A method for highly selective synthesis of high-quality ortho-vanillin

Abstract

This invention relates to the field of chemical engineering, specifically to a method for the highly selective synthesis of high-quality ortho-vanillin. Using 3-methoxysalicylic acid as a starting material, a hydroxyl group protection reaction is performed under weakly alkaline conditions to generate compound 2. Compound 2 undergoes esterification, followed by reductive hydrogenation under a strong reducing agent to generate compound 3. In the presence of a nitrile radical catalyst, compound 3 reacts with an oxidizing agent to generate compound 4. In the presence of an acidic catalyst, compound 4 undergoes aldehyde group protection to generate compound 5. In the presence of a transition metal catalyst, the hydroxyl protecting group of compound 5 is removed to generate compound 6. Under strong acid conditions, compound 6 undergoes acetal hydrolysis to generate ortho-vanillin. This method achieves high regioselectivity and a simple process flow from the source through directional functional group transformation and protecting group strategies, avoiding the use of toxic and harmful reagents; it meets the requirements of industrial production for selectivity, environmental friendliness, and economy.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, and specifically to a method for highly selectively synthesizing high-quality 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 highly selectively synthesizing high-quality ortho-vanillin, with readily available raw materials, achieving high regioselectivity from the source, a simple process flow, and avoiding the use of toxic and harmful reagents; it meets the requirements of industrial production for selectivity, environmental protection, and economy.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for highly selectively synthesizing high-quality ortho-vanillin is provided, comprising the following steps: S1. Using 3-methoxysalicylic acid as the starting material, under weakly alkaline conditions, compound 2 is generated through a hydroxyl protection reaction; S2. Compound 2 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 3. S3. In the presence of a nitric oxide radical catalyst, compound 3 undergoes a selective oxidation reaction with an oxidant to generate compound 4; S4. In the presence of an acidic catalyst, compound 4 undergoes an aldehyde protection reaction to generate compound 5; S5. In the presence of a transition metal catalyst, the hydroxyl protecting group of compound 5 is removed to generate compound 6; S6. Under strong acid conditions, compound 6 generates ortho-vanillin via acetal hydrolysis. The synthetic route is as follows: ; In the synthetic route, R1 is a hydroxyl protecting group and R2 is an aldehyde protecting group.

[0008] Furthermore, R1 is independently selected from ester protecting groups, alkyl ether protecting groups, and silyl ether protecting groups; among them, acetyl, as an ester protecting group, has mild reaction conditions and is relatively easy to deprotect; benzyl, as an alkyl ether protecting group, can be specifically removed under subsequent hydrogenation conditions and has good orthogonality with other protecting groups; while silyl ether protecting groups such as trimethylsilyl are acid-sensitive and can be selectively removed under specific acidic conditions. R2 is independently selected from acetal protecting groups, enol ether protecting groups, and thioacetal protecting groups. Among them, geminal alkoxy, as an acetal protecting group, is extremely stable to strong bases, reducing agents (such as NaBH4, LiAlH4), and organometallic reagents, and will only hydrolyze to restore its original form in dilute acid. Geminal alkoxy-enalkoxy, as an enol ether protecting group, has extremely high chemical inertness to strong bases, strong nucleophiles, and metal hydride reducing agents. Geminal thio, as a thioacetal protecting group, is exceptionally stable to strong bases (such as butyllithium) and organolithium reagents. Depending on the final deprotection conditions required, different R1 and R2 can be selected to achieve compatibility and selectivity between steps.

[0009] In one embodiment, R1 is selected from acetyl, benzoyl, substituted benzoyl, benzyl, p-methoxybenzyl, methoxymethyl ether, trimethylsilyl or dimethyl tert-butylsilyl; further, R1 is benzyl. In one embodiment, R2 is selected from -CH(SR)2, -CH(OR)2, or -CH(SR)2; further, R2 is -CH(OCH3)2. This structure is readily hydrolyzed under acidic conditions, thus allowing for gentle removal in subsequent steps.

[0010] Further, S1 specifically involves adding 3-methoxysalicylic acid and an alkaline substance into DMF, controlling the temperature below 45°C, slowly adding a hydroxyl protecting agent dropwise, and then maintaining the reaction at 70-75°C after the addition is complete. Compound 2 is generated after 5-6 hours; wherein the molar ratio of 3-methoxysalicylic acid and hydroxyl protecting agent is 1:(1-2); the alkaline substance is selected from one or more of NaHCO3, KHCO3, LiHCO3, Na2CO3, K2CO3, and Li2CO3; the hydroxyl protecting agent is selected from benzyl bromide and benzyl chloride.

