Process for the preparation of high purity o-vanillin
By using a specific reaction route and environmentally friendly reagents, the problems of low selectivity, high cost, and poor environmental performance in the synthesis of ortho-vanillin have been solved, achieving efficient and economical synthesis of high-purity ortho-vanillin, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIUWEI BIOCHEMISTRY (CHONGQING) CO LTD
- Filing Date
- 2026-05-09
- Publication Date
- 2026-06-09
AI Technical Summary
Existing methods for synthesizing ortho-vanillin suffer from low selectivity, use of toxic and harmful reagents, high production costs, and poor environmental performance, making it difficult to meet the economic and environmental requirements of industrial production.
Using o-methoxyaniline as the starting material, an indigo ring structure was constructed through steps such as condensation, hydroxylamine oxime, cyclization, oxidative ring opening, esterification, reduction, and diazotization. Environmentally friendly reagents such as chloral hydrate, hydroxylamine hydrochloride, hydrogen peroxide, sodium borohydride, and sodium hypochlorite were used to achieve highly selective synthesis of o-vanillin.
It has achieved efficient, environmentally friendly and economical synthesis of high-purity (≥99%) ortho-vanillin, avoiding the generation of isomer impurities, providing high-quality raw materials for drug synthesis, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical technology, specifically to a method for preparing high-purity ortho-vanillin. Background Technology
[0002] Ortho-vanillin (2-hydroxy-3-methoxybenzaldehyde) is a key isomer of vanillin. As an important fine chemical intermediate, it is a key raw material for the synthesis of berberine hydrochloride (berberine), o-veratrol and various Schiff base drugs. Its purity directly determines the quality and efficacy of the active pharmaceutical ingredient.
[0003] Currently, ortho-vanillin mainly relies on the following two types of production processes, but both have significant technical and economic drawbacks: Vanillin by-product separation method: This method separates and purifies ortho-vanillin from isomer by-products of vanillin (produced via the guaiacol-glyoxylic acid method or the Reimer-Tiemann method). Its advantage is that it relies on existing large-scale vanillin production facilities, resulting in lower initial material costs. However, its fundamental disadvantages are: ① The product depends on the main product production plan, making output uncontrollable and supply unstable; ② Vanillin and ortho-vanillin have similar properties, leading to complex and costly separation and purification processes, and the final product is prone to retaining isomer impurities, making it difficult to meet the purity requirements of high-end pharmaceuticals.
[0004] Direct formylation of guaiacol: This method uses guaiacol as a raw material and directly introduces a formyl group through a classical reaction. It mainly includes: 1. Reimer-Tiemann reaction: using chloroform and a strong base, the reaction yield is relatively high (approximately 79%), but the regioselectivity is extremely poor (the proportion of ortho-products is only about 21%), and the use of highly toxic chloroform generates a large amount of chlorine-containing wastewater, causing serious environmental pollution; 2. Duff reaction: using hexamethylenetetramine and a strong acid, the selectivity for ortho-products is improved (approximately 40%), but the reaction yield is significantly reduced (approximately 51%), and the raw material cost is high, resulting in poor atom economy.
[0005] It is evident that the existing mainstream synthetic routes for ortho-vanillin suffer from low selectivity, resulting in low yields of the target product and numerous isomer impurities, which severely restricts product purity. The production process uses toxic reagents and generates large amounts of waste, which contradicts the principles of green chemistry. Furthermore, either due to the main product or the high cost of separation and inefficient reactions, the final production costs are high and supply fluctuates, making it difficult to meet the comprehensive requirements of economic efficiency, safety, and environmental protection for industrial production. Summary of the Invention
[0006] To address the problems mentioned in the background art, the present invention aims to provide a method for preparing high-purity ortho-vanillin, thereby solving the technical problems of poor regioselectivity, use of toxic and harmful reagents, and poor economic efficiency due to low yield or complex separation and purification in the prior art, and achieving a synthesis that is highly selective, environmentally friendly, and suitable for industrial production.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing high-purity ortho-vanillin is provided, comprising the following steps: S1. Starting with o-methoxyaniline, chloral hydrate and hydroxylamine hydrochloride are reacted with chloral hydrate and hydroxylamine hydrochloride through condensation and hydroxylamine oxime reaction, followed by cyclization reaction under strong acid conditions to generate compound 2. S2. Compound 2 undergoes ring-opening oxidation under strongly alkaline conditions to generate compound 3; S3. Compound 3 is esterified with a primary alcohol to generate the corresponding ester, and then, under the action of a strong reducing agent, it undergoes a reducing hydrogenation reaction to generate compound 4. S4. In the presence of a nitric oxide radical catalyst, compound 4 undergoes a selective oxidation reaction with an oxidant to generate compound 5; S5. Compound 5 undergoes a diazotization hydrolysis reaction to generate ortho-vanillin; The synthetic route is as follows: .
