KR20170123748A - Novel intermediate compound and preparation process of iomeprol using thereof - Google Patents

Abstract

The present invention relates to a novel intermediate compound of iomeprol, a production method thereof, and a method for producing iomeprol using the same. More specifically, the present invention relates to a method for producing iomeprol used as X-ray vascular contrast agents in an economically feasible way with high purity using a novel intermediate N,N-bis(2,3-diacetylatepropyl)-5-(2-acetoxy-N-methylacetoamide)-2,4,6-triiodoisophthalamide. The present invention further relates to a purification method thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel intermediate compound and a method for preparing the same,

The present invention is directed to the Bracco, Italy. The present invention relates to a novel preparation method of Iomeprol (product name: Iomerone) which is an X-ray contrast agent developed by Imaging S.p.A., and more particularly to a novel intermediate compound for the production of Iomeprolol and a method for producing the same.

By preparing Iomeprol using the above-mentioned intermediate compound, separation of impurities such as inorganic salts produced during the production process is facilitated, and the resulting iomeprol is purified using an ion exchange resin or the like And a method of manufacturing the same.

The novel intermediate compound N, N'-bis (2,3-diacetylate propyl) -5- (2-acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide is obtained in the presence of an alcohol and an acid catalyst It can be easily produced with iomeprolol and can be obtained at a high purity of 98% or more without the purification process of the ion exchange resin.

Iodine Contrast medium is a component of the iodine contained in the composition of the body changes the X-ray diffraction of a specific tissue to make the X-ray absorption difference. Refers to a substance used to image the internal structure of a human body on an X-ray photograph using the absorption difference.

Among them, non-ionic contrast agent is a third-generation contrast agent, which does not cause ionization phenomenon in the human body, so it has a merit that the side effect can be remarkably reduced.

Currently, the non-ionic monomer derivative contrast agents such as Iopamidol, Iohexol, Ioversol, Iopromide, and Iomeprol are used in the pharmaceutical market.

Among them, N'-bis (2,3-dihydroxypropyl) -5- (2-hydroxy-N-methylacetamido) -2,4,6-triiodoisophthalamide is a nonionic X- As contrast medium, it was developed by Bracco Imaging SpA, Italy and first described in European patent EP0026281.

A synthetic route for the preparation of 5- (hydroxyacyl) amino derivatives based on the rearrangement reaction of Smiles is described in WO8809328 and WO0032561.

[Chemical Formula 1]

The merits of the synthesis method described in WO0032561 compared to the one described in WO0032561 are mainly due to the use of some reagents and solvents such as thionyl chloride, acetic anhydride, methyl iodide, methylene chloride and chloroform And to avoid reactions (for example, catalytic reduction by hydrogen), which are hazardous in terms of environment and toxicity under industrial production conditions and therefore require certain working conditions'. The synthesis scheme of the above contents is as follows.

                                  [Reaction Scheme 1]

As described above, the synthesis method of WO0032561 does not use harmful substances in terms of environment and toxicity under industrial production conditions, but it has a long synthetic step and has an alcohol group at the terminal group from the (III) And it shows water solubility.

This property has many problems in removing the toxic base NaOH used in steps 4 and 7.

The X-ray contrast medium, iomeprol, is a water-soluble substance that is very soluble in water.

To compensate for these problems, refinement is carried out using ion exchange resins in the final stages of not only Iomeprol but also other contrast agents in order to obtain objects of high purity.

In industrial production conditions, the cost of ion exchange resin equipment is low, and it has an economic disadvantage that the resin should be replaced according to a certain period of time.

The synthesis step described in WO8809328 has a shorter production process than WO0032561. However, since it is difficult to separate the iomeprol and the inorganic material generated by using the inorganic base in the last stage of WO8809328 by the general method, Exchange resins should be used.

