Preparation method of iomeprol impurity I
Through the reaction steps of chloroacetylation, amidation, methylation and chlorohydrolysis, the Iodomepur impurity I was generated, which solved the problem of impurity I generated under alkaline conditions in the synthesis of Iodomepur and achieved effective control of product quality and quantitative , improves the control ability of product purity and impurity limit.
Patent Information
- Application Number
- CN202311749865.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-19
- Publication Date
- 2024-12-24
AI Technical Summary
In the prior art, the formation of impurity I under alkaline conditions occurs during the synthesis of iodine mepur, which leads to difficulty in controlling product quality and impurity limits, and lacks an effective preparation method.
The reaction steps of chloroacetylation, amidation, methylation, chlorohydrolysis and ether combination are adopted to generate iodine mepur impurity I through sodium hydroxide, and the reaction conditions and product detection process are controlled to ensure quality and quantification.
An effective preparation method for iodomepur impurity I was provided, which solved the problems in condition control and product quality testing during the production process, and improved the purity and impurity limit control ability of the product.
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Figure CN119176785A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of chemical synthesis of iodine contrast agents, in particular to a method for preparing an impurity I of iomeprol. Background Art
[0002] The original developer of Iomeprol is the Italian company Bracco. Currently, except for Italian companies, no domestic pharmaceutical companies have launched this drug, but many companies are researching and preparing raw materials. At present, there are relatively few reports in the literature on the preparation of Iomeprol I related impurities.
[0003] Most of the synthetic routes of iodine meprol on the market are similar to those reported in Korean patent CN113166040A:
[0004]
[0005] In the above route, iodine prochloride and chloroacetyl chloride (CAC) undergo chloroacetylation reaction, and after the reaction, hydrolyze with sodium hydroxide to generate iodine prochloride ester hydrolyzate; iodine prochloride ester hydrolyzate and sodium acetate undergo chlorine hydrolysis reaction to generate iodine prochloride hydrolyzate; iodine prochloride hydrolyzate reacts with dimethyl sulfate under alkaline conditions to generate iodine prochloride. Because alkaline conditions exist in the above reaction processes, under alkaline conditions, the acetyl hydroxyl group and the iodine on the triiodobenzene ring mother core undergo etherification reaction to generate impurity I. Summary of the invention
[0006] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art and to provide a method for preparing iodine meprol impurity I.
[0007] The technical solution of the present invention is as follows:
[0008] A method for preparing iodine meprol impurity I comprises the following steps:
[0009] S1: Chloroacetylation reaction;
[0010] Compound (A) is subjected to chloroacetyl chloride chloroacetylation reaction to obtain compound (B);
[0011] S2: Acylation reaction
[0012] Compound (B) and 3-amino-1,2-propanediol undergo an amidation reaction to obtain compound (C);
[0013] S3: Methylation reaction
[0014] Compound (C) and dimethyl sulfate (DMS) undergo methylation reaction to generate compound (D);
[0015] S4: Chlorine hydrolysis and etherification reaction
[0016] Compound (D) and sodium hydroxide first undergo chlorine hydrolysis and then undergo etherification reaction to generate compound (E), i.e., iodine mepro impurity I;
[0017] The structural formula of the chemical (A) is:
[0018] The structural formula of the compound (B) is:
[0019] The structural formula of the compound (C) is:
[0020] The structural formula of the compound (D) is:
[0021] The structural formula of the compound (E) is:
[0022] As a preferred embodiment of the present invention, the preparation method of iomeprol is as follows:
[0023] Using potassium carbonate as a catalyst, compound (C) is dissolved in water and cooled to about 10°C. Potassium carbonate is added, and the mixture is stirred while being kept warm. Dimethyl sulfate is added dropwise while stirring. The mixture is kept warm for 20 hours. After the reaction is completed, the mixture is concentrated to dryness in vacuo at 60°C to obtain compound (D).
[0024] As a preferred embodiment of the present invention, the preparation method of the iodine meprolin impurity I is as follows:
[0025] Compound (D) is first subjected to chlorine hydrolysis with sodium acetate and sodium hydroxide, and then to etherification reaction, with methanol and water as solvents, and the reaction is carried out at 60-80°C for 24 hours. After the reaction is completed, the mixture is concentrated to dryness under reduced pressure, and methanol is added to dissolve it. The solid is filtered out and mixed with silica gel. The sample is loaded onto a silica gel column and eluted with dichloromethane and methanol. The target fraction is collected and concentrated to obtain compound (E), i.e., iodine meprole impurity I.
[0026] The invention discloses an iodine meprol impurity I, which is prepared by any of the above preparation methods.
[0027] The synthesis technology route is as follows:
[0028]
[0029] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing the impurity I of iodine propellant, and solves the problems of condition control of iodine propellant in the production process, and quality, impurity limit control and quantification in the product testing process. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 This is the detection spectrum of the impurity I of Iomeprol in Example 1;
[0031] Figure 2 This is the detection spectrum of the iodine meprolin impurity I in Example 2. DETAILED DESCRIPTION
[0032] In order to better understand the present invention, the technical solution of the present invention is further described in detail below through specific examples. It should be understood that the implementation of the present invention is not limited to the following examples, and any formal changes made to the present invention will be included in the protection scope of the present invention.
[0033] Embodiment 1:
[0034] Step 1: Chloroacetylation
[0035] 100 ml of N,N-dimethylacetamide (DMAC) was added to a reaction flask, the temperature was controlled below 50°C, 23.8 g of compound (A) was added with stirring, and the mixture was dissolved by stirring. The mixture was then cooled to 10°C, 1.0 g of 4-dimethylaminopyridine (DMAP) was added, and after stirring for 0.5 hour, 6.8 g of chloroacetyl chloride was added dropwise. After the addition was completed, the temperature was raised to 60°C, and the mixture was stirred for 3 hours to terminate the reaction. The mixture was cooled to 10°C, ice water was added dropwise, and the mixture was filtered, washed with ice water, and dried to obtain 25.5 g of compound (B).
