodinated aromatic derivatives belong to a class of compounds used as contrast agents in diagnostic techniques which rely on the absorption of X-rays by tissues or organs (e.g. radiography, tomography). Among these aromatic iodinated derivatives, particularly notable is iomeprol (N, N' -bis [2, 3-dihydroxypropyl ] -5 (hydroxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxamide), which is a well-known radiographic contrast agent and widely used in daily diagnostic practice (a.allotti et al, eur.j. Radio.1994, 18 (S1), S1-S12).

As with most iodinated X-ray contrast agents, the chemical structure of iomeprol includes a tri-iodinated aromatic nucleus, which provides enhanced contrast effects, and is typically obtained from derivatives of 5-hydroxy-1, 3-phthalic acid tri-iodinated at the 2, 4 and 6 positions of the aromatic ring. For general reference to synthetic routes for the industrial preparation of iomeprol see for example WO00/32561.

The tri-iodination on the aromatic nucleus may be carried out according to different methods known in the art. In the current industrial processes for the preparation of iomeprol or other iodinated X-ray contrast agents, iodination of an aromatic substrate is typically performed using a solution of iodine monochloride (ICl) in concentrated hydrochloric acid (HCl).

However, said process has several drawbacks, mainly related to the extremely acidic working conditions, which are becoming more and more severe due to the hydrochloric acid generated during the reaction, the toxicity and corrosiveness of the iodinating agent used and its limited shelf life.

Iodine monochloride (ICl) is prepared, for example, by the reaction of elemental iodine with chlorine, a very toxic gas, which, due to its toxicity and hazard, requires strict precautions and safety measures to be taken. Iodine monochloride (ICl) reacts with pure water to form HCl, iodine and oxygen, so that a stable aqueous ICl solution is obtained only in the presence of large amounts of chloride ions (e.g., naCl, KCl or HCl).

Alternatively, as described in WO2011/003894, 3 moles of ICl may be prepared by reacting an iodine derivative having an iodine oxidation state equal to (III) obtained by electrochemical oxidation of 1 mole of starting ICl with molecular iodine (I ₂). However, the iodide substance then needs to be transferred to a different compartment for the iodination reaction, which has problems of difficult handling and possibly low solution stability.

In any case, the iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide with ICl must be performed at a controlled pH and temperature (25 ℃) to obtain good yields and purity. This means that a large amount of base (e.g. NaOH) must be added to the reaction medium, not only to neutralize the acidity generated by the reaction, but also to neutralize the hydrochloric acid that dissolves ICl. Since the neutralization reaction is extremely exothermic, it is necessary to add the base slowly to maintain the temperature below 25 ℃ and avoid the formation of byproducts; as a result, a longer reaction time is required.

Instead of using ICl, the iodination reaction can also be carried out with molecular iodine (I ₂) in an aqueous medium, but this process has the disadvantage that half of the iodine added during the reaction is lost in the form of iodide ions, in particular to give hydroiodic acid (HI). Furthermore, the iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide alone with molecular iodine gives only low yields of the corresponding triiodinated compound, which is always as a mixture with byproducts such as monoiodinated and diiodinated intermediates, because during the reaction part of the molecular iodine combines with iodide ions in solution to form unreacted polyiodide ions, such as triiodide ions (I ₃ ^-).

In order to utilize all the iodine for the reaction and overcome the above problems, an oxidizing agent such as iodic acid (HIO ₃) is typically added to the mixture (see e.g. WO 2011/154500).

As another alternative, a process is described in WO2009/103666, wherein iodination of 3, 4-disubstituted phenols is achieved by electrochemically generated iodide cations (I ⁺). According to this publication, prior to iodination, an I ⁺ solution is obtained in a separate compartment by inserting a platinum sheet anode into a stock solution of iodine in a solvent (e.g., methanol) and performing electrolysis in constant current mode. The substrate to be iodinated is then added in portions to the I ⁺ solution thus obtained and iodinated by reflux to effect the conversion.

The above-described process has some drawbacks, for example because the solution of iodinating agent (I ⁺) must be transferred to a separate compartment for iodination, and thus the yield of the process can be affected by the limited stability and shelf life of I ⁺.

Iodine is a very expensive reagent and thus for an efficient and economical process it is desirable to use any amount thereof for the iodination reaction, for example by recovery and recycling, to minimize any possible losses.

Furthermore, for the above synthetic method, another step of removing the solvent by evaporation must be added.

