Methimazole drug impurity as well as preparation method and application thereof
High-purity methimazole drug impurities are prepared through a simple two-step reaction, which solves the problem of lack of high-purity impurity standards in the existing technology and realizes effective control of drug quality.
Patent Information
- Application Number
- CN202510806376.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-17
- Publication Date
- 2025-10-03
AI Technical Summary
The existing technology lacks high-purity methimazole drug impurity standards, which affects drug quality control.
A simple two-step reaction, including coupling and substitution reactions, is used to prepare methimazole drug impurities. By controlling the reaction conditions and post-processing steps, a high-purity target product is obtained.
The drug impurity of methimazole with a purity of up to 99.96% was successfully prepared, providing a high-purity impurity standard to support drug quality testing and production control.
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Figure CN120737033A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a methimazole drug impurity and a preparation method and application thereof. Background Art
[0002] Methimazole, an imidazole antithyroid drug, works by inhibiting thyroid peroxidase, thereby hindering the oxidation of iodide and the conjugation of tyrosine within the thyroid gland, thereby inhibiting the synthesis of thyroxine (T4) and triiodothyronine (T3). Animal studies have shown that methimazole can inhibit antibody synthesis by B lymphocytes, reduce circulating levels of thyroid-stimulating antibodies, and restore normal suppressor T cell function. In recent years, an increasing number of people have been diagnosed with hyperthyroidism due to factors such as work pressure, late nights, and irregular lifestyles. Methimazole is essential for the treatment of hyperthyroidism and is the drug of choice. Specific indications include: 1. Drug treatment of hyperthyroidism, especially for patients with no or mild thyroid enlargement (goiter) and young patients; 2. Preoperative preparation for various types of hyperthyroidism; 3. Preparatory medication for patients with hyperthyroidism who are planned to use radioactive iodine treatment to prevent the occurrence of thyroid toxic crisis after treatment; 4. Treatment during the interval after radioactive iodine treatment; 5. As a preventive medication for patients with a history of hyperthyroidism who must use iodine irradiation (such as examination using iodine-containing contrast agents) and patients with functionally autonomous thyroid adenomas.
[0003] Methimazole will produce a very small amount of impurities during the production, storage and drug manufacturing process. This is one of the impurities. Currently, no method for synthesizing this impurity has been reported. However, during drug quality testing, high-purity impurity standards are required as reference substances to control the quality of drugs that may contain this impurity. Therefore, the synthesis of this impurity is of great significance to the research, development, and production of methimazole drugs. Summary of the Invention
[0004] The purpose of the present invention is to overcome the deficiencies of the prior art and to provide a methimazole drug impurity and a preparation method and application thereof.
[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:
[0006] The preparation method of methimazole drug impurities comprises the following steps:
[0007] Step 1: adding methimazole and an organic solvent into a reaction vessel and stirring uniformly to obtain a solution I;
[0008] Step 2: adding elemental iodine to an organic solvent to obtain solution II;
[0009] Step 3: Add solution II dropwise to solution I. After the addition is complete, continue stirring and react for a certain period of time;
[0010] Step 4: After the reaction is completed, the reaction mixture is post-treated to obtain a methimazole drug impurity intermediate;
[0011] Step 5: Under a nitrogen atmosphere, methimazole is added to anhydrous tetrahydrofuran, cooled to -78°C to -80°C, stirred for 5-10min, and a hexane solution of n-butyl lithium is added dropwise. The addition rate is controlled so that the system temperature is controlled at -70°C to -78°C, and the reaction is carried out at -70°C to -78°C for 45 to 50min. The temperature is lowered to -78°C to -80°C, and the tetrahydrofuran solution of the methimazole drug impurity intermediate obtained in step 4 is added dropwise. The addition rate is controlled so that the system temperature is controlled at -70°C to -78°C, and the reaction is carried out at -70°C to -78°C for 5 to 30min. The temperature is raised to -25 to -35°C and stirring is continued for 45 to 50min. The temperature is then naturally raised to room temperature, the reaction is stirred overnight, and the reaction is cooled to 0°C. The reaction solution is post-treated to obtain the methimazole drug impurity.
[0012] Furthermore, in the method for preparing methimazole drug impurities, the molar ratio of the methimazole in step 1 to the elemental iodine in step 2 is 4.38:5.
[0013] Furthermore, in the method for preparing methimazole drug impurities, the reaction temperature of the reaction in step 3 is 20-30° C., and the reaction time is 45-50 min.
