Synthesis of non-ionic radiographic contrast agents by reactive extrusion

Abstract

The invention relates to the industrial preparation of non-ionic X-ray contrast agents. In particular, the present invention relates to a process for the synthesis of iopamidol using a continuous reactive extrusion process which enables efficient conversion of the relevant key intermediates, preferably in the absence of any solvent. The invention also relates to the preparation of radiographic X-ray contrast agents or key intermediates thereof by using reactive extrusion techniques.

Description

[0001] Invention Field

[0002] This invention relates to the industrial preparation of nonionic X-ray contrast agents. In particular, this invention relates to a method for synthesizing iopamidol using a continuous reactive extrusion process, which efficiently converts key intermediates, preferably in the absence of any solvent. This invention also relates to the preparation of radiographic X-ray contrast agents or key intermediates thereof using reactive extrusion technology. Background of the Invention

[0004] Iodinated contrast agents are well-known compounds widely used in X-ray imaging diagnostic techniques. Among these compounds, SN... 1 N 3 bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-1-oxopropyl]-amino]-2,4,6-triiodo-1,3-phenylenediamide (iophanate-methyl) is a radiographic contrast agent widely used in routine X-ray diagnostic research (The Merck Index, RSC Publishing, 15). th Ed., 2013, 940-941; Lusic, H. et al., Chem.Rev. 2013, 113, 1641-1666). This compound can be prepared using synthetic procedures known since the 1980s and disclosed, for example, in GB 1,472,050. The industrial synthesis of iopamidol is also shown in Scheme 1 below and described, for example, in US 4,001,323.

[0005] Option 1

[0006]

[0007] Currently, industrial methods for manufacturing iopamidol involve the amidation reaction of S-5-[[2-(acetoxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzoyl chloride (IV) with 2-amino-1,3-propanediol (commonly known as serine, V) to obtain acetylioopamidol (VI), which is further hydrolyzed to obtain iopamidol. Such reactions are typically carried out in dipolar aprotic solvents (e.g., N,N- two Methylacetamide (DMAC) or N,N- two The process is carried out in methylformamide (DMF), which represents the best solution for dissolving both the lipophilic aryl intermediate (IV) and the hydrophilic hydroxy-alkylamine (V), thereby promoting their interaction.

[0008] However, such solvents have drawbacks, including reproductive toxicity and being designated as Substances of Very High Concern (SHC) under the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulations, especially when used in large volumes in industrial production. Regulatory agencies are increasingly inviting the use of sustainable and environmentally friendly solutions in chemical reactions within the pharmaceutical industry and are making significant efforts in this direction, particularly aimed at reducing or eliminating hazardous substances. Furthermore, avoiding the use of toxic solvents not only reduces potential hazards but also lowers the overall cost of the process, including costs associated with waste disposal.

[0009] Other aprotic dipolar solvents, such as N-methylpyrrolidone (NMP) or N-ethylpyrrolidone (NEP), have shown good results in these reactions (see, for example, GB 2,311,524), but also exhibit reproductive toxicity and are therefore unsuitable for addressing this safety concern. Furthermore, they exhibit higher boiling points and are difficult to remove from the product at the end of the reaction and from the drug substance, especially in industrial-scale methods.

[0010] An alternative to undesirable polar aprotic solvents has been described, for example, in WO00 / 15602, which discloses a method for preparing acetyliopalatine by reacting compound (IV) with serine (V) under heating and in the absence of any solvent and any base. However, to obtain a good conversion, it is necessary to use a very high excess of serine, with a molar ratio between serine (V) and compound (IV) ranging from 6 to 25.

[0011] Alternatively, a mechanochemical approach is considered, which typically involves grinding two or more solid reagents together to initiate a chemical reaction. WO2018 / 104228 reports a relevant example, disclosing a mechanochemical method that utilizes the mechanical crushing of specific reactants to produce key intermediates (such as compound (VI)) for radiographic contrast agents, without providing any external heating and with substantially no added solvent.

[0012] However, this method has limited scalability, particularly for safety reasons. In fact, the use of large ball mills, suitable for processing large quantities (e.g., kilograms) of products for industrial manufacturing, has never been proven for chemical synthesis. Furthermore, mechanochemical methods can only be carried out in batch mode, and in some cases, they can suffer from limited temperature control.

[0013] Therefore, there is a growing need for more sustainable methods for the preparation of iopamidol and its intermediates, providing safer and more effective alternatives to the use of toxic solvents, which should also be applicable to industrial scale with good productivity results.

[0014] Recently, there has been a strong industrial interest in the application of reactive extrusion technology in compound manufacturing, which offers a solvent-free, continuous and scalable approach as a potentially effective alternative to traditional chemical methods or other methods that utilize mechanical means (e.g., by grinding and crushing pure reactants).

[0015] Reactive extrusion (REX) is a well-known technology that refers to a series of continuous processing techniques that combine conventional chemical methods (synthesis and / or modification, typically of polymer materials) with extrusion (pushing material through a die by applying compression and shear forces) into a single process carried out on an extruder.

