MX2011010333A - Process for the iodination of aromatic compounds. - Google Patents

Abstract

The present invention relates to a process for the preparation of iodinated anilines; in particular, it relates to a process including the direct iodination, with suitably activated iodine, of 3,5-disubstituted anilines to the corresponding 3,5- disubstituted-2,4,6-triiodoanilines, which are useful intermediates for the synthesis of x-ray contrast media, and to the preparation of the contrast media themselves.

Description

PROCESS FOR THE YODATION OF AROMATIC COMPOUNDS FIELD OF THE INVENTION The present invention relates to a process for the preparation of poly-iodinated aromatic compounds. More particularly, it relates to a process that includes the direct iodination of 3, 5-disubstituted anilines to the corresponding 3,5-disubstituted 2,4,6-triiodoanilines, which are useful intermediates for the synthesis of lightning contrast medium. -X, and the preparation of the same contrast media.

BACKGROUND OF THE INVENTION Iodinated contrast agents are well-known compounds widely used in diagnostic X-ray imaging. Suitable examples of the compounds include, for example, diatrizoate, yotalamate, yoxitalamate, metrizoate, yohexol, yomeprol, yopamidol, yopentol, yopromide, yoversol, yoxilan, iodixanol, yosarcol, yogolamide, yoglunide, yogluamide, acetrizoate, yodamide, yocetamide and metrizamide, all having a monomeric structure, and yoxaglate, yotrolan, yotasul, yodipamide, yocarmate, iodoxamate, yotroxate, yotrolan, and the like, which, preferably, are dimers. Additional examples of agents iodinated contrast agents are described, for example, in WO 94/14478 (Braceo).

As a common feature, its chemical structure carries a tri-oxide aromatic core which provides the enhanced contrast effect.

The compounds can be prepared by a variety of routes, which generally include the iodination of aromatic substrates given, for example, of suitable 3, 5-disubstituted phenols, which undergo triiodination at positions 2,4, and 6 available, of this mode leading to the corresponding 3, 5-disubstituted 2,4,6-triiodophenols. The latter, in turn, can also be converted and processed through the so-called Smile rearrangement, to the expected final compounds.

For a general reference to the above synthetic route and Smile rearrangement see, for example, WO 88/09328, WO 97/05097 and WO 00/32561 (Braceo). Alternatively, the aromatic iodination can be carried out in suitable anilines, so as to provide the corresponding 2,, β-triiodoaniline derivatives, to be further converted and processed to the final radiographic agent, for example as described in US Pat. No. 5,075,502.

The iodization step can be carried out using different procedures.

In this regard, in industrial processes currently used to prepare the above radiographic contrast agents, the iodination of the aromatic ring is generally carried out using solutions of iodine mono-chloride (IC1) in concentrated hydrochloric acid (HCl) (44.5% I). and 14% HCl) at high temperature (approximately 90 ° C) or, alternatively, by means of analogous iodination agents such as, for example, KIC12 or NaCll2 in aqueous solution; see, for a general reference, WO 92/14695 (Guerbet), US 5,013,865 (allinckrodt), WO 96/37458 and WO 96/37459 (Fructamine).

The above methods suffer from major disadvantages due to the extremely acidic working conditions, which become more difficult due to the HCl produced during the reaction, and the corrosive property and limited storage life of the iodinating agents.

In addition, significant problems arise mainly from the presence of chlorine atoms within the iodinating agents themselves, (formed at the high reaction temperature necessary for the exhaustive iodination of aniline substrates), which can lead to the formation of secondary products chlorinated solids that are difficult to remove, which can thus affect the yields of the reaction and purity of the final compounds.

On the other hand, and from a different point of view, it is an increasingly recognized need to have industrial manufacturing processes which can combine low production costs, high production efficiency and minimized environmental impact.

Thus, attempts have been made to address new iodization methods based on the use of alternative iodination agents to iodine mono-chloride or derivatives thereof.

These include, for example, the electromechanical iodination process of 3, 5-disubstituted anilines or 3, 5-disubstituted phenols, as described in WO 96/37461 and WO2009 / 103666, respectively.

In addition to the above procedures, alternative iodination of aromatic nuclei with iodine suitably activated with an oxidizing agent has also been experienced. For example, the iodation of given phenol derivatives, referred to as ortho-hydroxy-substituted aromatic carbonyl compounds, in the presence of molecular activated iodine with a strong oxidizing agent, including iodic acid, has been described by Patil et al. in Tetrahedron Letters 2005, 46, 7179-7181, and in ARKIVOC 2006, 104-108.

This technique is, however, silent in the possibility of using such described synthetic process, ie, the combined use of molecular iodine and an oxidizing agent, for iodinated or poly-iodinated aniline or aniline derivatives.

US 2007/0219396 discloses a method for producing 2-amino-5-iodobenzoic acid by iodination of 2-aminobenzoic acid, solubilized in acetic acid, with iodine and in the presence of an oxidizing agent, especially hydrogen peroxide.

This application, however, does not mention or suggest the possibility of using the described procedure to provide poly-iodinated compounds and, in particular, triiodinated aniline derivatives which, however, could hardly have been achieved under the described iodination conditions, as evidence by Comparative Example 1 of the following experimental section.

The use of iodine and iodic acid to produce 3-amino-2,4,6-triiodobenzoic acid and 3, 5-diamino-2, 6-triiodobenzoic acid is also mentioned in Chem. Ber. , 1897, 30 (2), 1943-1948 and in Chem. Ber., 1896, 29 (3), 2833-2839, respectively. These references, however, are almost deficient in the complete description of the iodization conditions used, in order to prevent their exact reproduction.

In any case, the iodization conditions described and the amount of iodinating agent, in particular of the iodic acid, appears to be sufficient enough to allow the triiodination of the substrate, at least with appreciable yield and purity, as discussed in greater detail in Comparative Example 2 of the following experimental section . However, in both articles cited, the brown precipitation obtained needs to be washed with sulfuric acid, solubilized in diluted ammonia and then precipitated with sulfuric acid to have a product of the desired purity.