[0011] Further, S2 specifically involves mixing compound 2 with anhydrous methanol, controlling the temperature below 35°C, slowly adding thionyl chloride and DMF dropwise, and after the addition is complete, refluxing for 1-2 hours until the esterification reaction is finished; then, controlling the temperature at 0-10°C, stirring and adding a strong reducing agent, and carrying out a reduction hydrogenation reaction at room temperature for 5-6 hours to generate compound 3; wherein, the molar ratio of compound 2, thionyl chloride and strong reducing agent is 1:(1-1.2):(2-3); the strong reducing agent is selected from one or more of sodium borohydride, lithium aluminum hydride, red aluminum, and sodium cyanoborohydride.

[0012] Further, S3 specifically involves adding compound 3 into dichloromethane, adding an oxidant and a nitric oxide radical catalyst in batches at 0-5°C, and then maintaining the reaction at 0-10°C for 1-2 hours to generate compound 4; wherein the molar ratio of compound 3, oxidant, and nitric oxide radical catalyst is 1:(1.2-1.5):(0.01-0.2). 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 (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine oxide (TMHPO), and 4-acetamido-2,2,6,6-tetramethylpiperidine oxide (ACT).

[0013] Further, S4 specifically involves adding compound 4, an acidic catalyst, and an aldehyde protecting agent to anhydrous methanol and refluxing for 2-3 hours to generate compound 5; wherein the molar ratio of compound 4 to the aldehyde protecting agent is 1:(2-4); the aldehyde protecting agent is selected from one of trimethyl orthoformate, trimethylchlorosilane, tert-butyldimethoxysilyltrifluoromethanesulfonate, and trimethyltrifluoromethanesulfonate; the acidic catalyst is selected from one or more of trifluoromethanesulfonate, pyridine p-toluenesulfonate (PPTS), p-toluenesulfonic acid (TsOH), methanesulfonic acid, and aminosulfonic acid.

[0014] Further, S5 specifically involves adding compound 5 and a transition metal catalyst into anhydrous methanol, introducing hydrogen gas, and reacting at 55-60°C for 3-4 hours to generate compound 6; wherein the amount of transition metal catalyst added is 5-15%wt of compound 5; the transition metal catalyst is selected from palladium catalyst, nickel catalyst, or platinum catalyst.

[0015] Further, S6 specifically involves dissolving compound 5 in a methanol solution, adding 6N hydrochloric acid at a temperature controlled below 30°C, and then reacting at 50-55°C for 2-3 hours to generate ortho-vanillin; wherein the mass ratio of compound 5 to 6N hydrochloric acid is (3-6):1.

[0016] Compared with existing technologies, this invention has the following advantages: This invention develops a novel synthetic method using readily available and inexpensive 3-methoxysalicylic acid as a raw material. This method achieves high regioselectivity from the source, avoids the use of toxic and harmful reagents, and has a simple process flow. The entire synthetic route cleverly utilizes different functional group protection strategies to avoid uncontrollable selectivity problems, fundamentally circumventing the regioselectivity competition caused by the similar activity of two adjacent positions in traditional methods, thus achieving near-specific high-selectivity synthesis. This process significantly reduces the generation of isomer impurities, directly producing high-purity ortho-vanillin products, completely solving the shortcomings of low purity and poor quality of existing ortho-vanillin on the market, providing reliable assurance for downstream pharmaceutical quality, and possessing significant industrialization value. Detailed Implementation

[0017] 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.

[0018] Ortho-vanillin is an important intermediate in the synthesis of berberine hydrochloride, o-veratrol, and various Schiff base drugs. Its purity directly affects the quality and efficacy of downstream active pharmaceutical ingredients. Traditional synthetic methods are limited by the structural characteristics of the raw materials themselves, and face serious regioselectivity problems in the key formylation step, resulting in low yield of the target product, high content of isomer impurities, and high costs for subsequent separation and purification.