[0016] A typical continuous extrusion line consists at least of a feeder (volume or gravimetric feeding system) and a barrel, in which material is intensely mixed and forced through a confined space. Such a barrel can be heated and may contain one or more screws that transport the material along the interior of the barrel and subject it to shear and mixing forces before exiting. Several extrusion parameters are typically tuned to optimize the process, including screw speed, screw profile, feed rate, residence time, and temperature. Extruders can also be integrated into continuous manufacturing processes, either as part of a processing line or as the entire line itself.

[0017] Reactive extrusion can be scaled up to several tons of product per hour, allowing reactions to proceed with little or no solvent. Therefore, extrusion technology has been applied across several industries, including food, polymer, and pharmaceutical manufacturing (primarily in pharmaceutical formulations). Most applications of reactive extrusion technology have been described in the production of high molecular weight polymers, such as the manufacture of chemically modified natural macromolecules or synthetic polymers.

[0018] Conversely, extrusion has not been widely applied to the preparation of active pharmaceutical ingredients (APIs). In fact, only recently has the use of extrusion technology been explored in other areas, such as the synthesis of organic compounds via reactions like Knoevenagel condensation, Michael addition, and aldol condensation, typically without the need for post-synthetic separation or additional purification. Examples of these methods are reported in Crawford DE et al, Green Chem., 2017, 19, 1507 and Crawford DE et al, Chem. Commun. 2017, 53, 13067-13070.

[0019] The amidation reactions of the active pharmaceutical ingredients teriflunomide and moclobemide synthesized by reactive extrusion are described in Lavayssiere M. et al, Chem. Commun. 2023, 59, 3439-3442, using a vertical conical extruder. The amidation reactions of these compounds were carried out in batches using a recycling system and coupling agents such as CDI, EDC.HCl, and COMU in the presence of liquid additives and preferably a base.

[0020] Examples of the public use of extruders for continuous organic chemical reactions are illustrated by the following patents: US5,859,269, which describes a method for the continuous production of monocarboxylic acids from a corresponding alcohol, wherein the oxidation reaction is carried out continuously in an extrusion reactor; US5,859,263, which describes a continuous method for the preparation of levulinic acid from starch in a reactive extrusion process; and US9,453,107, which describes the preparation of polyamides from selected monomers, which are introduced into the extruder without any pretreatment.

[0021] Despite the aforementioned disclosures, further development is needed to evaluate the potential applications of reactive extrusion for the continuous preparation of various classes of organic products and intermediates. Indeed, each molecule can exhibit different characteristics in terms of reactivity, solubility, temperature- and pressure-based states of matter (solid, liquid, gas), rheological behavior, and viscosity, making it necessary to optimize specific operating conditions (e.g., temperature and / or screw speed) for different compounds and reaction types. Furthermore, from an industrial perspective, scaling up reactions is not always feasible and straightforward, for example, due to the design and cost of the necessary equipment.

[0022] Surprisingly, reactive extrusion processes have been found to be effective for the preparation of radiographic contrast agents (e.g., iopamidol), particularly for the continuous amidation of the compound (IV) described above with serine (V). According to the invention, compounds (IV) and (V) are used as the sole reactants, continuously fed and mixed in the reaction chamber of an extruder, thereby interacting while being conveyed to the outlet of the reaction chamber itself to provide an intermediate, acetyl-iopamidol (VI), partially mixed with iopamidol, which can then be hydrolyzed to provide the final product, iopamidol.

[0023] It has also been found that the method of the present invention is scalable and applicable to the industrial manufacture of iopamidol, and more generally, to the industrial manufacture of radiographic contrast agents. Invention Overview

[0025] This invention generally relates to the industrial preparation of the nonionic X-ray contrast agent iopamidol, providing a sustainable method that avoids the use of toxic and high-boiling-point solvents. In particular, according to the invention, iopamidol can be obtained through a continuous process utilizing reactive extrusion technology for the interaction and transformation of its key intermediates.

[0026] In fact, it has been unexpectedly discovered that, according to the present invention, the extrusion processing of a slurry comprising S-5-[[2-(acetoxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzoyl chloride (IV) mixed with 2-amino-1,3-propanediol (V) provides a very efficient method for producing iopamidol without the use of any harmful solvents, because the reactive extrusion of the present invention is carried out continuously by directly feeding reactants (IV) and (V) into a suitable extruder.

[0027] Therefore, in one aspect, the present invention relates to a novel continuous method for manufacturing the radiographic agent iopamidol, according to embodiment 2, wherein the method utilizes reactive extrusion technology to amidate S-5-[[2-(acetoxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzoyl chloride (IV) with 2-amino-1,3-propanediol (V), to obtain an intermediate acetyl-iopamidol (VI) mixed with a certain amount of iopamidol:

[0028] Option 2

[0029]

[0030] The remaining intermediate (VI) was then completely converted into the final radiographic agent, iopamidol, by hydrolysis of the acetyl group under alkaline aqueous conditions.

[0031] Compared to the methods described in the prior art, the extrusion method (step a) of the present invention has the advantage that the method is continuous, requires fewer steps and has a reduced reaction time, and is more sustainable and economical because it is essentially solvent-free.