In this regard, it is worth noting that the use of strong oxidizing conditions with aniline or even halogenated anilines is known to lead to the formation of mixtures of colored derivatives, mainly azo compounds that are derived from oxidative coupling reactions involving the amino group aromatic (see, for example Erich Baer and Anthony L. Tosoni, J. Am. Chem. Soc, 1956, 78 (12), 2857-2858), while all the prior art does not direct or even suggest how to solve this problem.

On the contrary, the need to collect process intermediates and final compounds with a high degree of purity is of utmost importance to optimize, to a significant extent, the purification steps required for the final agent, which have to be in accordance with the strict purity profile and the limits imposed by the Pharmacopoeia, in particular for products proposed for administration. For example, the analytical specifications set by the EP Pharmacopeia for 5-amino-2,4,6-triiodoisophthalic acid are: Loss in dryness = 3.5% Title: 98.0-102% Ashes: < 1.0% Total related substances: = 1% (proposed as the sum of all known and unknown impurities, mainly represented by partially iodinated compounds and chlorinated compounds) of which the sum of the chlorinated impurities should be = 0.35%.

It has been found that the triiodination of suitable 3,5-disubstituted anilines can be advantageously carried out in high yields and purity using an iodination system comprising molecular iodine and an oxidizing agent which overcomes the above main disadvantages.

SUMMARY OF THE INVENTION The present invention provides a process for the triiodination of 3, 5-disubstituted anilines with suitably activated iodine and, also, a method for the preparation of X-ray contrast agents which includes the previous iodization stage. particularly, a first object of the present invention is represented by a process for the preparation of the 5-amino-2,4,6-triiodoisophthalic acid of formula (II) wherein the process comprises iodinating 5-aminoisophthalic acid of formula (I) or a salt thereof with molecular iodine in the presence of a suitable oxidizing agent. The process of the invention is particularly advantageous in that it allows the complete triiodination of the 5-aminoisophthalic acid of formula (I), or corresponding salt thereof, and leads to the corresponding 5-amino-2,4,4-β-triiodoisophthalic acid of formula (II) in high yields and purity.

Notably, and distinct from the previous teachings on oxidability of anilines, the above process is not affected by the presence of by-products that are derived from partial iodination of the aromatic ring or coupling oxidative that occurs in the amino group.

Advantageously, therefore, the process of the invention does not require any purification step of the triiodinated compound obtained which is isolated from the raw solution by filtration and, fully covering the analytical specifications for the industrially produced intermediate, can thus be used as such in the next reaction step to the iodinated agent of interest.

In addition, by efficiently consuming all the aggregated molecular iodine and producing water as the sole derivative of reaction, as per further details, the need for subsequent steps to recover and recycle unreacted iodine and treat industrial flow streams can be minimized to a very significant degree. .

As previously reported, in the process of the present invention, the iodination reaction leading to the formation of 5-amino-2,4,6-triiodoisophthalic acid of formula (II) occurs with molecular iodine (I2) in the presence of a suitable oxidizing agent, in accordance with the well known electrophilic substitution mechanism.

In this context, the species of effective iodization can be represented by iodine cations (I +), at least a portion of which is first generated by molecular iodine (I2), while the non-reactive iodide counterions (I ") thus produced are conveniently oxidized by the oxidizing agent again to the molecular iodine, or even to iodine cations with a higher oxidation state, thereby making them still available for the iodination of the aromatic ring.

From the foregoing, and unless otherwise provided, oxidizing agents suitable for use in the process of the invention are those commonly used on an industrial scale and which are capable of oxidizing iodine ions to an active higher oxidation state. for iodization, as detailed in the following paragraphs.

Suitable examples of oxidizing agents in this manner include, for example, nitric acid, sulfuric acid, iodic acid, sulfur trioxide, hydrogen peroxide, ozone, and the like. Generally speaking, the choice of oxidizing agents will depend on several factors, among which are, for example, the operating conditions that allow them to properly exercise their oxidative function during the course of the reaction, thus leading to the formation of the compound desired, as well as its availability. As such, and in accordance with a first embodiment of the process of the invention, the oxidizing agent is preferably selected from hydrogen peroxide and Yodic acid, the latter is even more preferred.

When molecular iodine is used in the presence of iodic acid (HI03), in effect, the non-reactive iodine ions formed in the iodation reaction are converted back to molecular iodine through the so-called Dushman reaction, in accordance with the Following Reaction Scheme 1 I03- + 5 I- +6 H "3 l; j + 3H; p Notably, this reaction further leads to a convenient reduction of the iodate ions (I03 ~) to molecular iodine, still available for the iodination of the aromatic ring (see, for example, Furuichi, R. and Liebhafsky, HA Radioactive iodine exchange and the Dushman reaction, Bull, Chem. Soc. Japan 1973, 46, 2008-2010 and Bull, Chem. Soc. Japan 1975, 48, 745-750).

As a result, a complete triiodination of the 5-aminoisophthalic substrate is thus achieved to obtain, very advantageously, the desired compound of formula (II) in high yields and purity, consuming a stoichiometric amount of iodination species, which is calculated as the sum of both the added I2 and HI03, as per the following General Reaction Scheme 2 In other words, the combined use of iodine and iodic acid, as per the preferred embodiment of the invention, allows the complete triiodination of the aromatic substrate of formula (I) avoiding, on the one hand, the need for any excess of iodinating agent, especially of molecular iodine and, on the other hand, the formation of derivatives, especially non-reactive poly iodide ions, for example of I3 ions, mainly that are derived from the combination of I2 with ions of iodine.

In this regard, it is clear to the skilled person that the equivalent ratio between the 5-aminoisophthalic acid substrate and the species of iodination considered, as such, as the sum of both I2 and HIO3, must be at least equal to 1: 3, as for the General Reaction Scheme 2 above.

