The present invention relates to a process for preparing organo-iodine compounds and its preparation intermediates. More particularly, the present invention relates to a process for preparing organo-iodine compounds useful as intermediates for the preparation in the synthesis of iodinated contrast agents.
Currently, most methods for the synthesis of iodinated contrast agents using the dichloride of 5-amino-2,4,6-triiodoisophtalique acid (also called DiCOCI) of the following formula:

This compound is especially used as an intermediate in the synthesis of many contrast agents such as iopamidol (lopamiron®), iohexol (Omnipaque®), ioversol (Optiray®), iomeprol (lomeron®) or 'iobitridol (Xenetix®).

In the synthesis of iodinated contrast agents, it is necessary to realize long steps of separation and purification to result in synthesis intermediates with a good degree of purity. These steps significantly increase the time of completion of the synthesis and thus increase and the cost of implementing the preparation of contrast media processes.

One of the steps of manufacturing the DiCOCI is a step of chlorination (also called chlorination) of 5-amino-2,4,6-triiodoisophtalique acid (AATI) with a chlorinating agent such as thionyl chloride, also known as thionyl dichloride (SOCI 2 ). This chlorination step is slow (over 7 hours 30 minutes reaction time) and energy-intensive, since it is carried out at an elevated temperature of over 48 ° C. A large excess of the chlorinating agent to the AATI provides a higher kinetic but the use of this excess is not acceptable from an industrial and environmental point of view. Indeed, thionyl chloride, in contact with water, releases hydrogen chloride (HCl) and sulfur dioxide (S0 2), Which are corrosive and irritating gases. The use of catalysts of this chlorination reaction was advocated so as to reduce the amount of SOCI 2 used while getting a good industrial performance.

The DiCOCI preparation methods used also have the disadvantage of generating a large amount of waste, due to the use of large amounts of water during hydrolysis "dashing" of DiCOCI obtained by chlorination step . For example, in patent application EP 0794937 is described the addition of 22.2 to 33 equivalents of water per equivalent of AATI (Examples 1 to 3) or in patent application EP 0773925 is described the addition of 120 equivalents of water (see example 1 -E) to hydrolyze the thionyl chloride. Finally, these processes require the construction of purification steps by precipitation, filtration and drying, to ensure optimum performance and competitive responsiveness in the following steps. Note also that the drying step can s'

Following this step of chlorination, the DiCOCI is acylated. This step is very long because it can last several tens of hours (up to 70 hours sometimes). It also involves the steps of purification and isolation by filtration and drying to obtain an intermediate of synthesis of iodinated contrast agents. The drying step presents the risk outlined above. Moreover, this step involves the use of large excesses of certain reagents which may for some be costly whether to purchase or even their synthesis. The handling of some of these reagents (eg DiCOCI) can also cause problems because of their size. For this one step acylation, yields are obtained limited to approximately 87.5%. The yield of chlorinating step is about 90.5%. The performance of the combination of steps of chlorination and acylation is then about 79.2%.

It is also known methods of preparation involving acylation followed by chlorination which present the same drawbacks as mentioned above.

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

Therefore, a need exists for a method of improved iodinated contrast agents. Specifically, there is a need for contrast media iodinated preparation method applicable on an industrial scale, economical, fast and safe.

The present invention aims to provide a process for preparing organo-iodine products, and more particularly to synthetic intermediates of iodinated contrast agents, which overcomes the disadvantages mentioned above.

The present invention also aims to provide a process for preparing organo-iodine compounds applicable on an industrial scale, in particular a method safe, fast, economical and acceptable from an environmental point of view.

The present invention aims to provide a process for preparing organo-iodine compounds having a good performance, including improved performance over known methods.

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

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

to obtain an intermediate compound Y;

then

b) chlorination of the intermediate compound Y obtained in step a);

steps a) and b) being carried out without isolation of the intermediate compound Y.

Surprisingly, the inventors have implemented a one-pot method for making the steps a) and acylation b) chlorination in the same reaction medium, without need to isolate the acylated reaction intermediates obtained in step a) (intermediate compounds Y). Thus, the acylation of the AATI is performed is then directly followed by the chlorination of said AATI thus resulting acylated organo-iodine compound of interest with a satisfactory level of purity and without isolating the acylated AATI.

The sequence of steps a) and acylation b) chlorination as according to the invention corresponds to a sequence pot.

The preparation process according to the invention advantageously avoids the steps of separation and purification of intermediates of synthesis Y: the precipitation solvent or washing are avoided, as well as treatment of the corresponding mother liquors. The preparation process according to the invention is more economical, faster and more environmentally friendly.

The method according to the invention is especially applicable to the industrial scale and provides cumulative yields of at least 80% for the one-pot sequence of steps a) and b).

The preparation process as that according to the invention also has the advantage of generating soluble intermediate ( "soluble" is meant that the method does not generate crystals).

Definitions

The method according to the invention comprises a one-pot sequence of steps a) and b) (also called "one pot" in English), wherein the intermediate compound Y resulting from the acylation (step a)) is not isolated before to carry out the chlorination (step b)).