To overcome the above problems, it has been found that N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide can be efficiently prepared by using molecular iodine (I ₂) as an iodide species, which is electrochemically regenerated in situ once reacted or generated by reducing iodide ions present in the reaction medium.

Advantageously, the synthesis of the present invention achieves conversion yields of 90% or higher with minimal loss of iodine.

Summary of The Invention

The present invention relates to a process for the preparation of N, N '-bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide by reacting the intermediate N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide with molecular iodine (I ₂) which is electrochemically generated in situ from a source of iodide ions (I ^-). Such iodide ions may result from the dissolution of HI or alkali metal iodides (e.g., naI, KI) in the reaction medium, or may be obtained directly from the reaction of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide with molecular iodine (I ₂).

Brief Description of Drawings

Fig. 1 shows a reaction scheme for preparing 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 (I ₂) generated electrochemically in situ from iodide ions (I ^-) obtained by dissolving sodium iodide (NaI) in water, according to one embodiment of the present invention. The electrochemical cell is an undivided cell equipped with a graphite cathode and a platinum anode (25 x 25 mm) and the electrochemical reaction is carried out under constant current control.

FIG. 2 shows a reaction scheme for preparing 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 (I ₂) that is electrochemically regenerated in situ from iodide ions (I ^-) obtained by reaction of compound (II) with I ₂, according to another embodiment of the present invention. The electrochemical cell is an undivided cell equipped with a graphite cathode and a platinum anode (25 x 25 mm) and the electrochemical reaction is carried out under constant current control.

FIG. 3 shows a two-compartment electrochemical cell for preparing 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 (I ₂) that is electrochemically regenerated in situ from iodide ions (I ^-) obtained by reaction of compound (II) with I ₂, according to another preferred embodiment of the present invention. Two compartments are separated by a cationic membrane (one compartment is equipped with a working electrode WE and a reference electrode RE, and the other compartment is equipped with a counter electrode CE), and electrolysis is performed in potentiostatic mode.

Fig. 4 shows a representative example of a flow electrochemical cell with (a) alone and (b) integrated in a flow system, wherein anolyte and catholyte solutions are recycled, according to one embodiment of the invention.

Detailed Description

A first aspect of the present invention is a process for preparing N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I), comprising the steps of

A) Dissolving N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) in the reaction medium in the presence of molecular iodine (I ₂);

b) Subjecting the compound (II) to molecular iodine (I ₂) to obtain the compound (I),

Wherein the reaction medium is an aqueous solution and the molecular iodine (I ₂) is electrochemically generated in situ from a source of iodide ions (I ^-).

Preferably, the aqueous solution is water.

The electrochemical step b) of the present invention may be carried out in constant current or potentiostatic mode.

According to a preferred embodiment, the iodide ion (I ^-) is provided by adding and dissolving Hydrogen Iodide (HI) or an alkali metal iodide into the reaction medium or is generated during the reaction of I ₂ according to step b) with the compound of formula (II).

Step b) of the method can also be represented by scheme 1 below

Scheme 1

The reaction is an electrophilic substitution in which one atom of iodine (I ₂) replaces a hydrogen atom in an aromatic ring, while the second atom of iodine is released as iodide (I ^-).

Due to the stoichiometry of the iodination reaction according to the present invention, at least 3 moles of active substance I ₂ are required per mole of aromatic substrate of formula (II) to be tri-iodinated into the corresponding compound of formula (I).

Preferably, the molar ratio of molecular iodine (I ₂) to N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) can vary from 3:1 to 1.5:1, preferably from 2:1 to 1.5:1.

In some preferred embodiments, steps a) and b) of the method are both carried out in the same single compartment of an undivided electrolytic cell comprising two electrodes, namely an anode and a cathode, selected from those conventionally employed in industrial applications.

Preferably, the cell comprising an aqueous solution of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) is equipped with a carbon-based cathode (for example made of graphite) and an anode made of a metal selected from those commonly used in similar electrochemical systems (for example platinum or other elements of group VIIIB of the periodic table). Such metal may be in the form of a mesh, foil or mesh, for example. The anode may also be made of a material suitably coated with a sufficiently thick film of the above-mentioned metals.

Or for pulsed or alternating current experiments, cathodes made of platinum or other layers commonly employed in industrial electrochemical anodes (e.g., ta ₂O₂,IrO₂,RuO₂ or SnO ₂) may be used.

