Method for producing 2,4,6-triiodoisophthalic acid bisamide

Abstract

The present invention relates to a novel method for preparing 2,4,6-triiodoisophthalic acid bisamide derivatives, which are useful intermediates in the preparation of non-ionic X-ray contrast agents, by amidating the corresponding acyl chloride intermediates in a mixture of specific hydrophilic solvents in the presence of a small amount of water.Furthermore, the present invention relates to the use of such hydrophilic solvents in the preparation of said 2,4,6-triiodoisophthalic acid bisamide intermediates for the preparation of non-ionic X-ray contrast agents.

Description

[Technical field]

[0001] The present invention relates to a novel process for the preparation of 2,4,6-triiodoisophthalic acid bisamide derivatives, which are useful intermediates in the preparation of non-ionic X-ray contrast agents. More specifically, the present invention relates to the amidation reaction of the corresponding acyl dichloride intermediates, which is carried out in a mixture of specific hydrophilic solvents in the presence of small amounts of water. Furthermore, the present invention relates to the use of such hydrophilic solvents in the preparation of said 2,4,6-triiodoisophthalic acid bisamide intermediates for the preparation of non-ionic X-ray contrast agents. [Background technology]

[0002] The present invention relates to the preparation of intermediates useful for the synthesis of non-ionic X-ray contrast agents such as iopamidol, iohexol, iopentol, iodixanol, ioversol, iomeprol and iobitridol, characterized by the presence of a 2,4,6-triiodo-phenyl skeleton (isophthalic acid derivative) bearing two aminocarbonyl moieties at positions 1 and 3 (Lusic, H. et al, Chem. Rev. 2013, 113, 1641-1666).

[0003] The industrial processes currently used for the preparation of these compounds comprise the amidation reaction of the corresponding acyl chloride intermediate in their synthesis. The formation of the amide bond, usually achieved by the reaction of an acyl dichloride with an amine, is one of the most critical steps in the synthetic process for the preparation of such compounds. In fact, such amidation processes involve the reaction of a water-soluble amine (forming the side chain) with a water-insoluble substrate (comprising the triiodized core), making it difficult to select a suitable solvent for the reaction.

[0004] Typically, dipolar aprotic solvents such as DMAC or DMF are used in such transformations to overcome reactivity and solubility issues, as they can solubilize both the lipophilic aryl intermediate and the hydrophilic hydroxyalkylamine.

[0005] However, such solvents have the drawback of being reproductively toxic and are listed as Substances of Very High Concern under the Registration, Evaluation, Authorisation and Restriction of Chemicals Act (REACH), especially when used in large quantities in industrial production. Other aprotic dipolar solvents such as N-methylpyrrolidone (NMP) and N-ethylpyrrolidone (NEP) have been tried in these reactions with good results, but they are also reproductively toxic and therefore not suitable to solve this safety issue. Furthermore, they have very high boiling points, making them difficult to remove at the end of the reaction or from the drug substance.

[0006] Regulatory agencies are calling for the more frequent use of environmentally friendly solvent systems in the pharmaceutical industry. For example, the use of less toxic solvents, such as alcohols, has already been described and proven to be efficient for the above transformations.

[0007] One approach towards the replacement of undesirable polar aprotic solvents involves the use of aqueous micellization techniques, as described for example in Shi M. et al., Org. Process Res. Dev 2020, 24: 1543-1548. This document discloses the reaction of acyl chlorides with amines in a 2 wt% aqueous solution of DL-α-tocopherol methoxypolyethylene glycol succinate (TPGS-750-M) in the presence of a base such as DIPEA. TPGS-750-M is a known surfactant with amphiphilic properties, which allows reactions to proceed in heterogeneous systems, e.g. suspensions and emulsions, taking advantage of the micellar effect, the intrinsic solubility of the partners, and the highly dynamic exchange between bulk water and the lipophilic layer formed by the micelles.

[0008] However, the micellization approach has several limitations, such as the difficulty of removing the surfactant at the end of the reaction, especially for highly water-soluble substances such as iopamidol and other non-ionic X-ray contrast agents.