A method for preparing or a series of one-pot reactions is a method / concatenation wherein a feedstock, e.g. AATI, undergoes several successive reactions and / or simultaneous in the reaction medium, avoiding the steps of separation and purification intermediate compounds (e.g., the intermediate compounds Y).

By compound "organo-iodine" means 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), hydrogen, oxygen, nitrogen, sulfur, phosphorus, halogen or a combination of these atoms. Preferably, the organo-iodine compound comprises one or more hydrogen (hydrocarbon compound), oxygen, nitrogen and optionally chlorine.

The term "acylating" means a chemical reaction in which an acyl group is added to an organic compound such as AATI, by the action of an acylating agent.

By "chlorination", also known chlorination is meant the substitution of an atom and / or an atomic group of an organic compound with a chlorine atom, preferably the substitution of a hydroxyl group (-OH ) by a chlorine atom (-Cl), by the action of a chlorinating agent or chlorinating, more preferably the double substitution of the hydroxyl groups (-OH) present on two carboxylic acid functions by a chlorine atom (-Cl) .

According to the present invention, the term "reaction medium" means the medium in which are held the steps a) and acylation b) chlorination of the invention. 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 chlorinating agent.

By "isolated" is meant the separation of an organo-iodine compound, preferably the intermediate compound Y of the reaction medium as according to the invention, optionally followed by purification. The methods of separation and / or purification of an organo-iodine compound are known to those skilled in the art. Can for example be cited filtration, chromatography (e.g. on silica grafted or not), centrifugation, solvent extraction, crystallization, adsorption (e.g. charcoal) and distillation.

The term "(Ci-C 2 o) alkyl" means a saturated hydrocarbon group comprising from 1 to 20 carbon atoms, linear or branched. By "branched" means one or more alkyl groups (s) are attached to a linear alkyl. Preferably, the alkyl are selected from methyl, ethyl, propyl and isopropyl.

The term "(Ci-C 2 o) alkenyl" means alkyl as defined above and comprising one or more double (s) link (s) carbon-carbon (ethylenically unsaturated). When they comprise a single double bond, they may typically be represented by the formula C n H 2n , where n is the number of carbon atoms. Among the alkenyl radicals, there may be mentioned allyl or vinyl radicals.

The term "(Ci-C 20 ) alkynyl" means alkyl as defined above and comprising one or more triple (s) link (s) carbon-carbon (acetylenic unsaturation). When they comprise a single triple bond, which may typically be represented by the formula C n H 2n - 2 , n representing the number of carbon atoms. Among the alkynyl radicals, there may be mentioned acetylene, ethynyl or propynyl.

The term "(C 3 -Cio) cycloalkyl" means a saturated cyclic hydrocarbon group and, for example monocyclic or bicyclic, comprising from 3 to 10 carbon atoms. Among cycloalkyls include cyclopropyl, cyclopentyl or cyclohexyl.

The term "(C 6 -C 10 ) aryl" means a cyclic aromatic group (monocyclic, bicyclic or tricyclic) comprising 6 to 10 carbon atoms, eg phenyl and naphthyl. Preferably the aryl moiety is phenyl.

The term "heterocyclyl comprising 3 to 10 carbon" is meant a cycloalkyl as defined above and wherein one or more carbon atoms are replaced by one or more hétérotatomes such as oxygen, sulfur or nitrogen. For example, heterocyclyl with 1 or 2 sulfur atom (s) of nitrogen, 1 or 2 sulfur atom (s) oxygen, 1 or 2 sulfur atom (s) of sulfur or a combination thereof. Among heterocyclyls, there may be mentioned the epoxyethyl, the oxiranyl, aziridinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, the dithiolanyl, thiazolidinyl, tetrahydropyranyl, dioxanyl , morpholinyl, piperidyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydrofuranyl, 2-imidazolinyl, 2, -3-pyrrolinyl, pyrazolinyl, dihydrothiophenyl, dihydropyranyl, pyranyl, tetrahydropyridyl, dihydropyridyl the the tétrahydropyrinidinyle the dihydrothiopyranyl, and the corresponding groups derived from fusion with a phenyl nucleus, and more particularly morpholinyl cycles, dioxalanyl, benzothiazolidinyl, pyrrolidinyl, benzopyrrolidinyl. Preferably, the heterocyclyl is a dioxanyl.

By "heteroaryl comprising from 6 to 10 carbon atoms" means aryl as defined above and wherein one or more carbon atoms are replaced by one or more hétérotatomes such as oxygen, sulfur or nitrogen. For example, heteroaryls have 1 or 2 oxygen atom (s) of nitrogen, 1 or 2 sulfur atom (s) oxygen, 1 or 2 sulfur atom (s) of sulfur or a combination thereof. Among the heteroaryl radicals that may be mentioned pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1, 2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1 , 2-a] pyridine, imidazo [2,1-b] thiazolyl, cinnolinyl, triazinyl, benzofurazanyl, the azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl the, the pyrrolopyridyl,

The term "halogen" refers to atoms of group 17 of the periodic table and includes in particular fluorine, chlorine, bromine and iodine. Preferably, the halogen is chlorine.