[0014] Furthermore, in the method for preparing methimazole drug impurities, the organic solvent in step 1 and step 2 is dichloromethane.
[0015] Furthermore, in the preparation method of methimazole drug impurities, the post-treatment described in step 4 is specifically as follows: after the reaction is completed, the reaction mixture is washed with a sodium thiosulfate aqueous solution, washed with water, the aqueous phase is extracted with dichloromethane, the organic phases are combined, dried with anhydrous sodium sulfate, and the organic solvent is removed by rotary evaporation to obtain a crude product, which is purified by silica gel column chromatography, and the eluent is: dichloromethane: methanol = 10:1, V / V.
[0016] Furthermore, in the method for preparing the methimazole drug impurity, the molar ratio of the methimazole, the n-butyl lithium, and the methimazole drug impurity intermediate in step five is 1:1:0.9-1.09.
[0017] Furthermore, in the method for preparing methimazole drug impurities, the molar concentration of the hexane solution of n-butyl lithium in step five is 1.6M.
[0018] Furthermore, the preparation method of the methimazole drug impurity, wherein the post-treatment described in step five is specifically as follows: after the reaction is completed, quenching with saturated ammonium chloride, extracting the reaction mixture with ethyl acetate, then washing with water and saturated brine, drying with anhydrous magnesium sulfate, and removing the solvent by reduced pressure rotary evaporation to obtain a crude product, and the crude product is purified by silica gel column chromatography, and the eluent is dichloromethane: methanol = 20:1, V / V, to obtain the methimazole drug impurity.
[0019] The present invention also provides methimazole drug impurities prepared by the preparation method of methimazole drug impurities described in any of the above technical solutions.
[0020] The present invention also provides application of the methimazole drug impurities in methimazole drug impurity analysis.
[0021] Compared with the prior art, the present invention has the following beneficial effects:
[0022] The present invention starts from a single raw material and prepares the target product, i.e., the impurity of the methimazole drug, for the first time through a simple two-step reaction, namely, coupling and substitution reaction. Ultimately, the methimazole drug impurity with a purity of up to 99.96% is obtained, providing a high-purity impurity standard for the production process of the antithyroid drug methimazole and product quality control.
[0023] The preparation method of the present invention has a short process and a fast and efficient synthetic route. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is a high performance liquid chromatogram of the target product obtained in Example 2 of the present invention;
[0025] Figure 2 The target product obtained in Example 2 of the present invention 1 H NMR spectrum;
[0026] Figure 3 The target product obtained in Example 2 of the present invention 13 C NMR spectrum;
[0027] Figure 4 This is the mass spectrum of the target product obtained in Example 2 of the present invention. DETAILED DESCRIPTION
[0028] The present invention is described in further detail below with reference to the embodiments.
[0029] Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the methods were performed according to the techniques or conditions described in the literature in the art or according to the product specifications. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased.
[0030] Example 1
[0031] The synthesis of 1,2-bis(1-methyl-1H-imidazol-2-yl)disulfane is as follows:
[0032]
[0033] Methimazole (5.0 g, 43.8 mmol) and dichloromethane (200 ml) were added to a 500 ml three-necked flask and stirred to obtain a clear solution. Elemental iodine (12.7 g, 50.0 mmol) and dichloromethane (100 ml) were added to a dropping funnel and slowly added dropwise to the flask at room temperature over approximately 30 minutes. After the addition was complete, the iodine-dichloromethane solution was stirred at room temperature for 45 minutes before the reaction was stopped. The reaction mixture was washed with a 10% aqueous sodium thiosulfate solution and then with water. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the dichloromethane was removed by rotary evaporation to obtain a crude product. The crude product was further purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1, v / v) to obtain 4.3 g of the product with 96.84% purity, a yield of 86%, and qualified by mass spectrometry.