Except for this point, in the process of the present invention the triiodination of the 5-aminoisophthalic substrate with iodine and iodic acid, will be carried out using at least one mole of molecular iodine per mole of 5-aminoisophthalic substrate of formula (I). Preferably, the relationship molar between the iodine and 5-aminoisophthalic substrate (I) [I2 / (I)] will vary from 1 to 1.5, more preferably from 1 to 1.3; even more preferably, triiodination of the 5-aminoisophthalic substrate with iodine and iodic acid will be performed using only 1.2 mole of iodine per mole of substrate (I).

On the other hand, due to the stoichiometry of the reaction involved, the molar ratio between iodine and iodic acid should be at least equal to 1: 0.5, while the molar ratio between the substrate 5-aminoisophthalic (I) and iodic acid should be at less equal to 1: 0.6.

Accordingly, in a particularly preferred embodiment of the invention, triiodination of the 5-aminoisophthalic substrate with iodine and iodic acid will be performed using a molar ratio of 5-aminoisophthalic substrate (I): iodine: iodic acid of 1: 1.2: 0.6.

However, a slight excess, on the minimum stoichiometric amount, of the yodic acid on molecular iodine can, optionally, be used with equally good results, as reported in the experimental section.

Accordingly, in a different embodiment of the invention, a molar ratio of iodine to iodic acid will be employed ranging from 1: 0.5 to about 1: 1 and, more preferably, from 1: 0.5 to about 1: 0.8.

In this regard, a minimum amount of bisulfite Sodium can, for example, be added to the final reaction medium to destroy any of the optional residual iodization species. In this case, the optimum amount can, for example, be potentiometrically determined as the minimum amount of bisulphite leading to a redox potential of the final mixture preferably lower than 250 mV.

The iodation reaction of the invention, which comprises using the iodination system I2 / HIO3, as discussed above, is preferably carried out in the presence of a polar solvent, and preferably a protic solvent, and under acidic conditions.

Non-limiting examples of suitable solvents can thus include, for example: water or aqueous solvents, including aqueous saline solutions, lower Ci-C4 alcohols, for example methanol or ethanol, and hydroalcoholic mixtures thereof, dioxane, glycols such as , for example, diethylene glycol, triethylene glycol, and polyethylene glycols such as PEG 600, PEG1000 or PEG2000 or mixtures thereof, and aqueous mixtures thereof.

Preferred solvents are water or aqueous solutions, methanol, ethanol and dioxane as well as mixtures thereof with water or an aqueous solution.

In a particularly preferred embodiment of invention, the iodization process is carried out in water or aqueous solvents, which contribute significantly to reduce costs and environmental impact of the process provided.

In a still highly preferred embodiment, the iodination process is carried out directly in the raw aqueous solution which is derived from the industrial process for the preparation of the starting 5-aminoisophthalic substrate, for example, carried out as described in WO 96/37459 , optionally diluted with water and suitably acidified.

Suitable acidic conditions are achieved in the presence of a suitable acid including, for example, phosphoric, methanesulfonic or sulfuric acid, for example 96% H2SO4. Preferably, suitable acidic conditions are obtained using 96% of H2SO4, for example in an amount ranging from about 0.5 to 2 mol and, preferably, from 0.7 to 1.5 mol of H2SO4 per mol of substrate compound (I).

In this context, and in accordance with a preferred embodiment of the invention, the iodation reaction is carried out at a pH (of the reaction mixture) of less than 3.5, preferably comprised of from 1 to 3.0 and, even more preferably, from 1.5 to 2.5, preferably achieved using concentrated H2SO4.

In this regard, it is worth noting that once acidified to this last range with sulfuric acid, the pH of the reaction advantageously self-maintains from 1.5 to 2.5 during the reaction time, while the addition of a base, for example NaOH dilute, it is necessary to maintain the reaction at pH around 3.

Interestingly, due to the fact that the above pH conditions are known to strongly deactivate any electrophilic substitution on aniline substrates, these apparently unfavorable conditions allow to obtain 5-amino-2,4,6-triiodoisophthalic acid with yields very high, and, however, essentially not contaminated by byproducts of partial iodization or colored impurities.

Preferably, at higher pH, for example higher than 4, the desired triiodinated product can be obtained, but with lower yields and purity, so as to require additional purification to achieve the analytical specifications set by the industrially produced intermediary.

When operating under such acidic conditions, the aromatic substrate undergoing triiodination is represented by the 5-aminoisophthalic acid of formula (I), either used as the starting material of the process or, alternatively, formed in situ from the corresponding salt.

The latter, unless provided in the present description, is preferably selected from the alkaline earth metal salts or alkalies of 5-aminoisophthalic acid as such, for example, sodium, lithium, potassium, calcium or magnesium salts.

Particularly preferred, among them, is the sodium salt of 5-aminoisophthalic acid, which can be used as such, that is, as a pure compound or, alternatively, comprised within a crude solution that is derived directly from a previous step in the process for the preparation of triiodinated contrast agents, for example yopamidol.

Interestingly, in accordance with the above operating conditions, that is, in the presence of an aqueous acidic environment, 5-amino-2, 6-triiodoisophthalic acid is unexpectedly obtained in high yields and purity due to practical insolubility of the starting aromatic substrate to be iodinated.

When the 5-aminoisophthalic acid is used as the starting material, in effect, an appropriate amount of this substrate compound is first suspended and thus maintained in the reaction medium before the iodation reaction step takes place. Alternatively, when a aqueous solution of the corresponding salt is used, for example, starting from the industrial aqueous solution of the corresponding sodium salt, the acidic environment is such as to promote the precipitation of the insoluble acid of formula (I) which is kept in suspension in accordance with conventional, for example, under magnetic or mechanical agitation.

The same is true for iodine, which is charged as a solid in the suspension of the isophthalic substrate, appropriately acidified as such.

