Synthesis of vanillin

Abstract

The application belongs to the technical field of synthetic technology of perfume chemicals, and particularly relates to a synthesis method of vanillin. The synthesis method is as follows: first, o-diphenol and dimethyl sulfate are subjected to a methylation reaction to obtain o-dimethyl ether, the o-dimethyl ether is subjected to an aldehyde group reaction to generate 3,4-dimethoxybenzaldehyde, and finally, the 3,4-dimethoxybenzaldehyde and triethylamine hydrochloride are subjected to a selective demethylation reaction to generate vanillin. The application uses inexpensive o-diphenol as raw material, has mild reaction conditions, does not require high equipment, and has low energy consumption, solves the problems of traditional vanillin synthesis methods, such as difficult acquisition of raw materials, high price, difficult separation and serious generation of three wastes, and provides a new method for synthesis of vanillin.

Description

Technical Field

[0001] This invention belongs to the field of fragrance chemical synthesis technology, specifically relating to a method for synthesizing vanillin. Background Technology

[0002] Vanillin is the most produced and widely used edible flavoring. It exists naturally in vanilla beans, but commercially available products are mainly produced through chemical synthesis or biotechnology, and possess a rich milky and vanilla aroma. This flavoring is widely used in food (such as chocolate, ice cream, and beverages), daily chemical products (such as perfumes and toothpaste), and pharmaceuticals, where, in addition to enhancing flavor, it also possesses natural antibacterial and antioxidant properties.

[0003] The chemical synthesis methods of vanillin include:

[0004] 1. Guaiacin route: Among them, the nitrosyl method is complex to separate and produces serious waste, with an overall yield of less than 60%. The chloroacetaldehyde method has complex waste treatment and an overall yield of about 70%. The glyoxylic acid method has mild process conditions and an overall yield of about 80%. However, copper oxide exists in colloidal form and is difficult to separate from the reaction solution.

[0005] 2. The lignin process has a wide range of raw material sources and low cost, but it requires a large amount of acid and alkali, has a lengthy process, and the yield is mostly below 30%.

[0006] While the one-pot process reported in patent CN115417756A increases vanillin yield to 80%, it still has several shortcomings: the natural eugenol raw material mainly relies on Southeast Asia for supply, which is limited and costly; the process requires strong alkaline, high-temperature, and pressurized oxygen conditions, which places stringent requirements on the corrosion resistance and safety of the equipment and poses a risk of oxidation and explosion; the one-pot process results in complex byproducts, affecting product purity, especially since the deprotection with dilute acid may be incomplete, introducing impurities; in addition, the use of strong alkali and dilute acid generates a large amount of high-salt wastewater, increasing the burden on environmental treatment, and it is still unclear whether the catalyst can be recycled. Overall, it is still far from green and economical industrial production.

[0007] In summary, existing technologies still have the following shortcomings: the glyoxylic acid method faces the challenge of catalyst recovery; the lignin method is inefficient and generates a large amount of waste; and the eugenol method suffers from limited raw materials and severe pollution in some routes. Therefore, developing a novel synthetic route that uses readily available raw materials, is highly efficient, and is environmentally friendly is of significant practical importance. Summary of the Invention

[0008] To overcome the shortcomings pointed out in the background art, the present invention provides a method for synthesizing vanillin: catechol (2) and dimethyl carbonate undergo a methylation reaction in the strongly polar aprotic solvent N,N-dimethylpropenylurea catalyzed by potassium iodide to obtain phthalic acid (3), phthalic acid (3) and 1,2-dichloromethyl methyl ether undergo an aldehyde reaction to generate 3,4-dimethoxybenzaldehyde (4), 3,4-dimethoxybenzaldehyde (4) and triethylamine hydrochloride undergo selective demethylation to generate vanillin (1).

[0009]

[0010] Synthetic route of vanillin (Formula 1)

[0011] The specific synthesis method is as follows:

[0012] (1) Synthesis of o-phenylenediamine compound 3

[0013] Under nitrogen protection, catechol was added to a three-necked round-bottom flask and dissolved in N,N-dimethylpropenyl urea (DMPU). Then, dimethyl carbonate and potassium iodide were added, and the temperature was raised to 180°C. TLC analysis showed that the reaction was complete. After the reaction flask was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a yellow oily compound, 3-phthalic acid dimethyl ether.