[0034] Example 2
[0035] The synthesis of target drug impurities is as follows:
[0036]
[0037] Anhydrous tetrahydrofuran (100 ml) was added to a 250 ml three-necked flask equipped with a thermometer and dropping funnel. Methimazole (1.1 g, 9.6 mmol) was added under nitrogen. The mixture was cooled to -78°C (dry ice-ethanol bath) and stirred for 5-10 min. A 1.6 M solution of n-butyllithium in hexane (6 ml, 9.6 mmol) was slowly added dropwise, controlling the addition rate to keep the system temperature below -70°C. The reaction was continued at this temperature for 45 min. The mixture was then cooled again to -78°C and a solution of 1,2-bis(1-methyl-1H-imidazol-2-yl)disulfane (2.0 g, 8.8 mmol) in tetrahydrofuran (15 ml) was slowly added dropwise, controlling the addition rate to keep the system temperature below -70°C. The reaction was continued at this temperature for 30 min. The mixture was then heated to -30°C and stirred for 45 min. The mixture was then allowed to warm to room temperature and stirred overnight. The mixture was then cooled to 0°C and quenched with saturated ammonium chloride. The mixture was extracted three times with ethyl acetate, and the organic phase was washed sequentially with water and saturated brine. Finally, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to yield 2.2 g of a yellow oil. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to obtain 1.3 g of the target drug impurity in a 65% yield. NMR, mass spectrometry, and HPLC analysis confirmed that the product had a structure consistent with a methimazole drug impurity and a purity greater than 99.96%.
[0038] The above embodiments provide detailed descriptions of the implementation methods of the present invention. However, the present invention is not limited to the above embodiments. Various modifications can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. The above descriptions are merely preferred embodiments of the present invention and do not limit the scope of the present invention. Any equivalent structural changes made using the contents of the present invention description are included within the scope of the present invention.
Claims
1. A method for preparing methimazole drug impurities, characterized in that: The steps include: Step 1: adding methimazole and an organic solvent into a reaction vessel and stirring uniformly to obtain a solution I; Step 2: adding elemental iodine to an organic solvent to obtain solution II; Step 3: Add solution II dropwise to solution I. After the addition is complete, continue stirring and react for a certain period of time; Step 4: After the reaction is completed, the reaction mixture is post-treated to obtain a methimazole drug impurity intermediate; Step 5: Under a nitrogen atmosphere, methimazole is added to anhydrous tetrahydrofuran, cooled to -78°C to -80°C, stirred for 5-10min, and a hexane solution of n-butyl lithium is added dropwise. The addition rate is controlled so that the system temperature is controlled at -70°C to -78°C, and the reaction is carried out at -70°C to -78°C for 45 to 50min. The temperature is lowered to -78°C to -80°C, and the tetrahydrofuran solution of the methimazole drug impurity intermediate obtained in step 4 is added dropwise. The addition rate is controlled so that the system temperature is controlled at -70°C to -78°C, and the reaction is carried out at -70°C to -78°C for 5 to 30min. The temperature is raised to -25 to -35°C and stirring is continued for 45 to 50min. The temperature is then naturally raised to room temperature, the reaction is stirred overnight, and the reaction is cooled to 0°C. The reaction solution is post-treated to obtain the methimazole drug impurity.
2. The method for preparing methimazole drug impurities according to claim 1, wherein The molar ratio of the methimazole in step 1 to the elemental iodine in step 2 is 4.38:
5.
3. The preparation method of methimazole drug impurities according to claim 1, wherein The reaction temperature of the reaction in step 3 is 20-30° C., and the reaction time is 45-50 min.
4. The method for preparing methimazole drug impurities according to claim 1, wherein The organic solvent in step 1 and step 2 is dichloromethane.
5. The method for preparing methimazole drug impurities according to claim 1, wherein The post-treatment described in step 4 is specifically as follows: after the reaction is completed, the reaction mixture is washed with an aqueous solution of sodium thiosulfate, washed with water, the aqueous phase is extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and the organic solvent is removed by rotary evaporation to obtain a crude product, which is purified by silica gel column chromatography with an eluent of dichloromethane: methanol = 10:1, V / V.
6. The method for preparing methimazole drug impurities according to claim 1, wherein In step 5, the molar ratio of the methimazole, the n-butyl lithium, and the methimazole drug impurity intermediate is 1:1:0.9-1.
09.
7. The method for preparing methimazole drug impurities according to claim 1, wherein The molar concentration of the hexane solution of n-butyl lithium in step 5 is 1.6M.
8. The method for preparing methimazole drug impurities according to claim 1, wherein The post-treatment described in step 5 is specifically as follows: after the reaction is completed, quenching with saturated ammonium chloride, extracting the reaction mixture with ethyl acetate, then washing with water and saturated brine, drying over anhydrous magnesium sulfate, and removing the solvent by vacuum rotary evaporation to obtain a crude product, which is purified by silica gel column chromatography with an eluent of dichloromethane: methanol = 20:1, V / V, to obtain methimazole drug impurities.
9. The methimazole drug impurity obtained by the method for preparing the methimazole drug impurity according to any one of claims 1 to 8.
10. Use of the methimazole drug impurity according to claim 9 in the analysis of methimazole drug impurities.