Preparation method of etimicin sulfate impurity A
After dissolving etimaccin sulfuric acid in sulfuric acid or trifluoroacetic acid, combined with weak acid ionic resin column and gradient analysis technology, the high-purity etimaccin sulfuric acid impurity A was successfully prepared, which solved the problem of lack of preparation methods in the existing technology, and achieved effective control of drug quality and improved drug safety.
Patent Information
- Application Number
- CN202311425394.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-30
- Publication Date
- 2025-05-02
AI Technical Summary
The lack of preparation method for etimixin sulfuric acid impurity A in the prior art makes it difficult to effectively control the quality of the drug and reduce the risk of drug use.
Sulfuric acid or trifluoroacetic acid was used to dissolve etimeccin sulfuric acid, and then the solid was precipitated by adjusting the pH value, adding ethanol, and using weak acid ion resin column adsorption and gradient analysis, combined with HPLC monitoring, the impurity A of etimeccin sulfuric acid was isolated and purified.
High-purity etimixin sulfuric acid impurity A is provided, which is used as a reference product for drug quality control, reduce drug use risks and improve drug safety.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing impurity A of ezetimibe sulfate. Background Art
[0002] Etimicin sulfate is a new generation of semi-synthetic aminoglycoside antibiotics with high efficiency, low toxicity and resistance to drug-resistant bacteria, which is independently developed by the applicant and has independent intellectual property rights. Etimicin sulfate is suitable for various infections caused by Escherichia coli, Klebsiella pneumoniae, Serratia, Citrobacter, Enterobacter, Acinetobacter, Proteus, Haemophilus influenzae, Pseudomonas aeruginosa and Staphylococcus aureus that are sensitive to it.
[0003] The 2020 edition of the Chinese Pharmacopoeia, Part II, records the impurity A of ezetimibe sulfate. The structural formula of impurity A is as follows: .
[0004] In order to ensure the safety and effectiveness of drugs and reduce the risks of drug use, it is very necessary to study and control impurities. This requires determining the preparation method of impurity compounds and providing qualified reference materials. However, there are currently no reports on such impurity preparation methods at home and abroad. Summary of the invention
[0005] The technical problem to be solved by the present invention is to provide a method for preparing impurity A of ezetimibe sulfate.
[0006] The first technical solution to achieve the purpose of the present invention is a method for preparing an impurity A of ezetimibe sulfate, wherein the impurity A has the following structural formula: ; The following steps are involved: ① Dissolve azithromycin sulfate in aqueous sulfuric acid solution, and react at 40°C under reflux for 16 h to 72 h. The reaction of azithromycin sulfate is completed by TLC monitoring, and the reaction solution is set aside.
[0007] ② The reaction solution obtained in step ① is adjusted to pH 6-8 with sodium hydroxide solution, ethanol is added and stirred, solid is precipitated, and the solid is filtered and the filtrate is concentrated under reduced pressure to remove ethanol.
[0008] The filtrate after removing ethanol is passed into a weakly acidic ion resin column for adsorption; after the column is loaded, pure water is passed for rinsing until the conductivity of the outlet solution is lower than 100 μS / cm; ammonia water is then used for gradient analysis, HPLC monitoring is performed, and components with higher purity are selected, combined, and concentrated under reduced pressure to obtain the ethimicin sulfate impurity A.
[0009] In the above step ①, the mass fraction of the aqueous sulfuric acid solution is 10% to 50%.
[0010] In the above step ②, the amount of ethanol used is twice the volume of the aqueous sulfuric acid solution in step ①.
[0011] In the above step ②, the resin filled in the weakly acidic ion resin column is D152, HD-2 or 107 resin.
[0012] When the ammonia water is subjected to gradient analysis in the above step ②, the concentration of the ammonia water is 0.05-0.4 Mol / L.
[0013] The second technical solution to achieve the purpose of the present invention is a method for preparing an impurity A of ezetimibe sulfate, comprising the following steps: ① React azithromycin sulfate with trifluoroacetic acid or trifluoroacetic acid aqueous solution at 40°C under reflux until the reaction of azithromycin sulfate is completed under TLC monitoring. After the reaction is completed, concentrate under reduced pressure until no liquid drops to obtain a crude oily product, which is dissolved in water for later use.
[0014] ② The material obtained in step ① is adjusted to pH 6-8 with sodium hydroxide solution, ethanol is added and stirred, solid is precipitated, and the solid is filtered and the filtrate is concentrated under reduced pressure to remove ethanol.
[0015] The filtrate after removing ethanol is passed into a weakly acidic ion resin column for adsorption; after the column is loaded, pure water is passed for rinsing until the conductivity of the outlet solution is lower than 100 μS / cm; ammonia water is then used for gradient analysis, HPLC monitoring is performed, and components with higher purity are selected, combined, and concentrated under reduced pressure to obtain the ethimicin sulfate impurity A.
[0016] In the above step ①, the concentration of the trifluoroacetic acid aqueous solution is 30% to 100%.