[0032] In particular, the method of the present invention allows for the efficient production of the final product, iopamidol, without the use of any toxic substances (such as solvents DMAC or DMF, which are strictly restricted by the REACH Directive). In fact, the method of the present invention can provide up to 96% conversion of compound (IV) and a final yield of over 70% of iopamidol after hydrolysis within a very short reaction time.

[0033] Furthermore, the method of the present invention has universal applicability and provides a synthetic method that can generally be used to prepare radiographic contrast agents and / or their related key intermediates.

[0034] Another object of the present invention is to provide a continuous method for preparing iopamidol by reactive extrusion, wherein excess serine (V) contained in the extrusion stream is recovered and recycled in the method. Brief description of the attached diagram

[0036] Those skilled in the art can better understand the purpose and advantages of the present invention by referring to the accompanying drawings, in which:

[0037] Figure 1 A schematic diagram of a reactive extruder equipped with a screw and an inlet section according to a preferred embodiment of the invention is shown.

[0038] Figure 2 A schematic diagram of a reactive extruder equipped with two screws rotating in the same direction and two inlet sections according to another preferred embodiment of the invention is shown. Invention Details

[0040] In one aspect, the present invention relates to a method for preparing N 1 N 3 A method for bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-1-oxopropyl]amino]-2,4,6-triiodo-1,3-phenylenediamide (iophanate-methyl), the method comprising the following steps:

[0041] a) S-5-[[2-(acetoxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzoyl chloride (IV) is mixed with 2-amino-1,3-propanediol (V) and reacted to obtain a mixture of intermediate acetyl-iophanate-methyl (VI) and iopamidol.

[0042] ;

[0043] b) The resulting mixture was treated under alkaline aqueous conditions by promoting the removal of acetyl groups from the intermediate acetyl-iophanate-methyl (VI).

[0044]

[0045] Step a) of the method is carried out continuously in a reactive extruder.

[0046] Preferably, the reaction in step a) is carried out at a temperature in the range of 40°C to 150°C. More preferably, the temperature is in the range of 55°C to 90°C.

[0047] In a preferred embodiment, the residence time of compounds (IV) and (V) in the reactive extruder is less than 15 minutes. More preferably, the residence time is 3 to 10 minutes.

[0048] The molar ratio between compound (V) and compound (IV) is preferably 3 to 15. More preferably, the molar ratio is 3 to 8.

[0049] More specifically, step a) of the method defined above is carried out in a reactive extruder comprising at least one inlet section (A) and a reaction chamber (B), and includes the following steps:

[0050] i. Continuously feed compounds (IV) and (V) into at least one inlet section (A) of the reactive extruder;

[0051] ii. While mixing and delivering reactant compounds (IV) and (V), the reaction chamber (B) is heated to form a product stream containing a mixture of acetyl-iophanol (VI) and iopamidol;

[0052] iii. Collect the product stream at the outlet section (C) of the reactive extruder.

[0053] In another aspect, the present invention provides formulation compounds produced by the method of the present invention.

[0054] The key extrusion parameters for the successful formation of iopamidol and / or acetyl-iopamidol are primarily represented by temperature and residence time. In a preferred embodiment of the invention, extrusion is performed under heating in the extruder.

[0055] Preferably, the temperature of the reaction chamber (B) in step ii) and optionally the temperature of at least one inlet portion (A) in step i) are in the range of 40°C to 120°C, or 55°C to 90°C, or 60°C to 80°C, or 70°C to 80°C. More preferably, it is in the range of 55°C to 90°C. Even more preferably, the temperature of the reaction chamber (B) is set at about 60°C, or 65°C, or 70°C, or 75°C, or 80°C, or 85°C, or 90°C.

[0056] In a preferred embodiment, in order to obtain a uniform temperature during slurry flow, the reaction can be carried out in an extruder having multiple heating devices along the reaction chamber (B) and equipped with temperature measuring sensors, which is optionally also suitable for providing temperature gradients or different temperature zones.

[0057] Preferably, in the method of the present invention, the residence time of the slurry formed by compounds (IV) and (V) in the reaction chamber (B) is about less than 30 minutes; preferably, the residence time is less than 15 minutes; more preferably, it is 3 to 10 minutes.

[0058] In a preferred embodiment, the reaction in step a) is carried out in a reactive extruder selected from single-screw extruders, multi-screw extruders (e.g., twin-screw extruders), vertical extruders, planetary roll extruders, and annular extruders. More preferably, the reaction is carried out in a single-screw extruder or a twin-screw extruder. In a preferred embodiment, the twin-screw extruder has two screws rotating in the same direction. In another embodiment, the twin-screw extruder has two screws rotating in opposite directions.

[0059] Preferably, the reactive extruder of the present invention includes at least one screw operating at a speed of 1 to 150 rpm.

[0060] The preferred molar ratio between serine (V) and compound (IV) is 3 to 20 or 3 to 15; more preferably, the molar ratio is 3 to 8.

[0061] Depending on the conditions applied, the acetyl group of compound (VI) tends to partially hydrolyze, such that the mixture obtained at the end of step a) may contain an amount ranging from 0.5% to 20% of iopamidol. Preferably, such an amount is ranging from 0.5% to 10%, more preferably from 0.5% to 5%. The remaining amount of acetyl-iopamidol (VI) obtained from step a) is then hydrolyzed during step b) to obtain the final iopamidol.

