Preparation method of 5-nitrovanillic acid

Abstract

The invention belongs to the technical field of preparation of pharmaceutical compounds, and particularly relates to a preparation method of 5-nitrovanillic acid. According to the method, the use of acetic acid as a solvent and nitric acid with corrosivity and volatility is effectively avoided, safe, cheap and easy-to-operate nitrate such as iron nitrate nonahydrate is selected as a nitrate source, the yield is high, energy conservation is facilitated, and the equipment investment is reduced. The synthesis method disclosed by the invention is carried out at normal temperature and normal pressure in an air atmosphere, dichloromethane, hexafluoroisopropanol and the like which are easy to recover are used as solvents, the post-treatment is simpler and more environment-friendly, and the production cost is reduced while the environmental pollution is reduced. The synthesis method is simple in process flow, simple and convenient to operate, efficient and easy to control reaction conditions.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical compound preparation, and particularly relates to a method for preparing 5-nitrovanillic acid. Background Art

[0002] Opicapone can make the effects of dopamine drugs last longer, thereby alleviating movement disorder symptoms such as muscle stiffness, tremor, and decreased movement. In addition, opicapone can also reduce the dose of dopamine drugs, thereby reducing the risk of adverse reactions. 5-Nitrovanillic acid is an important intermediate in the synthesis of opicapone. The combined use of opicapone with other Parkinson's disease drugs (such as levodopa) can significantly improve the efficacy of the drug and reduce adverse reactions. 5-Nitrovanillic acid can also be used as a biosynthetic precursor for the synthesis of rifamycin antibiotics (such as 3-hydroxymethoxyrifamycin, 3-hydroxyrifamycin).

[0003] 4,6-Dinitroguaiacol is an important raw material for the synthesis of 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydropyrrolo[4,3,2-d]quinoline, which is an important intermediate in the synthesis of certain marine alkaloids (such as discorhabdins and makaluvamines), which exhibit potent biological activities, including cytotoxicity and topoisomerase II inhibition.

[0004]

[0005] The existing synthesis method of 5-nitrovanillic acid requires the use of volatile and corrosive nitric acid as a nitric acid source and acetic acid as a solvent. The yield is low at 40% when vanillic acid is directly used as a raw material and nitrated with nitric acid. The reaction equation is as follows:

[0006] The further improved scheme uses water and 1,4-dioxane as solvents, uses methyl vanillate as raw material, uses sodium nitrite and nitric acid for nitration, hydrolyzes with sodium hydroxide solution, and acidifies with dilute hydrochloric acid to obtain 5-nitrovanillic acid. The reaction equation is as follows: Summary of the invention

[0007] On the one hand, the present invention aims to overcome the defects of the prior art 5-nitrovanillic acid synthesis process using corrosive and volatile nitric acid, poor safety, high cost, low yield and large environmental pollution, and provides a preparation method of 5-nitrovanillic acid to overcome the above defects.

[0008] On the other hand, the present invention also provides a method for preparing 4,6-dinitroguaiacol.

[0009] To achieve the above-mentioned purpose, the present invention is implemented by the following technical solutions: A method for preparing 5-nitrovanillic acid comprises the following steps: (S.1) vanillic acid and methanol are mixed, concentrated sulfuric acid is added and heated for reaction, and after the reaction is completed, ethyl acetate is used for extraction to obtain vanillic acid methyl ester; (S.2) mixing the methyl vanillate obtained in step (S.1) and the first solvent, adding nitrate, drying by spin drying after the reaction is completed, and extracting with ethyl acetate to obtain 5-nitrovanillate methyl ester; (S.3) Mixing the 5-nitrovanillic acid methyl ester obtained in step (S.2) and the second solvent, adding an aqueous solution of alkali and heating the mixture for reaction, and acidifying the mixture with dilute hydrochloric acid to obtain 5-nitrovanillic acid.