Conveniently, in such embodiments, the electrolytic generation of I ₂ according to the present invention may be carried out in constant current mode, i.e. by applying a constant current density during the process, while magnetically stirring the aqueous solution. Preferably, a constant current is passed through the solution during the process, the constant current being in the range of 5 to 100mA/cm ². More preferably, the constant current is in the range of 5 to 20mA/cm ².

Or in another preferred embodiment, steps a) and b) of the method may be performed in a two-compartment electrolytic cell. One advantage of using this type of cell is that once the final product (I) reaches its maximum concentration, it limits the risk of deiodination at the cathode.

The compartments may be separated by a permeable separator, such as a porous barrier or membrane, or a permeable membrane, such as an ion exchange membrane.

In one embodiment, the presence of the porous membrane provides a poor separation between the compartments, which allows the pH to be kept constant while still being able to diffuse and/or migrate the OH ^- and H ⁺/Na⁺ ions.

Or the membrane ensures a stronger separation. Examples of suitable membranes are represented by anionic membranes which allow an automatic flux of OH ^- ions from cathode to anode to balance the pH decrease of the latter, or cationic membranes which can be traversed by the fluxes of H ⁺ and Na ⁺ from anode to cathode (see one example of such a configuration in fig. 3). More conveniently, cationic membranes are used in the process of the invention, particularly in the case of an industrial scale up.

Preferred anionic membranes are made from polymeric cores, such as polyamides, polyesters, polystyrene, polyvinylbenzene, and the like.

Preferred cationic membranes are polymeric fluorocarbon membranes selected from, for example, polytetrafluoroethylene (PTFE), tetrafluoroethylene-perfluoropropylene copolymer (FEP), tetrafluoroethylene-perfluoroalkoxy copolymer (PFA), ethylene-tetrafluoroethylene copolymer (ETFE), polyvinylidene fluoride (PVDF) membranes, and derivatives thereof. More preferably, the cationic membrane is tetrafluoroethylene-perfluoro-3, 6-dioxa-4-methyl-7-octenesulfonic acid copolymer [ ]117)。

In this case, suitable anodes may include graphite or glassy carbon anodes. Preferably, the anode may be made of graphite, carbon paper or carbon cloth, the latter optionally combined with a carbon felt.

As the cathode, a conventional metal may be used. Preferably, the cathode may be made of platinum, nickel, stainless steel (inox steel), or the like, and may be an electron conducting material having a different structure, such as an all-solid material or a material forming a three-dimensional network of electron conducting paths.

Preferably, the two-compartment cell is a filter-press type cell (filter-PRESS CELL), which is also applicable to industrial scale flow electrolysis reactions.

In a first embodiment of the invention, molecular iodine (I ₂) is electrochemically generated from an external source of iodide ions (I ^-) added to the reaction medium. 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 to which has been added a source of iodide ions (I ^-), and

B') subjecting said compound (II) to molecular iodine (I ₂) to obtain said compound (I),

Wherein the reaction medium is an aqueous solution and the molecular iodine (I ₂) is electrochemically generated in situ from an added source of iodide ions (I ^-).

Preferably, the aqueous solution is water.

Preferably, the electrochemical reaction according to this embodiment is performed in a constant current mode.

The source of iodide ions (I ^-) may be obtained by dissolving Hydrogen Iodide (HI) or dissolving alkali metal iodides added to the reaction medium.

Typically, the alkali metal iodide is selected from sodium iodide (NaI), potassium iodide (KI), lithium iodide (LiI), and cesium iodide (CsI), preferably from NaI and KI.

Hydroiodic acid (HI) or a suitable metal iodide (e.g. NaI or KI) is dissolved in the reaction medium in a molar ratio of iodide (I ^-) to N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) of from 6:1 to 3:1, preferably from 4:1 to 3:1. Normally, the iodide is used in a slight excess.

Preferably, during the iodination reaction of step b'), the solution is maintained at a constant temperature of 20 ℃ to 75 ℃, more preferably 50 ℃ to 60 ℃, by operating according to conventional methods. Even more preferably, the reaction of step b') is carried out at a temperature of 50 ℃.

The reaction medium is maintained at neutral pH, i.e. in the range of 5 to 7.5, preferably between 6 and 7, by continuous addition of a protic acid, e.g. H ₂SO₄.