[0014] The molar ratio of catechol, dimethyl carbonate, and potassium iodide is 1:2-4:0.2.

[0015] (2) Synthesis of compound 4, 3,4-dimethoxybenzaldehyde

[0016] Compound 3 and zinc chloride were added to a round-bottom flask and dissolved in dichloromethane. 1,2-Dichloromethyl methyl ether was added dropwise under ice bath conditions. After the addition was complete, the mixture was moved to room temperature and stirred. TLC was used to detect the reaction. The reaction proceeded completely. The reaction was quenched with water and extracted three times with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate and sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a brown solid. Recrystallization gave a white powdery compound 4 (3,4-dimethoxybenzaldehyde).

[0017] The molar ratio of compound 3, zinc chloride and 1,2-dichloromethyl methyl ether is 1:1.2:1.2.

[0018] (3) Synthesis of Compound 1

[0019] Dichloromethane and aluminum chloride were added to a round-bottom flask, followed by the addition of triethylamine hydrochloride in batches. The mixture was kept warm for one hour, and then compound 4 dissolved in dichloromethane was added. The mixture was refluxed for one hour, and the reaction was monitored by TLC until it was complete. After the reaction flask was cooled, water was added to quench the reaction in an ice bath. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain vanillin powder, which was a light yellow color.

[0020] The molar ratio of compound 4, aluminum chloride and triethylamine hydrochloride is 1:1-5:1-3.

[0021] Beneficial effects:

[0022] (1) This invention uses inexpensive and readily available catechol as raw material, which is methylated, aldehyde-treated, and selectively demethylated to produce vanillin; the methylating agent is dimethyl carbonate, which is green and environmentally friendly. As a low-toxicity and biodegradable "green reagent", dimethyl carbonate is non-toxic, produces almost no salt-containing waste during the reaction, and the raw material is inexpensive.

[0023] (2) The reaction route of this invention is short, requiring fewer reaction steps, reactants, and energy consumption, directly reducing raw material, equipment investment, and labor costs. It can shorten the production cycle, increase equipment turnover, and reduce material loss caused by multi-step reactions, resulting in a higher overall yield. It reduces the separation, purification, and storage of intermediate products, and also reduces the amount of waste generated, which is in line with the atom economy concept of green chemistry. Attached Figure Description

[0024] Figure 1 o-phenylenediamine 1 H NMR (300 MHz, CDCl3) δ 6.99 – 6.62 (m, 4H), 3.81 (s, 6H).

[0025] Figure 2 It is 3,4-dimethoxybenzaldehyde 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.46 –7.27 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 3.89 (d, J = 10.1 Hz, 6H).;

[0026] Figure 3 Vanillin 1 H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.44 – 7.42 (m,2H), 7.00 – 6.95 (m, 1H), 3.99 (s, 3H) Detailed Implementation

[0027] The present invention will now be described in detail with reference to specific embodiments.

[0028] Example 1

[0029] (1) Take a 50 mL round-bottom flask, dissolve accurately weighed catechol (0.55 g, 5 mmol) in 5 mL DMPU, add dimethyl carbonate (1.35 g, 15 mmol) dropwise, then add potassium iodide (0.166 g, 1 mmol), purge with nitrogen, heat to 180 °C, monitor by TLC, and after half an hour, the reaction is complete according to TLC. Add 10 mL of water, and extract twice with 10 mL of ethyl acetate. No product is detected in the aqueous phase by TLC. Combine the organic phases, wash the organic phase three times with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure. 6.1357 g of colorless transparent liquid compound 3 is obtained, with a yield of 97.8%.

[0030] In addition, the reaction conditions were set as follows: molar ratio of catechol: dimethyl carbonate: potassium iodide was 1:4:0.2, and the mass-volume ratio of catechol to polar aprotic solvent was 1:5 (g / mL). The effects of different polar aprotic solvents, DMPU, N,N-dimethylformamide (DMF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), on the reaction under reflux were investigated.

