One-pot preparation process of organo-iodine compounds intermediate in the synthesis of loversol

The present invention relates to a process for the preparation of organo-iodine compounds, as well as its preparation intermediates. More particularly, the present invention relates to a process for the preparation of organo-iodine compounds useful as preparation intermediates in the synthesis of the iodinated contrast product ioversol (Optiray®).

loversol is described as a nonionic contrast medium in US Patent 4,396,598.

Currently, the majority of the processes for the synthesis of iodinated contrast products and in particular that concerning ioversol, use as an intermediate product 5-amino-2,4,6-triiodoisophthalic acid dichloride (also called DiCOCI), of the following formula:

During the synthesis of iodinated contrast products, it is necessary to carry out long separation and purification steps in order to obtain synthetic intermediates with a good degree of purity. These steps considerably increase the time for carrying out the synthesis and therefore increase the cost of implementing the methods for preparing the contrast products.

One of the manufacturing steps of DiCOCI is a step of chlorination (also called chlorination) of 5-amino-2,4,6-triiodoisophthalic acid (AATI) with a chlorinating agent such as thionyl chloride, also called thionyl dichloride (SOCI 2 ). This chlorination is a slow step (more than 7 hours 30 minutes of reaction time) and consumes energy, since it is carried out at a high temperature of more than 48 ° C. A large excess of the chlorinating agent relative to AATI makes it possible to obtain higher kinetics, but the use of this excess is not acceptable from an industrial and environmental point of view. Indeed, thionyl chloride, on contact with water, releases hydrogen chloride (HCl) and sulfur dioxide (S0 2), which are corrosive and irritating gases. The use of catalysts for this chlorination reaction has been recommended so as to be able to reduce the amount of SOCI 2 used while obtaining a good industrial yield.

The DiCOCI preparation processes used also have the drawback of generating a large amount of effluents, due to the use of large amounts of water at the time of the “precipitating” hydrolysis of the DiCOCI obtained by the chlorination step. . For example, in application EP 0 794 937 is described the addition of 22.2 to 33 equivalents of water per equivalent of AATI (Examples 1 to 3) or in application EP 0 773 925 is described the addition of 120 equivalents of water (see example 1 -E) to hydrolyze thionyl chloride. Finally, these processes require the performance of purification steps by precipitation, filtration and drying, in order to ensure optimum reactivity and competitive yield in the following steps.

Following this chlorination step, the DiCOCI is acylated. This stage is very long since it can last several tens of hours (up to 70 hours sometimes). It also involves stages of purification and isolation by draining and drying to obtain an intermediate for the synthesis of iodinated contrast products. The drying step presents the risk outlined above. In addition, this step involves the use of large excess of certain reagents which, for some, may prove to be costly whether it is when they are purchased or even when they are synthesized. The handling of some of these reagents (for example DiCOCI) can also pose problems because of their particle size. For this single acylation step, yields limited to approximately 87.5% are obtained. The yield of the chlorination step is about 90.5%.

Preparation processes involving acylation followed by chlorination are also known, which have the same drawbacks as mentioned above.

In particular, application WO 2012/175903 describes the production of an acylated AATI, obtained from a large excess of acylating agent. This acylated intermediate compound is then isolated, filtered and dried before being chlorinated.

Therefore, there is a need for an improved process for preparing iodinated contrast media. More particularly, there is a need for a process for the preparation of iodinated contrast products applicable on an industrial scale, which is more economical, rapid and safe.

Several patents describe processes for the preparation of ioversol or some of its synthetic intermediates: US 4,997,983, EP 0 484 328 (process of preparation

de GAATI), ER 0 598 751 (process for preparing an intermediate for the synthesis of ioversol from a compound other than GAATI, without the use of acetoxyacetyl chloride (also called 2-chloro-2-oxoethyl acetate or AAC ) and using DMAC and chloroacetyl chloride (also called CAC), EP 0 640 067 (process for preparing ioversol from a compound other than GAATI). Others describe processes for the purification of these compounds: EP 0 618 836, EP 0 646 021, EP 0 863 782, EP 1 551 522, EP 0 700 377, EP 0 470 247, EP 0 907 395, EP 0 515 480.

Other patents describe parts of this synthesis: EP 2,281,807 and EP 2,277,846.

The object of the present invention is to provide a process for the preparation of organo-iodine products, and more particularly of intermediates for the synthesis of the iodinated contrast product ioversol, making it possible to overcome the drawbacks mentioned above.