Also included according to the present invention the stereoisomers, hydrates, solvates, organic or inorganic salts of organo-iodine compounds, preferably of the general formula (I), and intermediates are also included Y. their tautomeric forms, enantiomers, atropisomers, diastereoisomers and epimers.

A process for preparing an organo-iodine compound

According to one embodiment, steps a) and acylation b) chlorination of the method according to the invention are carried out without isolation of the intermediate compound Y in a single reactor or in multiple reactors, preferably in a single reactor.

According to one embodiment, the acylation of isophthalic 2,4,6-triiodo-5-acid of formula (A):

is performed with an acyl chloride.

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):

with a compound of general formula (II):

R 2 -C (0) CI (II)

to obtain an intermediate compound Y;

then

b) chlorination of the intermediate compound Y to obtain an organo-iodine compound of general formula (I):

Ri being H or methyl, R \ is preferably H, and

R 2 is selected from the group consisting of:

- (Ci-C 20 ) linear or branched alkyl;

- (Ci-C 20 ) alkenyl, linear or branched;

- (Ci-C 20 ) alkynyl, linear or branched;

- (C 3 -Cio) cycloalkyl;

- (C 6 -Cio) aryl;

- heterocyclyl comprising 3 to 10 atoms; and

- heteroaryl comprising from 6 to 10 atoms;

said alkyl, alkenyl and / or alkynyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen, oxygen and nitrogen;

said alkyl, alkenyl and / or alkynyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0-, and -OC (O) -; and

said cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups is optionally substituted by one or more substituent (s) selected (s) from the group consisting of (Ci-C 20 ) linear or branched alkyl, oxygen, halogen atoms and 'nitrogen.

According to one embodiment, to obtain compounds of formula (I) above wherein R is methyl, the process of the invention comprises an additional step of acylation of 2,4,6-triiodo-5 acid -aminoisophtalique with a compound of formula me-C (0) CI.

According to another embodiment, to obtain compounds of formula (I) above wherein R is methyl, the process of the invention comprises an additional step of acylation of the intermediate compound Y with a compound of formula Me-C (0) CI.

As indicated above, when R 2 is alkyl, alkenyl or alkynyl, the latter may be substituted by at least one nitrogen atom, for example alkyl, alkenyl or alkynyl may be substituted with at least one function amino (primary, secondary or tertiary), or be interrupted by a group -NH- or -N ((dC 6 ) alkyl), or when R 2 is alkynyl, be interrupted by at least one nitrogen atom .

According to one embodiment, R 2 is selected from the group consisting of:

- (CrCio) -straight or branched alkyl;

- (CrCio) alkenyl linear or branched;

- (Ci-Cio) alkynyl, linear or branched;

- (C 3 -Cio) cycloalkyl;

- heterocyclyl comprising 3 to 10 atoms; and

said alkyl, alkenyl and / or alkynyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen atoms;

said alkyl, alkenyl and / or alkynyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0-, and -OC (O) -; and

said cycloalkyl and / or heterocyclyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of (CC 10 ) linear or branched alkyl groups and halogen atoms.

Preferably, R 2 is selected from the group consisting of:

- (CC 2 o) -straight or branched alkyl; and

- heterocyclyl comprising 3 to 10 atoms;

said alkyl group being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen atoms; said alkyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0 or -OC (O) -; and said heterocyclyl group being optionally substituted by one or more substituent (s) selected (s) from the group consisting of (Ci-C 20 ) linear or branched alkyl groups and halogen atoms.

More particularly R 2 is selected from the group consisting of:

When referred to the group, it is also mentioned as well as its (R) isomer as its (S) isomer or a racemic mixture of the isomeric forms (R) and (S) of this group.

According to a particular embodiment, R 2 is selected from the group consisting of:

H 2 Cl; preferably R 2 is:

In particular, organo-iodine compounds obtained, preferably the organo-iodine compounds of general formula (I) are as follows and are useful for the preparation of the corresponding contrast agents, listed in Table 1 below.

Table 1: organo-iodinated compounds of general formula (I) and corresponding contrast agents

chemical formula of the organo-iodine compound name organo-iodine product name of general formula (I) of general formula (1) which contrast it is the synthesis intermediate

O Cl Dichloride 5 - [[[2- (1 - lobitridol

methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4,6-triiodo- 1, 3-benzènedicarbonyle (or

DICOA)

Dichloride, 5 - {[(2S) -2- Iopamidol

(Acetyloxy) -l -oxopropyljamino- 2,4,6-triiodo-1, 3-benzene

dicarbonyle

Dichlorure de 5-(acetylamino)- lohexol

2,4,6-triodobenzène-1 ,3- lodixanol dicarbonyle

Dichloride loversol 5- {[(acetyloxy) acetyl] amino} -2,4,6-triiodobenzene-1, 3-dicarbonyl

Dichlorure de 5- loversol [(chloroacétyl)amino]-2,4,6- triiodobenzène-1 ,3-dicarbonyle

Dichloride, 5 - {[(acetyloxy) - lomeprol acetyl] methylamino} -2,4,6-triiodobenzene-1, 3-dicarbonyl

0 1 1 0

The chemical formulas of these iodinated contrast agents are:

According to one embodiment, the organo-iodine compounds obtained, preferably of general formula (I) according to the invention are useful as synthetic intermediates of the following contrast agents: lobitridol, Iopamidol, lohexol, lodixanol, lomeprol and loversol.