[0031] Table 1. Effect of polar aprotic solvents on the reaction

[0032] DMPU 180 1 98.1 DMF 155 1.5 The reaction is complete, but purification is difficult. ACN 85 2 No response DMSO 180 1 The reaction is complete, but purification is difficult.

[0033] As shown in Table 1, the polar aprotic solvent ACN showed no reaction of the raw materials according to TLC, while the polar aprotic solvents DMF and DMSO showed complete reaction of the raw materials according to TLC. However, since the product and byproduct sites were very close, and the product o-phenylenediamine was a liquid, it could not be purified by recrystallization or pulping. If purification was required, column chromatography would be necessary. However, column chromatography has the characteristics of low throughput, high solvent consumption, intermittent operation, and high solid waste, which is not advantageous in terms of cost, efficiency, and environmental friendliness.

[0034] (2) Take a 100 mL round-bottom flask and dissolve the accurately weighed o-phenylenediamine (3) (2.79 g, 20.16 mmol) in 30 mL of dry dichloromethane. After dissolution, add zinc chloride (3.30 g, 24.20 mmol) and add 1,2-dichloromethyl ether (2.78 g, 24.20 mmol) dropwise under ice bath. After the addition is complete, transfer the flask to room temperature and monitor the reaction by TLC. The reaction was carried out for 4 hours and 30 minutes. TLC showed that the starting material had reacted completely. The reaction was quenched by slowly adding 30 mL of water dropwise under ice bath. Take a 100 mL separatory funnel and collect the lower organic phase. Extract the aqueous phase twice with 30 mL of dichloromethane. After confirming by TLC that there was no target product in the aqueous layer, combine the organic phases. Wash the organic phase once with 90 mL of saturated sodium bicarbonate solution and then twice with 90 mL of saturated saline solution. The combined organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then slurried with an ethanol-water system to obtain a white powdery pure product with a yield of 82.3%.

[0035] (3) Take a dry and clean 100 mL round-bottom flask, accurately weigh aluminum trichloride (20.06 g, 150 mmol) and add it, then add 25 mL of dichloromethane. Add triethylamine hydrochloride (12.42 g, 90 mmol) in four portions. This process is exothermic and accompanied by a temperature rise, so the internal temperature of the system needs to be controlled between 20°C and 30°C. After holding at this temperature for 1 hour, add 3,4-dimethoxybenzaldehyde (5 g, 30 mmol) pre-dissolved in dichloromethane. This step is also exothermic, so the internal temperature needs to be maintained between 20°C and 30°C. Then, heat the reaction system to 40°C and reflux the reaction. Monitor the reaction progress in real time by thin-layer chromatography (TLC). After the reaction continues for 1 hour, TLC shows that the starting material has been completely converted. Quench the reaction by adding 25 mL of water dropwise to the reaction system at a rate of one drop per second under ice bath conditions. The reaction mixture was transferred to a 250 mL separatory funnel, and 25 mL of dichloromethane was added for extraction. The upper organic phase was collected, and this extraction operation was repeated three times. The organic phases were combined. The organic phase was washed twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure and slurried with petroleum ether. The crude product was purified by rapid silica gel column chromatography to obtain vanillin as a white solid, with a yield of 83%.

[0036] Example 2

[0037] (1) Take a 50 mL round-bottom flask, dissolve accurately weighed catechol (0.55 g, 5 mmol) in 5 mL DMPU, add dimethyl carbonate (0.90 g, 10 mmol) dropwise, then add potassium iodide (0.166 g, 1 mmol), purge with nitrogen, heat to 180 °C, monitor by TLC, and react for 1 hour. The reaction is complete as detected by TLC. Add 10 mL of water, then extract twice with 10 mL of ethyl acetate. Combine the organic phases, wash three times with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure. Obtain colorless transparent liquid compound 3, with a yield of 78.2%.

