Preparation method of iomeprol

Abstract

The invention relates to a preparation method of N, N-dimethylformamide. The invention relates to a preparation method of N, N '-bis (2, 3-dihydroxy propyl)-5-[(hydroxyacetyl) methylamino]-2, 4, 6-triiodine-1, 3-benzenedicarboxamide (iomeprol), which breaks through the difficult problems of complicated post-treatment and high cost investment of ion resin equipment in a Smiles' rearrangement reaction route described by the patent WO2000032561A1, and provides a novel method for preparing the iodomeprol. The iomeprol prepared by the method is stable in quality, high in yield and good in purity, saves a large amount of equipment and personnel investment, reduces the use of toxic solvents, is low in cost, is green and environment-friendly, and is suitable for continuous industrial mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a method for preparing a non-ionic X-ray contrast agent iomeprol. Background Art

[0002] Iomeprol, commonly known as Iomeprol in English, and its product name is Iomeron, is a non-ionic X-ray contrast agent developed by Bracco, Italy, and was approved for marketing in Italy in May 1993 and in the UK in December 1992. Compared with non-ionic X-ray contrast agents of the same type (such as iopamidol, ioversol and iohexol, etc.), Iomeprol has the lowest osmotic pressure and lower viscosity at the same concentration, and can be made into a high-concentration preparation with an iodine content of 400 mg / ml. Its structural formula (I) is as follows: .

[0003] Regarding the synthesis of iomeprol, European Patent EP0026281A1 discloses two synthesis methods thereof.

[0004] The first synthesis method is to use 5-amino-2,4,6-triiodoisophthalic acid as the starting material, first nitrogen methylate, chlorinate to obtain diacyl chloride, then use acetoxyacetyl chloride for acylation, then carry out amidation reaction with 3-amino-1,2-propanediol, and finally hydrolyze with sodium hydroxide to obtain iodine meprol, as shown in Synthesis Route 1: , Synthesis route 1.

[0005] The acetoxyacetyl chloride used in this synthetic route has poor stability, high market purchase price, complex preparation process, low total yield and high cost, which ultimately leads to an increase in the production cost of iodine meprolin and is not suitable for large-scale production.

[0006] The second synthesis method is to use 5-amino-2,4,6-triiodoisophthaloyl chloride as the starting material, first with acetoxyacetyl chloride for acylation reaction, then with 3-amino-1,2-propylene glycol for amidation reaction, then with sodium hydroxide for hydrolysis reaction, and finally with methyl iodide for methylation reaction to obtain. As shown in Synthesis Route 2: , Synthesis route 2.

[0007] This method is the same as the previous synthesis method, both using relatively expensive acetoxyacetyl chloride and thionyl chloride to prepare the acyl chloride. The reaction produces a large amount of waste gas that needs to be treated, which is highly corrosive to the equipment. In addition, the last methylation reaction in this synthesis method uses expensive iodomethane, and the methylation yield is not high (77%), so this method has a higher preparation cost and is not suitable for large-scale industrial production.

[0008] In addition, International Patent Publication Nos. WO88 / 09328 and WO00 / 365541 describe synthetic preparation routes for obtaining iodine meprol based on Smiles' rearrangement reaction.

[0009] The advantages of the synthesis method described in International Publication No. WO00 / 365541 are mainly that some reagents and solvents, such as thionyl chloride, acetic anhydride, methyl iodide, dichloromethane and chloroform, are not used, or hydrogen reaction using a catalyst is avoided.

[0010] EP1133466A1 discloses an optimization scheme for this process, as shown in synthetic route 3: , Synthetic route 3.

[0011] This route avoids the chlorination process, reduces the corresponding pollution problems, does not use harmful substances under industrial production conditions, and the reaction system basically uses water as a solvent, which is green and friendly, and the raw material price is low.

[0012] However, the intermediates of this route have multiple alcohol hydroxyl groups and good water solubility, which cannot effectively remove water-soluble impurities and inorganic salts in the solution. The last step is a rearrangement reaction under alkaline conditions in water, which will produce 1-2% of unrearranged impurities, which are difficult to purify and remove, and bring in a large amount of inorganic salts, requiring a large amount of anion and cation resins for desalination.

[0013] In terms of industrial production conditions, ion exchange resin equipment has economic disadvantages, such as high equipment cost, required installation space, and the need to replace the resin within a certain period of time. The preparation cost is very high, which is also the main reason why this route has not been able to achieve large-scale industrial production.

[0014] Therefore, it is even more necessary to develop a preparation process and preparation technology that can make up for the shortcomings of the above-mentioned preparation process. In the preparation process, inorganic salts are removed without using ion exchange resins. The preparation technology can make the main product fat-soluble but poorly water-soluble through reaction, thereby completely separating water-soluble impurities and inorganic salts, minimizing impurities while reducing equipment investment and streamlining operations to ensure economy. Summary of the invention

[0015] In view of the shortcomings of the prior art, an improved method for preparing iodine meprol was proposed through research on the reaction mechanism and a large number of experimental explorations. The preparation route is as follows: .

[0016] The preparation method of the present invention comprises the following steps: Step 1: A solution of formula (1-1) (crude iodine meprone) (prepared according to the method described in Example 2 of patent WO2000032561A1) is adjusted to pH 10 with hydrochloric acid, acetic acid or sulfuric acid, and after evaporating the water under reduced pressure, acetic anhydride or propionic anhydride is added for reaction, and water is added for crystallization, and the mixture is washed to obtain a compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide; Step 2: The compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide is dissolved in methanol, and alcoholysis is carried out under the catalysis of sodium methoxide, sodium ethoxide or sodium hydroxide, and then H-type cationic resin is added for filtration, and the filtrate is distilled to remove methanol to obtain the compound of formula (1) N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide (iomeprol).

