Preparation process for synthesizing o-vanillin with low cost and high selectivity

Abstract

The invention belongs to the technical field of o-vanillin synthesis, and discloses a low-cost and high-selectivity preparation process for synthesizing o-vanillin, which specifically comprises the following steps: S1, fully dissolving a compound M1 in a compound M2; step S2, adding 2-chlorophenol into a reaction system; s3, dichloromethane is used for extraction and liquid separation, an organic phase is subjected to rotary evaporation, and an intermediate M3 is obtained; s4, under the ice-water bath condition, dissolving the intermediate M3 and sodium methoxide in a solvent together for nucleophilic substitution; and S5, after the reaction is finished, extracting by using ethyl acetate, and then carrying out reduced pressure distillation or column chromatography purification on an organic phase to obtain the target product o-vanillin. The invention provides a brand new o-vanillin synthesis path, breaks through the bottleneck of low yield in the prior art, and has industrial application value.

Description

Technical Field

[0001] This invention relates to the field of o-vanillin synthesis technology, specifically to a low-cost, highly selective synthesis process for o-vanillin. Background Technology

[0002] o-Vanillin (2-hydroxy-3-methoxybenzaldehyde, OVA), also known as ortho-vanillin, is an isomer of vanillin and possesses the typical chemical properties of a monohydric phenol (such as the easy oxidation of the phenolic hydroxyl group, leading to discoloration upon prolonged exposure to air). Due to its unique distribution of substituents (aldehyde, hydroxyl, methoxy), ortho-vanillin exhibits many special properties. Therefore, ortho-vanillin has extremely wide applications in pharmaceutical production, organic synthesis, cosmetic synthesis, and the electroplating industry. It is also an important raw material for the industrial synthesis of various compounds, such as berberine hydrochloride, o-bromopiperaldehyde, and epoxy phenolic resins.

[0003] In existing technologies, the production process of o-vanillin mainly relies on the resource utilization of the mother liquor from the A-method process of vanillin production. This mother liquor is recovered from the old mother liquor produced by the A-method of vanillin production, and its components include toluene, o-vanillin, para-vanillin, and high-boiling-point substances. Based on the differences in the boiling points of each component, effective separation is achieved through distillation, followed by crystallization centrifugation, washing, and drying to obtain the finished product. This production process is limited by the difficulty in separating o-vanillin and vanillin isomers, resulting in a low yield (<15%).

[0004] Currently, the well-known preparation processes for o-vanillin, in addition to the byproduct recovery method mentioned above, also include: 1) the Reimer-Tiemann reaction method, in which guaiacol reacts with chloroform under alkaline conditions to produce a mixture of o-vanillin and vanillin, but the proportion of o-vanillin is low, usually less than 13%, which limits industrial production; 2) the selective methylation-formylation method of catechol, in which catechol is first methylated and then formylated. This method has a short process flow and low cost, but its disadvantages are low methylation selectivity, harsh formylation reaction conditions, complex catalytic system and difficulty in product separation. 3) Patent application number 201910020932.5 discloses a method for preparing ortho-vanillin from catechol. This method uses a two-step synthesis of ortho-vanillin via methylation and formylation of catechol. The yield of the ortho-vanillin product is not disclosed in the patent. In their subsequent master's thesis ("Synthesis of ortho-vanillin from Catechol", Han Siyu, June 12, 2020), the research group disclosed a reaction yield of 4.03% and a conversion rate of 5.8% for ortho-vanillin obtained by this process. Therefore, the yield of ortho-vanillin product obtained by this method is low and not suitable for industrial application.

[0005] Therefore, the current synthesis of o-vanillin is more suitable for laboratory or small-scale production, and it suffers from poor selectivity and low product yield, making it difficult to meet the requirements of industrial production. Developing an efficient, low-cost, highly selective, and low-byproduct industrial synthesis process for o-vanillin has always been a challenge in the research field. Summary of the Invention

[0006] To address the aforementioned problems, the present invention aims to provide a low-cost, highly selective synthesis process for o-vanillin.