[0008] Furthermore, S1 includes a condensation reaction, a hydroxylamine oxime reaction, and a cyclization reaction; this step efficiently constructs the key indigo ring structure through a continuous one-pot reaction, laying the foundation for subsequent ring-opening and functional group transformation; wherein, the molar ratio of o-methoxyaniline, chloral hydrate, and hydroxylamine hydrochloride is 1:(1.0-1.3):(2.0-5.0); As one implementation method, the condensation reaction specifically involves mixing o-methoxyaniline with chloral hydrate and reacting at 70-75°C for 1-2 hours. As one implementation method, the hydroxylamine oxime reaction specifically involves adding hydroxylamine hydrochloride in batches after the condensation reaction is complete, and then maintaining the temperature at 65-75°C for 3-5 hours. As one implementation method, the cyclization reaction specifically involves adding the hydroxylamine oxime product into concentrated sulfuric acid and stirring the mixture at 70-80°C for 3-4 hours to generate compound 2.
[0009] Further, step S2 specifically involves reacting compound 2 with an inorganic alkali solution at 65-75℃ for 3-4 hours, then adding an oxidant. After the addition is complete, the reaction is maintained at 45-55℃ for 2-3 hours, followed by adding acid to adjust the pH of the system to 5-6. Compound 3 is then generated at 0-10℃. The molar ratio of compound 2, inorganic alkali, and oxidant is 1:(2-5):(1-2). This step achieves efficient conversion of indigo ring to aminobenzoic acid under mild conditions. The oxidant is selected from hydrogen peroxide, sodium perborate, and potassium persulfate composite salt; the inorganic alkali is selected from one or more of NaOH, KOH, and LiOH.
[0010] In one embodiment, the oxidant is an aqueous solution of hydrogen peroxide with a mass concentration of 15-35%.
[0011] Further, step S3 specifically involves mixing compound 3 with a primary alcohol, controlling the temperature below 35°C, and slowly adding thionyl chloride dropwise. After the addition is complete, the mixture is refluxed for 1-2 hours until the esterification reaction is finished. Then, the temperature is controlled at 0-10°C, and a strong reducing agent is added with stirring. The reduction hydrogenation reaction is carried out at room temperature for 5-6 hours to generate compound 4. This step, through a strategy of esterification followed by reduction, avoids the difficulties that may be encountered in the direct reduction of carboxylic acids, and improves the reduction efficiency and selectivity. The organic solvent is selected from one or more of DMF, methanol, dichloromethane, tetrahydrofuran, dichloromethane, ethyl acetate, diethyl ether, and methyl tert-butyl ether. The molar ratio of compound 3, thionyl chloride, and the strong reducing agent is 1:(1-1.2):(2-3). The strong reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, hydrazine hydrate, or aluminum hydroxide.
[0012] Further, step S4 specifically involves adding compound 4 to an organic solvent, adding an oxidant and a nitroxide radical catalyst in batches at 0-5°C, and then maintaining the reaction at 0-10°C for 1-2 hours to generate compound 5. The molar ratio of compound 4, oxidant, and nitroxide radical catalyst is 1:(1.2-1.5):0.1. This step precisely converts the primary amine into the target phenolic hydroxyl group through primary amine oxidation. The organic solvent is selected from one or more of DMF, methanol, dichloromethane, tetrahydrofuran, dichloromethane, ethyl acetate, diethyl ether, and methyl tert-butyl ether. The oxidant is selected from sodium hypochlorite, sodium chlorite, sodium periodate, sodium persulfate, or hydrogen peroxide. The nitroxide radical catalyst is selected from 2,2,6,6-tetramethylpiperidine oxide (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (TMHPO), and 4-acetamido-2,2,6,6-tetramethylpiperidine oxide (ACT).
[0013] Further, in S5, the diazotization hydrolysis reaction temperature is -10-30℃, or 0-30℃, or 0-20℃, or 0-10℃; the diazotization hydrolysis reaction time is 1-5h, or 1-4h, or 1-3h, or 2-3h; the molar ratio of compound 5 to the diazotizing reagent is 1:(1-2); wherein, the solvent system for the diazotization hydrolysis reaction is selected from at least one of sulfuric acid aqueous solution and phosphoric acid aqueous solution; the diazotizing reagent is selected from one of sodium nitrite, potassium nitrite, tert-butyl nitrite, and amyl nitrite.
