Preparation method and application of 2 '-ethyoxyl anisodamine
High-purity 2’-ethoxyanisolamine was prepared through extraction purification, column chromatography and crystallization drying, which solved the quality control problem of impurities in the raw materials for anisolamine hydrobromide, and improved the safety of drug and storage management.
Patent Information
- Application Number
- CN202510136848.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-07
- Publication Date
- 2025-07-04
AI Technical Summary
In the prior art, the 2’-ethoxyanisolamine impurities produced by the hydrobromide raw material drug in the process of production and storage lack high-purity preparation methods, resulting in the inability to effectively control.
High-purity 2’-ethoxyanisolamine was prepared by extraction purification, column chromatography, extraction purification and crystallization drying, and used as a reference product for the quality control of the anisolamine hydrobromide raw materials and its preparations.
It provides a high-purity 2’-ethoxyanisolamine reference product, which improves the quality control of the raw materials for anisolamine hydrobromide and its preparations, improves the safety of drugs, and reduces the storage cost of drugs that do not meet the standards.
Smart Images
Figure BDA0005263533200000021 
Figure HDA0005263533210000011 
Figure HDA0005263533210000012
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically to a preparation method and application of 2'-ethoxy anisodamine. Background Art
[0002] Anisodamine hydrobromide, whose structural formula is This product is an anticholinergic drug that blocks M cholinergic receptors, has the effects of relaxing smooth muscles, relieving vasospasm, improving microcirculation, and has an analgesic effect. However, its effects of dilating pupils and inhibiting glandular secretion are weak, and it rarely causes central excitatory symptoms.
[0003] Impurities with the structure of may be generated during the production and storage of anisodamine hydrobromide raw materials and their preparations. The generation mechanism is that anisodamine hydrobromide raw materials and their preparations decompose to produce anisodamine, and then anisodamine (C 17 H 23 NO4, with a molecular weight of 305.37) is affected by the alkaline environment to produce this impurity. This impurity is called 2'-ethoxy anisodamine, whose molecular formula is C 19 H 27 NO4, with a molecular weight of 333.43, and its chemical name is (1R,3R,5R,6S)-6-hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-ethoxy-2-phenylpropionate. The chemical equation of the generation mechanism of this impurity is as follows:
[0004]
[0005] Currently, there is no high-purity preparation method for the above substance, so a qualified 2'-ethoxy anisodamine reference substance cannot be obtained for quality control. Summary of the Invention
[0006] In view of this, the technical problem to be solved by the present invention is to provide a preparation method and application of 2'-ethoxy anisodamine. The preparation method provided by the present invention can prepare 2'-ethoxy anisodamine with high purity, which can be used as a reference substance in the quality control of anisodamine hydrobromide raw materials and their preparations.
[0007] The present invention provides a preparation method of 2'-ethoxy anisodamine, comprising the following steps:
[0008] S1) Extract and purify anisodamine hydrobromide to obtain anisodamine material; heat and react the anisodamine material with an alcoholic solution of an alkali to obtain a reaction solution;
[0009] S2) Adjust the pH of the reaction solution obtained in step S1) to 5.5 - 6.5, and then perform column chromatography to obtain a concentrated solution;
[0010] The column chromatography specifically is: using reversed-phase bonded silica gel as the stationary phase, using a mixed solution of acetonitrile and phosphoric acid as the mobile phase, and the elution program is:
[0011] Time min Mobile phase 0～40 Mixed solution of acetonitrile and phosphoric acid with a volume ratio of (15 - 25):(75 - 85) 40～55 Mixed solution of acetonitrile and phosphoric acid with a volume ratio of (75 - 85):(15 - 25)
[0012] S3) Subject the concentrated solution obtained in step S2) to extraction and purification, and crystallize and dry the material obtained after extraction and purification together with petroleum ether and dichloromethane to obtain 2'-ethoxy anisodamine.
[0013] The present invention first subjects anisodamine hydrobromide to extraction and purification to obtain anisodamine material. Specifically, an anisodamine hydrobromide solution with a pH of 9-10 is extracted and purified with dichloromethane to obtain anisodamine material. In certain embodiments of the present invention, the aqueous solution of anisodamine hydrobromide is adjusted to a pH of 9-10 with NaOH with a mass concentration of 8%-12%, and then extracted with dichloromethane. The obtained extract is dehydrated and concentrated to obtain anisodamine material. The amount of dichloromethane used in the present invention is 0.8 to 1.2 times the volume of the anisodamine hydrobromide raw material solution, preferably 1 time. The number of extractions in the present invention is 2 to 4 times. The present invention uses anhydrous sodium sulfate for dehydration. The concentration in the present invention specifically is vacuum concentration at 40°C to 60°C.