In this regard, the appropriate amount of the yodic acid can then be added to the suspension obtained once or, alternatively, gradually, either continuously with time or in the form of a portion in accordance with conventional means, thereby causing solubilization partial phase of the 5-aminoisophthalic substrate which is thus completely converted to the desired triiodinated product.

More particularly, and in accordance with the following experimental section, the iodic acid can be added rapidly, for example, in a few minutes or even at the same time, to a more slightly acidified reaction suspension, for example at pH > 2.5, that is, around 3. Preferably, when operating under acidic conditions stronger, that is, at a pH of about 2 or even lower, slow additions of the iodic acid are preferred, which can be carried out over time, for example in a time of up to 6 hours, and preferably, in a time of 2 hours. up to 6 hours.

In this aspect, an aqueous solution of the oxidizing agent can be used profitably, with a concentration varying, for example, from 8 to 50% (w / w).

The iodination reaction is carried out at a temperature ranging from 50 ° C to 85 ° C.

For example, in one option, the reaction temperature during the process can be kept constant at a value comprised from about 60 ° C to 85 ° C and, preferably, from about 65 ° C to 80 ° C, operating in accordance with methods conventional Alternatively, all reagents can be charged at room temperature in this manner to give a mixture that is then heated to a temperature ranging from 65 to 80 ° C, or, again, the iodination agents (I2 and HIO3) can be added to a suspension heated to about 45 ° C and then to raise and maintain the reaction temperature from 65 ° C to 80 ° C, as for the next experimental section.

The reaction time may vary according to with the selected operating conditions and, in general, may vary from about 2 to about 10 hours, more preferably from 5 to 8 hours.

Typically, by working at the temperatures given above, the process can reach the boiling point of the solvent, particularly when using lower boiling solvents, such as methanol. In addition, partial sublimation of iodine could also occur, even if the sublimated amount remains negligible when the reaction temperature remains within the previous range of values. However, standard condensing equipment or refrigerants may, for example, be used to condense both the solvent and the sublimed iodine which is then recycled to the reaction mixture in accordance with conventional methods, for example by adding small amounts of fresh solvent.

In this regard, it is worth noting that while the use, shown by the aforementioned technique (document US 2007/0219396), of acetic acid as a reaction solvent solves the problem of iodine solubilization, it does not, on the other hand, contribute to increase the solubilization of 5-aminoisophthalic acid, which remains insoluble in acetic acid still heated at 80 ° C. However, disadvantageously, it does not allow simple recovery of the iodization product, that is, 5-amino-2,4,6-triiodoisophthalic acid, which does not precipitate quantitatively from acetic acid, is not yet cooled to room temperature, unless properly diluted with water.

Still further, the solubility of HIO3 in acetic acid is very low. Therefore, when this oxidizing agent is added to an acetic reaction medium not properly diluted with water, as by the conditions shown by the cited technique, it leads to the formation of an inhomogeneous phase which significantly reduces its efficiency in the activation of the iodine, as evidenced by Comparative Example 1 provided, from the following experimental section.

The above disadvantages may not be solved by working under the conditions of iodination of the articles of Chem. Ber, which preferably show the use of an aqueous acidic medium as diluted as it allows, on the one hand, the desired solubilization of the starting substrate but , on the other hand, more likely to contribute to preventing precipitation of the triiodinated compound of the invention, ie 5-amino-2,4,6-triiodoisophthalic acid, which does not precipitate from the crude solution still cooled to room temperature, as is evidenced by Comparative Example 2 provided in the following experimental section.

In addition, the article Cher. Ber. , 1897, 30 (2), 1943-1948 cited, shows the use of an iodination solution prepared separately by solubilization of solid I2 in aqueous KOH (or NaOH), followed by the addition of solid HI03 and subsequent dilution with water.

In this regard, beyond the fact that the article cited does not refer in any way to the volume of the aqueous solution of KOH used or its concentration, it is worth noting that the suggested amount of HI03 used to prepare the iodization mixture is insufficient for retrograde -convert all the iodide ions formed in the iodination reaction. This necessarily implies, on the one hand, the need to use an excess of iodine over the minimum stoichiometric amount required, on the contrary, by the iodination process of the present invention. On the other hand, if it also results in unwanted accumulation of iodine ions in the reaction medium, they can probably affect the purity of the iodization product and its consistency with the analytical specifications for the industrially produced intermediary.

It is clear to a skilled person that alternative iodization systems between those previously reported and comprising molecular iodine in the presence of an oxidizing agent other than iodic acid, for example hydrogen peroxide, and their operating conditions, are also considered to be within the scope of the invention.

From all of the above, it should be clear to a skilled practitioner that the process of the present invention, essentially, comprises: obtaining a suspension of 5-aminoisophthalic acid in an aqueous solvent appropriately acidified, i.e. having a pH lower than 3.5, and add solid I2 and HIO3 to the suspension.

In great detail and in accordance with a practical embodiment of the invention, an appropriate amount of the 5-aminoisophthalic substrate is suspended or solubilized, as the case may be, in an aqueous solvent, typically water. The solution / suspension obtained is first diluted at a substrate concentration ranging from 8% to 3% (w / w) and, preferably, from 5% to 3%, and then acidified to a lower pH of 3.5, preferably around 2 , with an adequate amount of the acid, for example with 96% of H2SO4.

Preferably, a crude solution obtained directly from the industrial process and comprising the 5-aminoisophthalic substrate as the sodium salt (mainly monosodium, although the disodium is not excluded), at a concentration that typically varies around 7-8% (w / w) , it is used as starting material. This crude solution is then diluted, typically with water, to the range of previous concentration and then acidified to the values mentioned above, for example with 96% H2SO4. The solid I2 is then added to the suspension obtained from the 5-aminoisophthalic acid which is kept under stirring and heated to the temperature values indicated above.

An appropriate amount of an aqueous solution of HIO3 is added slowly in the suspension, thereby causing the progressive conversion of the 5-aminoisophthalic substrate into the desired triiodinated product.

