Preparation method and application of dronedarone intermediate impurity
By preparing and separating the impurity I and impurity II of the cognonidalone intermediate, the problem of difficulty in separation of impurities in the prior art affecting the purity of cognonidalone is solved, and a high-purity reference product is provided, which improves the quality monitoring ability of cognonidalone.
Patent Information
- Application Number
- CN202311740854.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-15
- Publication Date
- 2025-06-17
AI Technical Summary
During the synthesis of dronedarone, the intermediate impurity I and impurity II generated are difficult to separate, affecting the purity of dronedarone. The prior art lacks synthetic reports and reference materials for this impurity.
A method for preparing impurity I and impurity II of the jonidalon intermediate is provided. By adding compound III, compound IV, alkali and organic solvent, purifying after heating reaction, the high-purity impurity I and impurity II are separated by column chromatography technology.
The efficient preparation and separation of impurities of jonidalon intermediates is achieved, and the reference product for the purity control of the drug purity of the drug nudelaone raw materials is provided, which improves the quality monitoring ability of jonidalon.
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Figure CN120157641A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to a preparation method and application of impurities of dronedarone intermediates. Background Art
[0002] Dronedarone is a new drug for the treatment of atrial fibrillation developed by Sanofi-Aventis. Its structure and characteristics are similar to those of the cardiovascular drug amiodarone, and both are potassium channel blockers. However, this drug does not contain iodine and has a lower lipophilicity, so it will not cause iodine-related adverse reactions.
[0003] Dronedarone is an antiarrhythmic drug that has been proven in clinical trials to significantly reduce the morbidity and mortality of patients with atrial fibrillation / atrial flutter. It is a priority review variety of the US FDA and was approved by the FDA in July 2009 and by the EU in December 2009. Therefore, the development of dronedarone will bring good economic and social benefits.
[0004]
[0005] During the preparation of the compound dronedarone, intermediate impurities I and II will be generated, and the impurities are difficult to separate, affecting the purity of dronedarone. There is no synthesis report of the impurity compound I and compound II in the prior art. It is difficult for people to obtain a large amount of high-purity compound I and compound II, and there is a lack of corresponding reference substances. In view of the pharmaceutical value and good market prospects of dronedarone, it is urgent for us to monitor and detect impurities I and II during the synthesis of dronedarone, so as to control the quality of dronedarone. Summary of the Invention
[0006] Object of the Invention: The object of the present invention is to provide a preparation method and application of impurities of dronedarone intermediates.
[0007] To achieve the above object, the technical solution provided by the present invention is as follows:
[0008] The compounds of the present invention having the structures shown in Formula I and Formula II:
[0009]
[0010] The preparation method of the compounds of the present invention having the structures shown in Formula I and Formula II, the reaction route is as follows:
[0011]
[0012] Wherein: the molar ratio of the compound III: the compound IV: the base is 1:3-4:3-4.
[0013] The base is potassium carbonate, sodium carbonate or potassium hydroxide.
[0014] A preparation method of a dronedarone intermediate impurity, comprising the following steps:
[0015] Add compound III, compound IV, a base, and an organic solvent, raise the temperature for reaction, and perform post-treatment and purification to obtain compound I and compound II.
[0016] The temperature for raising the temperature is 50-70 °C.
[0017] The organic solvent is acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide.
[0018] The reaction time is 8-16 h.
[0019] The steps of the post-treatment and purification are as follows: add water and dichloromethane to the reaction solution, stir at room temperature, stand still, separate the layers, and stir the organic phase with water; perform column chromatography on the organic phase to obtain compound I and compound II.
[0020] The eluent for the column chromatography is gradient elution with petroleum ether and ethyl acetate. The ratio of petroleum ether to ethyl acetate is 15:1-20:1. First, obtain compound II; then adjust the ratio of petroleum ether to ethyl acetate to 5:1-10:1 to obtain compound I.
[0021] An application of a dronedarone intermediate impurity, characterized in that it is used as a reference substance for detecting related substances of a dronedarone intermediate and for controlling the purity of dronedarone bulk drug.
