WO2024256322A1 - Synthèse d'agents de contraste radiographiques non ioniques par extrusion réactive - Google Patents

Synthèse d'agents de contraste radiographiques non ioniques par extrusion réactive Download PDF

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Publication number
WO2024256322A1
WO2024256322A1 PCT/EP2024/065899 EP2024065899W WO2024256322A1 WO 2024256322 A1 WO2024256322 A1 WO 2024256322A1 EP 2024065899 W EP2024065899 W EP 2024065899W WO 2024256322 A1 WO2024256322 A1 WO 2024256322A1
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WIPO (PCT)
Prior art keywords
extruder
process according
reactive
lopamidol
compound
Prior art date
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PCT/EP2024/065899
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English (en)
Inventor
Luciano Lattuada
Roberto Sebastiano
Gabriella LEONARDI
Giancarlo Cravotto
Alessandro Barge
Fabio BUCCIOL
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Bracco Imaging SpA
Politecnico di Milano
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Bracco Imaging SpA
Politecnico di Milano
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Application filed by Bracco Imaging SpA, Politecnico di Milano filed Critical Bracco Imaging SpA
Priority to CN202480035263.8A priority Critical patent/CN121620501A/zh
Priority to EP24732599.6A priority patent/EP4727912A1/fr
Publication of WO2024256322A1 publication Critical patent/WO2024256322A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups

Definitions

  • the present invention relates to the industrial preparation of non-ionic X-ray contrast agents.
  • it relates to a process for the synthesis of lopamidol using a reactive extrusion process in continuous, which enable an efficient conversion of the relevant key intermediates, preferably in the absence of any solvent.
  • the invention further relates to the preparation of radiographic X-rays contrast agents or key intermediates thereof by exploiting the technology of reactive extrusion.
  • Iodinated contrast agents are well-known compounds widely used in X-ray imaging diagnostic techniques. Among these compounds, S-/V J ,/V 5 -bis[2-hydroxy-l-
  • DMAC /V,/V-di methylacetamide
  • DMF /V,/V-dimethyformamide
  • aprotic dipolar solvents such as /V-methylpyrrolidone (NMP) or /V-ethyl pyrrolidone (NEP), tested with good results in these reactions (see for instance GB 2,311,524), are equally reprotoxic, therefore not suitable to solve this safety issue. Moreover, they display a higher boiling point and they are difficult to be removed from the products at the end of the reactions and from the bulk drug substance, especially in an industrial scale process.
  • mechanochemical approaches were considered, which are generally conducted by grinding together two or more solid reagents to instigate a chemical reaction.
  • One relevant example is reported in WO2018/104228 which discloses a mechanochemical process exploiting the use of mechanical milling of specific reactants for the manufacturing of key intermediates of radiographic contrast agents, like compound (VI), without providing any external heating and substantially without the addition of solvents.
  • Reactive extrusion is a well-known technology referring to a family of continuous processing techniques, i.e. manufacturing methods combining the traditional chemical processes (syntheses and/or modifications, typically of polymeric materials) and extrusion (pushing materials through a die by applying compressive and shear forces) into a single process carried out onto an extruder.
  • a typical continuous equipment consists of at least a feeder (volumetric or gravimetric dosing system) and a barrel, wherein the materials are intensively mixed and forced through constrained spaces.
  • a feeder volumetric or gravimetric dosing system
  • Such barrel can be heated and can contain either one or more screws that convey the materials along the inside of the barrel and subject it to shearing and mixing forces before the exit.
  • extrusion parameters are generally tuned to optimize the processes, including screw speed, screw profile, feed rate, residence time and temperature.
  • An extruder can be also integrated into a continuous manufacturing process as either one component of a processing line or as the entire line itself.
  • Reactive extrusion is scalable up to tons of product per hour, allowing reactions to be carried out with little or no solvent. For this reason, the extrusion technology has been employed across several industries, including food, polymer and pharmaceutical manufacturing (mostly in the formulation of drugs). Most applications of reaction extrusion techniques have been described to produce polymers of high molecular weight, for instance in the manufacturing of chemically modified natural macromolecules or synthetic polymers.
  • extrusion approaches have not been yet extensively applied to the preparation of active pharmaceutical ingredients (APIs).