[0014] Compared with existing technologies, this invention develops a specific reaction route for ortho-vanillin using inexpensive and readily available ortho-methoxyaniline as a raw material. This avoids the poor regioselectivity problem caused by competition between two adjacent active sites during direct formylation on the benzene ring in traditional methods. Since each reaction step acts on a pre-positioned specific functional group or site, the reaction pathway is specific, thus eliminating the generation of isomer impurities at the source. Furthermore, the reagents used in this method, such as chloral hydrate, hydroxylamine hydrochloride, hydrogen peroxide, sodium borohydride, and sodium hypochlorite, are more environmentally friendly than the highly toxic chloroform or expensive reagents used in traditional methods. This achieves efficient, environmentally friendly, and economical synthesis of high-purity (≥99%) ortho-vanillin, providing a high-quality raw material guarantee for downstream pharmaceuticals. Detailed Implementation
[0015] To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be described in detail below with reference to specific embodiments. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise specified, the test materials used in the following embodiments were purchased from conventional biochemical reagent stores. Unless otherwise stated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar with the art. Furthermore, any methods and materials similar to or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.
[0016] The endpoints and any values of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
[0017] Ortho-vanillin is a crucial intermediate in the synthesis of berberine hydrochloride, o-veratrol, and various Schiff base drugs, and its purity directly impacts the quality and efficacy of downstream active pharmaceutical ingredients. Traditional synthetic methods face severe regioselectivity challenges in the critical formylation step and often employ highly toxic reagents, resulting in low product purity, poor environmental friendliness, and high production costs. This application provides a novel synthetic route aimed at addressing these problems at their source.
[0018] Specifically, this invention uses o-methoxyaniline as the starting material and cleverly locates the reaction site from the front end through a specific reaction sequence of "condensation-cyclization-ring-reduction-oxidation-diazotization". First, the amino group of o-methoxyaniline is converted to an indigo ring structure through reaction S1, determining the framework for subsequent reactions. Then, a carboxyl group is introduced through ring-opening oxidation in reaction S2, followed by reduction to hydroxymethyl in reaction S3, and selective oxidation to an aldehyde group in reaction S4. Finally, the amino group is converted to the target phenolic hydroxyl group through a diazotization-hydrolysis reaction in reaction S5. Throughout the entire route, each reaction acts on a pre-formed, well-defined functional group (such as carboxyl, hydroxymethyl, or amino groups), completely avoiding the reactivity competition between the two ortho-positions (hydroxyl ortho- and methoxy ortho-) when directly performing formylation on the benzene ring in traditional methods, thus achieving nearly 100% regioselectivity. Simultaneously, this route mainly uses relatively environmentally friendly reagents such as chloral hydrate, hydroxylamine hydrochloride, hydrogen peroxide, sodium borohydride, and sodium hypochlorite, avoiding the use of highly toxic reagents such as chloroform, making it green and environmentally friendly.
[0019] The synthetic method provided in this application is described in detail below, based on the total synthetic route from o-methoxyaniline (compound 1) to o-vanillin. The synthetic route is shown below, involving condensation, hydroxylamine oximeting, cyclization, oxidative ring-opening, esterification and reduction, selective oxidation, and diazotization hydrolysis:
[0020] In some specific embodiments, step S1 provided by the present invention includes a condensation reaction, a hydroxylamine oxime reaction, and a cyclization reaction. Specifically, o-methoxyaniline and chloral hydrate are mixed at 70-75°C and reacted at this temperature for 1-2 hours to ensure complete dissolution of aniline and full condensation with chloral hydrate; after the condensation reaction is complete, the temperature is controlled at 60-70°C, and hydroxylamine hydrochloride is added in batches. After the addition is complete, the reaction is maintained at 65-75°C for 3-5 hours to convert the intermediate into an oxime; the above reaction product is crystallized at 0-10°C, filtered, and washed with water. The resulting solid is then added in batches to concentrated sulfuric acid preheated to 70-80°C. After the addition is complete, the reaction is continued to be stirred at 70-80°C for 3-4 hours until the raw material disappears. After post-treatment, compound 2 is obtained. The synthetic route is as follows:
[0021] In some embodiments of this implementation, the molar ratio of o-methoxyaniline, chloral hydrate and hydroxylamine hydrochloride can be 1:(1.0-1.3):(2.0-5.0). In a preferred embodiment, the molar ratio is controlled at 1:1.1:2.5, which is beneficial for complete reaction and reduces by-products. In some specific embodiments, step S2 provided by the present invention is an oxidative ring-opening reaction. Specifically, compound 2 is mixed with an inorganic alkaline solution and reacted at 65-75°C for 3-4 hours to open the indigo ring under alkaline conditions; then, the temperature is controlled at 65-75°C, and an oxidizing agent is added dropwise. After the addition is complete, the temperature is controlled at 45-55°C and the reaction is continued for 2-3 hours to complete the oxidation process. Then, acid is added to adjust the pH of the system to 5-6, and compound 3 is generated at 0-10°C. The synthetic route is as follows:
[0022] In some embodiments of this implementation, the molar ratio of compound 2, inorganic base and oxidant can be 1:(2-5):(1-2); in preferred embodiments, the molar ratio can be controlled at 1:4:1.5 to ensure that the ring-opening and oxidation steps are fully carried out.