Another object of the present invention is to provide a process for the preparation of organo-iodine compounds applicable on an industrial scale, in particular a process that is safe, rapid, economical and acceptable from an environmental point of view.

The object of the present invention is to provide a process for the preparation of organo-iodine compounds intermediates for the synthesis of the iodinated contrast product ioversol exhibiting a good yield, and in particular a better yield compared to the known methods.

The present invention therefore relates to a process for preparing an organo-iodine compound comprising the following steps:

a) acylation of 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below:

to obtain an intermediate compound Ya;

then

b) chlorination of the intermediate compound Ya to obtain an organo-iodine intermediate compound Yb;

then

c) amidification of the organo-iodinated intermediate compound Yb to obtain an intermediate compound Yc;

then

d) deprotection of the intermediate compound Yc,

steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc.

Surprisingly, the inventors have implemented a one-pot process making it possible to carry out the steps a) of acylation, b) of chlorination, c) of amidification and d) of deprotection without the need to isolate at least one of the intermediate compounds. Ya and Yc, in particular without isolation of the intermediate compounds Ya and Yc. The acylation of the AATI is then carried out and then is directly followed by the chlorination of said acylated AATI without isolation of the intermediate compound Ya, itself followed by an amidification of the compound Yb, preferably without purification of the intermediate compound Yb and of the deprotection of compound Yc without isolation of intermediate compound Yc.

The succession of steps a) acylation, b) chlorination, c) amidification and d) deprotection as according to the invention is preferably carried out in the same reaction medium, and therefore corresponds to a monotopic sequence (also called “one pot” in English).

The preparation process according to the invention advantageously makes it possible to avoid the stages of separation and purification of intermediate compounds such as the synthesis intermediates Ya and / or Yc: the use of precipitation or washing solvents is reduced or avoided, as well as the treatment of the corresponding mother liquors. The preparation process according to the invention is therefore more economical, faster and more respectful of the environment.

Generally, the process is free from the addition of a non-solvent for the intermediate compound Ya during step a) and between steps a) and b). By “non-solvent of the intermediate compound” is meant a solvent in which the intermediate compound is not soluble (solubility less than 0.1 g / L, or even 0.01 g / L, at 25 ° C) and which is capable of inducing precipitation of the intermediate compound when the non-solvent is introduced into the reaction medium. An aqueous solution, such as water, is an example of a non-solvent for the intermediate compound Ya.

The solvent of step a) comprises dimethylacetamide, the process can comprise, between steps a) and b), the addition of a solvent of the intermediate compound Ya to the reaction medium obtained at the end of step a) , in order to make it more fluid. In fact, the following step b), which is carried out in the presence of a chlorinating agent, often leads to the formation of Vilsmeier complexes between the chlorinating agent and the dimethylacetamide, which can thicken the reaction medium by crystallizing. This solvent for the intermediate compound Yb is typically one of the solvents described below (preferably those devoid of an amide function) for steps a), b), c) and / or d), and is preferably propylene carbonate.

The method can comprise, at the end of step b):

the addition of a non-solvent for the intermediate compound Yb in the reaction medium obtained at the end of step b), whereby the intermediate compound Yb precipitates in the reaction medium and a reaction medium comprising a liquid phase and a precipitate is obtained,

- separation of the precipitate and the liquid phase, for example by filtration, decantation or centrifugation, then

- Dissolving the precipitate in a solvent for the intermediate compound Yb to obtain a solution which is that used to carry out step c).

The non-solvent of intermediate compound Yb is generally an aqueous solution, preferably an aqueous solution of alkali metal ion acetate, such as sodium acetate. The solvent for intermediate compound Yb is typically one of the solvents described below for steps a), b), c) and / or d).

The process is preferably free from purification of the intermediate compound Yb. Typically, when the three steps of adding a non-solvent / separating the precipitate / dissolving the precipitate are carried out, the precipitate does not undergo any purification between the separation of the precipitate from the liquid phase and its dissolution in the liquid phase. a solvent for the intermediate compound Yb, and in particular no recrystallization. The method according to the invention is applicable on an industrial scale and makes it possible in particular to obtain cumulative yields of at least 80% for the one-pot sequence of steps a), b), c) and d).

The preparation process as according to the invention also has the advantage of generating soluble intermediates (by “soluble” it is meant that the process does not generate crystals).