  • APIs active pharmaceutical ingredients
  • only very recently the use of the extrusion technique has been explored in other fields, such as in the synthesis of organic compounds through reactions like Knoevenagel condensations, Michael additions and aldol reactions, often without the need of post-synthetic isolation or additional purification. Examples of these methods are reported in Crawford D.E. et al, Green Chem., 2017, 19, 1507 and in Crawford D.E. et al, Chem. Commun. 2017, 53, 13067-13070. Reactions of amidation by reactive extrusion for the synthesis of active pharmaceutical ingredients teriflunomide and moclobemide are described in Lavayssiere M.
  • a reactive extrusion process can be efficiently exploited for the preparation of a radiographic contrast agent, such as lopamidol, and in particular to carry out the above described amidation in continuous of compound (IV) with serinol (V).
  • compounds (IV) and (V) are employed as the sole reactants which are continuously fed and mixed in the reaction chamber of an extruder, thereby interacting while being transported to the outlet of the reaction chamber itself, in order to provide the intermediate acetyl-Iopamidol (VI), partially in admixture with lopamidol, which can be then hydrolyzed to afford the final product lopamidol.
  • the process of the invention was also found scalable and suitable for an industrial manufacturing of lopamidol, and more generally of radiographic contrast agents.
  • the present invention generally relates to an industrial preparation of the non-ionic X- ray contrast agent lopamidol, providing a sustainable method that avoids the use of toxic and highly boiling solvents.
  • lopamidol can be obtained through a continuous process exploiting the reaction extrusion technology for the interaction and conversion of its key intermediates.
  • extrusion processing of a slurry comprising S-5-[[2-(acetyloxy)-l-oxopropyl]amino]-2,4,6- triiodo-l,3-benzenedicarboxylic acid dichloride (IV) in admixture with 2-amino-l,3- propanediol (V) provides a very efficient method for the production of lopamidol, without using any hazardous solvent, since the reaction extrusion of the invention is performed in continuous by directly feeding the reactants (IV) and (V) in a suitable extruder.
  • the present invention relates to a new process in continuous for the manufacturing of the radiographic agent lopamidol which exploits the use the technique of reaction extrusion to perform the amidation of S-5-[[2-(acetyloxy)-l- oxopropyl]amino]-2,4,6-triiodo-l,3-benzenedicarboxylic acid dichloride (IV) with 2-amino- 1,3-propanediol (V), obtaining the intermediate acetyl-Iopamidol (VI) in admixture with an amount of lopamidol, according to the following Scheme 2:
  • the residual amount of intermediate (VI) is then all converted into the final radiographic agent lopamidol by hydrolysis of the acetyl group in basic aqueous conditions.
  • step a is advantageous with respect to the methods described in the prior art in that the process is operated in continuous, requires few steps and reduced reaction times and is more sustainable and economic since it is substantially solventless.
  • the process of the invention allows to obtain the final product lopamidol with a good efficiency and without using any toxic material, such as the solvent DMAC or DMF which are under strict restrictions by the REACH Directive.
  • the process of the invention can provide conversions of compound (IV) up to 96% and final yields of lopamidol after hydrolysis higher than 70%, in very short reaction times.
  • the process of the invention is of general applicability and provides a synthetic approach generally exploitable for the preparation of radiographic contrast agents and/or their relevant key intermediates.
  • Figure 1 shows a schematic representation of a reactive extruder equipped with one screw and one inlet section according to a preferred embodiment of the present invention.
  • Figure 2 shows a schematic representation of a reactive extruder equipped with two corotating screws and two inlet sections according to another preferred embodiment of the present invention.
  • the invention relates to a process for the preparation of /V J ,/V 5 -bis[2- hydroxy-l-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-l-oxopropyl]amino]-2,4,6-triiodo- 1,3-benzenedicarboxamide (lopamidol) comprising the following steps: a) mixing and reacting S-5-[[2-(acetyloxy)-l-oxopropyl]amino]-2,4,6-triiodo- 1,3-benzenedicarboxylic acid dichloride (IV) with 2-amino-l,3-propanediol (V) thus obtaining a mixture of the intermediate acetyl-Iopamidol (VI) and lopamidol b) treating the mixture thus obtained in basic aqueous conditions by promoting the removal of the acetyl group from the intermediate acetyl-Iop
  • the reaction of step a) is carried out at a temperature comprised in the range from 40 °C to 150 °C. More preferably, said temperature is comprised in the range from 55 °C to 90 °C.
  • the residence time of compounds (IV) and (V) in the reactive extruder is less than 15 minutes. More preferably, said residence time is comprised between 3 and 10 minutes.