Proceeding with the addition of HIO3 to completion, the formed 5-amino-2,4,4, β-triiodoisophthalic acid precipitates from the reaction mixture as a solid. At this point, the acidification of the crude reaction, for example with 96% of H2SO4, at a pH of about 1 and cooling of the mixture at room temperature, promotes near complete precipitation of the triiodinated compound. However, the addition of a minimum amount of sodium bisulfite (to the final crude mixture) makes it possible to definitively destroy any optional residual iodinating agent and obtain an even purer solid product which is filtered and dried.

The filtered compound is pure and easy to be used in the following steps for the preparation of the desired contrast agent without the need for any further purification.

On the other hand, once obtained, the 5-amino-2,4,6-triiodoisophthalic acid of formula (II) can then be easily converted to the desired X-ray contrast agent by working in accordance with known methods.

In this aspect, the process object of the present invention is of general applicability and provides, very advantageously, a route for the preparation of iodinated contrast agents starting from the intermediate 5-amino-2,4,6-triiodoisophthalic acid.

Therefore, a further object of the present invention is a process for the preparation of the following compounds of formula (III) where: R and R 'represent, the same or different from each other, a group selected from carboxy (-COOH), carboxester (-COOR1) and carboxamido (-CONH2, -CONHR1 or -CONR2R3), wherein R1, R2 and R3 are , the same or different from each other, a linear or branched C1-C4 alkyl group optionally substituted by one or more hydroxyl groups, and R4 and R5 are, the same or different from each other, hydrogen or a linear or branched Ci-Cg alkyl group optionally substituted by one or more Cj.-C6 alkoxy or hydroxyl groups, the process comprises the preparation of an intermediate compound of formula (II) through the process of the present invention.

More preferably, the process comprises: a) preparing the 5-amino-2,4,6-triiodoisophthalic acid of formula (II) COOH subjecting to iodination the 5-aminoisophthalic acid of formula (I) or a salt thereof with molecular iodine in the presence of a suitable oxidizing agent; b) converting the compound of formula (II) to the corresponding acid dichloride, and c) using the dichloride as an intermediate compound for the preparation of the desired compounds of formula (III).

In accordance with the process, the iodization stage a) is performed as reported extensively in the previous sections while subsequent steps, completely experimental operating conditions and optional variants thereof, are all being performed in accordance with conventional methods reported in the art and which include, essentially, the conversion of the 5-amino-2,4,6-triiodoisophthalic acid (II) in the corresponding acid dichloride according to known methods, for example in the presence of thionyl chloride; its subsequent condensation with 2- [(acetyloxy)] propionic acid chloride, to thereby give rise to the corresponding 5-carboxamide derivative and, finally, the condensation of the latter with serinol and subsequent development which includes any possible cleavage of protecting groups, for thus obtain the expected final compound.

Preferably, the present process can be applied to the preparation of one of formula (III) in which both R and R 'are a group -CONH-CH (CH2OH) 2, R4 is hydrogen and R5 is a methyl group, commonly known as Yopamidol, or in accordance with an equally preferred embodiment, for the preparation of a compound of formula (III) in which both R and R 'are a -CONH-CH2-CH (OH) CH2OH, R4 is methyl and R5 is hydrogen, commonly known as Yomeprol.

Therefore, an additional object of the present invention relates to a process for the preparation of Yopamidol or Yomeprol which is characterized in that it comprises starting from a compound of formula (II) obtained through the process of the present invention.

In the process, as the preparation of the starting compound of formula (II) is carried out as widely reported above, while subsequent steps, completely from experimental operating conditions and optional variants thereof, are carried out in accordance with conventional methods and operating conditions for example, described in WO 96/037459, WO 96/037460, US 5362905, WO 97/047590 and WO 98/24757, EP0026281.

Additional details that relate to the process of the invention are reported in the following experimental section, with the sole purpose of better illustrating the present invention, without representing any limitation to it.

BRIEF DESCRIPTION OF THE FIGURES FIG 1: HPLC analysis of the iodinated product of the Example 3 FIG. 2: HPLC analysis of the iodinated product of Example 4 FIG. 3: HPLC analysis of the crude solution of the Comparative Example 1, after 3 hours at 22 ° C.

FIG. 4: HPLC analysis of the crude solution of Comparative Example 1, after 3 hours at 22 ° C and an additional 6 hours at 60 ° C.

FIG. 5: HPLC analysis of solid al.

FIG. 6: HPLC analysis of solid a2.

FIG. 7: HPLC analysis of the mother liquors of a2.

FIG. 8: HPLC analysis of the reaction mixture bl.

DETAILED DESCRIPTION OF THE INVENTION EXPERIMENTAL SECTION Characterization of the compound obtained The purity of the 5-amino-2,4,6-triiodoisophthalic acid obtained by HPLC was determined by comparison with a standard (pure compound) or by using benzoic acid as the internal standard.

General procedure Chromatographic method by HPLC Stationary phase: Zorbax SB-Phenyl 80 A 5 and m, 250 x .6 mra (Agilent Technologies) Mobile Phase: A: 0.015 M NaH2P04 + 0.028 M H3P04 B: CH3CN Elution gradient Gradient table: Temperature: 45 ° C Detection: UV (240 nm) Flow: 1 ml / min Sample concentration: 5 mg / ml Injection: 10 μ? Example 1 A sodium salt solution of 5-aminoisophthalic acid (I) in H2O corresponding to 3.86% (w / w) of the acid was charged to a 250 ml three-necked round bottom flask equipped with a thermometer, condenser and magnetic stirrer. (129.42 g of solution, 27.6 mmol) and acidified to pH at about 1 with 96% H2SO4 (2 mL, 35.3 mmol). Then the solid I2 (8.42 g, 33.2 mmol) was added, the mixture was heated to 72 ° C by means of an oil bath, and was added a solution of HI03 (w / v) at 18.65% in H20 (20 ml, 21.2 mmol) to the mixture heated for 5.2 h through a syringe pump. After an additional 1 h at 72 ° C (total reaction time 6.2 h) the reaction mixture was cooled to room temperature and filtered; the solid was washed with H20 and dried to give 5-amino-2,4,6-triiodoisophthalic acid (II) (12.74 g, 22.8 mmol) as a pale pink solid. Performance 82.6%. The product was analyzed by HPLC, by comparison with a standard, analytical specifications were made for industrially produced 5-amino-2,4,6-triiodoisophthalic acid.