According to the invention, iodide ions (I ^-) are oxidized to molecular iodine (I ₂) on the anode surface based on the following reaction:

2I^-→I₂+2e^-

In step b '), the molecular iodine thus produced is reacted in solution with N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II). The reaction is an electrophilic substitution in which one atom of the molecular iodine (I ₂) replaces a hydrogen atom in the aromatic ring of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II), while the second atom of iodine is released as an iodide ion (I ^-).

The released iodide ions (I ^-) are recycled in situ by electrochemical reoxidation to molecular iodine (I ₂). In this way, all iodine atoms placed in the cell compartment are fully used for the iodination reaction. Protons (H ⁺) are also generated in the process and they are reduced to gaseous hydrogen (H ₂) on the cathode surface.

The reactions involved in the process are schematically reported in fig. 1, wherein an alkali metal iodine NaI is used. The stoichiometry of the reactions involved in the process is as follows:

cathode reaction: 6H ₂O+6e^-→3H₂+6OH^-

Anode reaction: 6 NaI.fwdarw.3I ₂+6e^-+6Na⁺

Iodination of Compound (II) 3I ₂ + Compound (II) →Compound (I) +3H ⁺+3I^-

Total reaction: 3NaI+3H ₂ O+ Compound (II) →Compound (I) +3NaOH+3H ₂

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; purity of the product; temperature, etc. One of ordinary skill in the art can find the best conditions through his personal knowledge and experience. Completion of the reaction can be detected by common analytical means used in organic chemistry, such as spectrometry equipment, e.g., HPLC.

Typically, the reaction is completed in a period of 3 hours to 48 hours, typically 6 hours to 12 hours.

Since the production rate of I ₂ is generally higher than the consumption rate thereof in the reaction with N, N '- (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II), electrochemically produced I ₂ tends to deposit on the anode, which becomes purple and slowly dissolves by the reaction with N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II). In order to completely dissolve iodine deposited on the anode, the constant current may be periodically switched off.

In a preferred embodiment, the current is conveniently switched off for 30 to 60 seconds every 2 to 5 minutes.

As a further alternative, a pulsating current may be applied between the electrodes to achieve the same result.

In a second embodiment of the invention, I ₂ is electrochemically regenerated in situ from iodide ions (I ^-) generated by the reaction of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) with molecular iodine (I ₂) by applying a constant current.

According to this embodiment, the method comprises the steps of:

a ") dissolving N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) in the reaction medium in the presence of molecular iodine (I ₂);

b "₁) partial iodination of the compound (II) with molecular iodine (I ₂) in the absence of any current, and

B "₂) applying a current to the reaction obtained in step b" ₁) to complete iodination and obtain the compound (I),

Wherein the reaction medium is an aqueous solution and the molecular iodine (I ₂) is electrochemically regenerated in step b "₂) in situ from iodide ions (I ^-) generated during the reaction of step b" ₁).

Preferably, the aqueous solution is water.

In one embodiment, an aqueous solution of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) is placed into an undivided electrochemical cell equipped with a graphite cathode and a platinum anode.

After dissolution of compound (II), step a ") is carried out by adjusting the pH of the aqueous solution to >6, preferably >10, with a base such as NaOH or KOH, or by using a solution of preformed N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) in water at pH >6, preferably > 10.

Step b "₁) is performed without applying a current. In this way, partial iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) is achieved. Compound (I) and the corresponding mono-and di-iodinated intermediates are obtained, and iodide ions (I ^-) are liberated from the reaction. Preferably, the molar ratio of I ₂ 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 ℃ to 60 ℃, more conveniently about 55 ℃, for from 1 hour to 6 hours, typically from 2 hours to 3 hours.

Step b "₂) is carried out by applying an electric current, preferably a constant current (constant current 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 (I ₂), which reacts with the remaining N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) or with the corresponding mono-and di-iodinated intermediates present in the reaction mixture.

The solution is maintained at a temperature in the range 40 ℃ to 60 ℃, preferably 55 ℃. For example, the applied current may be in the range of 5 to 100mA/cm ². Typically, a constant current of 5 to 20mA/cm ² is applied for a period of 3 hours to 48 hours, typically 6 to 12 hours.

Since the regeneration rate of I ₂ in the reaction with N, N '- (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) is generally higher than its consumption rate, regenerated I ₂ tends to deposit on the anode, which turns purple and dissolves slowly by reaction with N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II). In order to completely dissolve iodine deposited on the anode, the constant current may be periodically switched off. In a preferred embodiment, the current is conveniently switched off every 2 to 5 minutes for an interval of 30 to 60 seconds.