                                 [Reaction Scheme 2]

In addition, Japanese Patent Application Laid-Open Publication No. 2015-82293 (published on May 15, 2015) discloses a method for producing an intermediate of an X-ray contrast agent that prevents the generation of impurities when producing Iodixanol and Iohexol.

However, in the above invention, alkali metal hydroxides (sodium hydroxide) and the like are used in the deacylation process, so that there is still a problem in preventing the generation of inorganic salts.

As described above, since the physical properties of the contrast agent are very water-soluble, the generation of water-soluble impurities such as inorganic salts must be minimized from the synthesis step.

That is, there is a demand for the development of a more economical production method and a new manufacturing technique for suppressing the by-products generated in the production of the omeprol.

In addition, since only original products are sold to the pharmaceutical market, the need for cheaper raw materials is increasing.

WO 0032561 A KR 1020150082293 A WO 8809328 A

An object of the present invention is to provide a process for producing an iomeprol which is used as a raw material and which is used as a starting material and which inhibits the generation of inorganic salts and is a process for producing a novel intermediate N, N'-bis ( (2-acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide was used to obtain high yield and high purity iomepropol And a method for producing the same.

The present invention also provides the above novel intermediate compounds and a process for their preparation.

(2)

The present invention according to Formula 1 the new preparation method of Io mepeu roll is represented by the following [Reaction Scheme 3] The novel intermediate, which is denoted by (D) as shown in N, N'- bis (2,3- Acetylate propyl) -5- (2-acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide is used to provide an improved process for producing inorganic salts.

[Reaction Scheme 3]

In the present invention, commercially available 5-amino-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodosuccinic acid as an intermediate of Ioversol, Iohexol, de-amide (a) using as the starting material novel intermediate N, N'- bis (2,3-diacetyl-rate propyl) -5- (2-acetoxy--N- methyl acetoacetate omicron]) -2,4, To prepare 6-triiodo isophthalamide (D ).

EP083964, US4396598, WO9727172, and WO9636590, which are heretofore known for manufacturing Ioversol, describe a process for producing the compound ( C ).

More specifically, it is possible to prepare a compound of formula ( I ) which is commercially available or can be easily obtained by reacting 5-amino-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodo isophthalamide And acetic anhydride can be reacted to four alcohols by condensing acetic anhydride with low industrial price.

In addition to acetic anhydride, anhydrous acetic acid derivatives such as anhydrous propionic acid and anhydrous butyric acid may be used, and acetic anhydride is preferably used.

As the solvent, a solvent having a carbonyl carbon, specifically, acetone or acetonitrile may be used. Ethyl acetate, dimethylformamide, and dimethylsulfoxide may also be used. Preferably acetone and ethylacetate.

The amount of the solvent is 1 to 10 times, preferably 2 times, the [ A ] compound.

The starting material, 5-amino-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodo isophthalamide ( A ) It is a substance that has an alcohol group and it is a water-soluble substance which dissolves well in an organic solvent.

When the terminal alcohol group is acetylated, the physical properties thereof are changed to a fat-soluble state which is easily dissolved in an organic solvent such as ethyl acetate, alcohol, acetone, or tetrahydrofuran.

The acetic acid should be 4 to 6 equivalents, preferably 4.5 equivalents.

The reaction temperature is 40 [deg.] C to 80 Deg.] C, and preferably the reflux temperature 80 RTI ID = 0.0 > ( C ). ≪ / RTI >

After completion of the reaction, the following reaction can proceed as it is, but it is preferably carried out after extraction with an aqueous solution of chloride or an aqueous solution of sodium bicarbonate.

As the physical properties change to liposoluble, impurities and the like can be easily removed by extraction to obtain an intermediate of high purity.

Acetoxyacetyl chloride can be condensed with the compound to form amide, thereby easily and easily obtaining the compound ( C ).

The prepared ( C ) compound also has acetylated all five terminal groups and is soluble in common organic solvents.

The equivalent of acetoxyacetyl chloride is 1 to 5 equivalents, preferably 1.5 equivalents.