Example 2 In a 250 ml three-necked round bottom flask equipped with thermometer, condenser and magnetic stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) in H20 was added corresponding to 3.86% (w / w) of the acid (129.42 g of solution, 27.6 mmol) and acidified to pH about 1 with 96% H2SO4 (2 mL, 35.3 mmol); then the solid I2 (5.26 g, 21.5 mmol) was added and the mixture was heated to 85 ° C by means of an oil bath. A solution of H202 in H20 at 3.08% (w / v) (25 mL, 22.6 mmol) was slowly added for 8.5 h through a syringe pump; the final additional solid I2 (5.26 g, 21.5 mmol) was added.

Respectively after 0.5h, 2.5h and 6h at 85 ° C three portions of a H202 solution in 7% (w / v) H20 (3 x 10 mL, total 61.7 mmol) were added slowly for 1.7 h each through of a syringe pump. The reaction mixture was maintained at 85 ° C for an additional 1 h then it was cooled to room temperature and filtered; the solid was washed with H20 and dried to give 5-amino-2,4,6-triiodoisophthalic acid (II) (12.41 g, 22.2 mmol) as a pale brown solid. Performance 80.4%. The product was analyzed by HPLC by comparison with a standard and analytical specifications were made for the industrially produced 5-amino-2,4,6-triiodoisophthalic acid.

Example 3 In a 3 L jacketed reactor equipped with a thermometer, condenser and mechanical stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) in H2O corresponding to 6.7% (w / w) of the acid (1194 g of solution) was charged. 0.442 mol), was diluted with H20 (636 ml) and acidified (to pH 2.8) with 50% H2SO (73.63 g, 0.375 mol). The mixture was then heated to 45-50 ° C and added with solid I2 (134.5 g, 0.530 mol). A solution of HI03 in H20 50% (w / w) (93.22 g, 0.265 mol) was added for 15 min, the obtained mixture was heated to 75 ° C and maintained at this temperature for 4 hours, during which the pH of the mixture is self-maintained in the range between 2.5 and 2.2. Then additional 50% H2SO4 (430 g, 2190 mol) was added to the crude suspension in 1.5 h (at a pH <1) and the suspension obtained was cooled to room temperature for 2 h. A solution of sodium bisulfite 18% (w / w) (13.48 g, 0.023 mol) was added under stirring. The solid was then filtered, washed with H2O (200 ml) and dried to give 5-amino-2,4,6-triiodoisophthalic acid (II) (228.9 g, 0.409 mol) as a pale pink solid. Yield 92.6%. The product was analyzed by HPLC by comparison with a standard and the analytical specifications were made for industrial produced 5-amino-2, 6-triiodoisophthalic acid.

Example 4 In a 1.5 L jacketed reactor equipped with thermometer, condenser and mechanical stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) in H2O corresponding to 6.7% (w / w) of the acid was charged (597 g of solution 0.221 mol), was diluted with H20 (318 ml) and acidified with 50% H2SO4 (30.32 g, 0.155 mol). The mixture was heated to 45-50 ° C and I2 (67.26 g, 0.265 mol) was added. A solution of HI03 in 50% H20 (w / w) (46.60 g, 0.132 mol) was added over 15 minutes (pH of the mixture obtained: approx. 3) and the mixture was heated to 75 ° C for 4 h, (during which the pH of the mixture dropped to about 2). Then 50% H2SO4 (222 g, 1.13 mol) was added (at a pH <1) for 2 h and the suspension was cooled down to 25 ° C for 2 h. A solution of sodium bisulfite at 18% (w / w) (5.91 g, 0.010 mol) was added, the mixture was kept under stirring, then the solid was filtered, washed with H20 (150 ml) and dried to give 5-amino-2,4,6-triiodoisophthalic acid (II) (109.8 g, 0.196 mol) as a whitish solid. Yield 88.9%. The product was analyzed by HPLC by comparison with a standard and analytical specifications were made for industrially produced 5-amino-2, 6-triiodoisophthalic acid.

Example 5 In a 1 L jacketed reactor equipped with thermometer, condenser and mechanical stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) in H20 corresponding to 6.7% (w / w) of the acid (373 g of solution) was charged. 0.138 mol), H20 (200 ml), a solution of HI03 in 50% H20 (w / w) (29.12 g, 0.083 mol), 50% H2SO4 (15.71 g, 0.080 mol) and I2 (42.03 g; 0.166 mol) at room temperature. The mixture was heated at 60 ° C for 30 min, acidified with 50% H2SO4 (7.64 g, 0.039 mol), and then heated to 75 ° C for 3 h (pH 1.9). The resulting suspension was then further acidified (to a pH <1) with 50% H2SO4 (120 g, 0.612 mol), slowly added for 2 h, and cooled down to 25 ° C for 2 h. then a solution of 18% sodium bisulfite (w / w) was added, under stirring, to the mixture until a redox potential <; 250 mV. The solid was then filtered, washed with H20 (100 ml) and dried to give 5-amino-2,6,6-triiodoisophthalic acid (II) (64.61 g, 0.116 mol) as an off-white solid. Performance 83.8%. The product was analyzed by HPLC by comparison with a standard and analytical specifications were made for industrially produced 5-amino-2, 6-triiodoisophthalic acid.