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

According to one embodiment, steps a) and b) are carried out in the presence of at least one solvent selected from the group consisting of dimethylacetamide, propylene carbonate, acetonitrile and tetrahydrofuran or a mixture thereof -this. Of

Preferably the solvent comprises a mixture of dimethylacetamide and propylene carbonate.

Steps a) and b) being carried out one-pot, step b) is performed in the reaction medium resulting from step a): (s) Solvent (s) (s) used as well as their (s) amount (s) are therefore preferably identical (s). According to one embodiment, during step b), one or more solvent (s) bit (s) may be added (s) to that (those) used (s) for step a).

According to another embodiment, the ratio in liters per kilogram of the amount of solvent (in liters) and the amount of 2,4,6-triiodo-5-aminoisophthalic acid (in kg) is between 5 to 1 and 1 to 1, preferably 3: 1 or 2.5: 1.

Etape a) d'acylation

According to one embodiment, the acylation step a) is carried out in the presence of an acylating agent selected from the DHP-COCI, acetyl chloride, 2- acetoxypropionyle, chloroacetyl chloride, and acetoxyacetyl chloride.

These acylating agents have the following chemical formulas:

Chloroacetyl chloride 79-04-9

Acetoxyacetyl chloride 13831 -31 -7 o

According to one embodiment, the acylation step a) is carried out in the presence of an acylating agent, preferably an acyl chloride, present in an amount 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 equivalents relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid.

Step b) chlorination

According to one embodiment, the chlorination step b) is carried out in the presence of a chlorinating agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride , phosphorus pentachloride and dichloride methanoyl. According to one embodiment, the chlorination step b) is carried out in the presence of a reagent selected from the group consisting of thionyl chloride, phosphorus trichloride and phosphorus pentachloride. Preferably, the chlorinating agent is thionyl chloride.

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 to 5 equivalents, more preferably between 3.2 and 4 equivalents relative to the amount of 2,4,6-triiodo-5-aminoisophthalic acid.

Preparation of the acylating agent

According to one embodiment, one of the acylating agent preparation step is performed prior to step a), preferably without isolation of the resulting acylating agent. According to one embodiment, the method comprises a one-pot sequence of steps of:

- preparation of the acylating agent;

- step a) acylating as defined above; and

- step b) chlorination as defined above.

In particular, the synthesis of the acylating agent is carried out in the same reactor as that in which will be carried out the steps a) and b) as of the invention. Preferably, the acylating agent is prepared by chlorination of the carboxylic acid corresponding thereto. Preferably, the carboxylic acid corresponding to the acylating agent used in the process of preparation according to the invention is chosen from 2- (1-methylethyl) -1, 3-dioxane-5-carboxylic acid, acetic acid the acetoxypropionic acid, chloroacetic acid and acetoxyacetic acid.

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

According to another embodiment, step a) is conducted at a temperature of 10 to 70 ° C, preferably from 15 to 60 ° C, even more preferably from 15 to 30 ° C, for example between 15 and 20 ° C. According to another embodiment, step b) is performed at a temperature from -15 to 30 ° C, preferably from -10 to 10 ° C, even more preferably from 0 to 10 ° C.

intermediates for preparing compounds Y

The present invention also relates to a compound of general formula (Y1) as follows:

Ri being H or methyl, R \ is preferably H, and

R 2 is selected from the group consisting of:

- (Ci-C 20 ) linear or branched alkyl;

- (Ci-C 20 ) alkenyl, linear or branched;

- (Ci-C 20 ) alkynyl, linear or branched;

- (C 3 -Cio) cycloalkyl;

- (C 6 -Cio) aryl;

- heterocyclyl comprising 3 to 10 atoms; and

- heteroaryl comprising from 6 to 10 atoms;

said alkyl, alkenyl and / or alkynyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen, oxygen and nitrogen;

said alkyl, alkenyl and / or alkynyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0-, and -OC (O) -; and

said cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups is optionally substituted by one or more substituent (s) selected (s) from the group consisting of (CC 2 o) -straight or branched alkyl, oxygen, halogen atoms and nitrogen;

provided that R 2 is different from the moiety

According to one embodiment, R 2 is as defined above for the com bold organo-iodine of general formula (I), provided that R 2 is different

of

Preferably, the above compound has one of the following formulas:

Preferably, the compounds are the compounds (y), (by) and (Cy). The compounds of general formula (Y1) correspond in particular to the intermediates Y are as defined above.

The present invention also relates to the use of compounds of general formula (Y1) as defined above for the preparation of organo-iodine compounds, preferably of the general formula (I) as defined above.

The present invention also relates to the use of compounds of general formula (Y1) as defined above for the preparation of contrast agents, preferably for the preparation of iodinated contrast agents and more preferably for the preparation of iopamidol (lopamiron®), iohexol (Omnipaque®), ioversol (Optiray®), iomeprol (lomeron®) or iobitridol (Xenetix®).