[0062] The reactants used in the methods of the present invention can be prepared according to methods described in the prior art. For example, compound (IV) is a known intermediate in the synthesis of iopamidol and can be prepared as disclosed in EP2365963B1 (Example 4); while serinel (V) is a commercial product or can be prepared as described in EP0348223B1.

[0063] In this specification, and unless otherwise specified, the following terms and phrases are intended to have the following meanings.

[0064] The term "residence time" refers to the average time required for a mixture of reactants to pass through an extruder. Typically, such a time depends on the screw length and pitch, as well as their rotational speed, and can range from several minutes to several hours. Calibrating the residence time is important to avoid any possible degradation of the product, and also because of temperature control, as the product may degrade at high temperatures during short residence times or at low temperatures during longer residence times. Residence time can be determined experimentally, for example, by using dyes and measuring the time required for the colored substance to pass through the extruder.

[0065] The term "hopper" refers to a cone-shaped component attached to the feed inlet to hold and feed reactants into the extruder (inlet section A). In some instruments, the hopper can be heated to keep the material in a high-temperature or liquid state before melting processing. One or more reactants can be manually loaded into the hopper or conveyed to it using an automated system.

[0066] The term "barrel" refers to the hollow chamber (reaction chamber B) in which the screw runs. It is typically made of thick alloy steel tubing or pipe to withstand the high pressures that may be generated inside the extruder, and can have different shapes depending on the screw configuration.

[0067] The reaction extruders suitable for the methods of the present invention can exhibit different configurations. However, it is preferred that the extruder is equipped with a heating device to heat the material introduced into the reaction chamber.

[0068] Preferably, the rotating screw has a constant diameter, particularly near the inlet portion (A). Alternatively, and especially in the central region of the extruder, the screw may have a continuously increasing bottom diameter, which gradually increases the compressive force on the reactants as they pass through the barrel.

[0069] In one embodiment, the reactive extruder is a single-screw extruder (SSE).

[0070] In another preferred embodiment, the reactive extruder is a twin-screw extruder (TSE) with two modular screws that move in the same or opposite directions. The shear applied to the reactant material is a result of enhanced mixing achieved through the interpenetration of the screws.

[0071] In a preferred embodiment, the at least one rotary screw is characterized by a continuous single segment having a uniform pitch. Alternatively, the screw is characterized by a profile obtained by interchanging different screw segments with variable pitch (e.g., a kneading block (causing vigorous mixing), a toothed segment (providing better dispersion mixing), or a reverse segment (increasing compression force and residence time)). For example, such a rotary screw with variable pitch can be used for high-viscosity materials when higher compression forces are required.

[0072] Another aspect of the invention is the method as described above, wherein step a) is carried out by additionally adding at least one component selected from liquid additives and / or alkalis and / or inert materials to the mixture.

[0073] In some embodiments, the reaction in step a) may additionally include adding a small amount of liquid additive to the mixture of reactants to facilitate material sliding under high viscosity conditions, increase its solubility, and accelerate the overall process. Preferably, the liquid additive is added to the hopper of the inlet section (A) at the beginning of the process along with at least one reactant. For example, it may be selected from safe and sustainable solvents that are also easily removed at the end of the process without leaving any residue. For example, in one embodiment, such solvents are preferably selected from glycerol, propylene glycol monomethyl ether (PGME), dipropylene glycol dimethyl ether (Proglyde), dipropylene glycol propyl ether, diethylene glycol diethyl ether, cyclopentylmethyl ether (CPME), γ-valerate (GVL), and acetonitrile. The amount of liquid additive is preferably from 0.1 to 10 equivalents. More preferably, the equivalent ratio between compound (IV) and liquid additive is from 1:0.1 to 1:5. Even more preferably, it is 1:0.5.

[0074] Alternatively, or simultaneously, a base may be added to the mixture of reactants to promote neutralization of the reaction and ultimately reduce the total amount of serine. Such a base is preferably an organic base selected from liquid materials, also serving as a suitable lubricant to promote better mixing of the reactants. Examples of organic bases that can be used in the reactions of the present invention are selected from potassium acetate and tertiary amines, such as triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpiperidine, or N-methylpyrrolidine. In another embodiment, an inorganic base may be used, such as that selected from Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, KHCO₃, CaO, etc. Preferably, the method of the present invention is carried out by using 0.1 to 10 equivalents of an additional base for each amount of compound (IV) undergoing amidation. More preferably, the method is carried out by using 5 equivalents of an additional base for each amount of compound (IV).

[0075] In other embodiments, the reaction in step a) may additionally include the addition of an inert material to the mixture of reactants to promote mechanochemical effects and to promote mixing of the reactants. For example, before the mixture of serinel (V) and compound (IV) is introduced into the extruder, an immiscible material such as NaCl or Na2SO4 may be added to the mixture, preferably in an amount of 10 to 30% by weight.

[0076] Reactants, optionally together with a base and / or liquid additives and / or inert materials, can be fed into the reaction chamber simultaneously or in separate steps. Alternatively, reactants can be fed into a single inlet section (A), optionally premixed in a separate container; or they can be fed separately into different inlet sections, (A') and (A'').