The solvent may be ethylacetate dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone, but preferably in dimethylform.

The reaction temperature is from room temperature to 80 Deg.] C, preferably at 40 [deg.] C.

( C ) compound is reacted with dimethylsulfate or iodomethane, which is used as a methyl group-introducing material, to obtain a novel intermediate compound N, N'-bis (2,3-diacetylate propyl) -Methylacetoamido) -2,4,6-triiodo isophthalamide ( D ) can be prepared.

In view of reactivity, it is preferable to use iodomethane, but it is preferable to use dimethyl sulfate for the proportion of the raw material unit price in the production process.

As the reaction solvent, ethylacetate, acetone, dimethylsulfoxide, dimethylformamide and dimethylacetamide can be used, but it is more preferable to react with acetone or ethyl acetate.

Typically, the ratio of acetone is 1 to 10 times as weight / volume ratio, and is preferably 2 times.

The reaction temperature may be -10 ° C to room temperature, preferably -5 Lt; 0 > C.

The lower the temperature, the slower the reaction time and the less the amount of impurities produced.

In order to obtain a non-ionic contrast agent iomeprol, the compound ( D ) may be dissolved in alcohol or water, followed by refluxing with an acid catalyst or a base catalyst.

As a solvent, alcohol is easier than water.

When water is used as a solvent, the efficiency of the production process is very low because the reaction must be completed after the completion of the reaction.

The alcohol may be methanol, ethanol, isopropanol, butanol or 2-butanol, preferably low-cost and low-carbon methanol.

The reaction in methanol is faster than other alcohols and the boiling point is lower than other alcohols.

The catalyst is 36% hydrochloric acid to concentrated sulfuric acid, preferably concentrated sulfuric acid.

36% hydrochloric acid contains a large amount of water, which may lower the yield during crystallization.

The amount of the catalyst is 5 mol% to 20 mol%, preferably 10 mol%.

The reaction is terminated by refluxing in methanol for 2 hours, and the cooled solution is added dropwise to ethyl acetate and toluene to give white crystals.

In the reaction in ethanol, white crystals precipitate in the reaction solution upon refluxing for 4 hours, and white crystals are also precipitated in isopropanol, normal butanol and 2-butanol.

The produced iomeprol has properties that are soluble only in methanol even in alcohol, and it precipitates as crystals in a solvent other than methanol.

The reaction by-product at the time of crystal precipitation is acetic acid, which is dissolved in alcohol.

Since the intermediate ( B ), ( C ), and ( D ) of each intermediate stage prepared as described above are dissolved in ethyl acetate, dichloromethane or the like capable of separating water and layer, have.

Particularly, since the novel intermediate ( D ) is dissolved in ethanol, isopropanol and butanol, it can be easily obtained as a crystal in a deprotection reaction under an acid catalyst.

The provided iomeprol can be purified by refluxing in anhydrous ethanol or 95-99% ethanol.

More specifically, And recrystallized in anhydrous ethanol or 95 to 99% ethanol, preferably 6 to 10 times, preferably anhydrous ethanol 6 times, or 95 to 99% ethanol 6 times, to obtain a high purity of 99% or more.

By using a novel intermediate compound, impurities such as inorganic salts are not produced in the present invention, so that a high purity iomeprol can be produced.

In addition, it is possible to produce economical iomeprol by omitting the purification process.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are merely examples of the present invention, and the scope of the present invention is not limited thereto.

5-Amino-2,4,6- Tree iodo -N, N ' - Bis - (2,3- Diacetoxypropyl ) - Isophthalamide  Produce

A 1000 ml flask was charged with 50 g of starting material ( A ), namely 5-amino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo isophthalamide, 0.5 g (5 mol%) of aminopyridine is suspended in 100 ml of ethyl acetate, 62.5 g of acetic anhydride is added to this solution, and the mixture is refluxed for 2 hours. Upon refluxing, the reactants slowly dissolve.