[0014] After the present invention obtains the anisodamine material, the anisodamine material and an alcoholic solution of an alkali are heated and reacted to obtain a reaction solution. The alcoholic solution of the alkali in the present invention is an ethanol solution of NaOH with a mass concentration of 0.1%-0.3%. Calculated based on 1 unit volume of anisodamine hydrobromide, the amount of the alcoholic solution of the alkali used in the present invention is 10 to 15 times the unit volume. The temperature of the heating reaction in the present invention is 60°C to 80°C, and the time of the heating reaction is 2h to 4h.
[0015] After the present invention obtains the reaction solution, the obtained reaction solution is adjusted to a pH of 5.5-6.5, and then column chromatography is carried out to obtain a concentrated solution. Specifically, the obtained reaction solution is adjusted to a pH of 5.5-6.5 with a 4wt%-6wt% sulfuric acid solution, and after removing the solvent, column chromatography is carried out to obtain a concentrated solution. More specifically, the obtained reaction solution is adjusted to a pH of 5.5-6.5 with a sulfuric acid solution with a volume concentration of 4%-6%, and then filtered to obtain a filtrate. The obtained filtrate is vacuum concentrated at 70°C to 80°C to remove the solvent and then column chromatography is carried out to obtain a concentrated solution. In certain embodiments of the present invention, the eluate after column chromatography is subjected to the column chromatography again, and then vacuum concentrated at 70°C to 80°C to obtain a concentrated solution.
[0016] Preferably, the column chromatography of the present invention uses reversed-phase bonded silica gel as the stationary phase, and a mixed solution of acetonitrile and phosphoric acid with a volume concentration of 0.1% to 0.3% as the mobile phase. The elution program is as follows:
[0017] Time min Mobile phase 0～40 Mixed solution of acetonitrile and 0.1% - 0.3% phosphoric acid with a volume ratio of 20:80 40～55 Mixed solution of acetonitrile and 0.1% - 0.3% phosphoric acid with a volume ratio of 80:20 .
[0018] After obtaining the concentrated solution of the present invention, the obtained concentrated solution is subjected to extraction and purification. The material obtained after extraction and purification, petroleum ether and dichloromethane are subjected to crystallization and drying together to obtain 2'-ethoxyscopolamine. Specifically, the obtained concentrated solution is adjusted to a pH of 10.0 to 11.0 with NaOH having a mass concentration of 8% to 12%, and then extracted with dichloromethane 2 to 4 times. The amount of dichloromethane used for extraction is 0.8 to 1.2 times the volume of the concentrated solution after adjusting the pH. The obtained extract is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure at 40°C to 60°C to obtain a paste. The obtained paste, petroleum ether and dichloromethane are subjected to crystallization and drying together, and dried at 40 to 50°C to obtain 2'-ethoxyscopolamine. The amount of petroleum ether used in the present invention is 0.9 to 1.1 times the volume of the weight of the paste, and the amount of dichloromethane used is 0.25 to 0.35 times the volume of the weight of the paste. For example, if the weight of the paste is 4 g, the amount of petroleum ether used is 3.6 to 4.4 mL, and the amount of dichloromethane used is 1 to 1.4 mL. The present invention also provides the use of 2'-ethoxyscopolamine obtained by the preparation method of any of the above technical solutions as a reference substance in the impurity detection of scopolamine hydrobromide raw materials and their preparations. The preparation method provided by this patent provides a qualified 2'-ethoxyscopolamine reference substance for the impurity research of scopolamine hydrobromide raw materials and their preparations, which is beneficial to improving the quality control of scopolamine hydrobromide raw materials and their preparations and enhancing the drug safety.
