Electrochemical synthesis of 5-nitrovanillic acid and its application
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WUXUE HONGYUAN PHARMACEUTICAL CO LTD
- Filing Date
- 2026-05-29
- Publication Date
- 2026-08-04
AI Technical Summary
硝酸硝化在生产过程中存在极大的安全风险，且生产过程中会产生大量废酸和废水，污染环境严重，治理费用高
[0015]与现有技术相比，本发明的有益效果包括：
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Figure CN122503884A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to an electrochemical synthesis method for 5-nitrovanillic acid and its application. Background Technology
[0002] Opicapon is a third-generation catechol-O-methyltransferase (COMT) inhibitor, with the chemical structure shown in Formula 1 below. It is primarily used as adjunctive therapy for Parkinson's disease, particularly to improve motor fluctuations and end-of-dose effects caused by levodopa treatment. It works by inhibiting peripheral COMT enzymes, reducing the breakdown of levodopa in the blood, allowing more drug to enter the brain, thereby prolonging the duration of levodopa's action.
[0003] Formula 1 5-Nitrovanillic acid is a key intermediate in the synthesis of octopcapone and is used as an active pharmaceutical ingredient in products. Currently, the most mature route for the synthesis of 5-nitrovanillic acid involves nitration of vanillic acid and nitric acid in glacial acetic acid or acetic anhydride, followed by purification. However, nitric acid nitration poses significant safety risks during production and generates large amounts of waste acid and wastewater, causing severe environmental pollution and incurring high treatment costs. Furthermore, the nitric acid nitration reaction suffers from poor selectivity, numerous byproducts, and substantial yield losses during purification. Summary of the Invention
[0004] The purpose of this invention is to overcome the above-mentioned technical deficiencies and propose an electrochemical synthesis method for 5-nitrovanillic acid and its application, aiming to achieve selective nitration of vanillic acid with mild reaction conditions, high yield, and good selectivity.
[0005] To achieve the above-mentioned technical objectives, the first aspect of the technical solution of the present invention provides an electrochemical synthesis method for 5-nitrovanillic acid, comprising the following steps: using vanillic acid as a starting material, nitrite as a nitrating agent, adding a solvent, stirring to dissolve, inserting an electrode, and carrying out a reaction under an electric current condition; after the reaction is completed, 5-nitrovanillic acid is obtained by purification treatment.
[0006] In some embodiments, the nitrite includes one or more of sodium nitrite, potassium nitrite, nitrosamine, tetrabutylnitrosamine, magnesium nitrite, and zinc nitrite.
[0007] In some embodiments, the solvent includes one or more of acetonitrile, acetic acid, water, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, trifluoroethanol, and hexafluoroisopropanol.
[0008] In some embodiments, the anode of the electrode includes any one of a carbon rod, a glassy carbon electrode, and a platinum electrode.
[0009] In some embodiments, the cathode of the electrode includes any one of a carbon rod, a glassy carbon electrode, and a platinum electrode.
[0010] In some embodiments, the molar ratio of vanillic acid to nitrite is 1:(1.2~4).
[0011] In some embodiments, the current of the reaction is 10mA to 200mA.
[0012] In some embodiments, the reaction temperature is 20°C to 70°C; and / or, the reaction is carried out in an inert gas atmosphere.
[0013] In a second aspect of the invention, the invention provides a 5-nitrovanillic acid, which is prepared by the electrochemical synthesis method of 5-nitrovanillic acid described in the first aspect of the invention.
[0014] In a third aspect of the invention, the invention provides an octopaine synthesized from an intermediate prepared by the electrochemical synthesis method of 5-nitrovanillic acid described in the first aspect of the invention.
[0015] Compared with the prior art, the beneficial effects of the present invention include: The electrochemical synthesis method for 5-nitrovanillic acid proposed in this invention uses nitrite as the nitro source and employs an electrochemical nitration method to synthesize 5-nitrovanillic acid. This method uses highly safe nitrite as the nitro source, electrochemically oxidizing it to generate a nitro cation, which then reacts with the substrate vanillic acid to generate the target product. The electrochemical nitration method achieves selective nitration of vanillic acid under mild reaction conditions, with high yield and good selectivity, allowing for large-scale production. Furthermore, the production process does not generate large amounts of waste acid and wastewater, resulting in no environmental pollution. Attached Figure Description
[0016] Figure 1 This is an HPLC chromatogram of 5-nitrovanillic acid synthesized in Example 1 of this invention.
[0017] Figure 2 It is the 5-nitrovanillic acid synthesized in Example 1 of this invention. 1 H-NMR spectrum.
[0018] Figure 3 5-Nitrovanillic acid synthesized in Example 1 of this invention 13 C-NMR spectrum. Detailed Implementation
[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0020] In a first aspect, the present invention provides an electrochemical synthesis method for 5-nitrovanillic acid, the method comprising the following steps: Vanillic acid was used as the starting material and nitrite as the nitrating agent. A solvent was added, the mixture was stirred and dissolved, an electrode was inserted, and the reaction was carried out under an electric current. After the reaction was completed, 5-nitrovanillic acid was obtained by purification.