[0009] Other documents disclose the use of various water-soluble solvents. For example, patent EP1075462 discloses the preparation of 2,4,6-triiodo-1,3-benzenecarboxamide starting from the corresponding acyl dichloride, in which DMAC, the solvent usually used in such reactions, is replaced by a solvent selected from lower alcohols, monoalkyl ether glycols, and cyclic, linear or branched alkyl ethers. For example, examples 6 and 7 describe the preparation of iopamidol, in which 2-methoxyethanol or 3-ethoxyethanol solvents are used to form the corresponding bisamide intermediate, but only in the presence of a very large excess of serinol, which is necessary to suppress the competitive esterification of the chloride with the solvent.

[0010] Patent application CN104098484 discloses that the amidation reaction (step c) of 2,4,6-triiodo-1,3-benzenedicarboxylic acid or acyl chloride or carboxylate intermediate with protected serinol can be carried out under alkaline conditions using a solvent selected from lower alcohols, preferably tert-butanol and sec-butanol, glycol monoalkyl ethers, preferably 2-methoxyethanol, 2-ethoxyethanol, and cyclic, linear or branched alkyl ethers, preferably 1,4-dioxane, diglyme and methyl tert-butyl ether. However, no examples of reactions using such solvents are given, and all exemplified amidations are carried out in conventional DMAC.

[0011] The drawback of such methods is that even solvents such as 2-methoxyethanol and 2-ethoxyethanol feature a similar toxicity profile to DMAC, making them less of an environmentally friendly alternative and unable to solve the above problems. Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, there is a need for an improved process for the bisamidation of 2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride that is safer, economical, uses readily available alternative solvents, and is applicable on an industrial scale with good productivity.

[0013] It has now been found that the above transformations can be easily and efficiently carried out in the presence of low proportions of water and in solvents selected from a subgroup of hydrophilic solvents.

[0014] Hydrotropes are a class of water-soluble compounds with amphiphilic structures that can increase the solubility of hydrophobic substances in water by methods other than solubilization through micellization. In general, hydrotropes consist of a hydrophilic part (like surfactants) and a hydrophobic part, but the latter is generally too small to cause spontaneous self-aggregation and the formation of micelles (Subbarao CV et al, Chem. Eng. Technol. 2012, 35:225-237; Dhapte V. et al, St. Petersburg Polytechnical University Journal: Physics and Mathematics 2015, 1: 424-435).

[0015] One class of such compounds is typified by, for example, monoethers of alkylene glycols which, depending on the length of the alkyl chain, can act as cosolvents, hydrotropes, or surfactants.

[0016] It has now been surprisingly found that some hydrophilic ethers or glycols act as useful and safe solvents for carrying out the reaction of the present invention in the presence of low amounts of water and without the need to add inorganic bases.Furthermore, by using such a group of ethers or glycols, the preparation method of the present invention can effectively overcome the aforementioned problems associated with the presence of DMAC, while at the same time providing the final product with surprising efficiency.

[0017] Indeed, unlike the above synthetic procedures, the preparation method of the present invention provides the 2,4,6-triiodoisophthalic acid bisamide intermediate in good yields by using safer and more easily removable chemicals to minimize the risk of side effects and toxicity to the patient. [Means for solving the problem]

[0018] SUMMARY OF THE PRESENT APPLICATION In a first aspect, the object of the present invention is to provide a method for the preparation of 2,4,6-triiodoisophthalic acid bisamide compounds by reacting the corresponding 2,4,6-triiodoacyl chloride intermediate with a suitable amino alcohol in the presence of a hydrophilic ether or glycol in the presence of low amounts of water. Such compounds are useful intermediates in the synthesis of non-ionic X-ray contrast agents and are prepared according to the present invention by a new method suitable for industrial scale production, which provides a particularly safe, selective and high yielding procedure.

[0019] Surprisingly, it has been found that such reactions can be easily carried out in the presence of water in the range of 0.1% to 15% v / v in mixtures comprising a group of ether or glycol derivatives exhibiting hydrophilic behavior.

[0020] Indeed, these particular solvents, which are miscible with water in all proportions and have an amphiphilic structure, are able to enhance the solubility of hydrophobic substrates in aqueous media without the processing problems associated with micellization.

[0021] It has been found that amounts of water in the range of 0.1% to 15% v / v are sufficient to aid in the solubilization of the reagents, allowing work at mild conditions such as temperatures close to ambient, and low enough to avoid possible hydrolysis problems and the formation of undesirable by-products. In some cases, the process of the invention can be easily carried out in the presence of water as low as 0.1% v / v, or even in the absence of water. Amounts lower than 3% can be expressed as water already present in the reagent bottle, such as water of crystallization or water of hydration, so that no separate water needs to be added to the reactor as a solvent. In such cases, the hydrophilic ether or glycol can be considered to dissolve the reagent without the addition of additional water.