  • the molar ratio between compound (V) and compound (IV) is preferably comprised between 3 and 15. More preferably, said molar ratio is comprised between 3 and 8.
  • said step a) of the process defined above is carried out in a reactive extruder including at least one inlet section (A), a reactive chamber (B) and comprises the following steps: i. continuously feeding the 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 transporting the reactant compounds (IV) and (V), thereby forming a product stream comprising a mixture of acetyl-Iopamidol (VI) and lopamidol; iii. collecting said product stream at the outlet section (C) of the reactive extruder.
  • the present invention provides for a compound of formulation produced by the process of the invention.
  • extrusion parameters for successful formation of lopamidol and/or acetyl-Iopamidol are mainly represented by the temperature and the residence time.
  • the extrusion takes place under heating of the extruder.
  • the temperature of the reaction chamber (B) in step ii), and optionally of the at least one inlet section (A) in step i), is comprised in the range from 40 °C to 120 °C or from 55 °C to 90°C or from 60 °C to 80°C or from 70 °C to 80°C. More preferably it is comprised in the range from 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.
  • the reaction can be performed in an extruder having a plurality of heating means along the reaction chamber (B) and equipped with temperature measuring sensors, optionally suitable to also provide a temperature gradient or different temperature zones.
  • the residence time of the slurry formed by compounds (IV) and (V) in the reaction chamber (B) is approximately less than 30 minutes; preferably the residence time is less than 15 minutes; more preferably it is comprised between 3 minutes and 10 minutes.
  • the reaction of step a) is carried out in a reactive extruder selected from the group consisting of a single-screw extruder, a multi-screw extruder, such as twin-screw extruder, a vertical extruder, a planetary roller extruder and a ring extruder. More preferably, said reaction is carried out in a single-screw extruder or in a twin-screw extruder. In a preferred embodiment said twin-screw extruder has two co-rotating screws. In another embodiment said twin-screw extruder has two counter-rotating screws.
  • the reactive extruder of the invention comprises at least one screw operating at a rotation speed comprised between 1 and 150 rpm.
  • the preferred molar ratio between serinol (V) and compound (IV) is comprised between 3 and 20 or between 3 and 15; more preferably said molar ratio is comprised between 3 and 8.
  • the acetyl group of compound (VI) tends to partially idrolyse so that the mixture obtained at the end of step a) can already comprise an amount of lopamidol ranging between 0.5% and 20%. Preferably such amount ranges between 0.5% and 10%, more preferably between 0.5% and 5%.
  • the remaining amount of acetyl-Iopamidol (VI) obtained from step a) is then hydrolysed during step b) to obtain the final lopamidol.
  • reactants for the process of the present invention can be prepared according to the methods described in the art.
  • compound (IV) is a known intermediate in the synthesis of lopamidol and can be prepared as disclosed in EP 2365963 Bl (example 4) while serinol (V) is a commercial product or can be prepared as described in EP 0348223 Bl.
  • the expression "residence time” refers to the average time required for the mixture of the reactants to pass through the extruder. Typically, such time depends on the length and pitch of the screw(s) and on their speed rotation and can last for a few minutes up to few hours. To avoid any possible degradation of the products it is important to calibrate the residence time also in view of the temperature control, since a product can be degraded during a short residence time at high temperature or during a longer residence time at lower temperature.
  • the residence time can be determined experimentally, for instance by using a dye and measuring the time taken for the colored material to pass through the extruder.
  • hopper refers to a unit, typically shaped like a tapered cone, which is attached at a feed port and used to hold and feed the reactants into the extruder (inlet section A). In some instruments the hopper can be heated to keep the material hot or in a liquid state before melt processing.
  • the one or more reactant(s) can be loaded in the hopper manually or therein conveyed using automatic systems.
  • barrel refers to a hollow chamber in which the screw(s) operates (reaction chamber B). It is generally made from thick alloy steel tubing or pipe in order to withstand the high pressures that can be generated within the extruder and can have different shapes depending on the configuration of the screw(s).
  • the reactive extruder suitable for the process of the invention can display different configurations. However, it is preferable that the extruder is equipped with heating means to provide for heating of the materials introduced into the reaction chamber.
  • the rotating screw(s) has a constant diameter, in particular close to the inlet section (A).
  • the screw(s) can have a continually increasing root diameter, which gradually increases the compressive forces on the reactants as they pass along the barrel.
  • the reactive extruder is a single screw extruder (SSE).