[0021] The reaction equation is as follows:
[0022] [M]NO2 represents nitrite.
[0023] In some embodiments, the nitrite includes one or more of sodium nitrite, potassium nitrite, nitrosamine, tetrabutylnitrosamine, magnesium nitrite, and zinc nitrite. Thus, the nitrite has good solubility in the solvent. Under energized conditions, the nitrite ions provided by the nitrite are oxidized to generate nitro cations, which then react with the substrate to generate 5-nitrovanillic acid.
[0024] In some embodiments, the solvent includes one or more of acetonitrile, acetic acid, water, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, trifluoroethanol, and hexafluoroisopropanol. These solvents exhibit good solubility for vanillic acid and nitrite, and good stability under electrolysis, further contributing to improved yield and selectivity of 5-nitrovanillic acid.
[0025] In some embodiments, the anode of the electrode comprises any one of a carbon rod, a glassy carbon electrode, and a platinum electrode. This further facilitates the selective nitration of vanillic acid, improving the yield and selectivity of 5-nitrovanillic acid.
[0026] In some embodiments, the cathode of the electrode comprises any one of a carbon rod, a glassy carbon electrode, and a platinum electrode. This further facilitates the selective nitration of vanillic acid, improving the yield and selectivity of 5-nitrovanillic acid.
[0027] In some embodiments, the molar ratio of vanillic acid to nitrite is 1:(1.2~4). As an example, the molar ratio of vanillic acid to nitrite can be 1:1.2, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, or any range of two of the above values, thereby further facilitating the selective nitration of vanillic acid and improving the yield and selectivity of 5-nitrovanillic acid.
[0028] In some embodiments, the reaction current is 10mA to 200mA. For example, the reaction current can be 10, 20mA, 50mA, 80mA, 100mA, 120mA, 150mA, 180mA, 200mA, or any combination of two of these values. Thus, controlling the reaction current within this range is sufficient to electrochemically convert nitrite ions into nitro cations and promote the selective nitration of vanillic acid, without causing excessively high current and resulting in numerous side reactions.
[0029] In some embodiments, the reaction temperature is 20°C to 70°C. For example, the reaction temperature can be 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, or any combination of two of the above values, which further facilitates the selective nitration of vanillic acid and improves the yield and selectivity of 5-nitrovanillic acid.
[0030] In some embodiments, the reaction is carried out under an inert gas atmosphere. This reduces the formation of side reactions, further facilitating the selective nitration of vanillic acid and improving the yield and selectivity of 5-nitrovanillic acid.
[0031] In summary, the electrochemical synthesis method for 5-nitrovanillic acid proposed in this invention uses nitrite as the nitro source and employs an electrochemical nitration method to synthesize 5-nitrovanillic acid. This method utilizes highly safe nitrite as the nitro source, electrochemically oxidizing it to generate a nitro cation, which then reacts with the substrate to produce the target product. Through electrochemical nitration, selective nitration of vanillic acid is achieved under mild reaction conditions, with high yield and good selectivity, allowing for large-scale production. Furthermore, the production process does not generate large amounts of waste acid and wastewater, resulting in no environmental pollution.
[0032] In some embodiments, taking a mixture of acetic acid and acetonitrile as an example, purification can be performed as follows: The reaction solution is concentrated under reduced pressure to remove acetonitrile; the residual acetic acid is added to ice water, and the mixture is stirred at 5°C for 1 hour to induce crystallization. The mixture is then filtered, and the filter cake is washed twice with purified water. The filter cake is dried at 50°C for 5 hours to obtain the product 5-nitrovanillic acid.
[0033] In a second aspect of the invention, the invention provides a 5-nitrovanillic acid, which is prepared by the electrochemical synthesis method of 5-nitrovanillic acid described in the first aspect of the invention.
[0034] The 5-nitrovanillic acid proposed in this invention possesses all the beneficial effects of the electrochemical synthesis method of the above-mentioned 5-nitrovanillic acid, which will not be elaborated here.
[0035] In a third aspect of the invention, the invention provides an octopaine synthesized from an intermediate prepared by the electrochemical synthesis method of 5-nitrovanillic acid described in the first aspect of the invention.
[0036] The octopaine proposed in this invention possesses all the beneficial effects of the electrochemical synthesis method of the above-mentioned 5-nitrovanillic acid, which will not be elaborated here.
[0037] The following are some specific embodiments. It should be noted that the embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.