[0007] To achieve the above objectives, the present invention employs a low-cost, highly selective synthesis process for o-vanillin, specifically comprising the following steps: Step S1: Dissolve compound M1 completely in compound M2, and gradually heat the reaction system to 30℃-110℃; The compound M1 is formyl chloride, trichloromethyl formate, paraformaldehyde, formic acid, formic anhydride, hexamethylenetetramine, methylene glycol, or an N-hydroxymethyl compound; The compound M2 is a protic acid catalyst; The equivalence ratio of compound M1 to compound M2 is 1:1.1 to 1:2.5; Step S2: Add 2-chlorophenol to the reaction system of step S1, wherein the equivalent ratio of 2-chlorophenol to compound M1 is 1:1.2-1:1.5, stir evenly, raise the temperature to 50℃-110℃, and continue the reaction for 1h-10h; after the reaction is completed, quench the reaction with ice water and adjust the pH value of the system to weakly acidic. Step S3: Extract and separate the liquid with dichloromethane, and then rotary evaporate the organic phase to obtain intermediate M3; Step S4: Under ice-water bath conditions, intermediate M3 and sodium methoxide are dissolved together in a solvent, and then reacted in an oil bath for 5-12 hours to carry out nucleophilic substitution. In step S5, after the reaction is complete, the organic phase and the aqueous phase are separated by extraction with ethyl acetate. Then, the organic phase is purified by vacuum distillation or column chromatography to obtain the target product, o-vanillin.

[0008] Further, in step S1, the compound M1 is hexamethylenetetramine, formic anhydride, trioxymethylene, or formyl chloride.

[0009] Further, in step S1, the protic acid catalyst is 10% dilute sulfuric acid, 2 mol / L hydrochloric acid, polyphosphoric acid, glacial acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid.

[0010] Further, in step S2, adjusting the pH of the system to a weakly acidic state specifically involves: The pH of the system was adjusted to a slightly acidic state, with a pH value of 3-7, using a 10% NaOH aqueous solution.

[0011] Furthermore, in step S3, the structural formula of the intermediate M3 is: .

[0012] Furthermore, in step S4, the equivalent ratio of intermediate M3 to sodium methoxide is 1:1 to 1:1.2.

[0013] Further, in step S4, the solvent is DMF, DMSO, THF, ACN, methanol, or ethanol.

[0014] Furthermore, in step S4, the amount of solvent added is 20 mL.

[0015] Furthermore, in step S4, the temperature of the oil bath is 50℃-140℃.

[0016] Compared with the prior art, the present invention has the following beneficial effects: This invention achieves high selectivity at the ortho position by employing a Friedel-Crafts acylation reaction. The increased yield is achieved through the interaction between the chlorine atom and sodium methoxide. Specifically: (1) In this invention, 2-chlorophenol is used as the reaction substrate, compound M1 provides the formyl source, and the formylation reaction is carried out under the promotion of compound M2 (protic acid catalyst). The ortho position of the hydroxyl group of 2-chlorophenol is introduced through Friedel-Crafts formylation to generate intermediate M3, thereby achieving highly selective formylation of the ortho position of the benzene ring of 2-chlorophenol and effectively avoiding the problem of difficult separation of isomers in the existing process. (2) The chlorine atom (-Cl) in intermediate M3 of the present invention is a good leaving group. In the nucleophilic substitution reaction with sodium methoxide, it can be efficiently substituted by methoxy (-OCH3) to generate the target product o-vanillin. Moreover, sodium methoxide, as a strong base, can promote the reaction to completion and increase the product yield.

[0017] (3) The reaction conditions of the present invention are mild and have few byproducts, which simplifies the subsequent separation and purification steps and makes it suitable for large-scale industrial production.

[0018] (4) The raw materials used in this invention are all highly economical. The raw materials selected in this invention are all easy to obtain and have low raw material costs, which can effectively reduce production costs by about 30%, ensuring the cost controllability of the entire process and making it suitable for large-scale industrial application.

[0019] In summary, this invention provides a novel synthetic route for o-vanillin, which yields o-vanillin by using 2-chlorophenol, compound M1, and compound M2 for highly selective formylation and efficient nucleophilic substitution reactions. This overcomes the bottleneck of low yield in existing technologies and demonstrates strong process stability, making it valuable for industrial applications. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is a liquid chromatogram of o-vanillin, the product of Example 1 of the present invention.

[0022] Figure 2 This is a liquid chromatogram of o-vanillin, the product of Example 2 of the present invention.

[0023] Figure 3 This is a liquid chromatogram of o-vanillin, the product of Example 3 of the present invention.