Definitions

The method according to the invention comprises a sequence, preferably monotopic:

- steps a) and b) in which the intermediate compound Ya resulting from the acylation (step a)) is not isolated before proceeding with the chlorination (step b)), and / or

- steps b) and c) in which the intermediate compound Yb resulting from the chlorination (step b)) is not purified before proceeding with the amidification (step c)), and / or - steps c) and d) in which the intermediate compound Yc resulting from the amidation (step c)) is not isolated before proceeding with the deprotection (step d)).

In one embodiment, in the method,

- the intermediate compound Ya resulting from the acylation (step a)) is not isolated before proceeding with the chlorination (step b)),

- the intermediate compound Yb resulting from the chlorination (step b)) is not purified before proceeding with the amidification (step c)), and

- the intermediate compound Yc resulting from the amidification (step c)) is not isolated before proceeding with the deprotection (step d).

In one embodiment, in the method:

- the intermediate compound Ya resulting from the acylation (step a)) is not separated from the reaction medium obtained at the end of step a) before proceeding with the chlorination (step b)),

- the intermediate compound Yb is not separated from the intermediate compound Ya optionally present in the reaction medium at the end of step b) before proceeding to the amidification step (step c)), and

- the intermediate compound Yc resulting from the amidification (step c)) is not separated from the reaction medium obtained at the end of step c) before proceeding with the deprotection (step d)).

A preparation process or a sequence of one-pot reactions is a process / sequence in which a synthetic intermediate, for example AATI, undergoes several successive and / or simultaneous reactions in its reaction medium, avoiding the stages of separation and purification intermediate compounds (process free of separation and purification of intermediate compounds Ya and / or Yc, and preferably free of purification of intermediate compound Yb).

The term “organo-iodine” compound is understood to mean an organic compound comprising at least one carbon atom and at least one iodine atom, for example 1, 2, 3, 4 or 5 iodine atoms, preferably 3. Said organic compound optionally comprises one or more atom (s) of hydrogen, oxygen, nitrogen, sulfur, phosphorus, halogen or a combination of these atoms. Preferably, the organo-iodine compound comprises one or more atoms of hydrogen (hydrocarbon compound), oxygen, nitrogen and optionally chlorine.

By “acylation” is meant a chemical reaction during which an acyl group is added to an organic compound such as AATI, by the action of an acylating agent.

The term “chlorination”, also called chlorination, is understood to mean the substitution of an atom and / or of a group of atoms of an organic compound by a chlorine atom, of

preferably the substitution of a hydroxyl group (-OH) by a chlorine atom (-Cl), by the action of a chlorinating or chlorinating agent, more preferably the double substitution of the hydroxyl groups (-OH) present on two functions carboxylic acids with a chlorine atom (-Cl).

By “amidification”, also called “amidation” in English, is meant the combination of an amine with a chemical group of a compound.

The term “deprotection” is understood to mean the elimination, typically by a deprotecting agent, of a functional group introduced into the molecule from a chemical function in order to mask all or part of its reactivity.

According to the present invention, the expression “reaction medium” denotes the medium in which the steps a) of acylation, b) of chlorination, c) of amidification and d) of deprotection take place. According to one embodiment, said reaction medium comprises at least one solvent and at least one reagent such as AATI and / or an acylating agent and / or a chlorinating agent and / or an amine and / or a deprotecting agent.

The term “isolation” denotes:

- the separation of an intermediate compound Ya, Yb and / or Yc from (s) the other organo-iodine compound (s) optionally present in the reaction medium,

- or even the separation of an intermediate compound Ya, Yb and / or Yc from the reaction medium,

possibly followed by its (their) purification (s). The methods of separating and / or purifying an organo-iodine compound are known to those skilled in the art. Mention may be made, for example, of filtration, chromatography (for example on grafted or ungrafted silica), centrifugation, solvent extraction, crystallization, adsorption (for example on carbon) and distillation. Preferably, the process is free from a step of separating the intermediate compound Ya from the reaction medium obtained at the end of step a) and / or from a step of separating the intermediate compound Yc from the reaction medium obtained at the end. of step c). The process is generally free from filtration of compound Ya between steps a) and b) (no separation of compound Ya) and / or it is generally free from filtration of compound Yc between steps c) and d) (no separation of compound Yc). Below are given examples of non-separation of an intermediate compound Ya, Yb and / or Yc from the other organo-iodine compound (s):

- at the end of step a), the intermediate compound Ya is not separated from GAATI possibly present in the reaction medium at the end of step a), and / or

- At the end of step b), the intermediate compound Yb is not separated from the intermediate compound Ya optionally present in the reaction medium at the end of step b), and / or

- At the end of step c), the intermediate compound Yc is not separated from the intermediate compound Yb optionally present in the reaction medium at the end of step c.