[0019] The present invention provides a preparation method and application of 2'-ethoxyscopolamine. The preparation method of 2'-ethoxyscopolamine provided by the present invention has not been reported. The preparation method of 2'-ethoxyscopolamine provided by this patent provides a qualified 2'-ethoxyscopolamine reference substance for the impurity research of scopolamine hydrobromide raw materials and their preparations, which is beneficial to improving the quality control of scopolamine hydrobromide raw materials and their preparations and enhancing the drug safety; and it also helps to timely process the substandard scopolamine hydrobromide raw materials and their preparations, reducing the storage cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 It is the liquid chromatogram of the refined product of 2'-ethoxyscopolamine obtained in Example 1 of the present invention;
[0021] Figure 2Mass spectrum of the refined product of 2'-ethoxy anisodamine obtained in Example 1 of the present invention;
[0022] Figure 3 1H NMR spectrum of the refined product of 2'-ethoxy anisodamine obtained in Example 1 of the present invention;
[0023] Figure 4 13C NMR spectrum of the refined product of 2'-ethoxy anisodamine obtained in Example 1 of the present invention. Detailed implementation manners
[0024] The present invention discloses a preparation method and application of 2'-ethoxy anisodamine. Those skilled in the art can draw on the content of this article and appropriately modify the process parameters to achieve. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate modifications and combinations to the methods and applications in this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.
[0025] The present invention is further elaborated below in conjunction with embodiments:
[0026] Example 1
[0027] (1) Synthesis
[0028] Take 42.3 g of anisodamine hydrobromide raw material medicine, dissolve it in 200 mL of water, adjust the pH value to 9.59 with 10% NaOH solution, extract it 3 times with dichloromethane of 1 times volume, combine the extraction liquid, add anhydrous sodium sulfate for dehydration, and concentrate it under reduced pressure at 50 °C to remove dichloromethane to obtain anisodamine paste. 300 mL of ethanol solution containing 0.2% NaOH was added to the paste, and the mixture was stirred and reacted at 70 °C for 3 h to obtain a reaction solution.
[0029] (2) Column chromatography purification
[0030] Under ice bath, add 5% sulfuric acid solution to the reaction solution obtained in (1) to adjust the pH to 6, filter, and concentrate the filtrate under reduced pressure at 75 °C until no solvent evaporates to obtain a sample loading solution of the basic ethanol reaction solution.
[0031] Load the sample loading solution of the basic ethanol reaction solution onto a reverse-phase silica gel column (10 μm, reverse-phase bonded silica gel), and elute with acetonitrile - 0.2% phosphoric acid.
[0032] Time min Mobile phase 0～40 Acetonitrile - 0.2% phosphoric acid [volume ratio 20:80] 40～55 Acetonitrile - 0.2% phosphoric acid [volume ratio 80:20] .
[0033] Collect the eluate containing the target component, load it onto the column for purification again, elute in the same way, enrich the target component again, and concentrate it under reduced pressure at 80 °C to obtain 200 mL of concentrated solution.
[0034] (3) Extraction and purification
[0035] Adjust the pH of the concentrated solution obtained in (2) to 10.5 with 10% NaOH solution, extract it 3 times with dichloromethane according to a volume ratio of 1:1, combine the extraction solutions, add anhydrous sodium sulfate for dehydration and filtration, and concentrate it under reduced pressure at 50 °C to a paste.
[0036] (4) Crystallization and drying
[0037] Add 4 mL of petroleum ether and 1 mL of dichloromethane to the paste obtained in (3), and stir to crystallize at room temperature. Filter the crystals and dry them at 45 °C to obtain 3.08 g of refined 2'-ethoxy scopolamine. Chromatographic purity: 96.80%. As Figure 1 shown, Figure 1 This is the liquid chromatogram of the refined 2'-ethoxy scopolamine obtained in Example 1 of the present invention. Figure 1 The corresponding data is as described in Table 1:
[0038] Table 1
[0039] Peak number Compound name Retention time Area Height Area % Theoretical plate number Resolution Tailing factor 1 5.147 15054 1417 0.13 5092 -- 1.12 2 34.795 99493 9601 0.87 240003 1.68 1.17 3 35.633 7725 1063 0.07 425988 3.34 1.04 4 (2'R)-Ethoxyscopolamine 36.277 11022642 894041 96.80 183837 2.31 1.70 5 36.889 204227 22938 1.79 348234 2.08 1.22 6 37.789 18588 1822 0.16 294326 3.40 1.39 7 38.378 18782 2100 0.16 374711 2.23 1.17 Total 11386510 932982 100.00
[0040] (5) Structure confirmation
[0041] Mass spectrum: As Figure 2 shown, Figure 2 This is the mass spectrum of the refined 2'-ethoxy scopolamine obtained in Example 1 of the present invention. It can be Figure 2 seen that the theoretical molecular weight is 321.37, and the measured molecular ion peaks are m / z 322.2 [M+1] and m / z 322.3 [M+2], which are consistent with the theoretical molecular weight.
