Preparation method of dronedarone hydrochloride impurity
During the synthesis of dronedarone hydrochloride, the coupling reaction of compound I and oxalyl chloride under low temperature conditions and purified by column chromatography, the high-purity dronedarone hydrochloride impurity compound II was successfully prepared, which solved the problem of lack of this impurity synthesis method in the prior art, and achieved efficient and high-purity impurity preparation.
Patent Information
- Application Number
- CN202311717438.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-13
- Publication Date
- 2025-06-13
AI Technical Summary
The prior art lacks the synthesis method of the intermediate impurity compound II of dronedarone hydrochloride and the lack of a reference product of high-purity compound II, which makes it difficult to conduct qualitative and quantitative detection of the impurity during the synthesis of dronedarone hydrochloride.
The coupling reaction of compound I and oxalyl chloride under low temperature conditions was carried out, and the dronedarone hydrochloride impurity compound II was prepared by the selection of solvent, acid chloride and subsequent column chromatography purification steps.
The efficient preparation of the dronedarone hydrochloride impurity compound II was achieved. The raw materials were cheap and easy to obtain, simple operation, mild reaction conditions, and the target product was transformed and yielded, and the purity could reach more than 98%.
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Figure CN120136828A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of a dronedarone hydrochloride impurity. Background Art
[0002] Dronedarone hydrochloride is an antiarrhythmic drug, which is applicable to patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), reducing the risk of hospitalization, recent AF / AFL attacks and patients with cardiovascular risk factors (i.e., age > 70, hypertension, diabetes, previous cardiovascular accident, left atrial diameter ≥ 50 mm or left ventricular ejection fraction [LVEF] < 40%), and patients with sinus rhythm or restorable rhythm.
[0003] Dronedarone hydrochloride is an antiarrhythmic drug developed by Sanofi-Aventis France, mainly used for controlling the heart rhythm of patients with atrial fibrillation and atrial flutter, maintaining sinus rhythm and slowing ventricular rhythm, etc. This drug has similar electrophysiological effects to amiodarone, but without iodine in its molecular structure, thus reducing lipophilicity, having less impact on the thyroid and thyroid hormones, no obvious cardiotoxicity, and also having less extracardiac adverse reactions.
[0004] Currently, the commonly used synthetic route of dronedarone hydrochloride is as follows:
[0005]
[0006] In the process of synthesizing compound VI above, compound V undergoes a coupling reaction with oxalyl chloride under low-temperature conditions, generating impurity compound II, which is difficult to remove in the process. Eventually, it will participate in the synthesis of dronedarone hydrochloride, thereby affecting the purity of the raw material drug dronedarone hydrochloride. It is necessary to monitor and detect impurity II during the synthesis of dronedarone hydrochloride to control the quality of the raw material drug dronedarone hydrochloride. As one of the main impurities generated during the synthesis of dronedarone hydrochloride, impurity II has a low content during the synthesis of dronedarone hydrochloride, is difficult to separate, and there is no synthesis report of this impurity compound II in the prior art. It is difficult for people to obtain a large amount of high-purity compound II, lacking corresponding reference substances, and it is difficult to qualitatively and quantitatively detect this impurity during the synthesis of dronedarone hydrochloride. Summary of the Invention
[0007] Object of the Invention: The object of the present invention is to overcome the lack of a synthesis method for the intermediate impurity compound II of dronedarone hydrochloride and the lack of a reference substance of high-purity compound II in the prior art, and provide a new preparation method for the dronedarone hydrochloride impurity compound II.
[0008] A compound having the chemical structure of dronedarone hydrochloride impurity compound II:
[0009]
[0010] Preparation method of impurity compound II of dronedarone hydrochloride intermediate, the reaction route is as follows:
[0011]
[0012] Wherein the acyl chloride is oxalyl chloride.
[0013] The molar ratio of the compound I to the acyl chloride is 1:1 to 3.
[0014] The oxalyl chloride is also prepared by reacting thionyl chloride with oxalic acid.
[0015] The preparation method of dronedarone hydrochloride impurity includes the following steps:
[0016] Dissolve the compound I with a solvent, and react with the acyl chloride under low temperature conditions with stirring. After post-treatment, impurity compound II of dronedarone hydrochloride is obtained.
[0017] The low temperature is -10 to 10 °C.
[0018] The solvent is one or more of acetonitrile, tetrahydrofuran, and dichloromethane.
[0019] The reaction time is 1 to 10 h.
[0020] The steps of the post-treatment are to drop water into the reaction system, separate the liquid, collect the organic phase, dry the organic phase, perform gradient elution, and column chromatography to obtain compound II.
[0021] The eluent for the gradient elution is dichloromethane:methanol 100:1 to 90:1.
[0022] Beneficial effects: The present invention provides a brand-new preparation method of impurity II of dronedarone hydrochloride intermediate. This method has cheap and easily available raw materials, simple operation, mild reaction conditions, high conversion rate and yield of the target product, and can reach a purity of more than 98% by column chromatography purification. Description of the drawings
[0023] Figure 1 1H NMR spectrum of compound II in Example 1;
[0024] Figure 2 Purity diagram of compound II in Example 1. Detailed implementation manners
[0025] The following specific embodiments further elaborate in detail the purpose, technical solution, and beneficial effects of the present application. It should be understood that the following are only 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 solution of the present application shall be included within the protection scope of the present application.