[0019] This invention aims to provide a method for the highly selective synthesis of high-quality ortho-vanillin. The method starts with the structurally defined 3-methoxysalicylic acid, whose phenolic hydroxyl and carboxyl groups are in positions completely identical to the target product, ortho-vanillin. By introducing a strategy of "protection first, then directional transformation, and finally deprotection," the synthetic pathway is broken down into a series of precisely manipulated functional group steps.

[0020] Specifically, this invention first protects the phenolic hydroxyl group to eliminate its interference; then, the carboxyl group located at a specific position is esterified and reduced to a hydroxymethyl group, and then selectively oxidized to an aldehyde group; next, the newly generated active aldehyde group is protected; finally, the protecting groups of the phenolic hydroxyl and aldehyde groups are removed stepwise. Because the target functional group of each reaction step is clearly defined and the reaction site is unique, the entire route fundamentally avoids the regioselectivity competition problem caused by similar activity of reaction sites in traditional methods, thereby achieving specific synthesis, directly obtaining high-purity ortho-vanillin, significantly reducing the generation of isomer impurities, and simplifying or even eliminating complex isomer separation procedures.

[0021] The synthetic method provided in this application is described in detail below, using the total synthetic route from 3-methoxysalicylic acid (compound 1) to ortho-vanillin as an example. The synthetic route is shown below, involving the introduction and removal of the hydroxyl protecting group R1 and the aldehyde protecting group R2: .

[0022] In some specific embodiments, step S1 provided by the present invention is a hydroxyl protection reaction. 3-Methoxysalicylic acid and a basic substance are added to DMF. Under conditions of ≤45°C, a hydroxyl protecting agent is slowly added dropwise. After the addition is complete, the reaction system is heated to 70-75°C and maintained at this temperature for 5-6 hours to generate compound 2. The synthetic route is as follows: .

[0023] In some embodiments of this implementation, the molar ratio of 3-methoxysalicylic acid to the hydroxyl protecting agent can be selected in the range of 1:1 to 1:2.

[0024] In some embodiments of this implementation, the alkaline substance may be selected from one or more of NaHCO3, KHCO3, LiHCO3, Na2CO3, K2CO3, and Li2CO3.

[0025] In some embodiments of this implementation, the hydroxyl protecting agent is selected from benzyl bromide and benzyl chloride. In a preferred embodiment, the hydroxyl protecting agent is benzyl chloride.

[0026] In some specific embodiments, step S2 of the present invention includes esterification and reductive hydrogenation reactions. Compound 2 obtained in step S1 is mixed with anhydrous methanol, and the reaction temperature is controlled at ≤35°C. A mixture of thionyl chloride and a small amount of DMF is slowly added dropwise. After the addition is complete, the reaction mixture is heated under reflux for 1-2 hours until the esterification reaction is complete, generating the corresponding methyl ester intermediate. Subsequently, the reaction system is cooled to 0-10°C, and a strong reducing agent is added in batches under stirring. After the addition is complete, the reaction is allowed to proceed with a reductive hydrogenation reaction at room temperature for 5-6 hours to generate compound 3. The synthetic route is as follows: .

[0027] In some embodiments of this implementation, the molar ratio of compound 2, thionyl chloride and strong reducing agent is controlled at 1:(1-1.2):(2-3).

[0028] In some embodiments of this implementation, the strong reducing agent may be selected from one or more of sodium borohydride, lithium aluminum hydride, red aluminum, and sodium cyanoborohydride. Sodium borohydride is a mild and selective reducing agent that can efficiently reduce esters to primary alcohols, and the post-reaction processing is simple.

[0029] In some specific embodiments, step S3 provided by the present invention is a selective oxidation reaction. Compound 3 is added to a suitable organic solvent (such as dichloromethane), and the reaction system is cooled to 0-5°C. At this low temperature, the oxidant and nitrile radical catalyst are added in batches. After the addition is complete, the reaction is kept at 0-10°C and stirred for 1-2 hours to selectively oxidize the hydroxymethyl group to an aldehyde group, generating compound 4; the synthetic route is as follows: .

[0030] In some embodiments of this implementation, the molar ratio of compound 3, oxidant and nitrile radical catalyst is 1:(1.2-1.5):(0.01-0.2).