[0042] 1H NMR spectrum: As Figure 3 described, Figure 3 This is the 1H NMR spectrum of the refined 2'-ethoxy scopolamine obtained in Example 1 of the present invention, and the corresponding data is 11H NMR (400 MHz, Methanol-d4) δ 7.39–7.26 (m, 5H), 4.92 (t, J = 5.4 Hz, 1H), 4.22 (dd, J = 7.3, 2.8 Hz, 1H), 4.02 (t, J = 9.3 Hz, 1H), 3.86 (dd, J = 9.4, 5.1 Hz, 1H), 3.64 (dd, J = 9.1, 5.1 Hz, 1H), 3.53 (q, J = 7.0 Hz, 2H), 3.32–3.25 (m, 1H), 2.91 (t, J = 2.9 Hz, 1H), 2.53–2.39 (m, 4H), 2.14–2.02 (m, 2H), 1.97–1.90 (m, 1H), 1.65–1.52 (m, 2H), 1.16 (t, J = 7.0 Hz, 3H).
[0043] Carbon spectrum: As Figure 4 described, Figure 4 the carbon spectrum of the refined product of 2'-ethoxy anisodamine obtained in Example 1 of the present invention, and the corresponding data are 13 13C NMR (101 MHz, Methanol-d4) δ 173.08, 137.16, 129.92, 129.92, 129.18, 129.18, 128.89, 76.47, 73.02, 69.04, 68.78, 67.71, 61.27, 53.78, 40.01, 39.08, 34.48, 32.95, 15.45.
[0044] As described above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.
Claims
1. Preparation method of 2'-ethoxy anisodamine, characterized in that, It includes the following steps: S1) Extract and purify anisodamine hydrobromide to obtain anisodamine material; heat and react the anisodamine material with an alcoholic solution of an alkali to obtain a reaction solution; S2) Adjust the pH of the reaction solution obtained in step S1) to 5.5 - 6.5, and then perform column chromatography to obtain a concentrated solution; The specific column chromatography is as follows: using reversed-phase silica gel as the stationary phase, and a mixed solution of acetonitrile and phosphoric acid as the mobile phase, and the elution program is: S3) Crystallize and dry the concentrated solution obtained in step S2) together with petroleum ether and dichloromethane to obtain 2'-ethoxy anisodamine.
2. The preparation method according to claim 1, wherein In step S1), an anisodamine hydrobromide solution with a pH of 9 - 10 is extracted and purified with dichloromethane to obtain anisodamine material.
3. The preparation method according to claim 1, characterized in that, In step S1), the alcoholic solution of the alkali is an ethanol solution of NaOH.
4. The preparation method according to claim 1, characterized in that, In step S1), the alcoholic solution of the alkali is an ethanol solution of NaOH with a mass concentration of 0.1% - 0.3%; Based on 1 unit volume of anisodamine hydrobromide, the dosage of the alcoholic solution of the alkali is 10 - 15 unit volumes.
5. The preparation method according to claim 1, characterized in that, In step S1), the temperature of the heating reaction is 60°C - 80°C, and the time of the heating reaction is 2 h - 4 h.
6. The preparation method according to claim 1, wherein In step S2), the pH of the reaction solution obtained in step S1) is adjusted with a sulfuric acid solution with a volume concentration of 4% - 6%.
7. The preparation method according to claim 1, characterized in that In step S2), a mixed solution of acetonitrile and phosphoric acid with a volume concentration of 0.1% - 0.3% is used as the mobile phase.
8. The preparation method according to claim 1, characterized in that, Step S3) specifically is: adjust the pH of the concentrated solution obtained in step S2) to 10.0 - 11.0, then extract and purify it with dichloromethane, and crystallize and dry the material obtained after extraction and purification together with petroleum ether and dichloromethane.
9. The preparation method according to claim 1, wherein In step S3), the concentrated solution obtained in step S2) is extracted and purified, the material obtained after extraction and purification is concentrated to obtain a paste, and the obtained paste is crystallized and dried together with petroleum ether and dichloromethane; The dosage of the petroleum ether is 1 times the volume of the weight of the paste, and the dosage of the dichloromethane is 0.25 - 0.35 times the volume of the weight of the paste.
10. The application of 2'-ethoxy anisodamine obtained by the preparation method according to any one of claims 1 - 9 as a reference substance in the impurity detection of anisodamine hydrobromide bulk drug and its preparations.