[0026] Example 1
[0027]
[0028] Preparation method of Compound II
[0029] Add 15 mL (10 v / m) of dichloromethane and 1.5 g (0.003 mol, 1.0 eq) of Compound I into a 50 mL four-necked flask. Cool the temperature to 0 - 10 °C, and dropwise add 0.48 g (0.0038 mol, 1.2 eq) of oxalyl chloride. Control the temperature of the whole process at -10 - 0 °C. Stir for 1 h. When the raw materials disappear in the reaction system monitored by thin-layer chromatography, add 15 mL of water (10 v / m) dropwise to the reaction system, separate the liquid, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, make sand with 15 g of silica gel of 200 - 300 mesh, perform column chromatography, and the eluent ratio is dichloromethane:methanol = 100:1. After passing through the column, 1.33 g of Compound II is obtained, with a yield of 89% and a purity of 98.54%. The proton nuclear magnetic resonance spectrum is as Figure 1 shown, 1 HNMR(CDCl 3 , 400 MHz) δ ppm: 9.34 (s, 1.00H), 7.84 - 7.82 (d, 2.00H), 7.73 - 7.70 (q, 1.09H), 7.54 - 7.48 (d, 1.05H), 7.28 (s, 0.99H), 6.97 - 6.95 (d, 2.05H), 4.19 - 4.17 (t, 2.09H), 3.05 (s, 1.87H), 2.92 - 2.84 (q, 5.94H), 2.29 (s, 1.98H), 1.77 - 1.69 (m, 6.07H), 1.40 - 1.32 (m, 6.00H), 0.97 - 0.92 (q, 6.03H), 0.90 - 0.88 (d, 3.24H); The purity determination results of Compound II are shown in Table 1 and Figure 2 shown.
[0030] Table 1 Purity determination results of Compound II:
[0031]
[0032] Example 2
[0033]
[0034] Preparation method of Compound II
[0035] Add 20 mL (10 v / m) of tetrahydrofuran and 1.5 g (0.003 mol, 1.0 eq) of Compound I into a 50 mL four-necked flask. Cool the temperature to 0 - 10 °C, and slowly add 0.76 g (0.006 mol, 2 eq) of oxalyl chloride dropwise while controlling the temperature at 0 - 10 °C throughout the process. Stir for 3 h. Monitor the disappearance of the raw materials by thin-layer chromatography of the reaction system. Add 15 mL of water (10 v / m) dropwise to the reaction system, separate the layers, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, prepare sand with 15 g of silica gel of 200 - 300 mesh, perform column chromatography, and use a dichloromethane:methanol ratio of 90:1 as the eluent. After passing through the column, 1.37 g of Compound II is obtained, with a yield of 90% and a purity of 98%.
[0036] Example 3
[0037]
[0038] Preparation method of Compound II
[0039] Add 30 mL (10 v / m) of acetonitrile and 3.0 g (0.006 mol, 1.0 eq) of Compound I into a 50 mL four-necked flask. Cool the temperature to 0 - 10 °C for standby. Slowly add thionyl chloride (0.018 mol, 3.0 eq) dropwise to oxalic acid (0.018 mol, 3.0 eq) while controlling the temperature at 0 - 10 °C, and stir for 0.5 h to prepare oxalyl chloride. Then add 1.2 g (0.0095 mol, 3.0 q) of oxalyl chloride dropwise to the reaction system while controlling the temperature at 0 - 10 °C throughout the process. Stir for 10 h. Monitor the disappearance of the raw materials by thin-layer chromatography of the reaction system. Add 30 mL of water (10 v / m) dropwise to the reaction system, separate the layers, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, prepare sand with 45 g of silica gel of 200 - 300 mesh, perform column chromatography, and use a dichloromethane:methanol ratio of 100:1 as the eluent. After passing through the column, 4.0 g of Compound II is obtained, with a yield of 90% and a purity of 98%.
Claims
1. A preparation method of dronedarone hydrochloride impurity, comprising:
2. The preparation method of dronedarone hydrochloride impurity according to claim 1, characterized in that, the acyl chloride is oxalyl chloride.
3. The preparation method of dronedarone hydrochloride impurity according to claim 1, characterized in that, the molar ratio of the compound I to the acyl chloride is 1:1 to 3.
4. The preparation method of dronedarone hydrochloride impurity according to claim 2, characterized in that, the oxalyl chloride can also be prepared by reacting thionyl chloride with oxalic acid.
5. The preparation method of dronedarone hydrochloride impurity according to claim 1, characterized in that, comprises the following steps: Dissolve the compound I with a solvent, and react with the acyl chloride under low temperature conditions with stirring. After post-treatment, the dronedarone hydrochloride impurity compound II is obtained.
6. The preparation method of dronedarone hydrochloride impurity according to claim 5, characterized in that, the low temperature is -10 to 10 °C.
7. The preparation method of dronedarone hydrochloride impurity according to claim 5, characterized in that, the solvent is one or more of acetonitrile, tetrahydrofuran, and dichloromethane.
8. The preparation method of dronedarone hydrochloride impurity according to claim 5, characterized in that, the reaction time is 1 to 10 h.
9. The preparation method of dronedarone hydrochloride impurity according to claim 5, characterized in that, the steps of the post-treatment are to drop water into the reaction system, separate the liquid, collect the organic phase, dry the organic phase, perform gradient elution, and column chromatography to obtain the compound II.
10. The preparation method of dronedarone hydrochloride impurity according to claim 9, characterized in that, the eluent for the gradient elution is dichloromethane:methanol 100:1 to 90:1.