[0038] (2) Take a 100 mL round-bottom flask, dissolve the accurately weighed compound 3 (20 g, 144.8 mmol) in 100 mL of dry dichloromethane, and after dissolution, add zinc chloride (23.68 g, 173.7 mmol). Add 1,2-dichloromethyl ether (19.96 g, 173.7 mmol) dropwise under ice bath. After the addition is complete, transfer the flask to room temperature and monitor the reaction by TLC. After 4 hours of reaction, the reaction of the starting material was confirmed by TLC to be complete. Quench the reaction by slowly adding 100 mL of water under ice bath. Collect the lower organic phase, extract the aqueous phase twice with 100 mL of dichloromethane, and combine the organic phases. Wash the organic phase once with 100 mL of saturated sodium bicarbonate solution, and then twice with 100 mL of saturated brine. Dry the mixture with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain a brown solid. Slurry the mixture in an ethanol-water system to obtain a white powdery pure product with a yield of 98.94%.

[0039] (3) Take a clean 100 mL round-bottom flask, accurately weigh aluminum trichloride (4.01 g, 30 mmol) and add it, then add 25 mL of dichloromethane. Add triethylamine hydrochloride (4.14 g, 30 mmol) in two portions, controlling the internal temperature at 20-30℃. After maintaining the temperature for 1 hour, add 3,4-dimethoxybenzaldehyde (5 g, 30 mmol) pre-dissolved in dichloromethane, again controlling the internal temperature. Refrigerate at 40℃, monitor by TLC, and react for 3 hours until the starting material is completely converted. Quench the reaction by adding 25 mL of water dropwise at a rate of one drop per second under ice bath. Extract three times with dichloromethane (25 mL each time), combine the organic phases, wash twice with 50 mL of saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, and obtain a pale yellow solid. Purify by rapid silica gel column chromatography to obtain white solid vanillin, with a yield of 57.2%.

[0040] Example 3

[0041] (1) Take a 50 mL round-bottom flask, dissolve accurately weighed catechol (0.55 g, 5 mmol) in 5 mL DMPU, add dimethyl carbonate (1.80 g, 20 mmol) dropwise, then add potassium iodide (0.166 g, 1 mmol), purge with nitrogen, heat to 180 °C, monitor by TLC, and react for 40 minutes until the reaction is complete. Post-treatment is the same as in Example 1, yielding a colorless, transparent liquid compound 3 with a yield of 98.1%.

[0042] (2) Take a 100 mL round-bottom flask and dissolve accurately weighed o-phthalic acid ether (3) (2.79 g, 20.16 mmol) in 30 mL of dry dichloromethane. After dissolution, add zinc chloride (3.30 g, 24.20 mmol). Add 1,2-dichloromethyl ether (2.78 g, 24.20 mmol) dropwise under ice bath. After the addition is complete, transfer the flask to room temperature and monitor the reaction by TLC. The reaction proceeds for 4 hours until the starting material is completely reacted. The post-treatment is the same as in Example 1, yielding a white powdery pure product with a yield of 83.2%.

[0043] (3) Take a clean 100 mL round-bottom flask, accurately weigh aluminum trichloride (12.00 g, 90 mmol) and add it, then add 25 mL of dichloromethane. Add triethylamine hydrochloride (8.26 g, 60 mmol) in three portions, controlling the internal temperature at 20-30℃. After maintaining the temperature for 1 hour, add 3,4-dimethoxybenzaldehyde (5 g, 30 mmol) pre-dissolved in dichloromethane, again controlling the internal temperature. Refrigerate at 40℃, monitor by TLC, and react for 3 hours until the starting material is completely converted. Quench the reaction by adding 25 mL of water dropwise at a rate of one drop per second under ice bath. Extract three times with dichloromethane (25 mL each time), combine the organic phases, wash twice with 50 mL of saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness under reduced pressure, and obtain a pale yellow solid. Purify by rapid silica gel column chromatography to obtain white solid vanillin, with a yield of 91.2%.

[0044] Example 4

[0045] (1) Take a 50 mL round-bottom flask, dissolve accurately weighed catechol (5.50 g, 50 mmol) in 50 mL DMPU, add dimethyl carbonate (18.00 g, 200 mmol) dropwise, then add potassium iodide (1.66 g, 10 mmol), purge with nitrogen, heat to 180 °C, monitor by TLC, and react for 40 minutes until the reaction is complete. Post-treatment is the same as in Example 1, yielding a colorless, transparent liquid compound 3 with a yield of 98.36%.