[0010] The inventors of the present invention adopt the existing synthesis method of 5-nitrovanillic acid, such as using acetic acid and nitric acid for mixed nitration reaction. After repeated experiments, the yield of the prepared 5-nitrovanillic acid is still low. At the same time, excessive acetic acid and volatile and corrosive nitric acid are required in the synthesis process, which is poor in safety, uneconomical and not environmentally friendly. In order to obtain a more economical and safe method to synthesize 5-nitrovanillic acid, the inventors of the present invention further explored and used vanillic acid as a substrate for reaction. The product was analyzed by nuclear magnetic hydrogen spectrum and carbon spectrum, and it was found that the carboxyl group was removed. It is speculated that the carboxyl group should be removed and replaced by nitro to form a dinitro product. Later, it was determined to be 4,6-dinitroguaiacol by nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrometry. So the inventors of the present invention used 5-nitrovanillic acid as a substrate for nitration reaction, and found that there was still a decarboxylation problem, and the products of the two experiments were mixed and analyzed by nuclear magnetic hydrogen spectrum, and the results verified that they were the same substance. Therefore, the inventors of the present invention used o-methoxyphenol as a substrate for nitration reaction, mixed it with the previous product and analyzed it by nuclear magnetic hydrogen spectrum. The results verified that they were the same substance, and from the perspective of synthetic economy, o-methoxyphenol was the most economical substrate. Considering that the carboxyl group is very easy to remove, the inventors of the present invention chose to protect the carboxyl group first. Therefore, vanillic acid was first converted into vanillic acid methyl ester, and then nitrated to generate 5-nitrovanillic acid methyl ester, and then hydrolyzed to finally obtain 5-nitrovanillic acid.

[0011] The present invention effectively avoids the use of acetic acid as a solvent and corrosive, volatile nitric acid, selects safe, cheap and easy-to-operate nitrates such as ferric nitrate nonahydrate as a nitric source, has a high yield, and is helpful to save energy and reduce equipment investment. The synthesis method of the present invention is carried out at normal temperature and pressure and atmospheric atmosphere, and uses easily recyclable dichloromethane, hexafluoroisopropanol, etc. as solvents, and the post-processing is simpler and more environmentally friendly, which helps to reduce environmental pollution while reducing production costs. At the same time, the synthesis method of the present invention has a simple process flow, is easy to operate, is efficient, and the reaction conditions are easy to control.

[0012] Preferably, the synthetic route of 5-nitrovanillic acid is as follows: In the above formula, (1) is the structural formula of vanillic acid; (2) is the structural formula of methyl vanillate; (3) is the structural formula of methyl 5-nitrovanillate; and (4) is the structural formula of 5-nitrovanillic acid.

[0013] Preferably, the reaction temperature in step (S.1) is 50-80°C, and the reaction time is 4-10 hours.

[0014] As a further preference, the reaction temperature in step (S.1) is 75°C and the reaction time is 8 hours.

[0015] Preferably, the first solvent in step (S.2) is any one or more combinations of dichloromethane, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, hexafluoroisopropanol, 1,4-dioxane, and water.

[0016] Preferably, the nitrate in step (S.2) is any one or more of ferric nitrate nonahydrate, gallium nitrate nonahydrate, bismuth nitrate pentahydrate, aluminum nitrate nonahydrate, copper nitrate trihydrate, sodium nitrate, potassium nitrate and silver nitrate.

[0017] Preferably, the molar ratio of methyl vanillate to nitrate added in step (S.2) is 1:(0.3-1).

[0018] As a further preference, the molar ratio of methyl vanillate and nitrate added in step (S.2) is 1:1.

[0019] Preferably, the reaction temperature in step (S.2) is 0 to 50°C, and the reaction time is 4 to 16 hours.

[0020] As a further preference, the reaction temperature in step (S.2) is 25°C and the reaction time is 12 h.

[0021] Preferably, the second solvent in step (S.3) is any one or more of dichloromethane, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, and 1,4-dioxane.

[0022] Preferably, the alkali in step (S.3) is any one of sodium hydroxide and potassium hydroxide or a combination of both.

[0023] Preferably, the molar ratio of 5-nitrovanillic acid methyl ester and the base added in step (S.3) is 1:(1 to 5).

[0024] As a further preference, the molar ratio of 5-nitrovanillic acid methyl ester and the base added in step (S.3) is 1:4.

[0025] Preferably, the reaction temperature in step (S.3) is 30-60°C, and the reaction time is 4-10 hours.

[0026] As a further preference, the reaction temperature in step (S.3) is 45°C and the reaction time is 6 hours.

[0027] Preferably, the reaction progress in steps (S.1) to (S.3) is monitored by TLC.