[0024] Figure 4 This is a liquid chromatogram of o-vanillin, the product of Example 4 of the present invention.

[0025] Figure 5 This is a liquid chromatogram of o-vanillin, the product of Example 5 of the present invention.

[0026] Figure 6 This is a liquid chromatogram of o-vanillin, the product of Example 6 of the present invention.

[0027] Figure 7 This is a liquid chromatogram of o-vanillin, the product of Comparative Example 1 of the present invention.

[0028] Figure 8 This is a liquid chromatogram of o-vanillin, the product of Comparative Example 2 of the present invention. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0030] The present invention will now be described in detail with reference to the accompanying drawings.

[0031] A low-cost, highly selective synthesis process for o-vanillin specifically includes the following steps: Step S1: Dissolve compound M1 completely in compound M2, and gradually heat the reaction system to 30℃-110℃; The compound M1 is formyl chloride, trichloromethyl formate, paraformaldehyde, formic acid, formic anhydride, hexamethylenetetramine, methylene glycol, or an N-hydroxymethyl compound; The compound M2 is a protic acid catalyst; The equivalence ratio of compound M1 to compound M2 is 1:1.1 to 1:2.5; Step S2: Add 2-chlorophenol to the reaction system of step S1, wherein the equivalent ratio of 2-chlorophenol to compound M1 is 1:1.2-1:1.5, stir evenly, raise the temperature to 50℃-110℃, and continue the reaction for 1h-10h; after the reaction is completed, quench the reaction with ice water and adjust the pH value of the system to weakly acidic. Step S3: Extract and separate the liquid with dichloromethane, and then rotary evaporate the organic phase to obtain intermediate M3; Step S4: Under ice-water bath conditions, intermediate M3 and sodium methoxide are dissolved together in a solvent, and then reacted in an oil bath for 5-12 hours to carry out nucleophilic substitution. In step S5, after the reaction is complete, the organic phase and the aqueous phase are separated by extraction with ethyl acetate. Then, the organic phase is purified by vacuum distillation or column chromatography to obtain the target product, o-vanillin.

[0032] In step S1, the protic acid catalyst is 10% dilute sulfuric acid, 2 mol / L hydrochloric acid, polyphosphoric acid, glacial acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid.

[0033] In step S2, adjusting the pH of the system to a weakly acidic state specifically involves: The pH of the system was adjusted to a slightly acidic state, with a pH value of 3-7, using a 10% NaOH aqueous solution.

[0034] In step S3, the structural formula of the intermediate M3 is: .

[0035] In step S4, the equivalent ratio of intermediate M3 to sodium methoxide is 1:1 to 1:1.2.

[0036] In step S4, the solvent is DMF, DMSO, THF, ACN, methanol, or ethanol.

[0037] In step S4, the amount of solvent added is 20 mL.

[0038] In step S4, the temperature of the oil bath is 50℃-140℃.

[0039] The synthetic route for o-vanillin in this invention is as follows: .

[0040] Example 1:

[0041] The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (methylene glycol), 1.89 mL, 30 mmol; Compound M2 (trifluoroacetic acid), 4 mL, 52 mmol; 2-Chlorophenol, 2.58 g, 20 mmol; The equivalence ratio of compound M1 to compound M2 is 1:1.7; The equivalence ratio of 2-chlorophenol to M1 is 1:1.5; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1; Solvent (DMF): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, trifluoroacetic acid (4 mL, 52 mmol) was added, followed by methylene glycol (1.89 mL, 30 mmol) under ice-water bath conditions. The mixture was stirred until fully dissolved, then the ice-water bath was removed, and the temperature was raised to 30 °C. Next, 2-chlorophenol (2.58 g, 20 mmol) was added to the reaction system, and the mixture was stirred until homogeneous. The temperature was gradually increased to 50 °C, and the reaction was continued for 10 h. After the reaction was complete, the reaction was quenched with water, and the pH was adjusted to weakly acidic (pH 3) with a 10% NaOH aqueous solution. The liquid-liquid phase was separated using dichloromethane, and the organic phase was rotary evaporated to obtain the crude product, intermediate M3 (1.26 g). Intermediate M3 (1.26 g, 8 mmol) and sodium methoxide (0.43 g, 8 mmol) were dissolved in 20 mL of DMF (N,N-dimethylformamide) under ice-water bath conditions, and then reacted in an oil bath at 50 °C for 12 h. After the reaction was completed, the organic phase and aqueous phase were separated by extraction with ethyl acetate. The organic phase was then purified by column chromatography (silica gel column chromatography, eluent was petroleum ether and dichloromethane, and the volume ratio of petroleum ether to dichloromethane was 1:2) to obtain o-vanillin (0.6 g, yield 49.28%).