[0022] Since the above hydrophilic solvents are not reproductively toxic, the use of mixtures of any of these solvents with low percentages of water is extremely safe relative to the use of dipolar aprotic solvents such as DMAC to carry out the reactions of the present invention.

[0023] Furthermore, these solvents have relatively low boiling points, and in particular are much more volatile and stable at their boiling points than dipolar aprotic solvents, and therefore can be easily removed from the reaction mixture by direct evaporation (e.g., distillation).

[0024] This advantageously makes the preparation process of the present invention simpler, cheaper and more environmentally friendly, replacing harmful solvents and providing at least 70% yield of the corresponding 2,4,6-triiodoisophthalic acid bisamide derivatives.

[0025] Further, the present invention relates to the use of such mixtures of hydrophilic ethers and glycols, in the presence of water in an amount of 0.1% to 15% v / v, in the preparation of 2,4,6-triiodoisophthalic acid bisamide derivatives useful in the synthesis of non-ionic X-ray contrast agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description of the Invention According to a first aspect, the present invention provides a compound of formula (I) [ka] [In the formula, R is selected from hydrogen, linear or branched C1-C6 alkyl-carbonyl, optionally substituted with -OCOCH3, and 2-(propan-2-yl)-1,3-dioxane-5-carbonyl; R1 is, independently at each occurrence, hydrogen or methyl; and R2 is, independently at each occurrence, -CH(CH2OH)2 or -CH2CH(OH)CH2OH. A method for producing 2,4,6-triiodoisophthalic acid bisamide represented by the following steps: a) Formula (II) [ka]

[0033] wherein R is as defined above. With a substituted 2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride represented by the formula: Formula (III): [ka] [wherein R1 and R2 are as defined above] with an amine represented by wherein the reaction in step a) is carried out in a mixture comprising a solvent selected from hydrophilic ethers and glycols in the presence of water in an amount ranging from 0.1% to 15% v / v, and the molar ratio between the amine of formula (III) and the acyl chloride of formula (II) is 3:1 to 7:1.

[0027] In a preferred embodiment, the solvent in step a) has formula (IV): [ka] [In the formula, R3 is a linear or branched C1-C6 alkyl; R4 is a linear or branched C3-C alkyl group, optionally interrupted by at least one oxygen atom. 10 is alkyl] It is a compound represented by the formula:

[0028] In another preferred embodiment of the present invention, in the definition of the compounds of formula (I), R is hydrogen or [ka] [In the formula, [ka] represents the bond position] represents a group selected from In a more preferred embodiment, in the definition of the compound of formula (I), R represents the group CH3CO-(i) as defined above.

[0029] In another embodiment of the invention, the amine of formula (III) is an amino alcohol selected from 2-amino-1,3-propanediol, 3-amino-1,2-propanediol and 3-(methylamino)propane-1,2-diol.

[0030] According to another embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: b) hydrolyzing the compound of formula (I) and / or removing the protecting groups to obtain a compound of formula (I'): [ka] [In the formula, R1 and R2 are as defined above; R' is selected from linear or branched C1-C6 alkyl-carbonyl, optionally substituted by one or more -OH. and / or obtaining the corresponding compound of formula (I) c) alkylating or amidating a compound of formula (I) or formula (I') to obtain a compound of formula (I''): [ka] [In the formula, R1, R2 and R' are as defined above; R″ is a linear or branched C1-C6 alkyl or C1-C6 alkyl-carbonyl, optionally substituted by one or more —OH and / or —OCH3. A process for obtaining a compound represented by the formula: The present invention relates to a method for producing a composition as defined above, further comprising:

[0031] In another embodiment, two equivalents of a compound of formula (I) are reacted with an alkylating agent to give a compound of formula (I''') [ka] [In the formula, R1, R2 and R' are as defined above; R5 is a linear or branched C1-C6 alkylene group optionally substituted with one or more -OH groups. A dimeric compound represented by the following formula can be obtained.

[0032] If necessary, the compounds of formula (I), (I') and / or (I'') may be purified, for example by reverse phase chromatography or by passage through an ion exchange resin, such as a strongly acidic Amberlite® resin.