[0077] Figure 1 A typical configuration of a reactive extruder suitable for the method of the present invention is illustrated, wherein the reaction chamber (B) consists of a single screw system continuously fed compounds (IV) and (V) through a single inlet section (A). Preferably, compounds (IV) and (V) can be premixed in a pretreatment step and then loaded into the inlet section (A) in one go or in batches at room temperature or optionally at a temperature of 30°C or higher. Such premixing allows for optimal mixing of the materials and the formation of a slurry suitable for continuous supply to the reactive extruder.

[0078] Figure 2 Another preferred configuration of a reactive extruder suitable for the method of the present invention is illustrated, wherein the reaction chamber (B) consists of a co-rotating twin-screw system that continuously feeds compounds (IV) and (V) through separate inlet portions (A') and (A'').

[0079] The inlet sections (A) or (A') and (A'') typically consist of hoppers of different possible forms and are located upstream of the start of the reaction chamber. In the case of two inlet sections (A') and (A''), the hoppers are configured such that inlet (A') is used for adding serinel (V) and is located upstream, while inlet (A'') is used for adding compound (IV) and is located downstream relative to (A'). Alternatively, (A') and (A'') may be located at different positions on the same cross-section of the barrel. In one embodiment, the extruder with separate, independent feeding devices may also be configured with a first mixing zone corresponding to the inlet section.

[0080] Preferably, the inlet portion is capable of heating the material introduced into the reaction chamber. For example, in one embodiment, when compound (IV) is fed in solid form, the inlet portion for feeding serine alcohol (V) is heated to a temperature above 50°C, causing serine alcohol (V) to melt and then mix in the reaction chamber. Preferably, in this case, compound (V) is fed in a preheated upstream inlet (A'), while compound (IV) is fed in a downstream or parallel inlet (A''), which may optionally be heated or unheated.

[0081] Typically, one or more screws, as described above, are characterized by a cylindrical or conical shape with a diameter in the range of 5-35 mm and operate at a speed in the range of 0.5 to 40 rpm.

[0082] In some embodiments of the invention, the extruder may also be equipped with an exhaust port for discharging any possible gases formed during the extrusion process.

[0083] Another parameter that can affect the efficiency of the extrusion method is the size distribution of the solid material (particularly compound (IV)) fed into the reaction chamber. In one embodiment, even when fed separately or after premixing, the reactants are preferably milled (e.g., in a mortar) before being loaded into the inlet section to reduce the particle size of the solid material to less than 1 mm. For example, powders of compound (IV) with small particle sizes can be produced by using micronization equipment or a planetary ball mill that mixes balls of different sizes and rotates at a suitable speed.

[0084] Typically, the reactants are fed into the inlet section at a feed rate of 5 to 30 g / min, depending on the screw speed. Such a speed is preferably set between 1 and 150 rpm, but more preferably the instrument is operated at a speed of 0.5 to 40 rpm. For example, when the screw speed is 5 rpm, the reactants are fed at a feed rate of 5 g / min; when the screw speed is 30 rpm, the reactants are fed at a feed rate of 30 g / min.

[0085] In one implementation, reactive extrusion can be combined with online monitoring, such as Raman or infrared spectroscopy, which can provide information about the chemical reactions occurring inside the extruder.

[0086] After extrusion, the extrudate mixture is collected at the outlet section (C). In some embodiments, such extrudate is represented as a paste that can be recycled into a container for further processing.

[0087] According to the method of the present invention, the conversion of the residual intermediate compound (VI) into iopamidol (step b) is carried out under alkaline aqueous conditions, for example as described in EP2365963B1 (Example 3).

[0088] The paste-like extrudate can be collected directly at the outlet (C) into a separate receiver containing an aqueous solution and conveniently processed by adding an aqueous alkaline solution, such as diluted sodium hydroxide (e.g., NaOH 30% wt.), until the pH is about 10, and heating at a temperature in the range of 25°C to 50°C for at least 1 hour to 10 hours, preferably 7 hours. Alternatively, hydrolysis can also be carried out using a basic exchange resin according to known methods.

[0089] The crude product obtained therefrom can then be neutralized to pH 6-7 with HCl and purified by ion exchange resin or any other suitable purification method (e.g., desalting with electrodialysis or ion exchange resin, distillation, chromatography, crystallization) according to procedures known in the art (e.g., as disclosed in EP2365963B1).

[0090] The iopamidol product obtained by the method of the present invention can be used to prepare formulations by dissolving it in an aqueous solution, for example, as an X-ray contrast agent for use in subjects.

[0091] The technical solution provided by this invention, represented by reactive extrusion using intermediate reactants for the manufacture of iopamidol, has universal applicability and provides a synthetic method that can generally be used to prepare radiographic contrast agents and / or their key intermediates.

[0092] Therefore, in another embodiment, the present invention relates to a method for synthesizing the radiographic intermediate of formula (VII).