[0031] In some embodiments of this implementation, the oxidant may be selected from sodium hypochlorite, sodium chlorite, sodium periodate, sodium persulfate, or hydrogen peroxide. The nitrogen oxide free 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). Among them, the oxidation system composed of 2,2,6,6-tetramethylpiperidine oxide and sodium hypochlorite can efficiently and selectively oxidize primary alcohols to aldehydes under neutral and mild conditions, while avoiding over-oxidation to carboxylic acids, and is one of the preferred options for this step.

[0032] In some specific embodiments, step S4 provided by the present invention is an aldehyde protection reaction. Compound 4, an acidic catalyst, and an aldehyde protecting agent are added to anhydrous methanol and heated under reflux for 2-3 hours to protect the unstable aldehyde group, generating compound 5; the synthetic route is as follows:

[0033] In some embodiments of this implementation, the molar ratio of compound 4 to the protective reagent is 1:(2-4).

[0034] In some embodiments of this implementation, the aldehyde protecting agent may be selected from trimethyl orthoformate, trimethylchlorosilane, tert-butyldimethoxysilyltrifluoromethanesulfonate, and trimethyltrifluoromethanesulfonate. In a preferred embodiment, the aldehyde protecting agent is trimethyl orthoformate.

[0035] In some embodiments of this implementation, the acidic catalyst is selected from one or more of trifluoromethanesulfonate, pyridine p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, and aminosulfonic acid.

[0036] In some specific embodiments, step S5 provided by the present invention is the removal reaction of the hydroxyl protecting group R1. Compound 5 and a transition metal catalyst are added to anhydrous methanol, hydrogen gas is introduced into the reaction system, and the reaction is carried out at 55-60°C for 3-4 hours to selectively remove the hydroxyl protecting group R1, generating compound 6; the synthetic route is as follows: .

[0037] In some embodiments of this implementation, the amount of transition metal catalyst added is 5%-15% of the mass of compound 5. The transition metal catalyst can be selected from palladium catalysts (such as Pd / C), nickel catalysts (such as Raney Ni), or platinum catalysts (such as PtO2). When R1 is benzyl, Pd / C catalytic hydrogenation is a highly efficient and specific deprotection method with mild reaction conditions, toluene as the only byproduct, and simple post-processing.

[0038] In some specific embodiments, step S6 provided by the present invention is the hydrolysis reaction of the aldehyde protecting group R2. Compound 6 is dissolved in a methanol solution, the temperature is controlled below 30°C, 6N hydrochloric acid is slowly added, and then the reaction is stirred at 50-55°C for 2-3 hours to hydrolyze and remove the aldehyde protecting group R2, ultimately generating the target product, ortho-vanillin. The mass ratio of compound 6 to 6N hydrochloric acid is controlled at (3-6):1. When R2 is a methoxy group (i.e., dimethyl acetal), this acidic hydrolysis condition can efficiently and quantitatively convert the acetal into a free aldehyde group, thereby obtaining the final ortho-vanillin product with high yield and high purity; the synthetic route is as follows: .

[0039] 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.

[0040] Example 1: Preparation of ortho-vanillin S1. Weigh 168 g (1 mol) of compound 1 (3-methoxysalicylic acid) and 276 g (2 mol) of anhydrous potassium carbonate and add them to 800 mL of DMF. Control the temperature not to exceed 45 °C and add 127 g (1 mol) of benzyl chloride dropwise while stirring. After the addition is complete, raise the temperature to 70-75 °C and keep the reaction at that temperature for 5-6 hours until the reactants are completely reacted. Cool to room temperature, concentrate under reduced pressure, wash with water, adjust the pH to 4-5 with concentrated hydrochloric acid, and stir to precipitate crystals. Filter, wash the filter cake with water, and dry to obtain compound 2 as a yellow solid, 243 g, with a total yield of 94%. 1H NMR (400 MHz, CDCl3): 7.68 (1H,dd, J = 6.3, 3.0 Hz), 7.43 (1H,d, J = 2.1 Hz), 7.36- 7.41 (5H,m), 7.19 (1H,d, J = 3.6 Hz), 5.27 (2H,s), 3.97 (3H,s);