[0033] All of the steps described above for preparing the compounds of the present invention can be completed, if necessary and if desired, by, for example, evaporation, filtration, solvent extraction, distillation, chromatography, crystallization, or other manipulations according to methods known to those skilled in the art.

[0034] In the context of the present invention, the expression "hydrophilic ether or glycol" refers in particular to highly polar solvents belonging to the class of hydroxy-alkyl ethers or alkylene glycol hydroxy-alkyl ethers, characterized by high volatility and capable of increasing the solubility of hydrophobic organic molecules that are poorly soluble or insoluble in water or in the aqueous phase of compositions containing them. Such solvents are miscible with water in all proportions and can promote the formation of clear homogeneous solutions. In some cases, especially in the presence of lipophilic compounds forming an oil phase, they can ultimately provide a colloidal dispersion system.

[0035] The terms "C1-C6 alkyl" or "C3-C 10 "Alkyl" refers to a saturated hydrocarbon group containing 1 to 6 or 3 to 10 carbon atoms, respectively, and may be linear or branched. Preferably, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, isohexyl, heptyl and isoheptyl.

[0036] The term "C1-C6 alkyl-carbonyl" refers to a carbonyl group substituted with a linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms. Preferably, a methyl-carbonyl (acetyl) group is used.

[0037] The expression "low proportion of water" means an amount of water of 15% v / v or less relative to the amount of hydrophilic solvent. For example, the amount of water may be between 0.1% and 15% v / v, taking into account that a small amount of water is already contained in the hydrophilic (not anhydrous) solvent as water of crystallization. In such a case, the process can proceed substantially without the addition of further water to the reactor.

[0038] The present invention also includes the stereoisomers, hydrates, solvates, organic or inorganic salts of the compounds of the present invention, preferably of formula (I), including their tautomeric, enantiomeric, diastereomeric and epimeric forms.

[0039] In one embodiment, the present invention relates to the use of a mixture comprising a solvent of general formula (IV) as defined above, as a hydrophilic solvent, in the preparation of a compound of formula (I) according to the preparation process as defined above, in the presence of water in an amount between 0.1% and 15% v / v.

[0040] In a preferred embodiment, the compound of formula (IV) is a solvent selected from 1-methoxy-2-propanol (PGME), 1-ethoxy-2-propanol (PGEE), 1-propoxy-2-propanol (PGPE), 1-butoxy-2-propanol (PnB), 3-methoxy-1-butanol (MeBuOH), propylene glycol butyl ether (PGBE), di(propylene glycol) butyl ether (DPnB), di(propylene glycol) propyl ether (DPnP), 1,3-diethoxy-2-propanol and 1-methoxy-3-butoxy-2-propanol.

[0041] More preferably, the compound of formula (IV) is selected from 1-methoxy-2-propanol (PGME), 1-ethoxy-2-propanol (PGEE), 1-propoxy-2-propanol (PGPE) and propylene glycol butyl ether (PGBE).Even more preferably, the compound of formula (IV) is 1-methoxy-2-propanol (PGME).

[0042] The use of a mixture of the solvent of formula (IV) as defined above with a low proportion of water is extremely safe with respect to the use of dipolar aprotic solvents such as DMAC to carry out the reaction of the present invention, since the above hydrophilic solvents are not reproductively toxic.

[0043] Preferably, the amount of water is 5% to 15% v / v, more preferably 5% to 10% v / v.

[0044] In another embodiment of the invention, the amount of water is 0.1% to 2% v / v. In some embodiments, such an amount of water may be represented by water of crystallization or water of hydration already contained in the hydrophilic solvent.

[0045] Preferably, the reaction of the present invention is carried out in a mixture comprising 1-methoxy-2-propanol and water in an amount of from 0.1% to 2% v / v, more preferably from 0.1% to 0.5% v / v, and it is believed that the reaction in 1-methoxy-2-propanol can be carried out substantially without the addition of further water to the mixture.

[0046] Indeed, it has been surprisingly found that the presence of a low proportion of water (up to 15% v / v) is useful for solubilizing the amine of formula (III), facilitating the reaction and making it possible to reduce the viscosity of the reaction medium whilst maintaining its homogeneity. Conversely, when the amount of water is higher than 15% v / v, such advantages are countered by the formation of some undesirable by-products, for example formed in hydrolysis side reactions.

[0047] In another preferred embodiment, the reaction of step a) is carried out at a temperature below 20° C. Indeed, temperature control, for example by means of an external bath, has been found to be beneficial in order to avoid possible side reactions associated with competitive esterification of the compound of formula (II) with the solvent of formula (IV), particularly when primary alcohols are used, and to prevent thermal decomposition of the compound.