[0022] Beneficial effects: The compounds of formula I and formula II provided by the present invention can be used as impurity reference substances to control the purity of dronedarone raw materials or preparations; the preparation method of the compounds of formula I and formula II provided by the present invention has cheap and easily available raw materials, simple operation, mild reaction conditions, and two compounds can be obtained simultaneously in one-step reaction.
[0023] The abbreviations of the reaction reagents involved in the specification are as follows:
[0024] DMF: N,N-dimethylformamide;
[0025] DMSO: dimethyl sulfoxide;
[0026] DCM: dichloromethane. Description of the Drawings
[0027] Figure 1 1H NMR spectrum of compound II in Example 1;
[0028] Figure 2 1H NMR spectrum of compound I in Example 1;
[0029] Figure 3 It is the purity diagram of Compound II in Example 1;
[0030] Figure 4 It is the purity diagram of Compound I in Example 1. Detailed implementation mode
[0031] Example 1
[0032]
[0033] Preparation methods of Compound I and Compound II
[0034] Add 10 g of Compound III, 8.58 g of Compound IV, 8.66 g of potassium carbonate, and 100 ml of DMF to a 250 mL reaction flask, react at 50 °C overnight until the raw materials disappear, end the reaction, cool down, add 100 mL of water and 200 mL of DCM to the reaction solution, stir at room temperature for 0.5 h, let stand, separate the layers, add 100 mL of water to the organic phase and stir for 0.5 h; let stand, separate the layers, add 20 g of silica gel to the organic phase to make sand, perform column chromatography, and elute with a solvent ratio of petroleum ether:ethyl acetate of 15:1 to obtain 4.6 g of Compound II with a purity of 97.27% and a yield of 37%. The 1H NMR spectrum is as Figure 1 shown 1 1H NMR (CDCl3, 400 MHz): δ ppm 1.24~1.32 (m, 15.10H), 1.33~1.41 (m, 10.19H), 1.42~1.51 (m, 7.91H), 1.73~1.77 (t, 2.08H), 1.94~1.98 (t, 1.98H), 2.42~2.46 (t, 4.07H), 2.60~2.63 (t, 2.01H), 2.93~3.18 (q, 3.92H), 4.09~4.12 (t, 1.98H), 6.55~6.56 (d, 1.00H), 6.68~6.71 (t, 1.00H), 6.95~6.97 (d, 2.00H), 7.30~7.32 (d, 1.11H), 7.85~7.87 (d, 1.98H), m / z [M+H] + : 592.65.
[0035] The purity determination results are shown in Table 1 and Figure 3 shown below.
[0036] Table 1 Purity determination results of Compound II:
[0037]
[0038] Elute with a solvent ratio of petroleum ether:ethyl acetate of 10:1 to obtain 4.8 g of Compound I with a purity of 98.35% and a yield of 43%. The 1H NMR spectrum is asFigure 2 As shown 1 HNMR(CDCl3, 400 MHz): δ ppm 0.90 - 0.96 (m, 12.21H), 1.27 - 1.37 (m, 5.89H), 1.39 - 1.48 (m, 6.03H), 1.55 - 1.59 (t, 1.85H), 1.71 - 1.75 (t, 1.98H), 1.94 - 1.98 (t, 1.92H), 2.42 - 2.46 (t, 3.96H), 2.83 - 2.87 (t, 1.88H), 3.02 - 3.05 (t, 1.93H), 4.10 - 4.13 (t, 2.02H), 6.58 - 6.60 (q, 1.85H), 6.96 - 6.98 (t, 2.00H), 7.26 - 7.28 (d, 1.07H), 7.85 - 7.87 (d, 1.90H), m / z [M + H] + : 536.06
[0039] The purity determination results are shown in Table 2 and Figure 4 as shown
[0040] Table 2 Purity determination results of Compound I:
[0041]
[0042] Example 2
[0043]
[0044] Preparation methods of Compound I and Compound II
[0045] Add 10 g of Compound III, 11.45 g of Compound IV, 8.49 g of sodium carbonate, and 100 mL of acetonitrile into a 250 mL reaction flask. React at 65 °C for 16 h until the raw materials disappear, then end the reaction and cool down. Add 100 mL of water and 200 mL of DCM to the reaction solution, stir at room temperature for 0.5 h, let it stand and separate the layers. Add 100 mL of water to the organic phase and stir for 0.5 h; let it stand and separate the layers. Add 20 g of silica gel to the organic phase to make sand, and perform column chromatography. The eluent ratio is petroleum ether:ethyl acetate = 15:1 to obtain 7.4 g of Compound II with a purity of 97.2% and a yield of 60%. The eluent ratio is petroleum ether:ethyl acetate = 10:1 to obtain 1.7 g of Compound I with a purity of 98.3% and a yield of 15%.