  • the reactive extruder is a twin-screw extruder (TSE), having two screws that are modular and move in a mutually co-rotating or counter- rota ting manner.
  • TSE twin-screw extruder
  • the shear applied to the reactant material is a result of the enhanced mixing achieved by the interpenetration of the screws.
  • At least one rotating screw is characterized by a continuous single segment with uniform pitch.
  • the screw is characterized by profiles obtained by interchanging different screw segments with variable pitch, such as for instance kneading blocks (causing aggressive mixing), toothed segments (giving better dispersive mixing) or reverse segments (increasing the compressive forces and residence time).
  • variable pitch such as for instance kneading blocks (causing aggressive mixing), toothed segments (giving better dispersive mixing) or reverse segments (increasing the compressive forces and residence time).
  • such rotating screws with variable pitch can be used with high viscosity materials, when a higher compressive force is needed.
  • such solvent is preferably selected from the group of 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.
  • the amount of liquid additive is preferably comprised between 0.1 and 10 equivalents. More preferably, the ratio of the equivalents between the compound (IV) and the liquid additive is comprised between 1:0.1 and 1:5. Even more preferably it is 1 :0.5.
  • a base can be added to the mixture of reactants in order to contribute to the neutralization of the reaction and to eventually reduce the total amount of serinol.
  • Such base can be preferably an organic base selected among liquid materials in order to also act as a suitable lubricant contributing to a better mixing of the reactants.
  • organic bases that can be used in the reaction of the invention are selected from potassium acetate and a tertiary amine, such as triethylamine, diisopropylethylamine (DIPEA), /V-methylmorpholine, N-methylpiperidine or N- methylpyrrolidine.
  • the reaction of step a) may further comprise the addition of an inert material to the mixture of the reactants, in order to facilitate the mechanochemical effect and foster the mixing of the reactants.
  • an immiscible material like NaCI or Na2SC>4 can be added to the mixture of serinol (V) and compound (IV) before their introduction in the extruder, preferably in an amount comprised between 10 and 30 weight %.
  • reactants optionally together with a base and/or a liquid additive and/or an inert material, can be continuously fed into the reaction chamber either simultaneously or in different steps.
  • reactants can be fed into one single inlet section (A), optionally after having been pre-mixed in a separate container, or they can be fed separately into different inlet sections, respectively (A') and (A").
  • reaction chamber (B) consists of a corotating twin-screws system which is continuously fed with compounds (IV) and (V) through separate inlet sections (A') and (A").
  • Said inlet sections (A) or (A') and (A") typically consist of a hopper of different possible forms and are positioned upstream, at the beginning of the reaction chamber.
  • these hoppers are configured so that the inlet (A') is used for adding serinol (V) and is located upstream, whilst the inlet (A") is used for adding the compound (IV) and is located downstream with respect to (A').
  • (A') and (A") can be located in different points of the same cross-section of the barrel.
  • the extruder with separate independent feeding means can be also configured with a first mixing zone in correspondence to the inlet section(s).
  • said inlet sections are able to provide heating to the materials introduced into the reaction chamber.
  • the inlet section for the feeding of serinol (V) is heated at a temperature higher than 50 °C so that it is melted and then mixed in the reaction chamber when compound (IV) is fed as a solid.
  • compound (V) is fed in a pre-heated upstream inlet (A') while compound (IV) is fed in the downstream or parallel inlet (A") which can be optionally heated or not heated.
  • the one or more screws as described above are characterized by a cylindrical or a conical shape, with a diameter comprised in the range of 5-35 mm, and are operated at a rotation speed comprised in the range between 0.5 and 40 rpm.
  • the extruder can be also equipped with a degassing port for venting any possible gas formed during the extrusion process.
  • the size distribution of the solid materials fed into the reactive chamber is represented by the size distribution of the solid materials fed into the reactive chamber, in particular of compound (IV).
  • the reactants even when fed separately or after premixing, are preferably grinded, e.g. in a mortar, before being loaded in the inlet section(s), in order to reduce the particle size of the solid material to a value below 1 mm.
  • a powder of compound (IV) with a small particle size can be accomplished by using a micronizing instrument or a planetary ball mill with a mix of balls of different size rotating at a suitable speed.
  • the reactants are fed into the inlet section(s) at a feed rate comprised between 5 and 30 g/min, depending on the screw rotation speed.
  • a feed rate comprised between 5 and 30 g/min, depending on the screw rotation speed.