[0041] S2. Add 188.5 g (0.73 mol) of compound 2 to 1000 mL of anhydrous methanol. Maintain the temperature no higher than 35 °C, and slowly add 91.2 g (0.77 mol) of thionyl chloride and 2-5 g of DMF dropwise. After the addition is complete, reflux the reaction for 1-2 hours until the starting material disappears. Maintain the temperature at 0-10 °C, and add 69 g (1.83 mol) of sodium borohydride in portions. After the addition is complete, react at room temperature for 5-6 hours until the starting material disappears. Cool to 0-5 °C, quench the reaction with dilute hydrochloric acid dropwise, evaporate the solvent, add water to the phase, extract the mother liquor with ethyl acetate, combine the organic phases, and concentrate under reduced pressure to obtain 151.6 g of compound 3 as a yellow solid, with a yield of 85%. 1 H NMR (400 MHz, CDCl3): 7.28-7.49 (5H, m), 7.01-7.12 (1H, m), 6.86-6.96 (2H, m), 5.09 (2H,s), 4.55 (2H, d, J=6.6 Hz), 3.91 (3H, s),1.97 (1H, t, J=6.6 Hz);

[0042] S3. 244 g (1 mol) of compound 3 was added to 1000 mL of dichloromethane. At 0-5 °C, 15.6 g (0.1 mol) of 2,2,6,6-tetramethylpiperidine oxide and 1120 mL (1.5 mol) of 10% sodium hypochlorite solution were added in portions. After the addition was complete, the temperature was controlled at 0-10 °C and the reaction was maintained for 1-2 hours until the starting material disappeared. Sodium bisulfite solution was added dropwise to quench the reaction. The phases were separated, and the organic phase was washed with tap water and concentrated under reduced pressure to obtain 174.4 g of compound 4 as a white solid, with a yield of 72%. 1H NMR (400MHz, CD3COCD3): 10.25 (s, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.41 - 7.32 (m, 4H), 7.30 (d, J = 7.0 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 5.23 (s, 2H), 3.98 (s, 3H);

[0043] S4. Weigh 242.2 g (1 mol) of compound 4, 68.8 g (0.4 mol) of p-toluenesulfonic acid, and 318 g (3 mol) of trimethyl orthoformate and add them to 1000 mL of anhydrous methanol. Heat under reflux for 2-3 hours until the raw materials are completely eliminated. Control the temperature not to exceed 25 °C and add 51 g of triethylamine dropwise to the system. After the addition is complete, continue stirring for 1 hour. Filter and wash the filter cake with water to obtain 274 g of compound 5 as a yellow solid, with a yield of 95%. Compound 5 can be directly used in S5.

[0044] S5. Add 274 g (0.95 mol) of compound 5 and 14 g of 10% palladium on carbon to 1000 mL of methanol, and replace with nitrogen and hydrogen three times respectively. After replacement, heat to 55-60 °C and stir for 3-4 hours until there is no obvious hydrogen absorption. Filter to remove palladium on carbon, and wash the filter cake with a small amount of methanol to obtain a methanol solution of compound 6, which can be used directly in S6. The dry yield of compound 6 is 88%.

[0045] S6. Take 1000 mL of methanol solution of compound 6 obtained in S5, and add 30 mL of 6N hydrochloric acid to the system while keeping the temperature below 30℃. After the addition is complete, continue stirring at 50-55℃ for 2-3 hours, concentrate under reduced pressure, add water, stir to precipitate crystals, filter, wash the filter cake with water, recrystallize, and obtain 108 g of ortho-vanillin as a white solid with a yield of 85% and a purity of ≥99%. 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 = 7.9Hz, 1H), 6.97 (t, J= 7.9 Hz, 1H), 3.92 (s, 3H); .

[0046] Example 2 Preparation of intermediate compound 2 Weigh 168 g (1 mol) of compound 1 (3-methoxysalicylic acid) and 276 g (2 mol) of anhydrous potassium carbonate and add them to 800 mL of LMF. Control the temperature not to exceed 45 °C and add 171 g (1 mol) of benzyl bromide dropwise while stirring. After the addition is complete, raise the temperature to 70-75 °C and keep it at that temperature for 4-5 hours until the reactants react completely. Cool to room temperature, concentrate under reduced pressure, wash with water, adjust the pH to 4-5 with concentrated hydrochloric acid, and stir to precipitate crystals. Filter, wash the filter cake with water, and dry to obtain 246 g of compound 2 as a yellow solid, with a total yield of 95%.