[0046] Example 3
[0047]
[0048] Preparation methods of Compound I and Compound II
[0049] 10 g of compound Ⅲ, 8.58 g of compound Ⅳ, 2.24 g of potassium hydroxide and 100 mL of DMSO were added to a 250 mL reaction flask, and the reaction was carried out at 70 °C for 8 h until the raw materials disappeared. After the reaction, the temperature was lowered. 100 mL of water and 200 mL of DCM were added to the reaction solution, and the mixture was stirred at room temperature for 0.5 h, then left to stand and separated into layers. 100 mL of water was added to the organic phase and stirred for 0.5 h; left to stand and separated into layers. 20 g of silica gel was added to the organic phase to make sand, and column chromatography was carried out. The eluent ratio was petroleum ether: ethyl acetate = 20:1. 4.4 g of compound Ⅱ was obtained by column chromatography, with a purity of 96.2% and a yield of 35%. The eluent ratio was petroleum ether: ethyl acetate = 5:1. 3.7 g of compound Ⅰ was obtained by column chromatography, with a purity of 97.1% and a yield of 33%.
[0050] The above specific embodiments have further detailed the purpose, technical solutions and beneficial effects of the present application. It should be understood that the above are only the specific embodiments of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent replacements, improvements, etc. made on the basis of the technical solutions of the present application shall be included in the protection scope of the present application.
Claims
1. A method for preparing a dronedarone intermediate impurity, characterized in that, Comprising: Wherein: the molar ratio of compound III: compound IV: base is 1: 3-4: 3-4.
2. The method for preparing a dronedarone intermediate impurity according to claim 1, characterized in that, The base is potassium carbonate, sodium carbonate or potassium hydroxide.
3. The method for preparing a dronedarone intermediate impurity according to claim 1, characterized in that, Comprising the following steps: Adding compound III, compound IV, base, and an organic solvent, heating the reaction, and performing post-treatment purification to obtain compound I and compound II.
4. The method for preparing a dronedarone intermediate impurity according to claim 3, characterized in that, The heating temperature is 50-70 °C.
5. The method for preparing a dronedarone intermediate impurity according to claim 3, characterized in that, The organic solvent is acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide.
6. The method for preparing a dronedarone intermediate impurity according to claim 3, characterized in that, The reaction time is 8-16 h.
7. The method for preparing a dronedarone intermediate impurity according to claim 3, characterized in that, The steps of the post-treatment purification are as follows: adding water and dichloromethane to the reaction solution, stirring at room temperature, standing, separating layers, and stirring the organic phase with water; subjecting the organic phase to column chromatography to obtain compound I and compound II.
8. The method for preparing a dronedarone intermediate impurity according to claim 7, characterized in that, The eluent for the column chromatography is gradient elution with petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 15: 1-20:
1. First, compound II is obtained; then, the ratio of petroleum ether to ethyl acetate is adjusted to 5: 1-10: 1 to obtain compound I.
9. An application of the dronedarone intermediate impurity according to claim 1, characterized in that, For the control product used in the detection of related substances of dronedarone intermediates and the purity control of dronedarone bulk drug.