[0028] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (a) mixing o-methoxyphenol and a first solvent, adding nitrate, and after the reaction is completed, spinning dryness is performed, and extraction is performed with ethyl acetate to obtain 4,6-dinitroguaiacol.

[0029] Preferably, the structural formula of o-methoxyphenol is as shown in the following formula (5); the structural formula of 4,6-dinitroguaiacol is as shown in the following formula (6):

[0030] Preferably, the molar ratio of o-methoxyphenol to nitrate added in step (a) is 1:(0.3-1).

[0031] As further preferred, the molar ratio of o-methoxyphenol to nitrate added in step (a) is 1:1.

[0032] Preferably, the reaction temperature in step (a) is 0 to 50° C., and the reaction time is 4 to 16 hours.

[0033] As further preferred, the reaction temperature in step (a) is 25° C. and the reaction time is 12 h.

[0034] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (b) vanillic acid and the first solvent are mixed, nitrate is added, after the reaction is completed, the mixture is spin-dried, and extracted with ethyl acetate to obtain 4,6-dinitroguaiacol.

[0035] Preferably, the molar ratio of vanillic acid to nitrate added in step (b) is 1:(0.3-1).

[0036] As further preferred, the molar ratio of vanillic acid and nitrate added in step (b) is 1:1.

[0037] Preferably, the reaction temperature in step (b) is 0-50° C., and the reaction time is 4-16 h.

[0038] As further preferred, the reaction temperature in step (b) is 25° C. and the reaction time is 12 h.

[0039] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (c) mixing 5-nitrovanillic acid and the first solvent, adding nitrate, and after the reaction is completed, drying by rotation, and extracting with ethyl acetate to obtain 4,6-dinitroguaiacol.

[0040] Preferably, the molar ratio of 5-nitrovanillic acid to nitrate added in step (c) is 1:(0.3-1).

[0041] As further preferred, the molar ratio of 5-nitrovanillic acid and nitrate added in step (c) is 1:1.

[0042] Preferably, the reaction temperature in step (c) is 0-50° C., and the reaction time is 4-16 h.

[0043] As further preferred, the reaction temperature in step (c) is 25° C. and the reaction time is 12 h.

[0044] Therefore, the present invention has the following beneficial effects: (1) The present invention effectively avoids the use of acetic acid as a solvent and corrosive and volatile nitric acid, and selects safe, cheap and easy-to-operate nitrates such as ferric nitrate nonahydrate as a nitric acid source, which has a high yield, helps save energy and reduce equipment investment; (2) The synthesis method of the present invention is carried out at room temperature and pressure in an atmospheric atmosphere, and uses easily recyclable dichloromethane, hexafluoroisopropanol, etc. as solvents, which makes post-processing simpler and more environmentally friendly, helping to reduce environmental pollution while reducing production costs; (3) The synthesis method of the present invention has a simple process flow, is easy to operate, is highly efficient, and the reaction conditions are easy to control. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 is the vanillic acid methyl ester in Example 11 H spectrum.

[0046] Figure 2 is the 5-nitrovanillic acid methyl ester in Example 1 1 H spectrum.

[0047] Figure 3 is the 5-nitrovanillic acid in Example 1 1 H spectrum.

[0048] Figure 4 is the 4,6-dinitroguaiacol in Example 4 1 H spectrum.

[0049] Figure 5 is the 4,6-dinitroguaiacol in Example 4 13 C spectrum.

[0050] Figure 6 This is the mass spectrum of 4,6-dinitroguaiacol in Example 4. DETAILED DESCRIPTION

[0051] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments of the specification. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0052] Example 1 This embodiment provides a method for preparing 5-nitrovanillic acid.

[0053] A method for preparing 5-nitrovanillic acid comprises the following steps: (S.1) Add vanillic acid (0.892mmol), methanol (2mL), and 2 drops of concentrated sulfuric acid to a round-bottom flask, place the mixture under reflux at 75°C with stirring, and monitor the reaction progress with TLC (petroleum ether: ethyl acetate = 6:1). The reaction ends after 8 hours. First, spin-dry the methanol in the reaction solution, then add water and ethyl acetate to extract 2 to 3 times, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and spin-dry the filtrate to obtain methyl vanillate. The yield of the product (i.e., methyl vanillate) is 95%. In this example, the yield of methyl vanillate 1 H spectrum Figure 1 shown.