[0017] During the reduced pressure concentration in the above step ①, the temperature is 50 to 60°C and the pressure is -0.08 to -0.1 MPa.
[0018] In the above step ②, the amount of ethanol used is twice the volume of the water added in step ① (the water added when dissolving).
[0019] In the above step ②, the resin filled in the weakly acidic ion resin column is D152, HD-2 or 107 resin; when ammonia water is used for gradient analysis, the concentration of ammonia water is 0.05-0.4 Mol / L.
[0020] The present invention has positive effects: the present invention provides a method for preparing an ezetimicin sulfate impurity A. The ezetimicin sulfate impurity A prepared by the method has high purity and can be used as an impurity reference substance for detecting related substances of ezetimicin sulfate and its preparations, which is beneficial to further control the quality of ezetimicin sulfate and reduce the risk of medication. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1The impurity A of ezetimibe sulfate prepared in Example 1 1 H NMR spectrum.
[0022] Figure 2 This is the LC-MS spectrum of the impurity A of ezetimibe sulfate prepared in Example 1.
[0023] Figure 3 This is the HPLC spectrum of the impurity A of ezetimibe sulfate prepared in Example 1. DETAILED DESCRIPTION
[0024] (Example 1) The structural formula of the ezetimibe sulfate impurity A prepared in this example is as follows: .
[0025] The reaction formula for preparing impurity A of ezetimibe sulfate in this example is as follows: .
[0026] The preparation method of the impurity A of ezetimibe sulfate in this embodiment comprises the following steps: ① Add 50 g of azithromycin sulfate to a reaction bottle, add 250 mL of 10% to 50% (50% by mass in this embodiment) sulfuric acid aqueous solution, heat to 40° C., react at this temperature for 16 h to 72 h, monitor the completion of the reaction of azithromycin sulfate by TLC, and set aside the reaction solution.
[0027] The above reaction is carried out at 40°C to reflux, and in this example, the reaction is carried out at 40°C.
[0028] The minimum amount of sulfuric acid solution can completely dissolve ezetimibe sulfate. The amount of sulfuric acid solution can be as high as 20 times that of ezetimibe sulfate. However, the post-processing operation is more complicated when the amount of solvent is large.
[0029] ② The reaction solution obtained in step ① was adjusted to pH 6-8 with 20% sodium hydroxide solution, 500 mL of ethanol was added and stirred, solid was precipitated, and the filtrate was filtered and concentrated under reduced pressure to remove ethanol.
[0030] When adding ethanol, the amount of ethanol used is twice the volume of the aqueous sulfuric acid solution in step ①.
[0031] The filtrate after removing ethanol was passed into a D152 resin column for adsorption. After the column was loaded, pure water was passed through the column for rinsing until the conductivity of the outlet solution was lower than 100 μS / cm. Then, 0.05-0.3 Mol / L ammonia water was used for gradient analysis. HPLC monitoring was performed, and the components with higher purity were selected, combined, and concentrated under reduced pressure (temperature 50-60°C, pressure -0.08 to -0.1 MPa) to obtain 3.6 g of ethimicin sulfate impurity A.
[0032] The obtained product was detected by hydrogen nuclear magnetic resonance spectrum, mass spectrum and HPLC.
[0033] H NMR spectrum Figure 1 , mass spectrum see Figure 2 According to the structure confirmation test data, the compound prepared in the present application is consistent with the structure of impurity A of ezetimibe sulfate.
[0034] The HPLC spectrum of the product in this example is shown in Figure 3 The product purity is 99.02%, which is relatively high and can be used as an impurity reference.
[0035] (Example 2) The preparation method of the impurity A of ezetimicin sulfate in this example is the same as that in Example 1 except that: In step ②, the filtrate after removing ethanol is passed into the HD-2 resin column for adsorption.
[0036] In this example, 2.5 g of ethimicin sulfate impurity A was obtained.
[0037] (Example 3) The preparation method of the impurity A of ezetimicin sulfate in this example is the same as that in Example 1 except that: In step ①, the concentration of the aqueous sulfuric acid solution is 10%, and the reaction is heated under reflux for 72 hours.
[0038] In step ②, the filtrate after removing ethanol is passed through a 107 resin column for adsorption; the concentration of ammonia water used in the analysis is 0.05-0.4 Mol / L, and 2.9 g of ethimicin sulfate impurity A is obtained after separation.
[0039] (Example 4) The preparation method of the impurity A of ezetimicin sulfate in this example is the same as that in Example 1 except that: The solvent added in step ① is 250 mL of trifluoroacetic acid.
[0040] The specific operation of step ① is as follows: 50 g of azithromycin sulfate is added to a reaction bottle, 250 mL of trifluoroacetic acid is added, and the mixture is heated to 40° C. and reacted at this temperature for 16 h. The reaction of azithromycin sulfate is completed by monitoring by TLC.
[0041] When trifluoroacetic acid is used as the acid, the reaction is carried out at a temperature from 40°C to reflux, and in this example, the reaction is carried out at 40°C.