[0038] Example 1 In a 100 mL electrolytic cell, vanillic acid (0.84 g, 5 mmol), sodium nitrite (1.0 g, 15 mmol), and acetonitrile / acetic acid = 25 mL / 25 mL were added sequentially. A magnetic stir bar was added, and electrodes (Pt(+)|Pt(-)) were inserted. Note: The electrode size is 1 cm. 2 The system was replaced with a nitrogen atmosphere and reacted at room temperature (25℃) and a current of 30mA for 18 hours. Nitrogen gas was continuously introduced during the reaction to remove the cathode byproduct hydrogen. After the reaction, the reaction solution was analyzed by high-performance liquid chromatography (HPLC) for quantification, and column chromatography was used for purification of higher yields. The HPLC quantification yield of 5-nitrovanillic acid in the reaction solution was 86%, and after column chromatography purification, 0.85 g of 5-nitrovanillic acid was obtained, with a yield of 80%. The HPLC chromatogram is shown below. Figure 1 As shown, 1 H-NMR spectrum and 13 C-NMR spectrum as shown Figure 2 and 3 As shown, 5-nitrovanillic acid was prepared in Example 1, and the purity of the 5-nitrovanillic acid prepared in Example 1 was 99.04%.
[0039] Examples 2-8 Other conditions are the same as in Example 1, except that the reaction solvent and ratio are changed. As shown in Table 1, it can be seen that 5-nitrovanillic acid can be prepared with different solvent ratios.
[0040] Table 1
[0041] Remark: a HPLC quantitative yield; b Separate yield, column chromatography purification.
[0042] Examples 9-14 Other conditions are the same as in Example 1, but the type and ratio of nitrite are changed. As shown in Table 2, it can be seen that 5-nitrovanillic acid can be prepared with different molar ratios of vanillic acid and nitrite.
[0043] Table 2
[0044] Remark: a HPLC quantitative yield; b Separate yield, column chromatography purification.
[0045] Examples 15-17 The other conditions are the same as in Example 1, but the type of electrode is changed. As shown in Table 3, it can be seen that 5-nitrovanillic acid can be prepared by different electrodes.
[0046] Table 3
[0047] Remark: a HPLC quantitative yield; b Separate yield, column chromatography purification.
[0048] Example 18 In a 1000 mL electrolytic cell, vanillic acid (8.4 g, 50 mmol), sodium nitrite (10.0 g, 150 mmol), and acetonitrile / acetic acid = 250 mL / 250 mL were added sequentially. A magnetic stir bar was added, and electrodes (Pt(+)|Pt(-)) were inserted. Note: The electrode size is 10 cm. 2 The system was replaced with a nitrogen atmosphere, and the reaction was carried out at room temperature (25℃) and a current of 300mA for 18 hours. Nitrogen gas was continuously introduced during the reaction to remove the hydrogen byproduct from the cathode. After the reaction, the reaction solution was analyzed by HPLC, and the content of 5-nitrovanillic acid in the reaction solution was 87%. The reaction solution was concentrated under reduced pressure to remove acetonitrile, and the residual acetic acid was added to 500mL of ice water and stirred at 5℃ for 1 hour to crystallize. The solution was filtered, and the filter cake was washed twice with purified water (10mL*2). The filter cake was dried at 50℃ for 5 hours to obtain 7.1g of 5-nitrovanillic acid, with a yield of 61%, as a yellow solid powder with an HPLC purity of 98.5%.
[0049] Comparative Example 1 Under the same conditions as Case 1, the reaction was carried out without electricity, and the product 5-nitrovanillic acid was not detected by HPLC.
[0050] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.
Claims
1. An electrochemical synthesis method for 5-nitrovanillic acid, characterized in that, Includes the following steps: Vanillic acid was used as the starting material and nitrite as the nitrating agent. A solvent was added, the mixture was stirred and dissolved, an electrode was inserted, and the reaction was carried out under an electric current. After the reaction was completed, 5-nitrovanillic acid was obtained by purification.
2. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The nitrites include one or more of sodium nitrite, potassium nitrite, nitrosamine, tetrabutylnitrosamine, magnesium nitrite, and zinc nitrite.
3. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The solvent includes one or more of acetonitrile, acetic acid, water, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, trifluoroethanol, and hexafluoroisopropanol.
4. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The anode of the electrode can be any one of a carbon rod, a glassy carbon electrode, or a platinum electrode.
5. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The cathode of the electrode includes any one of a carbon rod, a glassy carbon electrode, and a platinum electrode.
6. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The molar ratio of vanillic acid to nitrite is 1:(1.2~4).
7. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The current for the reaction is 10mA~200mA.
8. The electrochemical synthesis method of 5-nitrovanillic acid according to claim 1, characterized in that, The reaction temperature is 20℃~70℃; and / or, The reaction is carried out in an inert gas atmosphere.
9. A 5-nitrovanillic acid, characterized in that, The 5-nitrovanillic acid is prepared by the electrochemical synthesis method of 5-nitrovanillic acid according to any one of claims 1-8.
10. An octopaine, characterized in that, The octopaine is synthesized from an intermediate obtained by the electrochemical synthesis method of 5-nitrovanillic acid according to any one of claims 1-8.