The reaction mixture is cooled, 150 ml of ethyl acetate is added, and 150 ml of 5 to 10% brine is sequentially added thereto.

The layers are separated, the water layer is removed, and the mixture is extracted with 5% aqueous solution of sodium bicarbonate.

After the layer separation, 50 ml of ethyl acetate was added to the water layer for secondary extraction. After mixing the extracted organic solution layer, wash with 5 ~ 10% brine 50 ml.

After recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and concentration to obtain 61.3 g (99%) of the title compound as an oil solid.

The crystals were dissolved in 50 ml of methanol, and then 250 ml of ethyl ether was added thereto to precipitate a solid. 55.7 g (90%) of the title compound was obtained.

5- Acetoxyacetylamino -2,4,6- Tree iodo -N, N ' - (2,3- Diacetoxypropyl ) -Bis- (2,3- Diacetoxypropyl ) - Isophthalamide  Produce

The 5-amino-2,4,6-triiodo-N, N'-bis- (2,3-diacetoxypropyl) -isophthalamide prepared in Example 1 was dissolved in 55.7 g of dimethylformamide at room temperature And then 11.6 g of acetoxyacetyl chloride is added dropwise.

The temperature is raised and the mixture is stirred at 40 占 폚 for 4 hours.

After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with 150 ml of ethyl acetate and 150 ml of 5 to 10% brine.

The organic solution layer is recovered and washed with 50 ml of a 5% aqueous solution of sodium hydroxide.

After recovering the organic layer, magnesium sulfate was added, and the organic solution layer was dried and concentrated to obtain 68.3 g (99%) of the title compound as an oil type.

N, N ' - Bis (2,3- Diacetylate propyl ) -5- (2- Acetoxy -N- Methyl acetoamide ) -2,4,6-tri Riaiodoisophthalamate Manufacture of Id

[0154] The 5-acetoxyacetylamino-2,4,6-triiodo-N, N '- (2,3-diacetoxypropyl) -bis- (2,3- diacetoxy Propyl) -isophthalamide (68.3 g) was dissolved in 150 ml of acetone, and the reaction solution was cooled to -5 ° C.

29.4 g of potassium carbonate was added, and while stirring, 26.8 g of dimethyl sulfate was added dropwise at a constant temperature, and the reaction solution was maintained at the temperature and stirred for 12 hours.

After completion of the reaction, the reaction solution is filtered to remove the solid, and the filtrate is concentrated.

The concentrate is dissolved in 100 ml of ethyl acetate, and 100 ml of water is added to remove the remaining amount of the inorganic material in the organic solution.

After recovering the organic solution, magnesium sulfate was added to remove water, followed by filtration and concentration to obtain 64.9 g (94%) of the title compound as an oil type.

To obtain a solid, 50 ml of ethyl acetate was added to the concentrate to dissolve it, and then 500 ml of normal hexane was added to precipitate crystals to obtain 58.6 g (85%) of the final compound.

^{1 H-NMR (400MHz, DMSO-} d 6) δ2.04 (s, 12H), 2.10 (s, 3H), 2.98 (s, 3H), 4.15-4.40 (m, 6H), 5.10-5.20 (m, 2H), 8.66-8.65 (m, 2H)

N, N ' - Bis (2,3- Diacetylate propyl ) -5- (2- Acetoxy -N- Methyl acetoamide ) -2,4,6-tri Riaiodoisophthalamate Manufacture of Id

[0154] The 5-acetoxyacetylamino-2,4,6-triiodo-N, N '- (2,3-diacetoxypropyl) -bis- (2,3- diacetoxy Propyl) -isophthalamide was dissolved in 150 ml of acetone, 29.4 g of potassium carbonate was added at room temperature, 30.2 g of iodomethane was added dropwise with stirring, and the reaction solution was stirred at room temperature for 5 hours.

After completion of the reaction, the reaction solution is filtered to remove the solid, and the filtrate is concentrated.