[0042] After the reaction is completed, the mixture is concentrated under reduced pressure (temperature 50-60°C, pressure -0.08-0.1 MPa) until no liquid drops flow down to obtain a crude oil. Add 250 mL of water to dissolve it for later use.
[0043] The rest of step ② is the same as that of Example 1, except that when ethanol is added, the amount of ethanol used is twice the volume of the water added in step ① (the water added when dissolving).
[0044] In this example, 3.4 g of ethimicin impurity A was isolated.
[0045] (Example 5) The preparation method of the impurity A of ezetimicin sulfate in this example is the same as that in Example 4 except that: What is added in step ① is 30% trifluoroacetic acid aqueous solution.
[0046] In step ②, the resin used is HD-2 resin; the concentration of ammonia water used in the analysis is 0.05-0.3 Mol / L, and 3.0 g of azithromycin sulfate impurity A is obtained after separation.
[0047] (Application example) The impurity A of azithromycin sulfate is used as an impurity reference substance for the detection of related substances of azithromycin or its preparations.
[0048] When used as a reference substance, the impurity A of azithromycin is dissolved in a diluent solvent to prepare a 1 μg / mL solution as the reference substance solution. The chromatogram is recorded according to the injection conditions and compared with the chromatogram of azithromycin to determine the presence and content of the degradation impurity in azithromycin or its preparation.
Claims
1. A method for preparing impurity A of ezetimibe sulfate, wherein the impurity A has the following structural formula: ； Features The following steps are involved: ① Dissolve azithromycin sulfate in aqueous sulfuric acid solution, and react at 40°C under reflux for 16 h to 72 h. Monitor the completion of the reaction of azithromycin sulfate by TLC, and keep the reaction solution for later use; ② The reaction solution obtained in step ① is adjusted to pH 6-8 with sodium hydroxide solution, ethanol is added, stirred, solid is precipitated, filtered, and the filtrate is concentrated under reduced pressure to remove ethanol; The filtrate after removing ethanol is passed into a weakly acidic ion resin column for adsorption; after the column is loaded, pure water is passed for rinsing until the conductivity of the outlet solution is lower than 100 μS / cm; ammonia water is then used for gradient analysis, HPLC monitoring is performed, and components with higher purity are selected, combined, and concentrated under reduced pressure to obtain the ethimicin sulfate impurity A.
2. The method for preparing the impurity A of ezetimibe sulfate according to claim 1, characterized in that: In step ①, the mass fraction of the aqueous sulfuric acid solution is 10% to 50%.
3. The method for preparing the ethimicin sulfate impurity A according to claim 1, characterized in that: In step ②, the amount of ethanol used is twice the volume of the aqueous sulfuric acid solution in step ①.
4. The method for preparing the ethimicin sulfate impurity A according to claim 1, characterized in that: In step ②, the resin filled in the weakly acidic ion resin column is D152, HD-2 or 107 resin.
5. The method for preparing the impurity A of etimicin sulfate according to claim 1, characterized in that: When the ammonia water is subjected to gradient analysis in step ②, the concentration of the ammonia water is 0.05-0.4 Mol / L.
6. A method for preparing impurity A of ezetimibe sulfate, characterized in that The following steps are involved: ① reacting azithromycin sulfate with trifluoroacetic acid or trifluoroacetic acid aqueous solution at 40°C under reflux until the reaction of azithromycin sulfate is completed under TLC monitoring, and after the reaction is completed, the mixture is concentrated under reduced pressure until no liquid drops to obtain a crude oil, which is dissolved in water for later use; ② The material obtained in step ① is adjusted to pH 6-8 with sodium hydroxide solution, ethanol is added, stirred, solid is precipitated, filtered, and the filtrate is concentrated under reduced pressure to remove ethanol; The filtrate after removing ethanol is passed into a weakly acidic ion resin column for adsorption; after the column is loaded, pure water is passed for rinsing until the conductivity of the outlet solution is lower than 100 μS / cm; ammonia water is then used for gradient analysis, HPLC monitoring is performed, and components with higher purity are selected, combined, and concentrated under reduced pressure to obtain the ethimicin sulfate impurity A.
7. The method for preparing the impurity A of etimicin sulfate according to claim 6, characterized in that: In step ①, the concentration of the trifluoroacetic acid aqueous solution is 30% to 100%.
8. The method for preparing the impurity A of etimicin sulfate according to claim 6, characterized in that: During the reduced pressure concentration in step ①, the temperature is 50-60° C. and the pressure is -0.08--0.1 MPa.
9. The method for preparing the impurity A of etimicin sulfate according to claim 6, characterized in that: In step ②, the amount of ethanol used is twice the volume of water added in step ①.
10. The method for preparing the impurity A of etimicin sulfate according to claim 6, characterized in that: In step ②, the resin filled in the weakly acidic ion resin column is D152, HD-2 or 107 resin; when ammonia water is used for gradient analysis, the concentration of ammonia water is 0.05-0.4 Mol / L.