[0093]

[0094] in

[0095] R 1 It is a C1-C6-alkyl group substituted with one or more hydroxyl groups;

[0096] R 2 It is hydrogen or a C1-C6-alkyl group optionally substituted with one or more hydroxyl groups;

[0097] X is hydrogen or a group -COR 3 ,in

[0098] R 3 It is a C1-C6-alkyl group optionally substituted with one or more hydroxyl, C1-C4-alkoxy, or acetoxy (-OAc) groups.

[0099] R 4 It is hydrogen or C1-C6-alkyl.

[0100] The method includes:

[0101] c) Obtain 5-amino-2,4,6-triiodo-1,2-phthaloyl chloride of formula (VIII), wherein X and R 4 As defined above,

[0102]

[0103] and

[0104] d) React the obtained dichloride with the formula NHR 1 R 2 The amine reaction, in which R 1 and R 2 As defined above,

[0105] In this embodiment, according to the solution determined by the present invention, reaction step d) is carried out continuously by a reactive extrusion process.

[0106] Further details regarding the manufacture of iopamidol according to the present invention are reported in the following experimental section, the sole purpose of which is to better illustrate the invention and not to imply any limitation thereof.

[0107] Experimental Section

[0108] Materials and methods

[0109] All commercially available reagents and solvents were used without further purification. 2-Amino-1,3-propanediol (serine alcohol, V) was purchased from TCI Chemicals, while the intermediate compound (IV) was prepared substantially as described in EP2365963B1.

[0110] Reactive extrusion was performed using different extrusion apparatuses. For example, the equipment was selected from the following: i) a conical twin-screw extruder (Mod. REM-2CA, Zamak Mercator) equipped with co-rotating twin screws in a reaction chamber with a capacity of 5 to 20 mL; ii) a conical twin-screw extruder (Mod. MiniLab II HAAKE Rheomer CTW5, Termo FischerScientific) equipped with a conical screw with a diameter of 5 / 14 mm and a length of 109.5 mm; iii) a single-screw extruder (Mod. TR12 / 20GM, manufactured by Gimac, Italy) equipped with a single feeder, four independently controlled temperature zones, and a 35 cm long screw with a constant pitch.

[0111] Analytical characterization

[0112] The compounds were characterized by capillary electrophoresis (MEKC-CE), RP-HPLC, or MS under the following conditions:

[0113] MEKC-CE method

[0114] Instrument: Agilent HP G1600AX 3D capillary electrophoresis system

[0115] Capillary: Silica, 65cm, 50μm ID

[0116] Inlet = Outlet = Run buffer: Na₂B₄O₇ 25mM + SDS 20mM

[0117] Injection: 50 mbar x 3'' sample + 30 mbar x 2'' run buffer

[0118] Temperature: 45°C

[0119] Voltage: +25kV

[0120] UV detection: 227 - 240nm

[0121] RP-HPLC method

[0122] Column: Zorbax SB Phenyl 80Å, 5μm, 250 x 4.6mm

[0123] Flow rate: 2 mL / min

[0124] Injection volume: 20 μL

[0125] UV detector: spectral recording from 200 to 400 nm; analysis at 254 nm.

[0126] Mobile phase: Eluent A: Water, Eluent B: Acetonitrile / Water 1:1

[0127] gradient:

[0128]

[0129] Quantitative MS methods

[0130] Instrument: Waters Micromass ZQ

[0131] Ionization source: ESI+

[0132] Cone: 15V

[0133] M / z range: 90-300

[0134] Example 1 - Preparation of iopamidol in a twin-screw extruder

[0135] Serine alcohol (V) (99.5 g; 1.09 mol) and compound (IV) (77.51 g; 0.109 mol) prepared as described in EP2365963 were pretreated by grinding in a mortar (the molar ratio of compound (IV) to serine alcohol (V) was 1:10).

[0136] The mixture of reactants is then fed into a continuously operating twin-screw extruder maintained at a temperature of 100°C and atmospheric pressure. The mixture is continuously loaded into the inlet system (A) over a 16-minute loading time.

[0137] The reaction proceeded continuously, with an average residence time of 5 minutes in the apparatus. Approximately 10–20 g of the paste-like mixture was collected at the outlet into a separate container every 2 minutes. After 28 minutes, the extruder was stopped, and a total of 118 g of the final mixture was collected. Each sample (10–20 g) of the resulting extrudate was dissolved in 500 mL of an alkaline aqueous solution containing 7.5 g of KOH and kept in an ultrasonic bath at room temperature for 15 minutes to complete the hydrolysis of the remaining acetyl-iophanate-methyl. 5 mL of the resulting solution was diluted 1:1 with water, and after adding 60–100 mg of benzamide to each sample as an internal standard, the sample was analyzed by MECK-CE.

[0138] The conversion of compound (IV) was obtained in the range of 70% to 85%, based on the MECK-CE peak area %.

[0139] After hydrolysis, the yield of iopamidol in each sample was in the range of 60% to 70%.

[0140] Example 2 - Preparation of iopamidol in a single-screw extruder

[0141] 9.0 g of compound (IV) (0.013 mol) was milled at 350 rpm for 2 minutes in a Retsch PM100 planetary ball mill and then premixed with 6.0 g of serine alcohol (V) (0.066 mol) in a container (the molar ratio of compound (IV) to serine alcohol (V) was 1:5).