Preferably, the present invention relates to the use of the compound of general formula:

for the preparation of iobitridol

Use of compound of general formula

for the preparation of ioversol and / or use of the compound of general formula for the preparation of iomeprol.

The examples below are presented for illustrative purposes and are not restrictive of the invention.

EXAMPLES

Analytical methods

synthesis of the compounds are analyzed by both techniques of nuclear magnetic resonance: proton NMR at 400 MHz and carbon 13 NMR at 100 MHz. The compounds are solubilized in DMSO-d6. The compounds are also analyzed by mass spectrometry in negative mode and in positive mode. Identifying NMR is performed with a brand NMR Bruker, 400Mz. The MS identification with an Orbitrap type mass spectrometer Q-Brand Thermo Fischer Exactive,

By "V" is meant a volume ratio or the volume of a reagent or a solvent with respect to 1 kg AATI.

By "eq. "Is meant a number of molar equivalent or the ratio between the number of moles of a reagent and the number of moles of the AATI.

Example 1: Synthesis of dichloride of 5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino-2,4,6-triiodo-1, 3-benzènedicarbonyl (DICOA)

General scheme of the synthesis

Acid Chloride Acid 2,4,6-Triiodo-5-aminoisophthalique acid

2- (1-methylethyl) -1, 3 2- (1-methylethyl) -1, 3-dioxane - dioxane-5-carboxylic acid

5-carboxylic acid e (ape g) . acy | atjon

Acid

5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4,6-triiodo-1, 3-benzenedicarboxylic

step b): chlorination S0CI 2

Dichlorure de 5-[[[2-(1 -methylethyl)-1 ,3-dioxan-5-yl]carbonyl]amino]-2,4,6-triiodo-1 ,3-benzènedicarbonyle

"DICOA"

PROCEDURE 1:

acylation step:

Dimethylacetamide (33,7ml_; 1, 35V) and 2- (1-methylethyl) -1, 3- dioxane-5-carboxylic acid (. 8,7 g, 1, 125 eq) are mixed at 25 ° C until dissolution of the starting acid. The reaction medium is cooled to 0 ° C and then thionyl chloride

(6.31 g, 1 .06 eq./ starting acid) is added in 1 h-1 h 30 at 0 ° C and 15 ° C. The medium is

stirred for 3 h at 15 ° C to complete the reaction. Propylene carbonate (3,7ml_, 0,15V) was added at 15 ° C in a reactor of 250 mL.

Next, 5-amino-2,4,6-triiodoisophtalique acid (25 g; 1 eq.) Was added during 30 minutes. At the end of the introduction, the mixture is warmed to 18 ° C, then the acylation reaction is carried out for 24 hours at a temperature between 18 ° C and 30 ° C.

The intermediate 5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4,6-triiodo-1, 3-benzenedicarboxylic acid (compound (ay) ) is then formed.

The medium is then fluidized with propylene carbonate (25mL: 1 volume ratio) and then cooled to 5 ° C.

Step chlorination:

As soon as the medium has reached the temperature of 5 ° C, thionyl chloride (18 g; molar equivalent ratio of 3.5) was added. The thionyl chloride addition lasted 2 hours at 5 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 5 hours at 5 ° C.

Then the obtained conversion rate is 85% (s / s) dichloride, 5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4, 6-triiodo-1, 3 benzènedicarbonyl.

The reaction mixture is slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed.

The yield obtained is 82%.

ANALYTICAL RESULTS:

Nuclear Magnetic Resonance:

1H NMR (400 MHz, DMSO-d6) δ : 10.4 (s, 1 H), 4.3 (d, J = 4.9 Hz, 1 H), 4.3 (m, 2H), 3.9 (t, J = 1 1 .4 Hz, 2H), 3.0 (ddt, J = 1 1 .1 , 6.9, 4.6 Hz, 1 H), 1 .7 (dhept, J = 6.9, 4.8 Hz, 1 H), 0.9 (d, J = 6.8 Hz, 6H).

13C NMR (101 MHz, DMSO-d6) δ: 169.4-169.8, 168.3, 149.7-150.3, 143.1 -143.9, 105.0, 87.1 -102.0, 69.0, 41 .9, 32.5, 17.3.

Mass spectrometry :

[M - H] " = 749.7321 one (masse one exacte = 749.7310)

[M + H] + = 751 one .7453 (.7456 masse one exacte = 751)

PROCEDURE 2

acylation step:

Dimethylacetamide (40ml_; 1, 6V) and 2- (1-methylethyl) -1, 3-Dioxane-5-carboxylic acid (. 10.2 g, 1, 3 eq) were introduced into a reactor of 250 mL volume. The reaction medium is cooled to 0 ° C and thionyl chloride (5.4g 1 .06 eq./ starting acid) is added in 1 h-1 h 30 at 0 ° C and 15 ° C. The medium is stirred for 3 h at 15 ° C to complete the reaction. Next, 5-amino-2,4,6-triiodoisophtalique acid (25g, 1 eq.) Was added during 30 minutes.