[0023] In some embodiments of this implementation, the oxidant, in addition to hydrogen peroxide, may also be selected from sodium perborate or potassium persulfate compound salt; in preferred embodiments, the oxidant is an aqueous solution of hydrogen peroxide with a mass concentration of 15-35%, or a mass concentration of 20-35%, or a mass concentration of 30% hydrogen peroxide.
[0024] In some embodiments of this implementation, the inorganic alkaline solution is a sodium hydroxide solution with a mass concentration of 10-40%, and the inorganic alkaline solution may be selected from one or more of KOH and LiOH, in addition to sodium hydroxide.
[0025] In some specific embodiments, step S3 provided by the present invention includes esterification and reductive hydrogenation. Specifically, compound 3 is mixed with a primary alcohol, the reaction temperature is controlled not to exceed 35°C, thionyl chloride and a small amount of DMF are slowly added dropwise, and after the addition is complete, the mixture is heated under reflux for 1-2 hours to convert the carboxylic acid into the corresponding methyl ester; the esterification reaction solution is cooled to 0-5°C, the temperature is controlled at 0-10°C, a strong reducing agent is added in batches, and after the addition is complete, the mixture is stirred at room temperature for 5-6 hours to reduce the ester to the primary alcohol, generating compound 4. The synthetic route is as follows:
[0026] In some embodiments of this implementation, the molar ratio of compound 3, thionyl chloride and strong reducing agent can be 1:(1-1.2):(2-3). In a preferred embodiment, the molar ratio is controlled to be 1:1.05:2.5.
[0027] In some embodiments of this implementation, the strong reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, hydrazine hydrate, or red aluminum.
[0028] In some specific embodiments, step S4 is a selective oxidation reaction. Specifically, compound 4 is dissolved in an organic solvent and cooled to 0-5°C. A nitroxide radical catalyst (such as 2,2,6,6-tetramethylpiperidine oxide) and an oxidant (such as a 10% sodium hypochlorite solution) are added in batches under stirring. This oxidation system is mild and can efficiently oxidize alcohols to aldehydes while effectively suppressing the side reaction of excessive oxidation to carboxylic acids. After the addition is complete, the reaction is maintained at 0-10°C for 1-2 hours to selectively oxidize the primary alcohol to an aldehyde group, generating compound 5. The synthetic route is as follows:
[0029] In some specific embodiments, the molar ratio of compound 4, oxidant and nitric oxide free radical catalyst can be 1:(1.2-1.5):(0.01-0.2), and in preferred embodiments, the molar ratio is controlled at 1:1.5:0.1.
[0030] In some specific embodiments, the oxidant, in addition to sodium hypochlorite, may also be selected from sodium chlorite, sodium periodate, sodium persulfate, or hydrogen peroxide; the nitric oxide free radical catalyst, in addition to 2,2,6,6-tetramethylpiperidine oxide (TEMPO), may also be selected from 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (TMHPO) and 4-acetamido-2,2,6,6-tetramethylpiperidine oxide (ACT).