[0042] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 1The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 1 show that the peak position of o-vanillin is at 4.788 min, and its peak area percentage is 49.28%, that is, the yield is 49.28%.

[0043] Table 1. Liquid chromatography detection results of Example 1: .

[0044] Example 2:

[0045] The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (formic anhydride), 1.58 mL, 40 mmol; Compound M2 (2 mol / L hydrochloric acid), 30 mL, 60 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:1.5; The equivalence ratio of 2-chlorophenol to M1 is 1:1.5; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (DMSO): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, 30 mL (60 mmol) of 2 mol / L hydrochloric acid was added. Formic anhydride (1.58 mL, 40 mmol) was then added under ice-water bath conditions. The mixture was heated to 70 °C, stirred until fully dissolved, and allowed to react for another 1.5 h for acid catalysis. Next, 3.48 g (27 mmol) of 2-chlorophenol was added to the reaction system, stirred thoroughly, and the temperature was raised to 90 °C. The reaction was continued for another 7 h. After the reaction was complete, the reaction was quenched with ice water, and the pH of the system was adjusted to a weakly acidic level (pH 7) using a 10% NaOH aqueous solution. The product was then extracted with dichloromethane and the organic phase was rotary evaporated to obtain the crude product, intermediate M3 (2.07 g). Under ice-water bath conditions, intermediate M3 (2.07 g, 13.2 mmol) and sodium methoxide (0.85 g, 16 mmol) were dissolved in 20 mL of DMSO (dimethyl sulfoxide), and then reacted in an oil bath at 140 °C for 5 h. After the reaction was completed, the organic phase was separated by extraction with ethyl acetate and then subjected to vacuum distillation (pressure 10 mmHg). The fraction collected at 140 °C-155 °C was o-vanillin (1.07 g, yield 53.75%).

[0046] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 2The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 2 show that the peak position of o-vanillin is at 4.560 min, and its peak area percentage is 53.75%, that is, the yield is 53.75%.

[0047] Table 2. Liquid chromatography detection results of Example 2: .

[0048] Example 3: The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (formic acid), 1.22 mL, 32.4 mmol; Compound M2 (10% dilute sulfuric acid), 25 mL, 42.08 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:1.3; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1; Solvent (THF): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, 25 mL of 10% dilute sulfuric acid (42.08 mmol) was added. Formic acid (1.22 mL, 32.4 mmol) was added under ice-water bath conditions. The temperature was raised to 110 °C, and then 3.48 g of 27 mmol of 2-chlorophenol was added to the reaction system. The mixture was stirred until homogeneous, and the temperature was raised to 110 °C for 2.5 h. After the reaction was completed, the reaction was quenched with ice water, and the pH of the system was adjusted to weakly acidic (pH 4) with a 10% NaOH aqueous solution. Extraction with dichloromethane and separation were performed. The organic phase was then rotary evaporated to obtain the crude product, intermediate M3 (2.55 g). Intermediate M3 (2.55 g, 16.3 mmol) and sodium methoxide (0.88 g, 16.3 mmol) were dissolved in 20 mL of THF (tetrahydrofuran) under ice-water bath conditions. The mixture was then reacted in an oil bath at 70 °C for 9 h. After the reaction was completed, the organic phase was separated by extraction with ethyl acetate. The organic phase and the aqueous phase were then separated. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (1.26 g, yield 51.11%).

[0049] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 3The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 3 show that the peak position of o-vanillin is at 4.528 min, and its peak area percentage is 51.11%, that is, the yield is 51.11%.

[0050] Table 3. Liquid chromatography detection results of Example 3: .