[0054] Methyl vanillate 1 H spectrum: 1H NMR (500MHz, Chloroform-d) δ7.65(dd,J=8.43,1.95Hz,1H),7.56(d,J=1.97Hz,1H),6.95(d,J=8.35Hz,1H),6.11(s,1H),3.95(s,3H),3.90(s,3H).

[0055] (S.2) Add methyl vanillate (0.658 mmol), ferric nitrate nonahydrate (0.658 mmol) and dichloromethane (1.9 mL) obtained in step (S.1) into a round-bottom flask, stir at room temperature (25°C), detect by TLC (petroleum ether: ethyl acetate = 6:1), and terminate the reaction after 12 hours. The dichloromethane in the reaction solution is dried by spin-drying, and water is added thereto, extracted with ethyl acetate 2 to 3 times, the organic phases are combined and dried with anhydrous magnesium sulfate, filtered, and the filtrate is dried by spin-drying to obtain 5-nitrovanillic acid methyl ester. The yield of the product (i.e., 5-nitrovanillic acid methyl ester) is 94%. The yield of 5-nitrovanillic acid methyl ester in this embodiment is 1 H spectrum Figure 2 shown.

[0056] 5-Nitrovanillic acid methyl ester 1 H spectrum: 1 H NMR (500MHz, Chloroform-d) δ11.08 (s, 1H), 8.45 (d, J = 2.04Hz, 1H), 7.77 (d, J = 1.95Hz, 1H), 4.02 (s, 3H), 3.96 (s, 3H).

[0057] (S.3) Add 5-nitrovanillic acid methyl ester (0.616mmol), tetrahydrofuran (3mL), and 2.5mol / L sodium hydroxide aqueous solution (1mL) obtained in step (S.2) into a round-bottom flask, heat and stir at 45°C, detect by TLC (petroleum ether: ethyl acetate = 1:1), and react for 6 hours. Cool to room temperature, spin-dry tetrahydrofuran, add 0.1mol / L dilute hydrochloric acid (75mL) to precipitate a yellow solid, filter, and dry to obtain 5-nitrovanillic acid. Product (i.e., 5-nitrovanillic acid) yield: 96%. In this example, 5-nitrovanillic acid 1 H spectrum Figure 3 shown.

[0058] 5-Nitrovanillic acid 1 H spectrum: 1 H NMR (500MHz, DMSO-d6) δ13.17(s,1H),11.30(s,1H),8.00(d,J=1.85Hz,1H),7.66(d,J=1.94Hz,1H),3.94(s,3H).

[0059] Example 2 This embodiment provides a method for preparing 5-nitrovanillic acid.

[0060] The difference between this embodiment and embodiment 1 is that: A method for preparing 5-nitrovanillic acid, wherein in step (S.1), the mixture is placed under reflux stirring at 50°C, and the reaction is terminated after 10 hours; in step (S.2), methyl vanillate (0.620mmol), ferric nitrate nonahydrate (0.186mmol) and hexafluoroisopropanol (4mL) obtained in step (S.1) are added to a round-bottom flask, stirred at low temperature (0°C), detected by TLC (petroleum ether: ethyl acetate = 6:1), and the reaction is terminated after 16 hours; in step (S.3), methyl 5-nitrovanillate (0.615mmol), 1,4-dioxane (3mL), and 2.5mol / L potassium hydroxide aqueous solution (1mL) obtained in step (S.2) are added to a round-bottom flask, heated and stirred at 30°C, detected by TLC (petroleum ether: ethyl acetate = 1:1), and the reaction is terminated after 10 hours. The rest is the same as in Example 1.

[0061] Example 3 This embodiment provides a method for preparing 5-nitrovanillic acid.