The concentrate is dissolved in 100 ml of ethyl acetate, and 100 ml of water is added to remove the remaining amount of the inorganic material in the organic solution.

After recovering the organic solution, magnesium sulfate was added to remove water, followed by filtration and concentration to obtain 69.0 g (96%) of the title compound as an oil type.

To obtain a solid, 50 ml of ethyl acetate was added to the concentrate to dissolve it, and then 500 ml of normal hexane was added to precipitate crystals to obtain 60.0 g (87%) of the final product.

Iomeprol's  Produce

The prepared novel intermediate N, N'-bis (2,3-diacetylate propyl) -5- (2-acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide Was dissolved in 100 ml of methanol, 0.7 g of concentrated sulfuric acid was added as an acid catalyst, the temperature was raised, and the reaction solution was refluxed for 3 hours.

After completion of the reaction, the reaction mixture was concentrated, and 200 ml of ethanol was added to the concentrate. The mixture was refluxed for 4 hours to precipitate crystals. The reaction mixture was cooled to room temperature, filtered and dried under reduced pressure at 50 캜. g (65%) and 98.8% (HPLC), respectively.

Iomeprol's  Produce

The prepared novel intermediate N, N'-bis (2,3-diacetylate propyl) -5- (2-acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide Was dissolved in 100 ml of ethanol, 0.7 g of concentrated sulfuric acid was added as an acid catalyst, the temperature was raised, and the reaction solution was refluxed for 4 hours.

The reaction solution was cooled to room temperature, filtered, and dried under reduced pressure at 50 ° C. to obtain 33.0 g (60%) of iomeprole and 98.7% (HPLC) of iomeprol as a white solid .

Iomeprol's  refine

35.8 g of the prepared iomepropol was added to 215 ml of absolute ethanol, refluxed for 2 hours, cooled, and filtered.

Washed with 20 ml of anhydrous ethanol and dried under reduced pressure at 50 ° C to obtain 29.4 g (82%) and 99.8% (HPLC) of high purity iomeprol.

Iomeprol's  refine

35 g of iomeprol prepared by the method of Example 4 was added to 210 ml of ethanol containing 5% of water, refluxed for 2 hours, cooled and filtered.

Washed with 20 ml of anhydrous ethanol and dried under reduced pressure at 50 ° C to obtain 15.8 g (46%) and 99.9% (HPLC) of high purity iomeprol.

As described above, the present invention uses the compound of formula (2), which is a novel intermediate compound, to make the physical properties of the intermediate fat-soluble, thereby facilitating the extraction of impurities and the like, Therefore, it is possible to produce a highly pure IOMEPROL without the necessity of a purification step using a separate ion exchange resin device.

Claims (6)

N, N'-bis (2,3-diacetylate propyl) -5- (2-acetoxy-N-methylacetoamido) -2,4,6-triiodoisophthalate Amide < / RTI >
(2)

A first step of acetylating an alcohol group of 5-amino-N, N'-bis- (2,3-dihydroxypropyl) -2,4,6-triiodo isophthalamide to prepare compound B;
A second step of condensing acetylated compound B with acetoxyacetyl chloride to amide an amine group to prepare compound C;
(2,3-diacetylate propyl) -5- (2- (2, 3-diacetylate) propyl) -pyrimidine compound represented by the following general formula Acetoxy-N-methylacetoamido) -2,4,6-triiodo isophthalamide. 3. The method of claim 2,
Wherein the methylation reaction raw material is dimethylsulfate or iodomethane. 3. The method of claim 2,
Wherein the methylation reaction solvent is selected from the group consisting of ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide, and dimethylacetamide. 3. The method of claim 2,
Wherein the methylation reaction is carried out at room temperature to -5 占 폚. A process for producing an omeprole, comprising dissolving the compound of claim 1 in an alcohol, deacylating it with an acid catalyst, and refluxing in anhydrous ethanol or ethanol.