Example 6 In a 1 L jacketed reactor equipped with a thermometer, condenser and mechanical stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) was charged to H20 corresponding to 7.2% (w / w) of the acid (277.7 g of solution 0.110 mol), was diluted with H20 (220 ml) and acidified with 96% H2SO4 (8.8 ml, 0.159 mol). Ethanol (73 ml) and I2 (33.6 g, 0.132 mol) were then added. The mixture was heated to 80-82 ° C and a solution of HI03 in H20 at 32.6% (w / w) (35.62 g, 0.066 mol) was added dropwise over 3 h (pH of the mixture: 1.8). The mixture was maintained at the previous temperature for an additional 4 h, then acidified to pH < 1 with 50% H2SO4 (44 ml, 0.314 mol) and cooled down to 25 ° C for 2 h. Sodium bisulfite (0.820 g, 4.31 mmol) was added under stirring, then the solid was filtered, washed with ¾0 (100 mL) and dried to give 5-amino-2,4,6-triiodoisophthalic acid (51.36 g; 0.092 mol) as a pale pink solid. Performance 83%. The product was analyzed by HPLC by comparison with a standard and analytical specifications were made for the industrially produced 5-amino-2,4,6-triiodoisophthalic acid.

Example 7 In a 1 L jacketed reactor equipped with a thermometer, condenser and mechanical stirrer, a solution of sodium salt of 5-aminoisophthalic acid (I) was charged to H20 corresponding to 6.7% (w / w) of the acid (313.1 g of solution 0.138 mol), was diluted with H20 (200 ml) and acidified with 50% H2SO4 (41.15 g, 0.210 mol). Then solid I2 (42.03 g, 0.166 mol) was added at room temperature and the obtained mixture was then heated to 75 ° C. A solution of HI03 in H20 0.66 M (140.0 g, 0.0833 mol) was added dropwise over 1 hour and the resulting mixture was kept under stirring at 75 ° C for an additional 4 hours. During the entire heating ramp, the addition of HI03 and after the time of completion (4 hours) the pH of the reaction mixture was maintained at 3.0 by the addition of NaOH 2. The suspension was finally acidified to pH = 1 with 50% H2SO4 (143 g, 0.729 mol), slowly added for 1.5 h, cooled to 25 ° C for 2 hours. A solution of 18% sodium bisulfite (w / w) was added to a redox potential of the suspension < that 250 mV. The solid was then filtered, washed with H20 (100 mL) and dried to give 5-amino-2,4,4-β-triiodoisophthalic acid (II) (66.0 g, 0.118 mol). Performance 85%. The product was analyzed by HPLC by comparison with a standard and analytical specifications were made for industrially produced 5-amino-2, 6-triiodoisophthalic acid.

Comparative Example 1 This test was conducted to evaluate the exploitability of the iodization conditions described in US 2007/0219396, suitably adapted in the amount of the iodinating agent, to provide a triiodinated derivative.

In a 25 ml three-necked round bottom flask equipped with thermometer, condenser and magnetic stirrer, solid 5-aminoisophthalic acid (I) (1 g, 5.5 mmol), solid I2 (1.61 g, 6.34 mmol) and acid were added. acetic acid (15 ml), and stirred at 22 ° C. Then a solution of HIO3 was added in H20 at 70% (w / w) (0.96g, 3.8 mmol) for 0.5 h.

In this regard, it is worth noting that due to the very low solubility of the yodic acid in acetic acid, the addition of the oxidizing agent at the concentration shown by the cited technique, ie 70% w / w, leads to an inhomogeneous mixture . The obtained mixture was kept at this temperature for 3 hours and then analyzed by HPLC. The chromatogram obtained (FIG. 3) shows the total absence of any detectable conversion to an iodinated compound.

For exploration purpose only, nor is it suggested by the cited application, the reaction mixture was then heated at 60 ° C for an additional 6 hours (total reaction time 9 h). The dark mixture obtained was then cooled to room temperature, without providing any crystallization or precipitation of 5-amino-2,4,6-triiodoisophthalic acid (II).

The mixture was then analyzed by HPLC and the results, shown in Figure 4, indicate the presence of a very small amount of triiodinated derivative, and conversely, of a significant amount of an impurity identified as N-acetyl-5-aminoisophthalic acid of formula Comparative Example 2 This comparative example was made to test the iodization conditions described by the previous article of Chem. Ber., Especially by the article Chem, Ser., 1897 30 (2), 1943-1948, which provides some more experimental details that allow testing Its reproduction.

Therefore, the iodization conditions shown by the cited technique were first tested on the same substrate, ie 3-aminobenzoic acid and using the described amount of iodination agents, ie, the stoichiometric amount required for a hypothetically exhaustive diiodination of the composed of substrate.

In this regard, however, it is worth noting that the molar ratio of I2: HIC > 3 used and shown by the cited technique, ie 2.8, is not appropriate for the complete transfer of aggregated iodine (considered as the sum of I2 and HIO3) to the aromatic substrate. In fact, and as previously mentioned, to have a complete transfer, the molar ratio between iodine and iodic acid must be 2 (theoretical proportion) or less.

Just to get a better idea of the iodization conditions used, the reaction pH has also been verified at different reaction times. to. Iodination of 3-aminobenzoic acid The iodination solution was prepared by dissolving I2 (4 g, 15.74 mmol) in 20% aqueous KOH (9.5 ml) to give a suspension of a white solid in a pale yellow solution, which became a clear solution when diluted with H20 (30 ml); then a solution of HI03 (1 g, 5.69 mmol) in H20 (10 mL) was added and the final dark solution was diluted to 250 mL with H2O.