As a further alternative, an alternating current may be applied between the electrodes to achieve the same result.

The reactions involved in the second embodiment of the process are schematically reported in figure 2. The stoichiometry of the reactions involved in the process is as follows:

Iodination of compound (I): 6I ₂ +2 Compound (II) →2 Compound (I) +6H ⁺+6I^-

Cathode process: 6H ⁺+6e^-→3H₂

Anode reaction: 6I ^-→3I₂+6e^-

Total reaction: 3I ₂ +2 Compound (II) →2 Compound (I) +3H ₂

Iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) yields three iodide ions and three protons per product molecule.

Iodide ions will be lost during the work-up of the reaction, resulting in a 50% loss of valuable halogen atoms.

Advantageously, the electrochemical reaction of step b "₂) allows the reoxidation of the iodide ions produced and reintroduces them into the process until they are fully used and/or until the complete conversion of compound (II) into compound (I).

In a third embodiment of the invention, I ₂ is electrochemically regenerated in situ from iodide ions (I ^-) produced by the reaction of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) with molecular iodine (I ₂) by applying a constant voltage across the electrode such that the anode potential is from 0.5V to 0.9V relative to SCE (saturated calomel electrode as reference electrode).

According to this embodiment, the method comprises the steps of:

b "₁) partial iodination of the compound (II) with molecular iodine (I ₂) in the absence of any voltage, and

B "₂) applying a voltage to the reaction obtained in step b" ₁) to complete iodination and obtain the compound (I),

Wherein the reaction medium is an aqueous solution and molecular iodine (I ₂) is electrochemically regenerated in situ in step b "₂) from iodide ions (I ^-) generated during the reaction of step b" ₁).

The electrochemical reaction according to this embodiment is performed in potentiostatic mode.

Preferably, the aqueous solution is an electrolyte, such as an aqueous NaOH solution. More preferably, it is a NaOH solution with a concentration ranging from 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 cathode made of platinum or stainless steel.

Step a ") is carried out by adjusting the pH of the aqueous solution to 8 to 12 with a base such as NaOH or KOH after dissolution of compound (II).

Step b "₁) is a chemical stage, performed without any voltage applied. In this way, partial iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) is achieved. Compound (I) and the corresponding mono-and di-iodinated intermediates are obtained, and iodide ions (I ^-) are liberated from the reaction. Preferably, the molar ratio of I ₂ 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.

During step b "₁, only half of the provided iodine atoms can react with the substrate, as the high concentration of h+ ions prevents further removal of protons from compound (II), thus blocking electrophilic substitution. Thus, after this chemical step, the reaction mixture contains not only a certain percentage of compound (I) but also a residual amount of unreacted compound (II) and the corresponding mono-or di-iodinated intermediate.

The reaction is preferably carried out at a temperature of from 50 ℃ to 70 ℃, more conveniently about 60 ℃, 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, may be performed in separate containers and then transferred to the electrochemical cell when step b "₂ is performed, even though it may be more convenient to keep the solution in the same cell from the beginning.

Step b "₂) is performed by applying a constant potential (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 re-oxidized to molecular iodine (I ₂), which is reacted with the remaining N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) or with the corresponding mono-and di-iodinated intermediates present in the reaction mixture to complete the tri-iodination of compound (II).

The solution is maintained at a temperature in the range of 50 ℃ to 70 ℃, preferably 60 ℃.

Preferably, the reaction is carried out with an anode potential of 0.6V to 0.8V relative to SCE, more preferably 0.65V to 0.7V relative to SCE.

The reaction medium is maintained at a basic pH, i.e., about 8 to 12, by the addition of a strong base, such as NaOH particles, which buffers the developing acidity. Particularly when the reaction is carried out in a two-compartment cell with a cationic membrane, the pH must be controlled. The amount of base required for neutralization of the electrochemical reaction may be added in a single transfer or gradually before or during step b "₂. Preferably, a stoichiometric amount of NaOH is added before the electrochemical step b "₂ is performed.