[0031] In some specific embodiments, step S5 is a diazotization hydrolysis reaction. Specifically, compound 5 is dissolved in an acidic solvent system, the system temperature is controlled at 0-10°C, and a solution prepared by diazotizing reagent and water is added dropwise. After the addition is complete, the reaction is stirred at 0-10°C for 2-3 hours to complete the diazotization. Subsequently, the reaction system is slowly moved to room temperature and stirred overnight to allow the diazonium salt to be fully hydrolyzed. Finally, the pH is adjusted to 5-6 to precipitate the product, which is then post-processed to obtain high-purity ortho-vanillin. The synthetic route is as follows:
[0032] In some embodiments of this implementation, the molar ratio of compound 5 to the diazotizing agent is 1:(1-2); in a preferred embodiment, the molar ratio is controlled to be 1:1.05.
[0033] In some embodiments of this implementation, the solvent system can be selected from sulfuric acid aqueous solution and phosphoric acid aqueous solution, such as sulfuric acid aqueous solution with a mass fraction of 10%-50%, where the mass fraction can be selected as 10%, 20%, 30%, 40%, or 50%. Other specific values within this range can also be selected, and will not be described in detail here.
[0034] In some embodiments of this implementation, the diazotizing agent may be selected from sodium nitrite, potassium nitrite, tert-butyl nitrite, or isoamyl nitrite.
[0035] The organic solvents involved in the above steps can be independently selected from one or more of DMF, methanol, dichloromethane, tetrahydrofuran, ethyl acetate, diethyl ether, and methyl tert-butyl ether, depending on the reaction requirements of each step.
[0036] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only used to explain the present invention and are not intended to limit the present invention.
[0037] Example 1 S1. Add 182g (1.1mol) of chloral hydrate and 860g of tap water to a 2000mL three-necked flask equipped with a condenser, and start stirring. Add 123g (1mol) of o-methoxyaniline (compound 1), and heat to 70-75℃ and maintain the temperature for 1-2 hours until the aniline is completely dissolved. Control the temperature at 60-70℃ and add 172.5g (2.5mol) of hydroxylamine hydrochloride in batches. After the addition is complete, heat to 65-75℃ and maintain the temperature for 4 hours. Cool the reaction solution to 0-10℃ and stir to precipitate crystals. Filter and wash the filter cake with water. Add the obtained wet solid in batches to 500g of concentrated sulfuric acid preheated to 70-80℃, controlling the addition temperature at 70-80℃. After the addition is complete, continue stirring at 70-80℃ for 3-4 hours until the starting material disappears. The mixture was cooled to 25-30℃ and stirred to induce crystallization. After filtration, the filter cake was washed with water and dried to obtain compound 2 as a brick-red solid, 147 g, with a yield of 83%. 1 H NMR (400 MHz, CDCl3): 11.38 (s, 1H), 7.25 (dd, J = 7.5, 1.0Hz, 1H), 7.15 (dd, J = 8.2, 1.0Hz, 1H), 7.09 (dd, J = 8.2, 7.5Hz, 1H), 3.95 (s, 3H); S2. Add 147g (0.83mol) of compound 2 and 450g (3.375mol) of 30% sodium hydroxide solution to a 2000mL three-necked flask. Heat to 65-75℃ and stir for 3-4 hours until the starting material disappears. Control the temperature at 65-75℃ and add 175g (1.54mol) of 30% hydrogen peroxide dropwise. After the addition is complete, maintain the temperature at 45-55℃ and continue the reaction for 2-3 hours. Cool the reaction solution to 0-5℃, add concentrated hydrochloric acid to adjust the pH to 5-6, and stir at 0-10℃ to induce crystallization for 0.5 hours. Filter, wash the filter cake with water, and dry to obtain 122g of compound 3 as a yellow solid, yield 88%. 1 H NMR (400 MHz, DMSO): 12.52 (br s,1H), 7.36 (dd,J= 7.8, 1.4 Hz,1H), 7.06 (t,J= 7.9 Hz,1H), 6.52 (dd,J= 7.8Hz, 1.4 Hz,1H), 5.01 (br s, 2H), 3.85 (s, 3H); S3. Add 122 g (0.73 mol) of compound 3 and 1000 mL of anhydrous methanol to a 3 L three-necked flask, controlling the temperature not to exceed 35 °C. Slowly add a mixture of 91.2 g (0.77 mol) of thionyl chloride and 2-5 g of DMF dropwise. After the addition is complete, heat under reflux for 1-2 hours until the starting material disappears. Cool the reaction solution to 0-5 °C, control the temperature at 0-10 °C, and add 69 g (1.83 mol) of sodium borohydride in portions over 2-3 hours. After the addition is complete, stir the reaction at room temperature for 5-6 hours until the starting material disappears. Cool the reaction solution again to 0-5 °C and quench the reaction with dilute hydrochloric acid dropwise. After evaporating most of the solvent, add 800 mL of tap water to the residue and extract three times with ethyl acetate. Combine the organic phases and concentrate under reduced pressure to obtain compound 4 as a yellow oil, 95 g, yield 85%. 