At the end of the introduction, the mixture is warmed to 18 ° C, then the acylation reaction is carried out for 70 hours at a temperature of 18 ° C.

The intermediate 5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4,6-triiodo-1, 3-benzenedicarboxylic acid (compound (ay) ) is then formed.

Step chlorination:

The reaction medium is then cooled to -10 ° C. As soon as the medium reaches a temperature of -10 ° C, thionyl chloride (26,6g, 5 eq.) Was added. The thionyl chloride addition lasted 2 hours at the temperature of -10 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 12 hours at the temperature of -10 ° C.

Then the obtained conversion rate was 86% (s / s) dichloride, 5 - [[[2- (1-methylethyl) -1, 3-dioxan-5-yl] carbonyl] amino] -2,4, 6-triiodo-1, 3-benzènedicarbonyle.

The reaction mixture was then slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed.

The yield obtained is 84.5%

ANALYTICAL RESULTS:

Nuclear Magnetic Resonance:

1H NMR (400 MHz, DMSO-d6) δ : 10.4 (s, 1 H), 4.3 (d, J = 4.9 Hz, 1 H), 4.3 (m, 2H), 3.9 (t, J = 1 1 .4 Hz, 2H), 3.0 (ddt, J = 1 1 .1 , 6.9, 4.6 Hz, 1 H), 1 .7 (dhept, J = 6.9, 4.8 Hz, 1 H), 0.9 (d, J = 6.8 Hz, 6H).

13C NMR (101 MHz, DMSO-d6) δ : 169.4-169.8, 168.3, 149.7-150.3, 143.1 -143.9, 105.0, 87.1 -102.0, 69.0, 41 .9, 32.5, 17.3.

Mass spectrometry :

[M - H] " = 749.7321 one (masse one exacte = 749.7310)

[M + H] + = 751 one .7453 (.7456 masse one exacte = 751)

Example 2: Synthesis of dichloride of 5- (acetylamino) -2,4,6-triodobenzène-1, 3-dicarbonyl (synthesis intermediate of lohexol / lodixanol)

Schematic overview

Chlor

Acide 5-amino-2,4,6-triiodoisophtalique

step a): acylating

5- (ace 1, 3-dicarboxylic acid

is

step b):

Dichlorure de 5-(acetylamino)-2,4,6-triiodobenzène-1 ,3-dicarbonyle

acylation step:

Dimethylacetamide (67,5ml_; 1, 35V) and propylene carbonate (7,5ml_; 0,15V) were mixed in a reactor of 250 ml volume.

Acetyl chloride (7.7 g;. 1, 1 eq) was then added to the mixture. After cooling to 15 ° C, 5-amino-2,4,6-triiodoisophtalique acid (50 g; 1 eq.) Was added during 30 minutes. At the end of the introduction, the mixture is warmed to 18 ° C, then the acylation reaction is carried out for 36 hours at a temperature of 18 ° C.

The intermediate 5- (acetylamino) -2,4,6-triiodobenzene-1, 3-dicarboxylic acid (compound (dy)) is then formed.

The medium is then fluidized with dimethylacetamide (50 mL; 1 V) and propylene carbonate (50 mL; 1 V). The medium is then cooled to a temperature of 5 ° C.

Step chlorination:

As soon as the medium has reached the temperature of 5 ° C, thionyl chloride (52.8 g;

5 eq.) Was added. The thionyl chloride addition lasted 2 hours at 5 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 5 hours at 5 ° C.

Then the obtained conversion rate is 85% (s / s) dichloride 5- (acetylamino) -2,4,6-triiodobenzene-1, 3-dicarbonyl.

The reaction mixture is slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed.

The yield obtained is 60%.

ANALYTICAL RESULTS:

Nuclear Magnetic Resonance:

1H NMR (400 MHz, DMSO-d6) δ : 10.1 (s, 1 H), 2.1 (s, 3H).

13C NMR (101 MHz, DMSO-d6) δ : 168.3, 144.1 -150.2, 86.8-102.2, 169.5-169.8, 144.8, 23.4.

Mass spectrometry :

[M - H] " = 635.6634 one (masse one exacte = 635.6630)

[M + Na] + = 659.6593 one (masse one exacte = 659.6594)

Example 3: Synthesis of dichloride of 5 - {[(2S) -2- (acetyloxy) -1-oxopropyl} friend 2,4,6-triiodo-1, 3-dicarbonyl benzene (intermediate for the synthesis of Iopamidol)

Schematic overview

(2S)-1 -chloro-1 -oxopropan-2-yl acétate Acide 5-amino-2,4,6-triiodoisophtalique

step a): acylating

Acide 5-{[(2S)-2-(acetyloxy)-1 -oxopropyl]amino}-2,4,6-triiodo-1 ,3-benzènedicarboxylique

intermediate (ey) uninsulated

step b): Chlorination

SOCL

Dichlorure de 5-{[(2S)-2-(acetyloxy)-1 -oxopropyl]amino}-2,4,6-triiodo-1 ,3-benzènedicarbonyle

acylation step:

Dimethylacetamide (34 mL; 1, 35V) and propylene carbonate (3.75 ml_; 0,15V) were mixed in a reactor volume of 250 mL.