The stoichiometry of the reactions involved in this process is as follows:

iodination of Compound (I) 6I ₂ +2 Compound (II) →2 Compound (I) +6H ⁺+6I^-

Cathode process: 6H ⁺+6e^-→3H₂

Anode reaction: 6I ^-→3I₂+6e^-

Total reaction: 3I ₂ +2 Compound (II) →2 Compound (I) +3H ₂

Advantageously, the electrochemical reaction of step b "₂) allows the iodide ions produced at the anodic reoxidation, which will be lost during the work-up of the reaction, resulting in a loss of 50% of the valuable halogen atoms, and reintroduces them into the process until they are fully used and/or until the complete conversion of compound (II) into compound (I) by converting them directly in situ into iodinating agent I ₂. Protons (H ⁺) also produced in the process are reduced to gaseous hydrogen (H ₂) on the cathode surface. Optionally, in all embodiments, the gaseous hydrogen thus produced may then be recovered by methods conventionally used in electrochemical industrial processes, for example by recovering membranes and the like.

Preferably, the electrochemical reaction of step b "₂, which is performed in potentiostatic mode, can also be performed in a two-compartment filter press type electrolytic cell under flux conditions, wherein the electrolyte solution is recycled. For example, fig. 4 shows a representative example of a flow system comprising an electrolytic cell of the filter press type (a) and a circuit (b) with two pumps for recirculation of the solution (for example centrifugal or peristaltic pumps) and heating means for maintaining the temperature between 50 and 70 ℃. For example, according to the embodiments described later, the electrolyte solution is represented by an aqueous mixture of the compounds (II) and I ₂ defined in step a "(anolyte) and a 0.1M NaOH solution (catholyte).

Surprisingly, compound (I) was obtained in about 100% yield when operated with a flow system. Such a system thus demonstrates that the method of the present invention can potentially be used in large-scale plants and integrated into the industrial production of iomeprol or other iodinated contrast agents.

Thus, as exemplified in all of the above embodiments, the process of the present invention is a very efficient process that allows for the tri-iodination of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) in high yields without loss of iodine. Virtually all of the iodine atoms placed in the cell are used for the iodination reaction.

Subsequent work-up of the reaction mixture may be accomplished according to conventional methods known in the art to isolate the final compound of formula (I).

Another object of the present invention is that the above method further comprises step c): the compound of formula (I) obtained by electrochemical iodination of compound (II) according to the above-described method is isolated.

The intermediates of formula (II) are known starting materials, which can be prepared according to known methods. For general reference, see, e.g., WO00/32561, supra.

The compounds of formula (I) are useful intermediates for 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.

Accordingly, a further object of the present invention is the use of an intermediate compound of formula (I) obtained by electrochemical iodination of compound (II) according to steps a) and b) of the process of the present invention for the preparation of N, N' -bis [2, 3-dihydroxypropyl ] -5 (hydroxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxamide (IV, iomeprol).

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 steps of:

b) Subjecting the compound (II) to molecular iodine (I ₂) to obtain the compound (I);

c) Isolating said compound (I);

d) Reacting compound (I) with ClCH ₂(CO)NHCH₃ to obtain intermediate (III)

E) The intermediate (III) is subjected to a Smile rearrangement (Smile 'S 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)

Wherein the reaction medium of step a) is an aqueous solution and the molecular iodine (I ₂) of step b) is electrochemically generated in situ from a source of iodide ions (I ^-).

Preferably, the reaction medium of step a) is water.

For a general reference to the conditions of steps d) and e) above, see WO00/32561.

The compounds of formula (II) as starting materials for the process of the present invention are known and can be prepared according to the known methods described above. Also, any other reactants and/or solvents used in the process of the present invention are known and readily available.

In order to better illustrate the invention, without limiting it in any way, the following examples are given in which different embodiments of the invention are described in detail.

Experimental part

For the examples reported below, the following experimental conditions were used:

By mounting the electrodes in a usable neck (double electrode system), a multi-necked round bottom flask has been used as an undivided electrochemical cell. The power supply LAFAYETTE ALP-5A provides the constant current required to run the electrochemical step. Platinum foil (0.1 mm thick) was used as anode. In addition to the pulsation or alternating current experiments using platinum foil, graphite rods were used as cathodes. Electrolysis is carried out in a constant current mode; or (b)

-The two-compartment cell comprises three electrodes: a working electrode (WE, carbon-based anode), a counter electrode (CE, made of stainless steel) and a reference electrode (RE, denoted Saturated Calomel Electrode (SCE)). The two compartments are separated by a cationic membrane (e.g., nafion) and SCE is contained in Lu Jin (Luggin) capillary (polyethylene tube, 2mm diameter) in contact with the anolyte of the anode compartment. According to experiments, the system is equipped with one or more of the following: pH meter, thermostat, potentiostat, and hydraulic pump. Electrolysis was performed in potentiostatic mode, and chronoamperometry was set to constant potential.