[0047] Example 3 Preparation of intermediate compound 2 Weigh 168 g (1 mol) of compound 1 (3-methoxysalicylic acid) and 211 g (2 mol) of anhydrous sodium carbonate and add them to 800 mL of LDM. Control the temperature not to exceed 45 °C and add 127 g (1 mol) of benzyl chloride dropwise while stirring. After the addition is complete, raise the temperature to 70-75 °C and keep the reaction at this temperature for 8-12 hours until the reactants have reacted completely. Cool to room temperature, concentrate under reduced pressure, wash with water, adjust the pH to 4-5 with concentrated hydrochloric acid, and stir to precipitate crystals. Filter, wash the filter cake with water, and dry to obtain 243 g of compound 2 as a yellow solid, with a total yield of 94%.

[0048] Example 4 Preparation of intermediate compound 2 Weigh 169 g (1 mol) of compound 1 (3-methoxysalicylic acid) and 276 g (2 mol) of anhydrous potassium carbonate and add them to 800 mL of DMSO. Control the temperature not to exceed 45 °C and add 128 g (1 mol) of benzyl chloride dropwise while stirring. After the addition is complete, raise the temperature to 70-75 °C and keep it at that temperature for 5-6 hours until the reactants react completely. Cool to room temperature, concentrate under reduced pressure, wash with water, adjust the pH to 4-5 with concentrated hydrochloric acid, and stir to precipitate crystals. Filter, wash the filter cake with water, and dry to obtain 240 g of compound 2 as a yellow solid, with a total yield of 93%.

[0049] Example 5 Preparation of intermediate compound 3 188.5 g (0.73 mol) of compound 2 was added to 1000 mL of anhydrous methanol. The temperature was controlled not to exceed 35 °C. 91.2 g (0.77 mol) of thionyl chloride and 2-5 g of DMF were slowly added dropwise. After the addition was complete, the mixture was refluxed for 1-2 hours until the starting material disappeared. The temperature was controlled at 0-10 °C. 84 g (1.34 mol) of sodium cyanoborohydride was added in portions. After the addition was complete, the mixture was reacted at room temperature for 5-6 hours until the starting material disappeared. The mixture was cooled to 0-5 °C, and the reaction was quenched by adding dilute hydrochloric acid dropwise. The solvent was evaporated, water was added to the phase, and the mother liquor was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 146.2 g of compound 3 as a yellow solid, with a yield of 82%.

[0050] Example 6 Preparation of intermediate compound 3 188.5 g (0.73 mol) of compound 2 was added to 1000 mL of anhydrous methanol. The temperature was controlled not to exceed 35 °C. 109 g (0.92 mol) of thionyl chloride and 2-5 g of DMF were slowly added dropwise. After the addition was complete, the mixture was refluxed for 1-2 hours until the starting material disappeared. The temperature was controlled at 0-10 °C. 62.7 g (1.66 mol) of sodium borohydride was added in portions. After the addition was complete, the mixture was reacted at room temperature for 5-6 hours until the starting material disappeared. The mixture was cooled to 0-5 °C, and the reaction was quenched by adding dilute hydrochloric acid dropwise. The solvent was evaporated, water was added to the phase, and the mother liquor was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 150 g of compound 3 as a yellow solid, with a yield of 84%.

[0051] Example 7 Preparation of intermediate compound 4 244 g (1 mol) of compound 3 was added to 1000 mL of dichloromethane. At 0-5 °C, 15.2 g (0.08 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine nitride and 1120 mL (1.5 mol) of 10% sodium hypochlorite solution were added in portions. After the addition was complete, the temperature was maintained at 0-10 °C for 1-2 hours until the starting material disappeared. Sodium bisulfite solution was added dropwise to quench the reaction. The phases were separated, and the organic phase was washed with tap water and concentrated under reduced pressure to obtain 174.4 g of compound 4 as a white solid, with a yield of 72%.

[0052] Example 8 Preparation of intermediate compound 4 244.3 g (1 mol) of compound 3 was added to 1000 mL of dichloromethane. At 0-5 °C, 16.6 g (0.1 mol) of 2,2,6,6-tetramethylpiperidine oxide and 930 mL (1.25 mol) of 10% sodium hypochlorite solution were added in portions. After the addition was complete, the temperature was controlled at 0-10 °C and the reaction was maintained for 1-2 hours until the starting material disappeared. The reaction was quenched by adding sodium bisulfite solution dropwise. The phases were separated, and the organic phase was washed with tap water and concentrated under reduced pressure to obtain 169 g of compound 4 as a white solid, with a yield of 70%.