[0051] Example 4: The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (trichloromethyl formate), 6.34 g, 53 mmol; Compound M2 (p-toluenesulfonic acid), 10g, 58.3mmol; 2-Chlorophenol, 5.68 g, 44 mmol; The equivalence ratio of compound M1 to compound M2 is 1:1.1; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (ACN): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, 6.34 g (53 mmol) of trichloromethyl formate was added. Then, under ice-water bath conditions, 10 g (58.3 mmol) of p-toluenesulfonic acid was added to dissolve it completely, and the temperature was raised to 110 °C. Next, 5.68 g (44 mmol) of 2-chlorophenol was added to the reaction system, and the mixture was stirred thoroughly. The reaction was continued at 110 °C for 3.5 h. After the reaction was complete, the reaction was quenched with water, and the pH of the system was adjusted to a weakly acidic level (pH 6) using a 10% (w / w) NaOH aqueous solution. Extraction with dichloromethane and separation were performed. The organic phase was then rotary evaporated to obtain the crude product, intermediate M3 (4.26 g). Intermediate M3 (4.26 g, 27 mmol) and sodium methoxide (1.75 g, 32 mmol) were dissolved in 20 mL of ACN (acetonitrile) under ice-water bath conditions. The mixture was then reacted in an oil bath at 100 °C for 9 h. After the reaction was completed, the organic phase and aqueous phase were separated by extraction with ethyl acetate. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (2.34 g, yield 56.87%).

[0052] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 4The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 4 show that the peak position of o-vanillin is at 4.539 min, and its peak area percentage is 56.87%, that is, the yield is 56.87%.

[0053] Table 4. Liquid chromatography detection results of Example 4: .

[0054] Example 5: The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (hexamethylenetetramine), 4.49 g, 32 mmol; Compound M2 (glacial acetic acid), 4.58 mL, 80 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:2.5; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (DMF): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, glacial acetic acid (4.58 mL, 80 mmol) was added. Hexamethylenetetramine (4.49 g, 32 mmol) was then added under ice-water bath conditions, allowing it to dissolve completely. The temperature was raised to 110 °C, and then 2-chlorophenol (3.48 g, 27 mmol) was added to the reaction system. The mixture was stirred thoroughly and the reaction was continued at 110 °C for 3.5 h. After the reaction was complete, the reaction was quenched with water, and the pH of the system was adjusted to a weakly acidic level (pH 5) using a 10% NaOH aqueous solution. Extraction with dichloromethane and separation were performed. The organic phase was then rotary evaporated to obtain the crude product, intermediate M3 (2.62 g). Intermediate M3 (2.62 g, 16.7 mmol) and sodium methoxide (1.07 g, 20 mmol) were dissolved in 20 mL of DMF (N,N-dimethylformamide) under ice-water bath conditions. The mixture was then reacted in an oil bath at 120 °C for 6 h. After the reaction was completed, the organic phase and aqueous phase were separated by extraction with ethyl acetate. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (2.0 g, yield 79.39%).

[0055] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 5The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 5 show that the peak position of o-vanillin is at 4.770 min, and its peak area percentage is 79.39%, that is, the yield is 79.39%.

[0056] Table 5. Liquid chromatography detection results of Example 5: .

[0057] Example 5 is the preferred embodiment of the present invention.

[0058] Example 6:

[0059] The difference from the preferred embodiment 5 is that the compound M1 providing the CH2 source is specifically trioxymethylene.

[0060] The amounts and equivalent ratios of each substance in this embodiment are as follows: Compound M1 (trioxymethylene), 2.88 g, 32 mmol; Compound M2 (glacial acetic acid), 4.58 mL, 80 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:2.5; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (DMF): 20 mL; This embodiment provides a low-cost, highly selective synthesis process for o-vanillin. The specific preparation process is as follows: In a single-necked round-bottom flask, glacial acetic acid (4.58 mL, 80 mmol) was added, followed by paraformaldehyde (2.88 g, 32 mmol) under ice-water bath conditions. The mixture was allowed to dissolve completely, and the temperature was raised to 110 °C. Then, 2-chlorophenol (3.48 g, 27 mmol) was added to the reaction system, stirred thoroughly, and the reaction was continued at 110 °C for 3.5 h. After the reaction was complete, the reaction was quenched with ice water, and the pH of the system was adjusted to weakly acidic (pH 5) using a 10% NaOH aqueous solution. The mixture was then extracted with dichloromethane and the organic phase was rotary evaporated to obtain the crude product, intermediate M3 (1.91 g). Under ice-water bath conditions, intermediate M3 (1.91 g, 12.2 mmol) and sodium methoxide (1.01 g, 14.6 mmol) were dissolved in 20 mL of DMF (N,N-dimethylformamide), and then reacted in an oil bath at 120 °C for 6 h. After the reaction was completed, the organic phase and the aqueous phase were separated by extraction with ethyl acetate. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (1.555 g, yield 60.57%).