Example 1

Electrochemical iodination in constant current mode starting with iodide ions (NaI)

A23.5% w/w aqueous solution of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) (0.34 mmol) was placed in an undivided electrochemical cell equipped with a graphite cathode and a platinum anode, along with NaI (1.34 mmol) and water (50 mL). The electrolysis was carried out in constant current mode, i.e. the amount of current through the cell was kept constant, δ=8 mA/cm ². The solution was stirred at 50℃and the pH was kept constant at 7 by the continuous addition of 98% H ₂SO₄. The evolution of hydrogen is significant on the cathode surface. Iodine is immediately formed on the anode surface and slowly dissolved by reaction with N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II). The current is periodically cut off to completely dissolve the iodine deposited on the anode. After 3h of reaction, HPLC analysis showed the presence of mono-and di-iodinated intermediates. After 48h of reaction, HPLC showed 90% of the triiodo compound of formula (I) (HPLC peak area%).

Example 2

Electrochemical iodination in constant current mode starting from I ₂

A23.5% w/w aqueous solution of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) (0.34 mmol) was placed in an undivided electrochemical cell equipped with a graphite cathode and a platinum anode, along with molecular iodine (9.8 mmol) and water (7 mL). The mixture was magnetically stirred at 55 ℃. After 2h, HPLC analysis (peak area%) showed 54% content of the tri-iodo compound of formula (I) with the corresponding mono-and di-iodo intermediates present. At this time, the current was turned on, and electrolysis was performed in a constant current mode of δ=8 mA/cm ². The solution was stirred at 55℃and the pH was kept constant at 7 by the continuous addition of 98% H ₂SO₄. The evolution of hydrogen is remarkable on the cathode surface, while the formation of iodine is evident on the anode surface. After 48h, HPLC analysis (HPLC peak area%) showed that the content of N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I) was 90%.

Example 3

Electrochemical iodination starting from I ₂ in potentiostatic mode (two-compartment cell)

A23.3% w/w aqueous solution (72 mmol,100 mL) of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) and I ₂ (29.46 g) were placed in an electrochemical cell with two compartments separated by a cationic membrane (Nafion) equipped with an electrode (cathode) made of stainless steel, nickel or platinum foil, a graphite rod (anode) and a Saturated Calomel Electrode (SCE) as reference. The catholyte was a 0.5M NaOH aqueous solution.

The mixture was magnetically stirred at about 65 ℃ and the pH was maintained between 10 and 12 by continuous addition of NaOH pellets. After 10 minutes, the solution was yellow orange and HPLC analysis showed a content of 55% N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I) with the corresponding mono-and di-iodinated intermediates present. At this time, naOH (113 mmol) was gradually added, the temperature was still kept at 65℃and the pH was 10-12, and electrolysis was carried out in potentiostatic mode by setting the chronoamperometry to a constant potential of 0.7V vs SCE.

After 35 hours of reaction, HPLC analysis showed that the content of N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I) was 90% (HPLC peak area%).

Example 4

Electrochemical iodination amplification in potentiostatic mode (flow cell)

An aqueous solution (576 mmol,800 mL) of 23.3% w/w N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) and I ₂ (220.4 g) were slowly placed in a 1L glass bottle. The solution was kept under stirring and heated at about 55-60 ℃ until the color of the solution changed from dark red to clear orange-yellow, with the pH stabilized at about 10.

After 10 minutes, HPLC analysis showed 55% content of N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I), as well as the presence of the corresponding mono-and di-iodinated intermediates.

At this point, the solution was transferred to the anolyte compartment of a filter press type electrochemical cell for flow electrolysis, as shown in fig. 4. The battery with the size of 10 multiplied by 30cm is formed by passing through a cationic membrane117 A) two compartments separated and equipped with a stainless steel mesh Cathode (CE), a carbon cloth tape with a platinum foil as anode (WE) and a Saturated Calomel Electrode (SCE) contained in Lu Jin capillaries (polyethylene, 2mm diameter) as reference. The anode compartment (about 180cm ³) was completely filled with 5 layers of carbon felt (/ >)Style G300A) and the catholyte chamber was filled with 1L of 0.1M NaOH. The carbon cloth anode is connected to an external circuit through a metal (e.g., pt) foil. Both the compound (II) +i ₂ solution in the anode compartment and the 0.1M NaOH solution in the cathode compartment were recycled at 0.3L/min by using two membrane pumps.