[0017] Technical features The invention provides a method for preparing a contrast agent iomeprol. The crude iomeprol is prepared according to the method described in patent WO2000032561A1, and water is removed by vacuum distillation. Then, the crude iomeprol is reacted with acetic anhydride or propionic anhydride. Each alcohol group of the iomeprol is acylated to form a protective group. The obtained compound of formula (2) has strong lipid solubility and weak water solubility. After the reaction is completed, the compound is thoroughly washed with water to remove inorganic salts and water-soluble impurities. The high-purity compound of formula (2) is subjected to alcoholysis reaction in methanol using a catalytic amount of sodium methoxide, sodium ethoxide or sodium hydroxide to obtain high-purity iomeprol. Then, H-type cationic resin is added, filtered, and the filtrate is distilled to remove methanol. The compound of formula (1) N, N'-bis (2, 3-dihydroxypropyl) -5- [(hydroxyacetyl) methylamino] -2, 4, 6-triiodo-1, 3-benzenedicarbamide (iomeprol) is prepared with high yield and high purity.

[0018] The improved preparation method of iodine meprol of the present invention successfully breaks through the problem of complicated post-processing and high cost investment of ion resin equipment in the Smiles' rearrangement reaction route described in patent WO2000032561A1. The iodine meprol prepared without using a separate ion exchange resin has stable quality, high yield and good purity (HPLC purity is greater than 99.6%), which can improve the quality of the preparation product and the safety of medication, further simplify the process and operation, save a lot of equipment and personnel investment through process optimization, reduce the use of toxic solvents, low cost and green environmental protection, and is suitable for continuous large-scale industrial production. DETAILED DESCRIPTION

[0019] Hereinafter, the present invention will be described in more detail.

[0020] Example 1: Synthesis of the compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide 400 mL of a solution containing crude iodine mepro (prepared by the method described in Example 2 of patent WO2000032561A1) was adjusted to pH 10 with hydrochloric acid. The solution contained 70 g of iodine mepro and the following by-products and impurities (HPLC liquid phase area normalized spectrum): iodine proline 94.5%, unrearranged raw material 1.3%, ionic impurities 2.5%, non-ionic impurities 1.5%; about 12% NaCl (wt% of iodine proline), then evaporate water at 55-65°C under reduced pressure, add 92.5g acetic anhydride to the evaporated residue, keep warm at 45°C for 3 hours, add the reaction solution into 1000ml ice water, stir and crystallize at 0-5°C for 2h after adding, filter, add 500ml water to the filter cake, stir and wash once, filter, and dry the solid to obtain 87.2g of the compound of formula (2), 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide, with a molar yield of 98.0% and a purity of 99.8%.

[0021] Example 2: Synthesis of the compound of formula (1) N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]2,4,6-triiodo-1,3-benzenedicarbamide (iomeprol) 87.2g of the compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide was dissolved in 1200ml of methanol, and 0.4g of sodium methoxide was added, and the mixture was reacted at 25°C for 2h. 5g of H-type cationic resin was added, and the mixture was stirred for 1h, filtered, and the filtrate was distilled to remove methanol, to obtain 67.2g of the compound of formula (1) N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide (iomepro), with a yield of 98% and a purity of 99.7%. H-NMR (800MHz, DMS0-d) 8 (ppm): 8.47-8.60 (m, 2H), 4.89-4.90 (s, 1H) 4.71-4.75 (m, 2H), 4.50-4.56 (m, 2H), 3. 69-3.73 (d, 2H), 3.67-3.69 (m, 2H), 3.30-3.48 (m, 4H), 3.00-3.20 (, 4H), 2.50 (S, 3H) HRMS-ESI (m / z): 799.8432 [M+Na].

[0022] Although the technical solution of the present invention is described in detail by using specific embodiments in this specification, some modifications or improvements made by a person skilled in the art in the specific implementation mode and application scope according to the concept of the present invention belong to the scope of protection claimed by the present invention. Therefore, the contents recorded in this specification should not be understood as limiting the present invention.

Claims

1. A method for preparing iodine meprol, characterized in that N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide (iomeprol) was prepared by the following steps: , Step 1: A solution of formula (1-1) (crude iodine meprone) (prepared according to the method described in Example 2 of patent WO2000032561A1) is adjusted to pH 10, and after evaporating the water under reduced pressure, anhydride is added to react. After the reaction is completed, water is added to crystallize, and the mixture is washed to obtain a compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide; Step 2: The compound of formula (2) 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide is dissolved in methanol, and alcoholysis reaction is carried out under base catalysis, and then H-type cationic resin is added for filtration, and the filtrate is distilled to remove methanol to obtain the compound of formula (1) N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide (iomeprol).

2. The preparation method according to claim 1, characterized in that In step 1), the acid used to adjust the pH of the solution of crude iodine meprol (prepared according to the method described in Example 2 of patent WO2000032561A1) is hydrochloric acid, acetic acid, or sulfuric acid.

3. The preparation method according to claim 1, characterized in that In step 1), in the preparation of the compound of formula (2), 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide, the acid anhydride is acetic anhydride or propionic anhydride.

4. The preparation method according to claim 1, characterized in that In step 1), in the preparation of the compound of formula (2), 5-[(acetoxyacetyl)methylamino]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide, the reaction temperature for adding the acid anhydride is 40-50°C.

5. The preparation method according to claim 1, characterized in that In step 2), the preparation of the compound of formula (1), N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide, is characterized in that the base added to the reaction is sodium methoxide, sodium ethoxide or sodium hydroxide.

6. The preparation method according to claim 1, characterized in that In step 2), the preparation of the compound of formula (1), N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzenedicarbamide, is characterized in that the solvent is methanol, isopropanol or ethanol.

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