[0061] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 6 The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 6 show that the peak position of o-vanillin is at 4.515 min, and its peak area percentage is 60.57%, that is, the yield is 60.57%.

[0062] Table 6. Liquid chromatography detection results of Example 6: .

[0063] Comparative Example 1: In Comparative Example 1, compound M2 was a weak Lewis acid (boron trifluoride diethyl ether).

[0064] The amounts and equivalent ratios of each substance in this comparative example are as follows: Compound M1 (hexamethylenetetramine), 4.49 g, 32 mmol; Compound M2 (boron trifluoride diethyl ether), 10 mL, 80 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:2.5; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (DMF): 20 mL; This comparative example provides a preparation process for o-vanillin, the specific preparation process is as follows: In a single-necked round-bottom flask, 10 mL of boron trifluoride diethyl ether (80 mmol) was added, followed by 4.49 g of hexamethylenetetramine (32 mmol) under ice-water bath conditions. The mixture was allowed to dissolve completely, and the temperature was raised to 110 °C. Then, 3.48 g of 27 mmol of 2-chlorophenol was added to the reaction system, and the mixture was stirred thoroughly. The reaction was continued at 110 °C for 3.5 h. After the reaction was complete, the reaction was quenched with ice water, and the pH of the system was adjusted to a weakly acidic state (pH 5) using a 10% NaOH aqueous solution. The mixture was then extracted with dichloromethane and the organic phase was rotary evaporated to obtain the crude product, intermediate M3 (0.76 g). Intermediate M3 (0.76 g, 4.85 mmol) and sodium methoxide (0.354 g, 5.82 mmol) were dissolved in 20 mL of DMF (N,N-dimethylformamide) under ice-water bath conditions, and then reacted in an oil bath at 120 °C for 6 h. After the reaction was completed, the organic phase and the aqueous phase were separated by extraction with ethyl acetate. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (0.67 g, yield 28.76%).

[0065] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 7 The liquid chromatogram of Comparative Example 2 and the liquid chromatographic detection results shown in Table 7 show that the peak position of o-vanillin is at 4.530 min, and its peak area percentage is 28.76%, that is, the yield is 28.76%.

[0066] Table 7. Liquid chromatography detection results of Comparative Example 1: .

[0067] The experimental results of Comparative Example 1 show that when Lewis acid (boron trifluoride diethyl ether) is used as a catalyst, the yield of o-vanillin is significantly reduced to only 28.76%, which is much lower than the yield of protic acid catalysts used in Examples 1-6.

[0068] As shown in Comparative Example 1, the protonic acid catalyst used in this invention exhibits higher catalytic efficiency and selectivity compared to Lewis acid catalysts. This is mainly because protonic acids can more effectively activate the reaction substrate, promote the formation of intermediates, and reduce the occurrence of side reactions.

[0069] Comparative Example 2: In Comparative Example 2, the nucleophilic substitution step uses the weak base sodium bicarbonate to react with intermediate M3.

[0070] The amounts and equivalent ratios of each substance in this comparative example are as follows: Compound M1 (hexamethylenetetramine), 4.49 g, 32 mmol; Compound M2 (glacial acetic acid), 4.58 mL, 80 mmol; 2-Chlorophenol, 3.48 g, 27 mmol; The equivalence ratio of compound M1 to compound M2 is 1:2.5; The equivalent ratio of 2-chlorophenol to M1 is 1:1.2; The equivalent ratio of intermediate M3 to sodium methoxide is 1:1.2; Solvent (DMF): 20 mL; This comparative example provides a preparation process for o-vanillin, the specific preparation process is as follows: In a single-necked round-bottom flask, glacial acetic acid (4.58 mL, 80 mmol) was added. Hexamethylenetetramine (4.49 g, 32 mmol) was then added under ice-water bath conditions, allowing it to dissolve completely. The temperature was raised to 110 °C, and then 2-chlorophenol (3.48 g, 27 mmol) was added to the reaction system. The mixture was stirred thoroughly and the reaction was continued at 110 °C for 3.5 h. After the reaction was complete, the reaction was quenched with water, and the pH of the system was adjusted to a weakly acidic level (pH 5) using a 10% NaOH aqueous solution. Extraction with dichloromethane and separation were performed. The organic phase was then rotary evaporated to obtain the crude product, intermediate M3 (2.62 g). Intermediate M3 (2.62 g, 16.7 mmol) and sodium bicarbonate (1.68 g, 20 mmol) were dissolved in 20 mL of DMF (N,N-dimethylformamide) under ice-water bath conditions. The mixture was then reacted in an oil bath at 120 °C for 6 h. After the reaction was completed, the organic and aqueous phases were separated by extraction with ethyl acetate. The organic phase was then purified by silica gel chromatography (eluent as in Example 1) to obtain o-vanillin (0.89 g, yield 35.46%).