The anolyte temperature was maintained at about 65 ℃ by heat exchange with hot water and electrolysis was performed in potentiostatic mode by setting the chronoamperometry at a constant potential of 0.65V vs SCE. About 35g of NaOH particles was added continuously to maintain the pH between 10-12.

After 9.3 hours of reaction, the anolyte was orange in color and HPLC analysis showed 100% of N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I) (HPLC peak area%).

Due to the strongly basic pH of the mixture, as a result of the addition of NaOH during the reaction, the product was isolated and characterized as the corresponding sodium phenolate.

¹ H-and ¹³ C-NMR analysis confirmed the absence of any by-products, such as hydrolysis products.

Spectral data: ¹H-NMR(400MHz,DMSO-d₆, 363K):

7.34ppm wide s 2H, 2 XNH

4.32Ppm wide s 2H, 2 xOH

4.15Ppm wide s 2H, 2 xOH

3.73Ppm app.q, J=5.6 Hz (average), [2H ],2 XCH-OH

3.51ppm dd,J_a＝11.1Hz,J_b＝5.1Hz[2H],2×H_a CH₂-OH

3.46ppm dd,J_a＝11.1Hz,J_b＝5.6Hz[2H],2×H_b CH₂-OH

3.33ppm dd,J_a＝13.2Hz,J_b＝6.0Hz[2H],2×H_a CH₂-NH

3.16ppm dd,J_a＝13.2Hz,J_b＝5.7Hz[2H],2×H_b CH₂-NH

¹³C NMR(100MHz,DMSO-d₆,300K):

170.73ppm 2×CONH

164.89ppm C5

147.29Ppm C1 and C3

87.79Ppm C2 and C4

70.20ppm 2×CH-OH

63.98ppm 2×CH₂-OH

57.91ppm C6

42.64ppm 2×CH₂-NH

Reference to the literature

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 steps of:

a) Dissolving N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) in the reaction medium in the presence of molecular iodine (I ₂); and

B) Iodination of the compound (II) with molecular iodine (I ₂) to obtain the compound (I),

Wherein the reaction medium is an aqueous solution and molecular iodine (I ₂) is electrochemically generated in situ from a source of iodide ions (I ^-).

2. The method of claim 1, wherein the aqueous solution is water.

3. The method according to claim 1 or 2, wherein steps a) and b) are performed in constant current mode using an undivided electrolytic cell.

4. A method according to any one of claims 1 to 3, wherein molecular iodine (I ₂) is electrochemically generated from a source of iodide ions (I ^-) selected from HI and alkali iodides such as NaI or KI by applying a constant current.

5. A method according to any one of claims 1 to 3, wherein molecular iodine (I ₂) is electrochemically regenerated from iodide ions (I ^-) generated by the reaction of N, N' - (2, 3-dihydroxypropyl) -5-hydroxy-1, 3-benzenedicarboxamide (II) with I ₂ by applying a constant current, which is switched on after a period of 1 to 6 hours.

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

7. The process according to any one of claims 3 to 6, wherein the reaction medium is maintained at a pH in the range of 5 to 7.5 and at a temperature of 40 ℃ to 60 ℃ by addition of a protic acid.

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

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

10. The process according to claim 8 or 9, wherein the reaction medium is maintained at a pH of 10 to 12 and at a temperature of 50 ℃ to 70 ℃ by addition of a strong base.

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

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

13. The method of claim 12, performed by recycling the anolyte and catholyte solutions under flux conditions.

14. The method according to any of the preceding claims, further comprising the step of:

c) Isolating the compound of formula (I) obtained by electrochemical iodination of compound (II) according to the process of claim 1.

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 steps of:

b) Iodinating said compound (II) with molecular iodine (I ₂) to obtain N, N' -bis- (2, 3-dihydroxypropyl) -5-hydroxy-2, 4, 6-triiodo-1, 3-benzenedicarboxamide (I);

c) Isolating said compound (I);

d) Reacting the compound (I) with ClCH ₂(CO)NHCH₃ to obtain an intermediate (III)

E) The intermediate (III) is subjected to a step rearrangement in the presence of a base to obtain the final compound N, N' -bis [2, 3-dihydroxypropyl ] -5 (hydroxyacetyl) methylamino ] -2,4, 6-triiodo-1, 3-benzenedicarboxamide (IV)