[0046] (2) Take a 100 mL round-bottom flask, dissolve accurately weighed compound 3 (2.00 g, 14.48 mmol) in 10 mL of dry dichloromethane, and after dissolution, add zinc chloride (2.37 g, 17.37 mmol). Add 1,2-dichloromethyl ether (2.00 g, 17.37 mmol) dropwise under ice bath. After the addition is complete, transfer to room temperature and monitor the reaction by TLC. After 4 hours of reaction, the reaction of the starting material was confirmed by TLC to be complete. Quench the reaction by slowly adding 10 mL of water under ice bath. Collect the lower organic phase, extract the aqueous phase twice with 10 mL of dichloromethane, and combine the organic phases. Wash the organic phase once with 10 mL of saturated sodium bicarbonate solution, and then twice with 10 mL of saturated brine. Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain a brown solid. Slurry the solid in an ethanol-water system to obtain a white powdery pure product with a yield of 98.87%.

[0047] (3) Take a clean 100 mL round-bottom flask, accurately weigh aluminum trichloride (2.00 g, 15 mmol) and add it, then add 10 mL of dichloromethane. Add triethylamine hydrochloride (1.38 g, 10 mmol) in two portions, controlling the internal temperature at 20-30℃. After maintaining the temperature for 1 hour, add 3,4-dimethoxybenzaldehyde (0.83 g, 5 mmol) pre-dissolved in dichloromethane, again controlling the internal temperature. Refrigerate at 40℃, monitor by TLC, and react for 3 hours until the starting material is completely converted. Quench the reaction by adding 25 mL of water dropwise at a rate of one drop per second under ice bath conditions. Extract three times with dichloromethane (10 mL each time), combine the organic phases, wash twice with 40 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain a pale yellow solid. Purify by rapid silica gel column chromatography to obtain white solid vanillin, with a yield of 92.55%.

Claims

1. A method for synthesizing vanillin, characterized in that: The synthesis method is as follows: catechol and dimethyl carbonate are methylated to obtain phthalic ether, phthalic ether is aldehyde-modified to generate 3,4-dimethoxybenzaldehyde, and 3,4-dimethoxybenzaldehyde is selectively demethylated with triethylamine hydrochloride to generate vanillin.

2. The method for synthesizing vanillin as described in claim 1, characterized in that: The synthesis method steps are as follows: (1) Synthesis of o-phenylenediamine Under nitrogen protection, catechol was added to a three-necked round-bottom flask and dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). Dimethyl carbonate and potassium iodide were then added, and the temperature was raised to 180°C. TLC analysis showed that the reaction was complete. After the reaction flask was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain dimethyl phthalate. (2) Synthesis of 3,4-dimethoxybenzaldehyde Phthalic dimethyl ether and zinc chloride were added to a round-bottom flask, dissolved in dichloromethane, and 1,2-dichloromethyl methyl ether was added dropwise under ice bath. After the addition was complete, the mixture was moved to room temperature and stirred. TLC was used to detect that the reactants were completely reacted. The reaction was quenched with water, extracted three times with dichloromethane, and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate and sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a brown solid. Recrystallization gave 3,4-dimethoxybenzaldehyde. (3) Synthesis of vanillin Dichloromethane and aluminum chloride were added to a round-bottom flask, followed by the addition of triethylamine hydrochloride in batches. The mixture was kept warm for one hour, and then 3,4-dimethoxybenzaldehyde dissolved in dichloromethane was added. The mixture was refluxed for one hour, and the reaction was confirmed to be complete by TLC. After the reaction flask was cooled, water was added to quench the reaction in an ice bath. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain vanillin.

3. The method for synthesizing vanillin as described in claim 2, characterized in that: In step (1), the molar ratio of catechol, dimethyl carbonate and potassium iodide is 1:2-4:0.

2.

4. The method for synthesizing vanillin as described in claim 2, characterized in that: In step (2), the molar ratio of phthalic acid, zinc chloride and 1,2-dichloromethyl methyl ether is 1:1.2:1.

2.

5. The method for synthesizing vanillin as described in claim 2, characterized in that: In step (3), the molar ratio of 3,4-dimethoxybenzaldehyde, aluminum chloride and triethylamine hydrochloride is 1:1-5:1-3.

6. A vanillin synthesized by the method according to any one of claims 1-5.

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