[0053] Example 9 Preparation of intermediate compound 4 244 g (1 mol) of compound 3 was added to 1000 mL of dichloromethane. 20.6 g (0.13 mol) of 2,2,6,6-tetramethylpiperidine oxide and 1120 mL (1.5 mol) of 10% sodium hypochlorite solution were added in portions at 0-5 °C. After the addition was complete, the temperature was maintained at 0-10 °C for 1-2 hours until the starting material disappeared. Sodium bisulfite solution was added dropwise to quench the reaction. The phases were separated, and the organic phase was washed with tap water and concentrated under reduced pressure to obtain 174.4 g of compound 4 as a white solid, with a yield of 72%.

[0054] Example 10 Preparation of intermediate compound 5 Weigh 242.2 g (1 mol) of compound 4, 68.8 g (0.4 mol) of p-toluenesulfonic acid, and 327 g (3 mol) of trimethylchlorosilane and add them to 1000 mL of anhydrous methanol. Heat under reflux for 2-3 hours until the raw materials are completely eliminated. Control the temperature not to exceed 25 °C and add 51 g of triethylamine dropwise to the system. After the addition is complete, continue stirring for 1 hour. Filter and wash the filter cake with water to obtain 250.8 g of compound 5 as a yellow solid, with a yield of 88%. Compound 5 can be directly used in S5.

[0055] Example 11 Preparation of intermediate compound 5 Weigh 242.2 g (1 mol) of compound 4, 38 g of p-toluenesulfonic acid, and 318 g (3 mol) of trimethyl orthoformate and add them to 1000 mL of anhydrous methanol. Heat and reflux for 2-3 hours until the raw materials are completely eliminated. Control the temperature not to exceed 25 °C and add 51 g of triethylamine dropwise to the system. After the addition is complete, continue stirring for 1 hour. Filter and wash the filter cake with water to obtain 264 g of compound 5 as a yellow solid, with a yield of 91%. Compound 5 can be directly used for S5.

[0056] Example 12 Preparation of intermediate compound 5 Weigh 242.2 g (1 mol) of compound 4, 68.8 g of p-toluenesulfonic acid, and 477 g (4.5 mol) of trimethyl orthoformate and add them to 1000 mL of anhydrous methanol. Heat under reflux for 2-3 hours until all the raw materials disappear. Control the temperature not to exceed 25 °C and add 51 g of triethylamine dropwise to the system. After the addition is complete, continue stirring for 1 hour. Filter and wash the filter cake with water to obtain 274 g of compound 5 as a yellow solid, with a yield of 95%. Compound 5 can be directly used for S5.

[0057] Example 13 Preparation of intermediate compound 6 274 g (0.95 mol) of compound 5 and 28 g of 5% palladium on carbon were added to 1000 mL of methanol. The mixture was then purged three times with nitrogen and three times with hydrogen, respectively. After the purging was completed, the mixture was heated to 55-60 °C and stirred for 6-8 hours until no significant hydrogen absorption was observed. The palladium on carbon was removed by filtration, and the filter cake was washed with a small amount of methanol to obtain a methanol solution of compound 6, which can be used directly for S6. The dry yield of compound 6 was 88%.

[0058] Example 14 Preparation of intermediate compound 6 274 g (0.95 mol) of compound 5 and 28 g of 10% palladium on carbon were added to 1000 mL of methanol. The mixture was then replaced three times with nitrogen and three times with hydrogen, respectively. After the replacement was completed, the mixture was heated to 55-60 °C and stirred for 6-8 hours until no obvious hydrogen absorption was observed. The palladium on carbon was removed by filtration, and the filter cake was washed with a small amount of methanol to obtain a methanol solution of compound 6, which can be used directly for S6. The dry yield of compound 6 was 88%.