Process for preparing an organo-iodine compound

According to one embodiment, the steps a) of acylation, b) of chlorination, c) of amidification and d) of deprotection of the process according to the invention are carried out without isolation of at least one intermediate compound chosen from Ya and Yc in a single reactor or in several reactors, preferably in a single reactor.

According to one embodiment, step a) of acylating the 2,4,6-triiodo-5-aminoisophthalic acid of the following formula (A):

is produced by an acyl chloride, preferably by chloroacetyl chloride (CAC) or acetoxyacetyl chloride (AAC), more preferably by acetoxyacetyl chloride.

AAC has the advantage of not being considered a toxic and carcinogenic, mutagenic or toxic for reproduction (CMR) compound and it acts very quickly as an acylating agent.

According to a particular embodiment, the method according to the invention comprises the following steps:

a) acylation of 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below:

with a compound of the following general formula (I):

R 2 -C (0) CI (I),

R 2 being a -CH 2 -GP group in which GP is a leaving group selected from a halide, an acetate, a mesylate, a tosylate and a triflate, R 2 being from

preferably chosen from -CH 2 CI

to obtain an intermediate compound Ya;

then

b) chlorination of the intermediate compound Ya to obtain an organo-iodine intermediate compound Yb of the following general formula (II):

R 1 being H or a methyl group, preferably H, and

R 2 being as defined above, then

c) amidification of the organo-iodinated intermediate compound Yb to obtain an intermediate compound Yc;

then

d) deprotection of the intermediate compound Yc,

steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc, preferably without isolation of the intermediate compounds Ya and Yc.

Step c) is generally carried out in the presence of an amine of formula (IV):

R 3 -NH 2 (IV),

in which R 3 represents an alkyl group comprising from 1 to 6 carbon atoms, in particular from 2, 3 or 4 carbon atoms, said alkyl group being optionally substituted by one or more hydroxyl groups, preferably two hydroxyl groups, or a salt of it. The preferred amine is aminopropanediol.

Preferably, the amount of amine of formula (IV) used during step c) is such that the molar ratio of the amine of formula (IV) relative to the AATI used during step a) is from 1.5 to 4.0, in particular from 1.8 to 3.0, and preferably from 2.0 to 2.3.

The organo-iodine compound Yd obtained at the end of step d), preferably the compound of general formula (V) as defined below, is useful as an intermediate for the synthesis of the ioversol contrast product.

Ioversol is sold under the brand name Optiject® or Optiray® and has the following chemical formula:

According to one embodiment, steps a), b), c) and / or d) are carried out in the presence of an aprotic and polar solvent.

According to one embodiment, steps a), b), c) and / or d) are carried out in the presence of at least one solvent chosen from the group consisting of dimethylacetamide, propylene carbonate, acetonitrile and tetrahydrofuran or a mixture thereof. Preferably, the solvent comprises a mixture of dimethylacetamide and propylene carbonate. In particular, for the reasons detailed above, it is advantageous for the solvent of step b) to be a mixture of propylene carbonate and dimethylacetamide.

In a preferred embodiment:

- the solvent of step a) is dimethylacetamide, and / or

- the solvent of step b) is a mixture of propylene carbonate and dimethylacetamide, and / or

the solvent of step c) and / or of step d) is a mixture of dimethylacetamide and of an aqueous solution.

Steps a), b), c) and d) being preferably carried out monotopically, step b) is carried out in the reaction medium resulting from step a), step c) is carried out in the medium reaction resulting from step b) and step d) carried out in the reaction medium resulting from step c): the solvent (s) used as well as their quantity (s) are therefore preferably identical (s). According to one embodiment, during step b), one or more solvent (s) can be added to that (those) used for step a) and / or during of step c), one or more solvent (s) can be added to that (those) used for step b) and / or during step d), one or more solvent (s) can be added to that (those) used for step c).