[0142] The mixture of reactants is then simultaneously fed into a continuous single-screw extruder with four distinct temperature zones: two zones near the inlet and outlet are maintained at 50°C, while the two central zones are maintained at 70°C (atmospheric pressure). The mixture is continuously loaded into the inlet system (A) over a 6-minute feeding period.

[0143] The reaction proceeded continuously, with an average residence time of 5.5 minutes in the apparatus. After 1 minute, the extruder was stopped, and a total of 2.7 g of the final mixture was collected. The resulting extrudate was then dissolved directly in 2.0 mL of 20% NaOH aqueous solution at room temperature and stirred for 1 hour to complete the hydrolysis of the remaining acetyl-iophanol and convert it to iopamidol.

[0144] The alkaline solution was then neutralized with 2N HCl. The yield of the derived iopamidol was determined by RP-HPLC analysis of the crude solution using an external standard.

[0145] The conversion rate of compound (IV) was 96% based on the HPLC peak area percentage.

[0146] The yield of iopamidol after hydrolysis was 74%.

[0147] Example 3 - Preparation of iopamidol in a single-screw extruder in the presence of a liquid additive

[0148] 9.0 g of compound (IV) (1 eq, 0.013 mol) was premixed with 6.0 g of serine alcohol (V) (5 eq, 0.066 mol) in a container, and then 1.2 mL of DPnP (0.5 eq, 0.007 mol) was added dropwise.

[0149] The mixture of reactants is manually fed into the inlet system (A) of a single-screw extruder, which has four distinct temperature zones: two zones near the inlet and outlet are maintained at 50°C, while the two central zones are maintained at 70°C (atmospheric pressure). The reaction proceeds continuously, with a residence time of 8 minutes within the equipment.

[0150] The extrudate was then collected directly into a 50 mL vial containing 2.0 mL of 20% NaOH aqueous solution at room temperature; the vial was stirred for 1 hour to hydrolyze acetyl-iophanate-methyl and obtain iopamidol.

[0151] The alkaline solution was then neutralized with 2N HCl. The yield of iopamidol was determined by RP-HPLC analysis of the crude solution using an external standard.

[0152] The conversion rate of compound (IV) was 81.9% based on the HPLC peak area percentage.

[0153] The yield of iopamidol after hydrolysis was 69.7%.

[0154] Example 4 - Preparation of iopamidol in a single-screw extruder in the presence of alkali

[0155] 9.0 g of compound (IV) (1 eq, 0.013 mol) was premixed with 6.0 g of serine alcohol (V) (5 eq, 0.066 mol) and 8.8 g of K2CO3 (5 eq, 0.064 mol) in a container.

[0156] The mixture of reactants is manually fed into the inlet system (A) of a single-screw extruder, which has four distinct temperature zones: two zones near the inlet and outlet are maintained at 50°C, while the two central zones are maintained at 70°C (atmospheric pressure). The reaction proceeds continuously, with a residence time of 8 minutes within the equipment.

[0157] The extrudate was then collected directly into a 50 mL vial containing 2.0 mL of 20% NaOH aqueous solution at room temperature; it was stirred for 1 hour to hydrolyze acetyl-iophanate-methyl and obtain iopamidol.

[0158] The alkaline solution was then neutralized with 2N HCl. The yield of iopamidol was determined by RP-HPLC analysis of the crude solution using an external standard.

[0159] The conversion rate of compound (IV) was 81.8% based on the HPLC peak area percentage.

[0160] The yield of iopamidol after hydrolysis was 66.2%.

[0161] Example 5 - Preparation of iopamidol in a single-screw extruder in the presence of an inert component

[0162] 9.0 g of compound (IV) (1 eq, 0.013 mol) was premixed with 6.0 g of serine alcohol (V) (5 eq, 0.066 mol) and 2.6 g of NaCl (15% w / w, 0.044 mol) in a container.

[0163] The mixture of reactants is manually fed into the inlet system (A) of a single-screw extruder, which has four distinct temperature zones: two zones near the inlet and outlet are maintained at 50°C, while the two central zones are maintained at 70°C (atmospheric pressure). The reaction proceeds continuously, with a residence time of 8 minutes within the equipment.

[0164] The extrudate was then collected directly into a 50 mL vial containing 2.0 mL of 20% NaOH aqueous solution at room temperature; it was stirred for 1 hour to hydrolyze acetyl-iophanate-methyl and obtain iopamidol.

[0165] The alkaline solution was then neutralized with 2N HCl. The yield of iopamidol was determined by RP-HPLC analysis of the crude solution using an external standard.

[0166] The conversion rate of compound (IV) was 81.4% based on HPLC peak area percentage.

[0167] The yield of iopamidol after hydrolysis was 71.8%.