[0059] 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 highly selectively synthesizing high-quality ortho-vanillin, characterized in that... Includes the following steps: S1. Using 3-methoxysalicylic acid as the starting material, under weakly alkaline conditions, compound 2 is generated through a hydroxyl protection reaction; S2. Compound 2 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 3. S3. In the presence of a nitric oxide radical catalyst, compound 3 undergoes a selective oxidation reaction with an oxidant to generate compound 4; S4. In the presence of an acidic catalyst, compound 4 undergoes an aldehyde protection reaction to generate compound 5; S5. In the presence of a transition metal catalyst, the hydroxyl protecting group of compound 5 is removed to generate compound 6; S6. Under strong acid conditions, compound 6 generates ortho-vanillin via acetal hydrolysis. The synthetic route is as follows: ; In the synthetic route, R1 is a hydroxyl protecting group and R2 is an aldehyde protecting group.

2. The method according to claim 1, characterized in that, R1 is independently selected from ester protecting groups, alkyl ether protecting groups, and silyl ether protecting groups; R2 is independently selected from acetal protecting groups, enol ether protecting groups, and thioacetal protecting groups.

3. The method according to claim 1, characterized in that, R1 is selected from acetyl, benzoyl, substituted benzoyl, benzyl, p-methoxybenzyl, methoxymethyl ether, trimethylsilyl or dimethyl tert-butylsilyl; and / or, R2 is selected from -CH(SR)2, -CH(OR)2, -CH(SR)2; or, R2 is -CH(OCH3)2.

4. The method according to claim 1, characterized in that, Specifically, S1 involves adding 3-methoxysalicylic acid and a basic substance to an organic solvent, controlling the temperature below 45°C, and slowly adding a hydroxyl protecting agent dropwise. After the addition is complete, the reaction is maintained at 70-75°C for 5-6 hours to generate compound 2; wherein the molar ratio of 3-methoxysalicylic acid to the hydroxyl protecting agent is 1:(1-2); and / or, The alkaline substance is selected from one or more of NaHCO3, KHCO3, LiHCO3, Na2CO3, K2CO3, and Li2CO3; and / or, The hydroxyl protecting agent is selected from benzyl bromide and benzyl chloride.

5. The method according to claim 1, characterized in that, Specifically, S2 involves mixing compound 2 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 reduction hydrogenation reaction at room temperature for 5-6 hours to generate compound 3. Wherein, the molar ratio of compound 2, 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, lithium aluminum hydride, red aluminum, and sodium cyanoborohydride.

6. The method according to claim 1, characterized in that, Specifically, S3 involves adding compound 3 to an organic solvent, and then adding an oxidant and a nitrile radical catalyst in batches at 0-5°C. After the addition is complete, the mixture is kept at 0-10°C for 1-2 hours to generate compound 4. The molar ratio of compound 3, oxidant, and nitrile radical catalyst is 1:(1.2-1.5):(0.01-0.2). And / or, 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.

7. The method according to claim 1, characterized in that, Specifically, step S4 involves adding compound 4, an acidic catalyst, and an aldehyde protecting agent to an organic solvent and refluxing for 2-3 hours to generate compound 5; wherein the molar ratio of compound 4 to the aldehyde protecting agent is 1:(2-4); and / or, The aldehyde protecting agent is selected from one of trimethyl orthoformate, triethyl orthoformate, 1,1-diethoxyethylene, 2,2-dimethoxypropane, and 1,1-diethoxyethylene; and / or, The acidic catalyst is selected from one or more of trifluoromethanesulfonate, pyridine p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, and aminosulfonic acid.

8. The method according to claim 1, characterized in that, Specifically, step S5 involves adding compound 5 and a transition metal catalyst to an organic solvent, introducing hydrogen gas, and reacting at 55-60°C for 3-4 hours to generate compound 6; wherein the amount of transition metal catalyst added is 5-15% wt of compound 5; and / or, The transition metal catalyst is selected from palladium catalysts, nickel catalysts, or platinum catalysts.

9. The method according to claim 1, characterized in that, Specifically, S6 involves dissolving compound 5 in a methanol solution, adding 6N hydrochloric acid at a temperature below 30°C, and then reacting at 50-55°C for 2-3 hours to generate ortho-vanillin; wherein the mass ratio of compound 5 to 6N hydrochloric acid is (3-6):

1.

10. The method according to any one of claims 4, 6, 7, and 8, characterized in that, The organic solvent is selected from one or more of DMF, methanol, dichloromethane, tetrahydrofuran, dichloromethane, ethyl acetate, diethyl ether, and methyl tert-butyl ether.

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