According to another embodiment, the ratio, in liters per kilogram, between the amount of solvent (in liters) and the amount of 2,4,6-triiodo-5-aminoisophthalic acid (in kg) is between 5 per 1 and 1 to 1, preferably 3 to 1 or 2.5 to 1. Such ratios advantageously make it possible to dissolve all of the intermediate compound Yb, which makes it possible to optimize the subsequent steps c) and d).

Generally, the organo-iodine compound obtained at the end of step d) has the following formula (VI):

in which R 2 and R 3 are as defined above.

Steps a), b), c) and d) can optionally be followed by a step e) of alkylation of the compound obtained at the end of step d) with an alkylating agent, in particular ethylene oxide. or an alkylating agent of formula (VII):

R 4 -GP '(VII),

in which :

- R 4 represents an alkyl group comprising from 1 to 6 carbon atoms, in particular from 2, 3 or 4 carbon atoms, said alkyl group being optionally substituted by one or more hydroxyl groups, and

- GP 'is a leaving group, in particular chosen from a halide, a mesylate, a tosylate and a triflate,

The alkylating agent is typically 2-chloroethanol or ethylene oxide, and step e) results in the formation of the ioversol.

The embodiments described below for each of steps a) to d) can be combined with one another.

Step a) acylation

According to one embodiment, the acylation of step a) is carried out in the presence of an acylating agent chosen from chloroacetyl chloride and acetoxyacetyl chloride.

These acylating agents have the following chemical formulas:

According to one embodiment, the acylation of step a) is carried out in the presence of an acylating agent, preferably an acyl chloride, present in an amount of between 1 and 1.5 molar equivalents relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid; preferably between 1, 1 and 1, 3, for example 1, 1 or 1, 3 molar equivalent relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid.

Chlorination step b)

According to one embodiment, the chlorination of step b) is carried out in the presence of a chlorinating agent chosen from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride , phosphorus pentachloride, methanoyl dichloride and a mixture thereof. According to one embodiment, the chlorination of step b) is carried out in the presence of a reagent chosen from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride and a mixture of these . Preferably, the chlorinating agent is thionyl chloride, since the phosphorus derivatives mentioned above generate phosphate salts which are more polluting and whose removal complicates the process.

According to a particular embodiment, the amount of chlorinating agent is between 2 and 6 molar equivalents relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid, preferably between 2.5 and 5 equivalents. , more preferably between 3 and 5 equivalents, for example 3.5 or 5 equivalents, even more preferably between 3.2 and 4 equivalents, relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid.

According to one embodiment, step a) is carried out for a period of 2 to 70 hours, preferably 2 to 24 hours; and / or step b) is carried out for a period of 2 to 22 hours, preferably 4 to 12 hours.

Step a) is typically carried out at a temperature of 10 to 70 ° C, preferably 15 to 60 ° C, even more preferably 30 to 60 ° C, in particular 45 to 55 ° C, for example at 50 ° C. vs. When the temperature is too low, this decreases the yield of step a), and therefore of the process, and when it is too high, there is generation of more impurities, therefore reduction in purity. The above temperature ranges are optimal for reducing the occurrence of certain impurities while maintaining an economically acceptable reaction time.

Step b) is preferably carried out at a temperature from -15 to 30 ° C, preferably from -10 to 10 ° C, even more preferably from 0 to 10 ° C.

Step c) of amidification

According to one embodiment, the amidification of step c) is carried out in the presence of aminopropanediol (also called APD).

Preferably, the amidation of step c) is carried out in the presence of a base, in particular an inorganic base, for example sodium hydroxide (NaOH). Inorganic bases are generally less toxic than some organic bases such as triethylamine. In addition, using an organic base comprising an amine function requires adding a step of removing the ammonium salt formed from this organic base, which complicates the process and makes it difficult to carry out the process without isolating the process. intermediate compound Yc. The use of an inorganic base such as NaOH generates salts, such as NaCl, which are less soluble in the reaction medium obtained at the end of step b) and therefore which will be more easily removable from the reaction medium.

Step c) is generally carried out in the presence of an aqueous solution, typically an aqueous solution of an inorganic base, such as an aqueous solution of NaOH. There was a technical prejudice to carry out step c) in the presence of an aqueous solution, because the person skilled in the art would have expected the

degradation of the acyl chloride functions of intermediate compound Yb in the presence of such a solution, degradation which would lead to reforming intermediate compound Ya. Water is known to be harmful for amidification starting from an acyl chloride.