[0036] Step 2: Acylation reaction
[0037] 100 ml of N,N-dimethylacetamide (DMAC) was added to the reaction flask, the temperature was controlled below 50°C, 25.0 g of compound (B) was added with stirring, and dissolved by stirring. Then the temperature was lowered to 10°C, 6.7 g of 3-amino-1,2-propanediol and 0.9 g of 4-dimethylaminopyridine (DMAP) were added, and then heated to 30°C and stirred for 8 hours to terminate the reaction. After cooling to below 10°C, the mixture was filtered. After the filtrate was evaporated to dryness under reduced pressure, the residue was dissolved in methanol, water was added and stirred evenly, and the mixture was allowed to stand. The precipitated solid was filtered, washed with water, and dried to obtain 26.19 g of compound (C).
[0038] Step 3: Methylation reaction
[0039] Dissolve 25.2 g of the compound (C) in 50 ml of water and cool to 10°C, add 5.2 g of potassium carbonate, keep warm and stir, add 7.9 g of dimethyl sulfate dropwise while stirring, keep warm and react for 20 hours. After the reaction is completed, concentrate to dryness in vacuo at 60°C to obtain 35.5 g of compound (D).
[0040] Step 4: Chlorine hydrolysis and etherification reaction:
[0041] 5.0 g of compound (D) in the previous step was dissolved in 10 ml of methanol, and 40.0 g of water was added, and 2.0 g of 30% sodium hydroxide aqueous solution was added, and the mixture was reacted at 60° C. for 24 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and methanol was added to dissolve the mixture. The solid was filtered out, and silica gel was added to mix the mixture. The mixture was loaded onto a silica gel column, and the column was eluted with dichloromethane and methanol. The target fraction was collected and concentrated to obtain 2.3 g of compound (E), i.e., iodine meprole impurity I, with a purity of 92%. The specific test results are as follows: Figure 1 .
[0042] Embodiment 2:
[0043] Steps 1 to 3 are as described in Example 1:
[0044] Step 4: Chlorine hydrolysis and etherification reaction:
[0045] 35.0 g of compound (D) in the previous step was dissolved in 10 ml of methanol, and 60.0 g of water was added, and 3.2 g of 30% sodium hydroxide aqueous solution was added, and the mixture was reacted at 80° C. for 24 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and methanol was added to dissolve the mixture. The solid was filtered out, and silica gel was added to mix the mixture. The mixture was loaded onto a silica gel column, and the column was eluted with dichloromethane and methanol. The target fraction was collected and concentrated to obtain 2.6 g of compound (E), i.e., iodine meprole impurity I, with a purity of 91%. The specific test results are as follows: Figure 2 .
[0046] The spectrum detection method of the above step 4 is:
[0047] Chromatographic column: C 18 Silica gel bonded chromatographic column 0.25*4.6
[0048] Mobile phase A: water, mobile phase B: acetonitrile: water = 75:25
[0049] Elution procedure:
[0050] Time (min) Mobile phase A (%) 0-10 100 10-30 100→80 30-40 80 40-42 80→50 42.1-47 50→100 47.1-55 100
[0051] Under the premise that no conflict occurs, those skilled in the art may freely combine and superimpose the above-mentioned additional technical features.
[0052] The above-mentioned embodiments only express the preferred implementation modes of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, various other corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all these changes and deformations should fall within the scope of protection of the claims of the present invention.
Claims
1. A method for preparing iodine meprolin impurity I, characterized in that: The following steps are involved: S1: Chloroacetylation reaction; Compound (A) is subjected to chloroacetyl chloride chloroacetylation reaction to obtain compound (B); S2: acylation reaction; Compound (B) and 3-amino-1,2-propanediol undergo an amidation reaction to obtain compound (C); S3: methylation reaction; Compound (C) and dimethyl sulfate (DMS) undergo methylation reaction to generate compound (D); S4: Chlorine hydrolysis and etherification reaction; Compound (D) and sodium acetate and sodium hydroxide are first subjected to chlorine hydrolysis and then to etherification reaction to generate compound (E), i.e., iodine mepro impurity I; The structural formula of the chemical (A) is: The structural formula of the compound (B) is: The structural formula of the compound (C) is: The structural formula of the compound (D) is: The structural formula of the compound (E) is:
2. The method for preparing an iodine meprolin impurity I according to claim 1, wherein: The preparation method of the iodine meprolate hydrolyzate is as follows: Using potassium carbonate as a catalyst, compound (C) is dispersed in water and cooled to about 10°C. Potassium carbonate is added, and the mixture is stirred while being kept warm. Dimethyl sulfate is added dropwise while stirring. The mixture is kept warm for about 20 hours. After the reaction is completed, the mixture is concentrated to dryness in a vacuum at 60°C to obtain compound (D).
3. The method for preparing an iodine meprolin impurity I according to claim 1, wherein: The preparation method of the iodine meprolin impurity I is as follows: Compound (D) is first subjected to chlorine hydrolysis with sodium acetate and sodium hydroxide, and then to etherification reaction, with methanol and water as solvents, and the reaction is carried out at 60-80°C for about 24 hours. After the reaction is completed, the mixture is concentrated to dryness under reduced pressure, and methanol is added to dissolve it. The solid is filtered out and mixed with silica gel. The sample is loaded onto a silica gel column and eluted with dichloromethane and methanol. The target fraction is collected and concentrated to obtain compound (E), i.e., iodine meprole impurity I.
4. An Iomeprol impurity I, characterized in that The method is prepared by any one of claims 1 to 7.