[0168] References:

[0169] 1. The Merck Index, RSC Publishing, 15 th Ed., 2013, 940-941

[0170] 2. Lusic, H. et al., Chem. Rev. 2013, 113, 1641-1666

[0171] 3. GB1,472,050

[0172] 4. US4,001,323

[0173] 5. GB2,311,524

[0174] 6. WO00 / 15602

[0175] 7. WO2018 / 104228

[0176] 8. Crawford D.E. et al, Green Chem. 2017, 19, 1507

[0177] 9. Crawford D.E. et al, Chem. Commun. 2017, 53, 13067-13070

[0178] 10. Lavayssiere M. et al, Chem. Commun. 2023, 59, 3439-3442

[0179] 11. US5,859,269

[0180] 12. US5,859,263

[0181] 13. US9,453,107

[0182] 14. EP2365963

[0183] 15. EP0348223

Claims

1. A process for the preparation of N 1 ,N 3 - Bis[2-hydroxy-l-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-l-oxopropyl]amino]- 2,4,6-triiodo-l,3-benzenedicarboxamide (Iopamidol) comprising the steps of: a) mixing and reacting S-5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3- benzenedicarbonyl chloride (IV) with 2-amino-1,3-propanediol (V) to obtain a mixture of intermediate acetyl-iodipamide (VI) and iodoipamide, ； b) treating the mixture thus obtained by promoting the removal of the acetyl group from intermediate acetyl-iodipamide (VI) under basic aqueous conditions, wherein step a) of the process is carried out continuously in a reactive extruder.

2. The process according to claim 1, wherein the reaction of step a) is carried out at a temperature ranging from 40°C to 150°C.

3. The process according to claim 2, wherein the temperature ranges from 55°C to 90°C.

4. The process according to any one of the preceding claims, wherein the residence time of compounds (IV) and (V) in the reactive extruder is less than 15 minutes.

5. The process according to claim 5, wherein the residence time of compounds (IV) and (V) in the reactive extruder is from 3 to 10 minutes.

6. The process according to any one of the preceding claims, wherein the molar ratio between compounds (V) and (IV) is from 3 to 15.

7. The process according to claim 6, wherein the molar ratio between compounds (V) and (IV) is from 3 to 8.

8. The process according to claim 1, wherein the reactive extruder comprises at least one inlet section (A), a reaction chamber (B) and an outlet section (C), and step a) comprises the following steps: i. continuously feeding compounds (IV) and (V) into the at least one inlet section (A) of the reactive extruder; ii. heating the reaction chamber (B) while mixing and conveying the reactant compounds (IV) and (V), thereby forming a product stream comprising a mixture of acetyl-iodipamide (VI) and iodoipamide; iii. collecting the product stream at the outlet section (C) of the reactive extruder.

9. The process according to claim 1, wherein the reactive extruder is selected from the group consisting of single-screw extruders, multi-screw extruders such as twin-screw extruders, vertical extruders, planetary roller extruders and ring extruders.

10. The process according to claim 1, wherein the reactive extruder is a single-screw extruder.

11. The process according to claim 1, wherein the reactive extruder is a twin-screw extruder, preferably having co-rotating screws.

12. The process according to claim 1, wherein the reactive extruder comprises at least one screw which operates at a rotational speed ranging from 1 to 150 rpm.

13. The process according to claim 1, wherein compounds (IV) and (V) in step a) are pre-mixed and the mixture is continuously fed into the inlet section (A).

14. The process according to claim 1, wherein compounds (IV) and (V) in step a) are fed separately into independent inlet sections (A') and (A'').

15. The process according to claim 1, wherein step a) is performed by additionally adding at least one ingredient selected from a liquid additive and / or a base and / or an inert material to the mixture.

16. The process according to claim 15, wherein the liquid additive is selected from glycerol, propylene glycol monomethyl ether (PGME), dipropylene glycol dimethyl ether (Proglyde), dipropylene glycol propyl ether, diethylene glycol diethyl ether, cyclopentyl methyl ether (CPME), gamma-valerolactone (GVL) and acetonitrile.

17. The process according to claim 15, wherein the base is selected from potassium acetate; tertiary amines such as triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpiperidine and N-methylpyrrolidine; and inorganic bases such as Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3 and CaO.

18. The process according to claim 15, wherein the inert material is selected from NaCl and Na2SO4.

19. The process according to claim 1, wherein the conversion of step b) is performed by adding the paste-like material collected from step a) to an aqueous alkaline solution and heating at a temperature in the range of 25 to 50 °C for at least 1 hour.

20. A process for the synthetic preparation of a radiographic intermediate of formula (VII), wherein R 1 Ci-C6-alkyl substituted by one or more hydroxyl groups; R 2 Ci-C6-alkyl; or R3and R4together with the carbon atom to which they are attached form a C3-C6-cycloalkylidene ring; or R3and R4together with the carbon atom to which they are attached form a C3-C6-cycloalkyl X is hydrogen or the group -COR 3 wherein R 3 Ci-C6-alkyl which is optionally substituted by one or more Ci-C4-alkoxy or acetoxy (-OAc) groups, R 4 is hydrogen or Ci-C6-alkyl, the process comprises: c) obtaining 5-amino-2,4,6-triiodo-1,2-benzenedicarbonyl chloride of formula (VIII), wherein X and R 4 as defined above, and d) reacting the obtained dichloride derivative (VIII) with an amine NHR 1 R 2 reaction, wherein R 1 and R 2 as defined above, wherein the reaction of step d) is continuously performed by a reactive extrusion process.

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