Step c) is generally carried out at a temperature of 5 to 30 ° C, preferably 5 to 20 ° C, even more preferably 5 to 15 ° C. Such temperatures make it possible in particular to reduce the content of polar impurities (for example, mono-amidified impurities).

Deprotection step d)

A person skilled in the art is able to determine, in view of his general knowledge illustrated by the book “Greene's Protective Groups in Organic Synthesis” by Wiley (ISBN-13: 978-0471697541) how to deprotect according to the nature of the protective group. and therefore the acylating agent used in step a).

According to one embodiment, the deprotection of step d) is carried out first by adding a base and then by adding an acid. Preferably, a base chosen from organic bases or inorganic bases will be used. More preferably, an organic base will be used chosen from a mixture of triethylamine and methanol, a mixture of pyridine and water and their mixtures. More preferably, an inorganic base will be used chosen from sodium hydroxide, aqueous ammonia, a mixture of ammonia and toluene, potassium carbonate (K 2 C0 3), a mixture of hydrazine and methanol and mixtures thereof. Preferably, an inorganic acid will be used. More preferably, an inorganic acid chosen from hydrochloric acid, phosphoric acid, sulfuric acid and their mixtures will be used.

According to one embodiment, the deprotection of step d) is carried out first by adding a base and then by adding an acid followed by the addition of a solvent. The solvent is preferably chosen from isopropanol, ethanol, methanol and their mixtures, more preferably isopropanol, ethanol and their mixtures.

According to one embodiment, the deprotection of step d) is carried out first by adding a base such as an inorganic base, typically a mixture of sodium hydroxide and water, then by adding an acid such as an inorganic acid such as hydrochloric acid, optionally followed by the addition of isopropanol. This embodiment is particularly suitable when the acylating agent of step a) was acetoxyacetyl chloride. The acetyl group is thus deprotected on the compound obtained in step c). Preferably, the deprotection of step d) is carried out at a temperature of 15 to 70 ° C, preferably 20 to 60 ° C, even more preferably from 30 to 55 ° C.

When chloroacetyl chloride is used as acylating agent in step a), the deprotection of step d) is carried out by

- addition of an acidic aqueous solution, such as an aqueous hydrochloric acid solution, typically up to a pH of 3.0 to 4.5, pressurized to a pressure of 1.05 to 1.5 bars , for example 1, 2 bars and heating to a temperature between 1 10 and 130 ° C, and the pH of the reaction medium between 3.0 and 4.5 by adding a base, for example sodium hydroxide, then

- Addition of a base, for example an aqueous solution of NaOH, until the pH of the reaction medium reaches 4.5 to 5.5.

The examples appearing below are presented by way of illustration and are not limiting of the invention.

EXAMPLES

The term “V” is intended to denote a volume ratio, ie the volume of a reagent or of a solvent relative to 1 kg of AATI.

By “eq. Is intended to denote a number of molar equivalents, ie the ratio between the number of moles of a reagent and the number of moles of AATI.

Example 1: Synthesis according to the invention of an intermediate for the synthesis of ioversol

Synthesis diagram

MP602 from AATI

Acylation step;

2-Chloro-2-oxoethyl acetate also called AAC (281g, 1.15 eq.) Is dissolved in dimethylacetamide (DMAC) (1.35L) and GAATI (1 kg, 1.0 eq.) Is gradually added at 50 ° C. The reaction mixture is mixed for 6 hours at 50 ° C. Propylene carbonate (1.15L) is added and the reaction is cooled to 5 ° C.

Chlorination step:

SOCI 2 thionyl chloride (745g, 3.5 eq.) Is poured at 5 ° C for 2 hours and the reaction medium is mixed for 5 hours at 5 ° C.

The reaction medium is poured into an aqueous solution of sodium acetate (AcONa) so as to precipitate the “DiCOA like” synthesis intermediate. The suspension is filtered and the solid part is re-dissolved in DMAC (1.5 mL) to obtain a solution.

Amidification step:

A mixture of aminopropanediol (APD) (359 g, 2.2 eq.) And a 30% aqueous sodium hydroxide solution (NaOH) (359 ml) is poured into the solution for 6 hours. The reaction medium is mixed for 2 hours at 12.5 ° C.