[0048] A further aspect of the invention relates to the use of a compound of formula (I), obtained as above, for the preparation of a non-ionic X-ray contrast agent.

[0049] A preferred embodiment of the present invention is a compound represented by formula (IIa) or (IIb), respectively: [ka] by reacting a compound represented by the formula: Formula (Ia) or (Ib): [ka] wherein the reaction is carried out in a mixture of a compound of formula (IV) as defined above and water in an amount ranging from 0.1% to 15% v / v.

[0050] In a more preferred embodiment, the reaction is carried out in a mixture of 1-methoxy-2-propanol in the presence of water in an amount between 0.1% and 15% v / v, more preferably between 0.1% and 2% v / v.

[0051] The present invention also provides b) hydrolyzing a compound of formula (Ia), or c) amidating a compound of formula (Ib), Formula (V): [ka] A process for obtaining a compound (iopamidol) represented by the formula: The method for producing the above further comprises:

[0052] Step b) can conveniently be carried out by removing the acetyl group of compound (Ia), for example as described in GB 1472050. Step c) can be carried out by amidating the amino group of compound (Ib), for example as described in WO 2015 / 067601.

[0053] Another embodiment of the present invention is a compound of formula (IIc): [ka] with 3-amino-1,2-propanediol to obtain a compound of formula (Ic): [ka] wherein the reaction is carried out in a mixture of a compound of formula (IV) as defined above and water in an amount ranging from 0.1% to 15% v / v.

[0054] In another embodiment, the present invention also provides a compound of formula (VI) (iohexol), (VII) (iodixanol) or (VIII) (iopentol), by alkylating the acetylamino group of compound (Ic): [ka] The method further comprises the step of obtaining a compound represented by the formula: Such alkylation steps can be carried out, for example, as described in US 5,705,692 A, ACS Omega 2018, 3, 7344-7349 and Org. Process Res & Dev 2001, 5, 472-478.

[0055] A further embodiment of the present invention is a compound of formula (IId): [ka] with 3-amino-1,2-propanediol to obtain a compound of formula (Id): [ka] wherein the reaction is carried out in a mixture of a compound of formula (IV) as defined above and water in an amount ranging from 0.1% to 15% v / v.

[0056] In another embodiment, the present invention further comprises the step of alkylating the carbonylamino group of (Id) and removing the acetyl protecting group, e.g., a compound of formula (IX) (iobersol) or (X) (iomeprol): [ka] The present invention provides a process for the preparation of a compound as defined above, Such reactions can be carried out, for example, as described in US Pat. No. 4,396,598A and US Pat. No. 4,352,788A, respectively.

[0057] A further embodiment of the present invention is a compound of formula (IIe): [ka] with 3-(methylamino)propane-1,2-diol to obtain a compound of formula (Ie): [ka] wherein the reaction is carried out in a mixture of a compound of formula (IV) as defined above and water in an amount ranging from 0.1% to 15% v / v.

[0058] In another embodiment, the present invention provides a compound of formula (XI): [ka] The present invention provides a process as defined above, further comprising the step of obtaining a compound represented by the formula: This step can be carried out, for example, as described in US Pat. No. 5,043,152A.

[0059] According to the invention, the amidation reaction of step a) can be carried out in a flask or reactor equipped with a mechanical stirrer and preferably maintained at a given temperature, for example by using a cooling bath or a jacketed reactor. For example, the reaction can be carried out at a temperature below 20°C, preferably between 10°C and 20°C, even more preferably between 15°C and 18°C. Indeed, it has been surprisingly found that at temperatures in the above ranges it is possible to suppress the eventual thermal decomposition of the reactants (e.g. esterification of the acyl chloride of formula (II) with the solvent) and the formation of impurities due to the exothermic heat of the amidation reaction, although the solubility of serinol may be reduced to some extent. In this case, the presence of water in a proportion of 0.1% v / v to 15% v / v has also been found to be useful for solubilizing serinol in the reaction mixture at temperatures below 20°C.