1 H NMR (400 MHz, CDCl3, ppm): 6.76 (dd,J = 6.7 Hz, 2.7 Hz, 1H), 6.69-6.63(m, 2H), 4.59 (s, 2H), 3.83 (s, 3H); S4. Add 153 g (1 mol) of compound 4 and 750 mL of dichloromethane to a 2000 mL three-necked flask, and cool the system to 0-5 °C. Add 15.6 g (0.1 mol) of 2,2,6,6-tetramethylpiperidine oxide and 1120 mL (1.5 mol) of a 10% sodium hypochlorite aqueous solution in portions. After the addition is complete, maintain the temperature at 0-10 °C and react for 1-2 hours until the reactants disappear. Quench excess oxidant by adding sodium bisulfite solution dropwise to the reaction solution. Separate the liquid, wash the organic phase with tap water, concentrate under reduced pressure to recover the solvent, and obtain compound 5 as a yellow oil, 113 g, yield 75%. 1 H NMR (400MHz, CDCl3): 9.88(s, 1H), 7.11 (dd, J = 8.0, 1.1 Hz, 1H), 6.88(t,J=7.8,1H), 6.68 (d, J = 7.8Hz, 1H), 6.39 (s, 2H), 3.87 (s, 3H); S5. Add 151 g (1 mol) of compound 5 and 1000 mL of 20% sulfuric acid aqueous solution to a 2000 mL three-necked flask, and cool the system to 0-10 °C. While stirring, add dropwise a solution prepared by dissolving 72.5 g (1.05 mol) of sodium nitrite in 150 mL of water, controlling the addition temperature at 0-10 °C. After the addition is complete, continue stirring the reaction at 0-10 °C for 2-3 hours. Slowly transfer the reaction mixture to room temperature and stir overnight. While stirring, add dropwise a 5% sodium hydroxide solution to the system to adjust the pH to 5; the solid gradually precipitates. Filter, and wash the filter cake with water to obtain a brown crude product. Recrystallize the crude product with methyl tert-butyl ether, filter, and vacuum dry the filter cake to obtain 134 g of white needle-like crystals of ortho-vanillin, with a yield of 88% and a purity of 99.5% as determined by HPLC. 1 H NMR (400 MHz, CDCl3): 11.12 (s, 1H), 9.92 (s, 1H), 7.18 (dd, J = 7.8,1.4 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.97 (t, J= 7.9 Hz, 1H), 3.92 (s, 3H).
[0038] Example 2 Add 215g (1.3mol) of chloral hydrate and 880g of tap water to a 2000mL three-necked flask equipped with a condenser, and start stirring. Add 123g (1mol) of o-methoxyaniline (compound 1), and heat to 70-75℃ and maintain the temperature for 1-2 hours until the aniline is completely dissolved. Maintain the temperature at 60-70℃ and add 186g (2.67mol) of hydroxylamine hydrochloride in portions. After the addition is complete, heat to 65-75℃ and maintain the temperature for 4 hours. Cool the reaction solution to 0-10℃ and stir to induce crystallization. Filter the solution, and wash the filter cake with water. Add the resulting wet solid in portions to 520g of concentrated sulfuric acid preheated to 70-80℃, controlling the addition temperature at 70-80℃. After the addition is complete, continue stirring at 70-80℃ for 3-4 hours until the starting material disappears. The mixture was cooled to 25-30℃ and stirred to induce crystallization. After filtration, the filter cake was washed with water and dried to obtain compound 2 as a brick-red solid, 151g, with a yield of 85%.
[0039] Example 3 Add 147 g (0.83 mol) of compound 2 and 450 g (3.375 mol) of 30% sodium hydroxide solution to a 2000 mL three-necked flask. Heat to 65-75 °C and stir for 3-4 hours until the starting material disappears. Maintain the temperature at 65-75 °C and add 110 g (0.97 mol) of 20% hydrogen peroxide dropwise. After the addition is complete, maintain the temperature at 45-55 °C and continue the reaction for 3 hours. Cool the reaction solution to 0-5 °C, add concentrated hydrochloric acid to adjust the pH to 5-6, and stir at 0-10 °C to induce crystallization for 0.5 hours. Filter, wash the filter cake with water, and dry to obtain 118 g of compound 3 as a yellow solid, yield 86%.