Deprotection step:

Water (1 L) and a 30% aqueous sodium hydroxide solution (NaOH) (359 ml) are added at 50 ° C. for 2 h 30 min. 37% hydrochloric acid (HCl) (900 mL) is then added at 50 ° C and the reaction is cooled to 5 ° C. The suspension is filtered, washed with an isopropanol (IPA) / water mixture and dried. The yield obtained is 83% and the purity obtained is 99%.

Example 2: synthesis of ioversol from the synthesis intermediate obtained according to the invention

The compound obtained in Example 1 is then alkylated using 2-chloroethanol or ethylene oxide. The compound thus obtained is then purified and dried in order to obtain the ioversol.

MP 602 Ioversol

Mw = 763.07 Mw = 807.12
CLAIMS

1. Process for preparing an organo-iodine compound comprising the following steps:

a) acylation of 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below:

to obtain an intermediate compound Ya;

then

b) chlorination of the intermediate compound Ya to obtain an organo-iodine intermediate compound Yb;

then

c) amidification of the organo-iodinated intermediate compound Yb to obtain an intermediate compound Yc;

then

d) deprotection of the intermediate compound Yc,

steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc.

2. Preparation process according to claim 1, comprising the following steps: a) acylation of 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below:

with a compound of the following general formula (I):

R 2 -C (0) CI (I),

R 2 being a -CH 2 -GP group in which GP is a leaving group chosen from a halide, an acetate, a mesylate, a tosylate and a triflate,

to obtain an intermediate compound Ya;

then

b) chlorination of the intermediate compound Ya to obtain an organo-iodine intermediate compound Yb of the following general formula (II):

R 1 being H or a methyl group, preferably H, and

R 2 being as defined above,

then

c) amidification of the organo-iodinated intermediate compound Yb to obtain an intermediate compound Yc;

then

d) deprotection of the intermediate compound Yc,

steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc.

3. Preparation process according to claim 1 or 2, free from a step of separating the intermediate compound Ya from the reaction medium obtained at the end of step a).

4. Preparation process according to any one of claims 1 to 3, free from a step of separating the intermediate compound Yc from the reaction medium obtained at the end of step c).

5. Preparation process according to any one of claims 1 to 4, in

which R 2 is selected from -CH 2 CI

6. Preparation process according to any one of claims 1 to 5, wherein steps a), b), c) and d) are carried out without isolation of the intermediate compounds Ya and Yc.

7. Preparation process according to any one of claims 1 to 6, wherein steps a), b), c) and d) are carried out without purification of the intermediate compound Yb.

8. Preparation process according to any one of claims 1 to 7, free of addition of a non-solvent of the intermediate compound Ya during step a) and between steps a) and b).

9. Preparation process according to any one of claims 1 to 8, wherein steps a), b) c) and d) are carried out in a single reactor.

10. Preparation process according to any one of the preceding claims, in which steps a), b), c) and d) are carried out in the presence of at least one solvent chosen from the group consisting of dimethylacetamide, carbonate of propylene, acetonitrile and tetrahydrofuran or a mixture thereof.

11. Preparation process according to any one of the preceding claims, in which the solvent of step b) is a mixture of propylene carbonate and dimethylacetamide.

12. Preparation process according to any one of the preceding claims, in which step c) is carried out in the presence of an aqueous solution, in particular an aqueous solution of an inorganic base, preferably an aqueous solution. of NaOH.

13. Preparation process according to any one of claims 10 to 12, wherein:

- the solvent of step a) is dimethylacetamide, and / or

the solvent of step c) and / or of step d) is a mixture of dimethylacetamide and of an aqueous solution.

14. Preparation process according to any one of the preceding claims, in which the chlorination of step b) is carried out in the presence of a chlorinating agent chosen from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, phosphorus pentachloride, methanoyl dichloride and a mixture thereof.

15. Preparation process according to any one of the preceding claims, comprising, at the end of step b):

the addition of a non-solvent for the intermediate compound Yb in the reaction medium obtained at the end of step b), whereby the intermediate compound Yb precipitates in the reaction medium and a reaction medium comprising a liquid phase and a precipitate is obtained,

- separation of the precipitate and the liquid phase, then

- Dissolving the precipitate in a solvent for the intermediate compound Yb to obtain a solution which is used to carry out step c).

16. Preparation process according to any one of the preceding claims, in which the amidification of step c) is carried out with aminopropanediol.

17. Preparation process according to any one of the preceding claims, in which the deprotection of step d) is carried out with sodium hydroxide, hydrochloric acid or a mixture thereof.