The solution thus obtained was added dropwise over 3 hours to an acidic solution of 3-aminobenzoic acid (2.5 g, 18.23 mmol) in a mixture of H20 (500 ml) and 36-38% aqueous HC1 (pH of the solution: around 0) was heated to 30 ° C. Once the addition was complete (pH 0.25), a solid initiated crystallization. The reaction mixture was then stirred at room temperature for 12 hours, then the solid was filtered, washed with H20 (15 mL), and dried to give a brownish solid (2.3 g). In line with the description, the additional iodination solution, prepared as described above (125 ml, I2 7.87 mmol, HI03 2.85 mmol) was added by dripping for 2 hours to the mother liquor keeping it at approximately 30 ° C, thus favoring precipitation from another solid. After 12 hours at room temperature this solid was filtered, washed with H20 and dried to give a brownish solid a2 (2.2 g). 1 HPLC analysis of the two solids obtained, (Figure 5 and 6, respectively) shows that both precipitates correspond to a mixture of two contained species, in both cases, with different proportion of HPLC area in%, as reported in the back table.

Table 1 By comparing the integrals of the 1H-NiyiR spectrum of the two solids with the relative abundance of HPLC of the two species, the component can be identified in t.r. 25.1 minutes as one of the three possible derivatives of diiodo and the component a t.r. 25.4 minutes as the derivative of triiodide.

On the other hand, the HPLC analysis of the mother liquor showed that the unreacted 3-aminobenzoic substrate is still present in the liquor together with the component a t.r. 25.1 minutes and three unknown species, (figure 7) thus confirming that the iodization conversion was different from the complete one (the yield of the obtained triiodide derivative can be hardly evaluated as approximately 30% of the theoretical) and the obtained product is different from the pure one. b. Iodization of 5-aminoisophthalic acid These same, appropriately adapted iodization conditions can provide the desired triiodinated compound, then they were tested on the substrate compound of the present invention.

Therefore, an iodination solution was prepared as described above (114 ml, I2 7.18 mmol, HI03 2.55 mmol) and added dropwise to an acidic solution of 5-aminoisophthalic acid (I) (1 g, 5.52 mmol) in a mixture of H20 (150 ml) and 36-38% aqueous HC1 (15 ml) (pH about 0) was heated to 30 ° C. In line with the teaching of the prior art, the mixture was kept under agitation at 30 ° C for 19 hours without observing any crystallization or precipitation. The mixture (pH 0.33) was cooled to room temperature and analyzed by HPLC. The observed results, reported in Figure 8, confirmed that the conversion of the starting material was different than the complete one and a significant amount of the starting substrate is still present in the crude solution.

A quantification of 5-amino-2,4,6-triiodoisophthalic acid prepared against an internal standard indicated a yield of 28.2%.

Claims (17)

NOVELTY OF THE INVENTION Having described the present is considered as a novelty, and therefore, the content of the following is claimed as property: CLAIMS

1. A process for the preparation of 5-amino-2,, β-triiodoisophthalic acid of formula (II) characterized in that it comprises the iodination of the 5-aminoisophthalic acid of formula (I) or a salt thereof with molecular iodine in the presence of an oxidizing agent.

2. The process in accordance with the claim 1, characterized in that the oxidizing agent is selected from the group consisting of: nitric acid, sulfuric acid, iodic acid, sulfur trioxide, hydrogen peroxide and ozone.

3. The process in accordance with the claim 2, characterized in that the oxidizing agent is iodic acid.

4. The process in accordance with the claim 3, characterized in that the molar ratio between molecular iodine and 5-aminoisophthalic substrate (I) is comprised from 1 to 1.3, and the molar ratio iodine to iodic acid is comprised of 1: 0.5 to 1: 0.8.

5. The process in accordance with the claim 4, characterized in that the triiodination of the 5-aminoisophthalic substrate with iodine and iodic acid is carried out using a molar ratio of 5-aminoisophthalic: iodine: iodic acid substrate of 1: 1.2: 0.6.

6. The process according to any of claims 3 to 5, characterized in that it is carried out in a polar solvent and in the presence of an acid selected from phosphoric, methanesulfonic or sulfuric acid.

7. The process in accordance with the claim 6, characterized in that the polar solvent is selected from water or an aqueous solvent, lower alcohols C1-C and hydroalcoholic, mixtures thereof, dioxane, glycols and aqueous mixtures thereof.

8. The process according to claims 6-7, characterized in that the solvent is water or an aqueous solvent.

9. The process according to claim 8, characterized in that it comprises adding molecular I2 and iodic acid to an aqueous suspension of the 5-aminoisophthalic substrate having a lower pH of 3.5.

10. The process according to claim 9, characterized in that the aqueous suspension is obtained by direct acidification of a crude solution of an industrial process comprising 5-aminoisophthalic substrate as the sodium salt.

11. The process according to claims 9-10, characterized in that the pH is comprised from 1 to 3.

12. The process according to any of claims 1-11, characterized in that it is carried out at a temperature comprised between 50 ° C and 85 ° C.

13. The process according to any of claims 1-12, characterized in that the reaction time is comprised between 2 and 10 hours.

14. A process for the preparation of the compounds of formula (III) characterized because: R and R 'represent, the same or different from each other, a group selected from carboxy (-COOH), carboxy ester (-COOR1) and carboxamido (-CONH2, -CONHR1 or -CONR2R3), wherein R1, R2 and R3 are, the same or different from each other, a linear or branched C1-C4 alkyl group optionally substituted by one or more groups hydroxyl, and R4 and R5 are, the same or different from each other, hydrogen or a straight or branched Ci-C6 alkyl group optionally substituted by one or more Ci-C6 alkoxy or hydroxyl groups, the process comprises preparing an intermediate compound of formula (II) in accordance with the process according to any of claims 1-13.

15. The process according to claim 14, characterized in that it is for the preparation of a compound of formula (III) wherein both R and R 'are a group -CONH-CH (CH2OH) 2, R4 is hydrogen and R5 is a group methyl.

16. The process according to claim 14, characterized in that it is for the preparation of a compound of formula (III) in which both R and R 'are a -CONH-CH2-CH (OH) CH2OH, R4 is methyl and R5 is hydrogen.

17. A process for the preparation of Yopamidol or Yomeprol, characterized in that it comprises starting from a compound of formula (II) obtained in accordance with the process of claims 1-13.