[0040] Example 4 Add 123 g (0.74 mol) of compound 3 and 1000 mL of anhydrous methanol to a 3 L three-necked flask, controlling the temperature to not exceed 35 °C. Slowly add a mixture of 94 g (0.79 mol) of thionyl chloride and 2-5 g of DMF dropwise. After the addition is complete, heat under reflux for 1-2 hours until the starting material disappears. Cool the reaction solution to 0-5 °C, control the temperature at 0-10 °C, and add 69 g (1.83 mol) of sodium borohydride in portions over 2.5 hours. After the addition is complete, stir the reaction at room temperature for 6 hours until the starting material disappears. Cool the reaction solution again to 0-5 °C, and quench the reaction dropwise with dilute hydrochloric acid. After evaporating most of the solvent, add 810 mL of tap water to the residue and extract three times with dichloromethane. Combine the organic phases and concentrate under reduced pressure to obtain 96 g of compound 4 as a yellow oil, with a yield of 85%.
[0041] Example 5 153 g (1 mol) of compound 4 and 750 mL of dichloromethane were added to a 2000 mL three-necked flask, and the system was cooled to 0-5 °C. 16.1 g (0.1 mol) of 2,2,6,6-tetramethylpiperidine oxide and 930 mL (1.25 mol) of a 10% sodium hypochlorite aqueous solution were added in portions. After the addition was complete, the temperature was maintained at 0-10 °C for 1-2 hours until the reactants disappeared. Excess oxidant was quenched by adding sodium bisulfite solution dropwise to the reaction mixture. The mixture was separated, the organic phase was washed with tap water, and the solvent was recovered by concentration under reduced pressure to obtain 113 g of compound 5 as a yellow oil, with a yield of 75%.
[0042] Example 6 Add 151 g (1 mol) of compound 5 and 900 mL of 30% sulfuric acid aqueous solution to a 2000 mL three-necked flask, and cool the system to 0-10 °C. While stirring, add dropwise a solution prepared by dissolving 72.5 g (1.05 mol) of sodium nitrite in 150 mL of water, controlling the addition temperature at 0-10 °C. After the addition is complete, continue stirring the reaction at 0-10 °C for 2-3 hours. Slowly transfer the reaction mixture to room temperature and stir overnight. While stirring, add dropwise a 5% sodium hydroxide solution to the system to adjust the pH to 5, and a solid gradually precipitates. Filter, and wash the filter cake with water to obtain a brown crude product. Recrystallize the crude product with methyl tert-butyl ether, filter, and vacuum dry the filter cake to obtain 128 g of white needle-like crystals of ortho-vanillin, with a yield of 84% and a purity of 99.2% as determined by HPLC.
[0043] Example 7 Add 151 g (1 mol) of compound 5 and 900 mL of 30% sulfuric acid aqueous solution to a 2000 mL three-necked flask, and cool the system to 0-10 °C. While stirring, add dropwise a solution prepared by dissolving 74 g (1.07 mol) of sodium nitrite in 150 mL of water, controlling the addition temperature at 0-10 °C. After the addition is complete, continue stirring the reaction at 0-10 °C for 2-3 hours. Slowly transfer the reaction mixture to room temperature and stir overnight. While stirring, add dropwise a saturated sodium bicarbonate solution to the system to adjust the pH to 5, and a solid gradually precipitates. Filter, and wash the filter cake with water to obtain a brown crude product. Recrystallize the crude product with methyl tert-butyl ether, filter, and vacuum dry the filter cake to obtain 126 g of white needle-like crystals of ortho-vanillin, with a yield of 85% and a purity of 99.3% as determined by HPLC.
[0044] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.