[0062] The difference between this embodiment and embodiment 1 is that: A method for preparing 5-nitrovanillic acid, wherein in step (S.1), the mixture is placed under reflux stirring at 80°C, and the reaction is terminated after 4 hours; in step (S.2), methyl vanillate (0.630mmol), ferric nitrate nonahydrate (0.315mmol) and hexafluoroisopropanol (4mL) obtained in step (S.1) are added to a round-bottom flask, stirred at room temperature (50°C), detected by TLC (petroleum ether: ethyl acetate = 6:1), and the reaction is terminated after 4 hours; in step (S.3), methyl 5-nitrovanillate (0.616mmol), dichloromethane (4mL), and 2.5mol / L sodium hydroxide aqueous solution (1.25mL) obtained in step (S.2) are added to a round-bottom flask, heated and stirred at 60°C, detected by TLC (petroleum ether: ethyl acetate = 1:1), and the reaction is terminated after 4 hours. The rest is the same as in Example 1.

[0063] Example 4 This embodiment provides a method for preparing 4,6-dinitroguaiacol.

[0064] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (a) Add o-methoxyphenol (4.02 mmol), ferric nitrate nonahydrate (4.02 mmol) and dichloromethane (8 mL) into a round-bottom flask and stir at room temperature (25°C) for 12 h. After the reaction is completed, the dichloromethane in the reaction solution is dried by rotary evaporation, water is added thereto, and the mixture is extracted with ethyl acetate for 2 to 3 times. The organic phases are combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate is dried by rotary evaporation to obtain 4,6-dinitroguaiacol. The yield of the product (i.e., 4,6-dinitroguaiacol) is 95%. In this embodiment, the yield of 4,6-dinitroguaiacol is 1 H spectrum Figure 4 In this embodiment, 4,6-dinitroguaiacol 13 C spectrum Figure 5 The mass spectrum of 4,6-dinitroguaiacol in this embodiment is shown in Figure 6 shown.

[0065] 4,6-Dinitroguaiacol 1 H spectrum, 13 The C spectrum data are as follows: 1 H NMR (500MHz, DMSO-d6) δ8.32 (d, J = 2.53Hz, 1H), 7.92 (d, J = 2.67Hz, 1H), 4.01 (s, 3H). 13 C NMR (125MHz, DMSO-d6) δ150.2,148.9,138.1,136.4,113.5,109.7,57.6.

[0066] from Figures 4-5 From the analysis, it can be inferred that the reaction mechanism is: the ortho and para positions of the phenolic hydroxyl group are relatively active, and the dichloromethane solvent helps polarize the O2N-O bond, so that the ortho and para positions of the phenolic hydroxyl group can attack the polarized NO2 part; the obtained σ complex is deprotonated by the oxygen ligand on the iron to obtain the nitration product.

[0067] Example 5 This embodiment provides a method for preparing 4,6-dinitroguaiacol.

[0068] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (b) Vanillic acid (2.97 mmol), ferric nitrate nonahydrate (2.97 mmol) and hexafluoroisopropanol (6 mL) were added to a round-bottom flask and stirred at room temperature (25°C) for 12 h. After the reaction was completed, the hexafluoroisopropanol in the reaction solution was dried by spin drying, water was added thereto, and the mixture was extracted with ethyl acetate for 2 to 3 times. The organic phases were combined and dried with anhydrous magnesium sulfate, filtered, and the filtrate was dried by spin drying to obtain 4,6-dinitroguaiacol. The yield of the product (i.e., 4,6-dinitroguaiacol) was 80%. The final product in this example was mixed with the final product in Example 4 for nuclear magnetic hydrogen spectrum, and it was verified that they were the same product. The reaction mechanism is speculated to be: decarboxylation first and then nitro addition, the OH bond of the carboxyl group is broken, and an Ar-COO* intermediate is formed, followed by C-COO cleavage, and CO2 is produced to complete the decarboxylation. The hexafluoroisopropanol solvent helps polarize the O2N-O bond of ferric nitrate nonahydrate, allowing the aromatic hydrocarbon to attack the polarized NO2 portion; the resulting σ complex is deprotonated by the oxygen ligand on the iron to give the nitration product.

[0069] Example 6 This embodiment provides a method for preparing 4,6-dinitroguaiacol.