  • Such rotation speed is preferably set between 1 and 150 rpm, but more preferably the instrument is operated with a rotation speed from 0.5 to 40 rpm.
  • the reactants are fed at a feed rate of 5 g/min when the screw rotation speed is 5 rpm and at a feed rate of 30 g/min when the screw rotation speed is 30 rpm.
  • the reaction extrusion may be possibly combined with on-line monitoring via e.g. Raman or infrared spectroscopy, which can provide information about the chemical reactions taking place inside the extruder.
  • on-line monitoring via e.g. Raman or infrared spectroscopy, which can provide information about the chemical reactions taking place inside the extruder.
  • the extrudate mixture is collected at the outlet section (C).
  • extrudate is represented by a pasty material which can be recovered in a container for further treatment.
  • the conversion of the residual amount of intermediate compound (VI) into lopamidol (step b) is carried out under basic aqueous conditions, for instance as described in EP2365963 Bl (example 3).
  • the pasty extrudate can be directly collected at the outlet (C) in a separate recipient comprising an aqueous solution, and conveniently treated by addition of an aqueous basic solution such as diluted sodium hydroxide (e.g. NaOH 30% wt.) up to a pH of about 10, and heating at a temperature ranging between 25 °C and 50°C for at least 1 hour up to 10 hours, preferably for 7 hours.
  • an aqueous basic solution such as diluted sodium hydroxide (e.g. NaOH 30% wt.) up to a pH of about 10
  • the hydrolysis can be also performed by means of a basic exchange resin, according to known methods.
  • reaction crude thus obtained may be then neutralized to a pH of 6-7 with HCI, and purified by ion exchange resins according to the procedures known in the art, e.g. as disclosed in EP2365963 Bl, or any other suitable method of purification (e.g. desalination with electrodialysis or ion exchange resins, distillation, chromatography, crystallization).
  • ion exchange resins e.g. desalination with electrodialysis or ion exchange resins, distillation, chromatography, crystallization.
  • the technical solution provided by the present invention represented by the use of the reactive extrusion of intermediate reactants for manufacturing lopamidol, is of general applicability and provides a synthetic approach generally exploitable for the preparation of radiographic contrast agents and/or their key intermediates.
  • R 2 is hydrogen or a Ci-Ce-alkyl optionally substituted by one or more hydroxyl groups
  • R 3 is a Ci-Ce-alkyl optionally substituted by one or more a hydroxy, Ci-C4-alkoxy or acetyloxy (-OAc) groups,
  • R 4 is hydrogen or Ci-Ce-alkyl, which comprises: c) obtaining a 5-amino-2,4,6-triiodo-l,2-benzenedicarboxylic acid dichloride of formula (VIII), wherein X and R 4 are as defined above and d) reacting the obtained dichloride with an amine of formula NHR X R 2 , wherein R 1 and
  • reaction step d) is carried out in continuous by means of a reactive extrusion process, according to the solution identified by the present invention.
  • the reactive extrusion was performed using different extrusion instruments.
  • the equipment was selected among the following: i) a conical twin-screw extruder (Mod. REM-2CA, Zamak Mercator) equipped with co-rotating twin-screws in a reaction chamber having a capacity from 5 to 20 mL; ii) a conical twin-screw Extruder (Mod. MiniLab II HAAKE Rheomer CTW5, Termo Fischer Scientific) equipped with conical screws having diameter of 5/14 mm and length of 109,5 mm; iii) a single screw extruder (Mod. TR12/20GM manufactured by Gimac, Italy) equipped with a single feed, four independently controlled temperature zones and a 35 cm long screw with constant pitch.
  • Capillary silica, 65 cm, 50 micron ID
  • UV detection 227 - 240 nm
  • UV detector spectrum recording between 200 and 400 nm; analysis at 254 nm
  • Serinol (V) (99.5 g; 1.09 mol) and compound (IV) (77.51 g; 0.109 mol), prepared as described in EP2365963 were pre-treated by grinding in a mortar (molar ratio of compound (IV) vs serinol (V) was 1 : 10).
  • the mixture of the reactants was then fed into a continuously operated twin-screw extruder maintained at a temperature of 100 °C and atmospheric pressure.
  • the mixture was continuously charged by in the inlet system (A) during a loading time of 16 minutes.
  • the reaction was carried out in continuous with an average residence time in the apparatus of 5 minutes. Samples of about 10-20 g of pasty mixture were collected every 2 minutes at the outlet into separate vessels. After 28 minutes the extruder was stopped, with a total collection of 118 g of final mixture.