[0060] Depending on the solubility of the starting materials and reagents in the reaction medium, the order of addition of the components can be adjusted in various ways to promote homogeneity and clarity of the mixture. In general, the compound of formula (II) is added in solid form in portions to a solution of the amine (III) in a mixture of compound (IV) and water at 0.1-15% v / v. Alternatively, a solution of the amine (III) dissolved in water may be added dropwise to a solution (or suspension) of compound (II) in a solvent of formula (IV). The dropwise addition can be carried out over a period of 0.5 minutes to 2 hours, while keeping the temperature constant, for example below 20°C.

[0061] Preferably, the concentration of the compound of formula (II) dissolved in the reaction medium is from 0.25 M to 0.75 M, more preferably from 0.4 M to 0.6 M.

[0062] Generally, a molar excess of the amine of formula (III) is added to the reaction. The molar ratio between the amine of formula (III) and the acyl chloride of formula (II) is 3:1 to 7:1. This range has been found to be advantageous for reducing the amount of the amine of formula (III) and the associated costs in the case of scale-up to an industrial plant as much as possible, without compromising the purity of the product. In fact, it has been found that in the absence of a base or a certain excess of the amine of formula (III), undesirable by-products may be generated due to the esterification reaction of the compound of formula (II) with the solvent, competing with the amidation reaction.

[0063] Preferably, the molar ratio between the amine of formula (III) and the acyl chloride of formula (II) is 4:1 to 6:1, more preferably 4.5:1 or 5:1.

[0064] The reaction time is 3 to 20 hours until the conversion is complete, preferably 4 to 6 hours.

[0065] After completion of the reaction, all volatile components are evaporated and the mixture is dissolved in water and purified by elution on an Amberlite IRC-120H column, after which the water is evaporated.

[0066] If necessary, the product may be purified, for example by preparative chromatography. More preferably, the product obtained in step a) is used directly in step b) by addition of water, after removing the solvent by evaporation, without further purification steps.

[0067] Step b) of hydrolyzing the crude product obtained in step a) is generally carried out according to standard methods. Preferably, the hydrolysis is carried out in an aqueous solution of NaOH, preferably in 30% aqueous NaOH solution. The hydrolysis step is preferably carried out at room temperature for 1 hour to 4 hours, preferably 2 hours to 3 hours.

[0068] The alkylation or amidation step c) of the intermediates obtained in step a) or b) is generally carried out according to standard methods.

[0069] Such processes for the preparation of the compounds of the invention may be completed, if necessary and desired, by evaporation, solvent extraction or distillation, filtration, chromatography or other manipulations according to methods known to those skilled in the art.

[0070] The following examples set forth the best experimental conditions for carrying out the manufacturing method of the present invention.

[0071] Experimental Part All compounds of formula (IV) above are commercially available and were purchased from Merck KGaA, except for 1-methoxy-3-butoxy-2-propanol (prepared as described in Leal-Duaso A. et al, Org. Process Res. Dev. 2020, 24 (2): 154-162).

[0072] In the examples below and throughout the specification, the following abbreviations have the following meanings: If not defined, terms have their generally accepted meanings.

[0073] List of Abbreviations TIFF2024545278000022.tif91143

[0074] Analysis method The reaction mixture and the product were analyzed by high performance liquid chromatography (HPLC) using an HPLC system equipped with a UV / VIS detector and an Agilent Zorbax SB-Phenyl (5 μm, 4.6 × 250 mm) column. Method 1: Mobile phase A was water and mobile phase B was acetonitrile. The gradient was held at 0% B for 18 min, then increased from 0% B to 38% B in 22 min, and then increased from 38% B to 50% B in 5 min. UV detection at 240 nm. Flow rate: 1 mL / min. Temperature: 60 °C. The yields reported below were calculated from the peak area % of the HPLC chromatogram.

[0075] Example 1 Preparation of compound (Ia), a synthetic intermediate of iopamidol (V) [ka] An excess of 2-amino-1,3 propanediol (12.8 g; 141 mmol; 5 equiv.) was dissolved in a mixture of PGME and water (13% v / v; 25 mL) and this solution was added slowly to a suspension of 5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (IIa) (20 g; 28.2 mmol; 1 equiv.) in PGME (30 mL) at 20° C. The suspension slowly became a clear homogeneous brown-yellow solution, which was stirred at 20° C. for 10 h and then evaporated. The residue of (Ia) thus obtained was dissolved in water (30 mL), 30% aqueous NaOH (11 mL) was added and the mixture was stirred at 20° C. for 3 hours. The solution was neutralized with concentrated hydrochloric acid and eluted on an Amberlite IR120H resin column. The eluate was evaporated to give Iopamidol (yield 93%). The above procedure was similarly carried out using other solvents of formula (IV) of the present invention or water in various proportions, giving the results shown in Table 1 below in terms of final yield of Iopamidol. [Table 1]