[0070] A method for preparing 4,6-dinitroguaiacol comprises the following steps: (c) 5-nitrovanillic acid (2.34 mmol), ferric nitrate nonahydrate (2.34 mmol) and hexafluoroisopropanol (5 mL) were added to a round-bottom flask and stirred at room temperature (25°C) for 12 h. After the reaction was completed, the hexafluoroisopropanol in the reaction solution was dried by spin drying, water was added thereto, and the mixture was extracted with ethyl acetate 2 to 3 times. The organic phases were combined and dried with anhydrous magnesium sulfate, filtered, and the filtrate was dried by spin drying to obtain 4,6-dinitroguaiacol. The yield of the product (i.e., 4,6-dinitroguaiacol) was 75%. The final product in this example was mixed with the final product in Example 4 for nuclear magnetic hydrogen spectrum, and it was verified that they were the same product. The reaction mechanism is speculated to be: decarboxylation first and then nitro addition, the OH bond of the carboxyl group is broken, and an Ar-COO* intermediate is formed, followed by the cleavage of C-COO to produce CO2 to complete the decarboxylation. The hexafluoroisopropanol solvent helps polarize the O2N-O bond of ferric nitrate nonahydrate, allowing the aromatic hydrocarbon to attack the polarized NO2 portion; the resulting σ complex is deprotonated by the oxygen ligand on the iron to give the nitration product.

[0071] Comparative Example 1 This comparative example provides an existing method for preparing 5-nitrovanillic acid.

[0072] A method for preparing 5-nitrovanillic acid comprises the following steps: Add methyl vanillate (18.11 mmol) and sodium nitrite (0.9 mmol) to a round-bottom flask, then add water (16 mL) and 1,4-dioxane (16 mL) at room temperature and mix well, heat the mixture to 40°C, add 65% nitric acid (1.6 g), and stir for 4 hours. Distill the water / nitric acid / 1,4-dioxane azeotrope at 40°C in a vacuum, add 50% sodium hydroxide solution (3.3 mL) to the obtained product suspension, stir, and stir for 16 hours. Add 18.5% HCl (7 mL) until the pH is below 1, filter, and wash with water (2.8 mL). Then dry the product in a vacuum at 50°C. 5-nitrovanillic acid is obtained. The total yield of 5-nitrovanillic acid is 81%.

[0073] The above description is only a detailed description of the preferred embodiments and principles of the present invention. For ordinary technicians in this field, according to the ideas provided by the present invention, there will be changes in the specific implementation methods, and these changes should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 5-nitrovanillic acid, characterized in that: The following steps are involved: (S.1) vanillic acid and methanol are mixed, concentrated sulfuric acid is added and heated for reaction, and after the reaction is completed, ethyl acetate is used for extraction to obtain vanillic acid methyl ester; (S.2) mixing the methyl vanillate obtained in step (S.1) and the first solvent, adding nitrate, drying by spin drying after the reaction is completed, and extracting with ethyl acetate to obtain 5-nitrovanillate methyl ester; (S.3) Mixing the 5-nitrovanillic acid methyl ester obtained in step (S.2) and the second solvent, adding an aqueous solution of alkali and heating the mixture for reaction, and acidifying the mixture with dilute hydrochloric acid to obtain 5-nitrovanillic acid.

2. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The reaction temperature in step (S.1) is 50-80°C, and the reaction time is 4-10 hours.

3. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The first solvent in step (S.2) is any one or more of dichloromethane, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, hexafluoroisopropanol, 1,4-dioxane, and water.

4. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The nitrate in step (S.2) is any one or more of ferric nitrate nonahydrate, gallium nitrate nonahydrate, bismuth nitrate pentahydrate, aluminum nitrate nonahydrate, copper nitrate trihydrate, sodium nitrate, potassium nitrate, and silver nitrate.

5. The method for preparing 5-nitrovanillic acid according to claim 1 or 4, characterized in that: The molar ratio of methyl vanillate and nitrate added in step (S.2) is 1:(0.3-1).

6. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The reaction temperature in step (S.2) is 0 to 50°C, and the reaction time is 4 to 16 hours.

7. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The second solvent in step (S.3) is any one or more of dichloromethane, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, and 1,4-dioxane.

8. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The alkali in step (S.3) is any one of sodium hydroxide and potassium hydroxide or a combination of the two.

9. The method for preparing 5-nitrovanillic acid according to claim 1 or 8, characterized in that: The molar ratio of 5-nitrovanillic acid methyl ester and the base added in step (S.3) is 1:(1 to 5).

10. The method for preparing 5-nitrovanillic acid according to claim 1, characterized in that: The reaction temperature in step (S.3) is 30-60°C, and the reaction time is 4-10 hours.

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