(2S) -1-chloro-1 -oxopropan-2-yl acetate (7.5 g;. 1, 1 eq) was then added to the mixture. After cooling to 15 ° C, 5-amino-2,4,6-triiodoisophtalique acid (25 g; 1 eq.), Is introduced for 30 minutes. At the end of the introduction, the mixture is warmed to 18 ° C, then the acylation reaction is carried out during 66 hours at a temperature of 18 ° C.

The intermediate acid 5 - {[(2S) -2- (acetyloxy) -1-oxopropyl} amino-2,4,6-triiodo-1, 3-benzendicarboxylique (compound (ey)) is then formed.

The medium is then diluted with propylene carbonate (25 mL, 1 V). The medium is then cooled to a temperature of 5 ° C.

Step chlorination:

As soon as the medium has reached the temperature of 5 ° C, thionyl chloride (18.5 g;. 3.5 eq) was added. The thionyl chloride addition lasted 1 hour at 5 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 5 hours at 5 ° C.

Then the obtained conversion rate is 87% (s / s) dichloride, 5 - {[(2S) -2- (acetyloxy) -1-oxopropyl} amino-2,4,6-triiodo-1, 3- benzendicarbonyle.

The reaction mixture is slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed.

The yield obtained is 70%.

ANALYTICAL RESULTS:

Nuclear Magnetic Resonance:

1H NMR (400 MHz, DMSO-d6) δ : 10.3 (s, 1 H), 5.2 (q, J = 6.9 Hz, 1 H), 2.1 (s, 3H), 1 .5 (d, J = 6.9Hz, 3H).

13C NMR (101 MHz, DMSO-d6) δ : 142.9-150.4, 87.2-101 .9, 168.5-170.0, 169.9, 168.9, 69.9, 21 .3, 18.0.

Mass spectrometry :

[M - H] " = 707.6847 one (masse one exacte = 707.6841)

[M + Na] + = 731 one .6806 (.6806 masse one exacte = 731)

Example 4: Synthesis of dichloride of 5 - {[(acetyloxy) acetyl] amino} -2,4,6-triiodobenzèn-1, 3-dicarbonyl (synthesis intermediate of loversol)

Schematic overview

Acetate 2-chloro-2-oxoethyl 5-Amino-2,4,6-triiodoisophtalique

step a): acylating

Acide 5-{[(acetyloxy)acetyl]amino}-2,4,6-triiodobenzène-1 ,3-dicarboxylique

intermediate (Cy) uninsulated

step b): chlorination SOCL

Dichlorure de 5-{[(acetyloxy)acetyl]amino}-2,4,6-triiodobenzène-1 ,3-dicarbonyle

acylation step:

Dimethylacetamide (67.5 mL, 1, 35V) and propylene carbonate (7.5 mL; 0,15V) were mixed in a reactor of 250 ml volume.

2-chloro-2-oxoethyl acetate (13.3 g;. 1, 1 eq) was then added to the mixture. After cooling to 15 ° C, 5-amino-2,4,6-triiodoisophtalique acid (50 g; 1 eq.) Was added during 45 minutes. At the end of the introduction the mixture is warmed to 18 ° C, then the acylation reaction is carried out for 65 hours at a temperature of 18 ° C.

acid The intermediate 5 - {[(acetyloxy) acetyl] amino} -2,4,6-triiodobenzene-1, 3-dicarboxylic acid (compound (Cy)) is then formed.

The medium is then diluted with propylene carbonate (50 mL; 1 V). The medium is then cooled to a temperature of 5 ° C.

Step chlorination:

As soon as the medium has reached the temperature of 5 ° C, thionyl chloride (37 g;. 3.5 eq) was added. The thionyl chloride addition lasted 2 hours at 5 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 4 hours at 5 ° C.

Then the obtained conversion rate was 90.5% (s / s) dichloride, 5 - {[(acetyloxy) acetyl] amino} -2,4,6-triiodobenzene-1, 3-dicarbonyl.

The reaction mixture is slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed. The yield obtained is 87%.

ANALYTICAL RESULTS:

Nuclear Magnetic Resonance:

1H NMR (400 MHz, DMSO-d6) δ : 10.4 (s, 1 H), 4.7 (s, 2H), 2.2 (s, 3H).

13C NMR (101 MHz, DMSO-d6) δ : 143.0-150.3, 87.3-102.0, 169.4-169.8, 170.1 , 166.1 , 62.6, 21 .0.

Mass spectrometry :

[M - H] " = 693.6691 one (masse one exacte = 693.6684)

[M + Na] + = 717.6645 one (masse one exacte = 717.6649)

Example 5: Synthesis of dichloride of 5 - [(chloroacetyl) amino] -2,4,6-triiodobenzene-1, 3-dicarbonyl (synthesis intermediate of loversol)

Schematic overview

chloride

Acide 5-amino-2,4,6-triiodoisophtalique

step a): acylating

5 - [(chloroacetyl) amino] -2,4,6-triiodobenzene-1, 3-dicarboxylic acid

intermediate (by) uninsulated

step b): chlorination SOCL

Dichloride, 5 - [(chloroacetyl) amino] -2,4,6-triiodobenzene-1, 3-dicarbonyl acylation step:

Dimethylacetamide (67.5 mL; 1, 35V) and propylene carbonate (7.5 mL; 0,15V) were mixed in a reactor volume of 250 mL.