[0076] Example 2 Preparation of compound (Ia) in a mixture of PGME and 0.1% v / v water An excess of 2-amino-1,3-propanediol (17.3 g; 190 mmol; 4.5 equiv.) was dissolved in a mixture of PGME and 0.1% v / v water (57 mL) at 60° C., the solution was cooled to 20° C. and slowly added to a suspension of S-5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride (IIa) (30 g; 42.3 mmol) at 20° C. over 2 h. The mixture was stirred at 20° C. for 5 h and then filtered to separate the resulting white precipitate of 2-amino-1,3-propanediol hydrochloride. The filtrate was added with 30% aqueous NaOH (30 g) and stirred for 2 h to obtain an emulsion. The solution was neutralized with hydrochloric acid, filtered to remove NaCl, and evaporated. The residue was dissolved in water and eluted on an Amberlite IR120H resin column. The eluate was evaporated to give iopamidol (yield 92%).

[0077] Example 3 Preparation of compound (Ib) [ka] In a jacketed reactor (T=18°C), 5-amino-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (10.00 g, 16.73 mmol) was dispersed in PGME (22 mL) while stirring with a magnetic stirrer. 2-amino-1,3 propanediol (6.865, 75.29 mmol) was dissolved in a solution of PGME (11 mL) and water (0.33 mL) while heating on a plate at 60°C. This solution was added dropwise to the reaction mixture over 60 min. At the end of the addition, the mixture was in solution and precipitation of a grey solid corresponding to 2-amino-1,3 propanediol chlorohydrate was observed. The reaction was monitored by TLC (BuOH, AcOH, H2O, 7:2:1). After 5 h the conversion was complete. The crude mixture was filtered through a fritted disk funnel and washed with 10 mL of PGME. The solvent was removed under reduced pressure, and the resulting solid was sonicated in 75 mL of water and triturated with a rotor-stator homogenizer. After filtration through a Büchner funnel, the product was obtained as a white solid (9.76 g, mass recovery: 83%, HPLC area %: 92%).

[0078] Example 4 Preparation of compound (Ic) [ka] 5-(Acetylamino)-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (30.00 g, 47.04 mmol) was suspended in 26 mL of PGME in a jacketed reactor with mechanical stirring. A solution of 3-amino-1,2-propanediol (18.86 g, 207 mmol) in 60 mL of PGME was added dropwise over 2 h. The mixture was stirred with a mechanical stirrer for 24 h. 200 mL of water was added and the suspension was filtered through a fritted disc funnel. The resulting white solid was washed with 50 mL of water and dried under vacuum at 50° C. overnight (35.10 g, mass recovery: 79%, HPLC area %: 96%).

[0079] Example 5 Preparation of compound (Id) [ka] 5-Amino-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (5.957 g, 10.00 mmol) was dispersed in 6.7 mL of DMAC in a round bottom flask equipped with a CaCl2 valve cooled at 0° C. with magnetic stirring. A solution of acetoxyacetyl chloride (2.090 g, 15.30 mmol) in 13.5 mL of DMAC was added dropwise to the reaction flask. After 2 hours, the cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was poured into 80 mL of deionized water, forming a grey solid, which was filtered and washed with 10 mL of water. The product (6.857 g, 98.55%) was dried in vacuum at 40° C. overnight. [ka] In a two-necked round-bottom flask, the acyl chloride (13.91 g, 19.99 mmol) was dispersed in 12.5 mL of PGME while stirring with a mechanical stirrer. The flask was kept at 18° C. with a cooling water bath. A solution of 8.010 g of 3-amino-1,2-propanediol in 26 mL of PGME was poured into the reaction flask over a period of 60 min. The reaction was complete in 18 h as monitored by TLC.