[0071] The yield of the obtained o-vanillin was determined by an Agilent high-performance liquid chromatograph (LC1260-DAD). Figure 8 The liquid chromatogram shown and the liquid chromatographic detection results shown in Table 8 show that the peak position of o-vanillin is at 4.530 min, and its peak area percentage is 35.46%, that is, the yield is 35.46%.

[0072] Table 8. Liquid chromatography detection results of Comparative Example 2: .

[0073] Comparative Example 2 shows that, in the nucleophilic substitution reaction of intermediate M3 with sodium methoxide and solvent, the use of the strong base sodium methoxide, compared to the weak base sodium bicarbonate, can improve the yield of o-vanillin. This result indicates that the strong base has stronger nucleophilicity in the reaction and can more effectively promote the conversion of intermediate M3, thereby improving the formation efficiency of the o-vanillin product. The experimental data from Comparative Example 2 show that when sodium bicarbonate is used as the base source, the yield of o-vanillin is only 35.46%, far lower than the yield using sodium methoxide in Examples 1-6.

[0074] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A low-cost, highly selective synthesis process for o-vanillin, characterized in that, Specifically, the following steps are included: Step S1: Dissolve compound M1 completely in compound M2, and gradually heat the reaction system to 30℃-110℃; The compound M1 is formyl chloride, trichloromethyl formate, paraformaldehyde, formic acid, formic anhydride, hexamethylenetetramine, methylene glycol, or an N-hydroxymethyl compound; The compound M2 is a protic acid catalyst; The equivalence ratio of compound M1 to compound M2 is 1:1.1 to 1:2.5; Step S2: Add 2-chlorophenol to the reaction system of step S1, wherein the equivalent ratio of 2-chlorophenol to compound M1 is 1:1.2-1:1.5, stir evenly, raise the temperature to 50℃-110℃, and continue the reaction for 1h-10h; after the reaction is completed, quench the reaction with ice water and adjust the pH value of the system to weakly acidic. Step S3: Extract and separate the liquid with dichloromethane, and then rotary evaporate the organic phase to obtain intermediate M3; Step S4: Under ice-water bath conditions, intermediate M3 and sodium methoxide are dissolved together in a solvent, and then reacted in an oil bath for 5-12 hours to carry out nucleophilic substitution. In step S5, after the reaction is complete, the organic phase and the aqueous phase are separated by extraction with ethyl acetate. Then, the organic phase is purified by vacuum distillation or column chromatography to obtain the target product, o-vanillin.

2. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S1, the compound M1 is hexamethylenetetramine, formic anhydride, trioxymethylene, or formyl chloride.

3. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S1, the protic acid catalyst is 10% dilute sulfuric acid, 2 mol / L hydrochloric acid, polyphosphoric acid, glacial acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid.

4. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S2, adjusting the pH of the system to a weakly acidic state specifically involves: The pH of the system was adjusted to a slightly acidic state, with a pH value of 3-7, using a 10% NaOH aqueous solution.

5. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S3, the structural formula of the intermediate M3 is: .

6. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S4, the equivalent ratio of intermediate M3 to sodium methoxide is 1:1 to 1:1.

2.

7. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S4, the solvent is DMF, DMSO, THF, ACN, methanol, or ethanol.

8. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S4, the amount of solvent added is 20 mL.

9. The preparation process for the low-cost, highly selective synthesis of o-vanillin as described in claim 1, characterized in that, In step S4, the temperature of the oil bath is 50℃-140℃.

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