Chloroacetyl chloride (1 1 g;. 1, 1 eq) was then added to the mixture. After cooling to 15 ° C, 5-amino-2,4,6-triiodoisophtalique acid (50 g; 1 eq.) Is introduced in portions, about 3.4 g every two minutes during 30 minutes. At the end of the introduction the mixture is warmed to 18 ° C, then the acylation reaction is carried out for 40 hours at a temperature of 18 ° C.

The intermediate 5 - [(chloroacetyl) amino] -2,4,6-triiodobenzene-1, 3-dicarboxylic acid (compound (by)) is then formed.

The medium is then fluidized with dimethylacetamide (50 mL; 1 V) and propylene carbonate (50 mL; 1 V). The medium is then cooled to a temperature of 5 ° C.

Step chlorination:

As soon as the medium has reached the temperature of 5 ° C, thionyl chloride (52.9 g,. 5 eq) was added. The thionyl chloride addition lasted 3 hours at 5 ° C. At the end of the introduction of the reagent, the chlorination reaction is carried out for 18 hours at 5 ° C.

Then the obtained conversion rate is 88% (s / s) dichloride, 5 - [(chloroacetyl) amino] -2,4,6-triiodobenzene-1, 3-dicarbonyl.

The reaction mixture is slowly added to a water / ethanol / sodium acetate. The solid obtained is filtered, washed, dried and then analyzed. The yield obtained is 86%.

Analytical results:

Nuclear magnetic resonance

1H NMR (400 MHz, DMSO-d6) δ : 10.6 (s, 1 H), 4.4 (s, 2H).

13C NMR (101 MHz, DMSO-d6) δ : 142.9-150.3, 87.5-101 .8, 169.4-169.8, 164.8, 98.4, 43.3.

Mass spectrometry :

[M - H] " = 669.6245 one (masse one exacte = 669.6240)

[M + Na] + = 693.6202 one (masse one exacte = 693.6205)

CLAIMS
1. A process for preparing an organo-iodine compound comprising the steps of:

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

(A)

with a compound of general formula (II):

R 2 -C (0) CI (II)

to obtain an intermediate compound Y;

then

b) chlorination of the intermediate compound Y to obtain an iodinated organoaluminum compound of general formula (I):

Ri being H or methyl, and

R 2 is selected from the group consisting of:

- (CC 2 o) -straight or branched alkyl;

- (Ci-C 2 o) alkenyl linear or branched;

- (Ci-C 2 o) alkynyl, linear or branched;

- (C 3 -C 10 ) cycloalkyl;

- (C 6 -C 10 ) aryl;

- heterocyclyl comprising 3 to 10 atoms; and

- heteroaryl comprising from 6 to 10 atoms;

said alkyl, alkenyl and / or alkynyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen, oxygen and nitrogen;

said alkyl, alkenyl and / or alkynyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0-, and -OC (O) -; and

said cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups is optionally substituted by one or more substituent (s) selected (s) from the group consisting of (CC 2 o) -straight or branched alkyl, oxygen, halogen atoms and nitrogen,

steps a) and b) being carried out without isolation of the intermediate compound Y.

2. Preparation process according to claim 1, wherein steps a) and b) are performed in a single reactor.

3. The method of claim 1 or 2, wherein R 2 is selected from the group consisting of:

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

5. Preparation process according to any preceding claim, wherein the chlorinating of step b) is performed in the presence of a chlorinating agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, phosphorus pentachloride and dichloride methanoyl.

6. A compound of general formula (Y1) as follows:

Ri is methyl, and

R 2 is selected from the group consisting of:

- (Ci-C 20 ) linear or branched alkyl;

- (Ci-C 20 ) alkenyl, linear or branched;

- (Ci-C 20 ) alkynyl, linear or branched;

- (C 3 -Cio) cycloalkyl;

- (C 6 -C 10 ) aryl;

- heterocyclyl comprising 3 to 10 atoms; and

heteroaryl comprising from 6 to 10 atoms;

said alkyl, alkenyl and / or alkynyl being optionally substituted by one or more substituent (s) selected (s) from the group consisting of halogen, oxygen and nitrogen;

said alkyl, alkenyl and / or alkynyl being optionally interrupted by one or more group (s) selected (s) from the group consisting of -O-, -C (0) -0-, and -OC (O) -; and

said cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups is optionally substituted by one or more substituent (s) selected (s) from the group consisting of (Ci-C 20 ) linear or branched alkyl, oxygen, halogen atoms and nitrogen;

provided that R 2 is different from the moiety

7. A compound having one of the following formulas

(cy)

8. Use of compounds of general formula (Y1) of claim 6 or 7, for the preparation of organo-iodine compounds.

9. Use of compounds of general formula (Y1) of claim 6 or 7, for the preparation of iodinated contrast agents.