[0080] References 1. Lusic, H. et al, Chem. Rev. 2013, 113, 1641-1666 2. Shi M. et al., Org. Process Res. Dev 2020, 24: 1543-1548 3. EP 1075462 4. CN104098484 5. Subbarao CV et al, Chem. Eng. Technol. 2012, 35:225-237 6. Dhapte V. et al, St. Petersburg Polytechnical University Journal: Physics and Mathematics 2015,1: 424-435 7. GB1472050 8. WO2015 / 067601 9. US 5,705,692 A 10. ACS Omega 2018, 3, 7344-7349 11. Org. Process Res & Dev 2001, 5, 472-478 12. US 4,396,598 A 13. US 4,352,788 A 14. US 5,043,152 A 15. Leal-Duaso A. et al, Org. Process Res. Dev. 2020, 24(2): 154-162

Claims

1. Formula (I) 【Chemical 1】 [In the formula, R is hydrogen, optionally -OCOCH ３ Linear or branched C substituted with １ -C ６ alkyl-carbonyl, and 2-(propan-2-yl)-1,3-dioxane-5-carbonyl; R １ are each independently hydrogen or methyl; and R ２ are each independently —CH(CH ２ OH) ２ or -CH ２ CH(OH)CH ２ OH] A method for producing 2,4,6-triiodoisophthalic acid bisamide represented by the following steps: a) Formula (II) 【Chemistry 2】 wherein R is as defined above. a substituted 2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride represented by Formula (III): 【Chemistry 3】 [In the formula, R １ and R ２ is as defined above] reacting with an amine represented by wherein the reaction of step a) is carried out in a mixture comprising a solvent selected from hydrophilic ethers and glycols in the presence of water in an amount of 0.1% to 15% v / v, and the molar ratio between the amine of formula (III) and the acyl chloride of formula (II) is 3:1 to 7:

1.

2. The solvent is a compound represented by formula (IV): 【Chemistry 4】 [In the formula, R ３ is a linear or branched C １ -C ６ is alkyl; R ４ is a linear or branched C optionally interrupted by at least one oxygen atom ３ -C １０ alkyl] The method according to claim 1, wherein the compound is represented by the formula:

3. R is hydrogen or 【Chemistry 5】 The method according to claim 1 or 2, wherein the group is selected from the group consisting of

4. R is CH ３ The method according to claim 3, wherein the compound is CO-(i).

5. 3. The process according to claim 2, wherein the compound of formula (IV) is in a solvent selected from 1-methoxy-2-propanol, 1-ethoxy-2-propanol, 1-propoxy-2-propanol, 1-butoxy-2-propanol, 3-methoxy-1-butanol, propylene glycol butyl ether, di(propylene glycol) butyl ether, di(propylene glycol) propyl ether, 1,3-diethoxy-2-propanol, and 1-methoxy-3-butoxy-2-propanol.

6. The method according to claim 5, wherein the compound of formula (IV) is 1-methoxy-2-propanol.

7. The process according to claim 1 or 2, wherein the amount of water in the mixture of step a) is between 5% and 15% v / v.

8. The method of claim 1 or 2, wherein the mixture of step a) comprises 1-methoxy-2-propanol and water in an amount of 0.1% to 2% v / v.

9. 2. The process according to claim 1, wherein the amine of formula (III) is an amino alcohol selected from 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, and 3-(methylamino)propane-1,2-diol.

10. 2. The process of claim 1, wherein step a) is carried out at a temperature of from 10°C to 20°C.

11. 11. The process of claim 10, wherein step a) is carried out at a temperature of 15°C to 18°C.

12. The method according to claim 1, wherein the concentration of the compound of formula (II) is 0.25M to 0.75M.

13. 2. The process according to claim 1, wherein the molar ratio between the amine of formula (III) and the acyl chloride of formula (II) is 4:1 to 6:

1.

14. The following steps: b) hydrolyzing the compound of formula (I) and / or removing the protecting groups to obtain a compound of formula (I'): 【Chemistry 6】 [In the formula, R １ and R ２ is as defined above, R' is a linear or branched C optionally substituted by one or more -OH. １ -C ６ alkyl-carbonyl] and / or obtaining the corresponding compound of formula c) alkylating or amidating a compound of formula (I) or formula (I') to obtain a compound of formula (I''): 【Chemistry 7】 [In the formula, R １ , R ２ and R' is as defined above; R'' optionally contains one or more -OH and / or -OCH ３ Linear or branched C substituted by １ -C ６ Alkyl or C １ -C ６ alkyl-carbonyl] A process for obtaining a compound represented by the formula: The method of claim 1 further comprising:

15. 10. Use of a mixture comprising a solvent of formula (IV) as defined in claim 2 and water in an amount of 0.1% to 15% v / v as a hydrophilic solvent in the preparation of a compound of formula (I) as defined in claim 1.

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