Claims
1. A method for preparing high-purity ortho-vanillin, characterized in that... Includes the following steps: S1. Starting with o-methoxyaniline, chloral hydrate and hydroxylamine hydrochloride are reacted with chloral hydrate and hydroxylamine hydrochloride through condensation and hydroxylamine oxime reaction, followed by cyclization reaction under strong acid conditions to generate compound 2. S2. Compound 2 undergoes ring-opening oxidation under strongly alkaline conditions to generate compound 3; S3. Compound 3 is esterified with a primary alcohol to generate the corresponding ester, and then, under the action of a strong reducing agent, it undergoes a reducing hydrogenation reaction to generate compound 4. S4. In the presence of a nitric oxide radical catalyst, compound 4 undergoes a selective oxidation reaction with an oxidant to generate compound 5; S5. Compound 5 undergoes a diazotization hydrolysis reaction to generate ortho-vanillin; The synthetic route is as follows: 。 2. The method for preparing high-purity ortho-vanillin according to claim 1, characterized in that, The condensation reaction in S1 specifically involves mixing o-methoxyaniline with chloral hydrate and reacting at 70-75°C for 1-2 hours; and / or, The hydroxylamine oxime reaction specifically involves adding hydroxylamine hydrochloride in batches after the condensation reaction is complete, and maintaining the reaction temperature at 65-75℃ for 3-5 hours; and / or, The molar ratio of o-methoxyaniline, chloral hydrate and hydroxylamine hydrochloride is 1:(1.0-1.3):(2.0-5.0). The cyclization reaction specifically involves adding the hydroxylamine oxime product into concentrated sulfuric acid and stirring the mixture at 70-80°C for 3-4 hours to generate compound 2.
3. The method for preparing high-purity ortho-vanillin according to claim 1, characterized in that, Specifically, S2 involves reacting compound 2 with an inorganic alkaline solution at 65-75℃ for 3-4 hours, then adding an oxidant. After the addition is complete, the reaction is maintained at 45-55℃ for 2-3 hours. Then, acid is added to adjust the pH of the system to 5-6, and compound 3 is generated at 0-10℃. Wherein, the molar ratio of compound 2, inorganic base and oxidant is 1:(2-5):(1-2); and / or, The oxidant is selected from one of hydrogen peroxide, sodium perborate, and potassium persulfate complex salt; and / or, The inorganic base is selected from one or more of NaOH, KOH, and LiOH.
4. The method for preparing high-purity ortho-vanillin according to claim 3, characterized in that, Specifically, S2 is an aqueous solution of hydrogen peroxide with a mass concentration of 15-35%, 20-35%, or 30%.
5. The method for preparing high-purity ortho-vanillin according to claim 1, characterized in that, Specifically, S3 involves mixing compound 3 with a primary alcohol, controlling the temperature below 35°C, slowly adding thionyl chloride dropwise, and then refluxing for 1-2 hours until the esterification reaction is complete. Then, controlling the temperature at 0-10°C, stirring and adding a strong reducing agent, and carrying out a reducing hydrogenation reaction at room temperature for 5-6 hours to generate compound 4. Wherein, the molar ratio of compound 3, thionyl chloride, and strong reducing agent is 1:(1-1.2):(2-3); and / or, The strong reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, hydrazine hydrate, or red aluminum.
6. The method for preparing high-purity ortho-vanillin according to claim 1, characterized in that, Specifically, S4 involves adding compound 4 to an organic solvent, adding an oxidant and a nitric oxide free radical catalyst in batches at 0-5°C, and then maintaining the temperature at 0-10°C for 1-2 hours to generate compound 5. The molar ratio of compound 4, oxidant, and nitric oxide free radical catalyst is 1:(1.2-1.5):0.
1.
7. The method for preparing high-purity ortho-vanillin according to claim 6, characterized in that, In step S4, the oxidant is selected from sodium hypochlorite, sodium chlorite, sodium periodate, sodium persulfate, or hydrogen peroxide; and / or, The nitrile radical catalyst is selected from 2,2,6,6-tetramethylpiperidine oxide, 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide, and 4-acetamido-2,2,6,6-tetramethylpiperidine oxide.
8. The method for preparing high-purity ortho-vanillin according to claim 1, characterized in that, In S5, the diazotization hydrolysis reaction temperature is -10 to 30°C, or 0 to 30°C, or 0 to 20°C, or 0 to 10°C; and / or, The diazotization hydrolysis reaction time is 1-5 h, or 1-4 h, or 1-3 h, or 2-3 h; and / or, The molar ratio of compound 5 to the diazotizing agent is 1:(1-2).
9. The method for preparing high-purity ortho-vanillin according to claim 8, characterized in that, In step S5, the solvent system for the diazotization hydrolysis reaction is selected from at least one of sulfuric acid aqueous solution and phosphoric acid aqueous solution, or a sulfuric acid aqueous solution with a mass fraction of 10%-50%, or a sulfuric acid aqueous solution with a mass fraction of 10%-40%, or a sulfuric acid aqueous solution with a mass fraction of 10%-30%, or a sulfuric acid aqueous solution with a mass fraction of 20%; and / or, The diazotizing agent is selected from one of sodium nitrite, potassium nitrite, tert-butyl nitrite, and isoamyl nitrite.