  • Each sample of extrudate thus obtained (10-20 g) was dissolved in 500 mL of a basic aqueous solution containing 7,5 g of KOH and kept for 15 minutes in ultrasonic bath at room temperature to complete the hydrolysis of the remaining acetyl-Iopamidol. 5 mL of the obtained solution were diluted 1 : 1 with water and analysed by MECK-CE, after adding 60-100 mg of benzamide to each sample as internal standard.
  • the conversion of compound (IV) was obtained in a range from 70% to 85%, calculated from the MECK-CE peak area %.
  • the yield of lopamidol in each sample after the hydrolysis was comprised in the range from 60% to 70%.
  • the mixture of the reactants was then fed simultaneously into a continuous single-screw extruder with 4 different temperature zones: two zones respectively next to the inlet and outlet sections were maintained at 50°C, while the two central zones were maintained at a temperature of 70 °C (atmospheric pressure).
  • the mixture was continuously charged in the inlet system (A) during a feeding time of 6 minutes.
  • the reaction was carried out in continuous with an average residence time in the apparatus of 5.5 minutes. After 1 minute the extruder was stopped, with a total collection of 2.7 g of final mixture. The extrudate thus obtained was then directly dissolved 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-Iopamidol and conversion to lopamidol.
  • the basic solution was then neutralized with 2N HCI.
  • the yield of the derived lopamidol was determined by RP-HPLC analysis of the crude solution by use of an external standard.
  • the mixture of the reactants was fed manually in the inlet system (A) of a single-screw extruder with 4 different temperature zones: two zones respectively next to the inlet and outlet sections were maintained at 50°C, while the two central zones were maintained at a temperature of 70 °C (atmospheric pressure).
  • the reaction was carried out in continuous with a residence time in the apparatus of 8 minutes.
  • the extrudate was then directly collected into 50 mL vials containing 2.0 mL of 20% NaOH aqueous solution at room temperature; the vials were stirred for 1 hour to carry out the hydrolysis of acetyl-Iopamidol and obtain lopamidol.
  • the mixture of the reactants was fed manually in the inlet system (A) of a single-screw extruder with 4 different temperature zones: two zones respectively next to the inlet and outlet sections were maintained at 50°C, while the two central zones were maintained at a temperature of 70 °C (atmospheric pressure).
  • the reaction was carried out in continuous with a residence time in the apparatus of 8 minutes.
  • the extrudate was then directly collected into 50 mL vials containing 2.0 mL of 20% NaOH aqueous solution at room temperature which were stirred for 1 hour to carry out the hydrolysis of acetyl-Iopamidol and obtain lopamidol.
  • the mixture of the reactants was fed manually in the inlet system (A) of a single-screw extruder with 4 different temperature zones: two zones respectively next to the inlet and outlet sections were maintained at 50°C, while the two central zones were maintained at a temperature of 70 °C (atmospheric pressure).
  • the reaction was carried out in continuous with a residence time in the apparatus of 8 minutes.
  • the extrudate was then directly collected into 50 mL vials containing 2.0 mL of 20% NaOH aqueous solution at room temperature which were stirred for 1 hour to carry out the hydrolysis of acetyl-Iopamidol and obtain lopamidol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne la préparation industrielle d'agents de contraste aux rayons X non ioniques. En particulier, l'invention concerne un procédé de synthèse de lopamidol à l'aide d'un procédé d'extrusion réactive en continu qui permet une conversion efficace des intermédiaires clés pertinents, de préférence en l'absence de tout solvant. L'invention concerne en outre la préparation d'agents de contraste aux rayons X radiographiques ou d'intermédiaires clés de ceux-ci par exploitation de la technologie d'extrusion réactive.
PCT/EP2024/065899 2023-06-13 2024-06-10 Synthèse d'agents de contraste radiographiques non ioniques par extrusion réactive Ceased WO2024256322A1 (fr)

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CN202480035263.8A CN121620501A (zh) 2023-06-13 2024-06-10 通过反应挤出合成非离子型射线摄影造影剂
EP24732599.6A EP4727912A1 (fr) 2023-06-13 2024-06-10 Synthèse d'agents de contraste radiographiques non ioniques par extrusion réactive

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EP23178956.1 2023-06-13
EP23178956 2023-06-13

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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EP0348223A2 (fr) 1988-06-23 1989-12-27 Angus Chemical Company Procédé pour la préparation de sérinol
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