Isovanillin and a highly selective method for its synthesis
By employing benzylation, Vilsmeier-Haack formylation, and acid-debenzylation reactions under alkaline catalyst and organic solvent conditions, the problems of low yield and Lewis acid pollution of isovandrin have been solved, achieving highly selective synthesis and environmentally friendly production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHONGQING FEIHUA ENVIRONMENTAL SCI & TECH CO LTD
- Filing Date
- 2026-04-21
- Publication Date
- 2026-07-10
AI Technical Summary
Existing technologies suffer from low yields of isovandin and severe Lewis acid pollution, resulting in high production costs and significant environmental pressure.
Guaiacin was reacted with a benzylating agent under alkaline catalyst and organic solvent conditions to generate o-benzyloxyanisole, which was then reacted with Vilsmeier-Haack reagent for formylation. Finally, the benzyl group was de-de-benzylated with sulfuric acid aqueous solution, and the product was obtained by recrystallization.
It significantly increased the yield of isovandin to over 70%, reduced production costs, decreased the use of organic solvents and the discharge of metal-containing wastewater, and met the requirements of green chemistry and clean production.
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Figure CN122355802A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of fine chemicals, specifically to an isovandin and its highly selective synthesis method. Background Technology
[0002] Isovanthanin (3-hydroxy-4-methoxybenzaldehyde) is an important fragrance and pharmaceutical intermediate, and its synthesis process has always been a research focus in the field of fine chemicals.
[0003] CN102617313A discloses a method for the concurrent synthesis of vanillin and isovanil. The method uses guaiacol as a starting material, first alkylating it with a haloalkanes (such as bromoisopropane or bromobutane) to obtain 1-methoxy-2-alkoxybenzene, then performing a Vilsmeier-Haack reaction with N,N-methylformylaniline / phosphorus oxychloride to generate a mixture of 3-methoxy-4-alkoxybenzaldehyde and 3-alkoxy-4-methoxybenzaldehyde, and finally selectively removing the alkyl group with a Lewis acid (aluminum trichloride) to obtain a mixture of vanillin and isovanil, which are then separated by column chromatography to obtain the two products.
[0004] Although this method has achieved the synthesis of isovanthanin from the inexpensive raw material guaiacol, it still has the following shortcomings:
[0005] The main product is vanillin, but the yield of isovandrin is relatively low.
[0006] The use of Lewis acids (such as AlCl3) presents problems such as the generation of aluminum-containing wastewater during post-treatment, equipment corrosion, and significant environmental pressure. Summary of the Invention
[0007] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing isovlandrin and its high selectivity, so as to overcome the problems of low yield of isovlandrin and serious Lewis acid pollution in the prior art.
[0008] To achieve the above objectives, the first aspect of the present invention adopts the following technical solution:
[0009] A highly selective method for synthesizing isovanthanin includes the following steps:
[0010] Step S1: In the presence of an alkaline catalyst and an organic solvent, guaiacol is reacted with a benzylating agent to generate o-benzyloxyanisole.
[0011] Step S2: The o-benzyloxyanisole is reacted with Vilsmeier-Haack reagent to formylate, yielding 3-benzyloxy-4-methoxybenzaldehyde;
[0012] Step S3: Mix 3-benzyloxy-4-methoxybenzaldehyde with a 65wt%-70wt% aqueous sulfuric acid solution to carry out an acid debenzylation reaction to obtain crude isovanthanin.
[0013] Furthermore, it also includes:
[0014] Step S4: Dissolve crude isovanillin in hot water, cool and crystallize, and then recrystallize to obtain pure isovanillin.
[0015] Furthermore, in step S1, the benzylating agent is benzyl chloride, the alkaline catalyst is potassium bicarbonate, sodium hydroxide or potassium hydroxide, and the organic solvent is acetone, anhydrous ethanol, 1,2-dichloroethane or N,N-dimethylformamide.
[0016] Furthermore, the molar ratio of the benzylating agent to guaiacol is 1-1.2:1, and the molar ratio of the alkaline catalyst to guaiacol is 1-1.5:1.
[0017] Furthermore, in step S2, the Vilsmeier-Haack reagent is prepared by reacting a formylated reagent with phosphorus oxychloride.
[0018] Furthermore, the molar ratio of phosphorus oxychloride to the formylation reagent is 1-1.3:1, and the reaction is carried out at 0-5°C for 0.5-1h;
[0019] The molar ratio of the formylation reagent to o-benzyloxyanisole is 1-1.3:1, and the reaction is carried out at 25-70℃ for 4-24 hours.
[0020] Furthermore, the formylation agent is N-methylformaniline or N,N-dimethylformamide.
[0021] Furthermore, in step S3, the molar ratio of sulfuric acid to 3-benzyloxy-4-methoxybenzaldehyde in the sulfuric acid aqueous solution is 1-2:0.5-1, and the reaction is carried out at a temperature of 70-90°C for 0.5-2 hours.
[0022] Furthermore, in step S4, the solvent used for recrystallization is a mixture of ethanol and water with a volume ratio of 1:1-3.
[0023] The second aspect of the present invention adopts the following technical solution: an isovanillin, which is prepared by the highly selective synthesis method of an isovanillin described in the first aspect of the present invention.
[0024] Technical principle:
[0025] This invention uses guaiacol, a widely available and inexpensive raw material, as the starting material, fundamentally solving the problem of high production costs caused by the reliance on expensive intermediates in traditional routes. The designed three-step reaction route of "phenolic hydroxyl benzyl protection → Vilsmeier formylation → acidic debenzylation" is logically clear and the steps are greatly simplified, significantly improving synthesis efficiency and reducing process complexity. The key is that the oxygen atom of the methoxy group is directly bonded to the electron-donating methyl group, and the conjugation electron-donating effect (+C) is not dispersed, while the electron-donating ability of the oxygen atom of the benzyl group is weakened due to the electron dispersion of the benzyl group and steric effects. Therefore, the electron-donating ability of the methoxy group is stronger than that of the benzyl group. Formylation is an electrophilic substitution reaction, and electrophilic reagents (such as formyl cations) tend to attack sites with higher electron cloud density on the benzene ring. The electron-donating group activates the benzene ring through conjugation effect (+C) and inductive effect (+I), and the stronger the electron-donating ability, the more significant the increase in electron cloud density at the ortho and para positions. According to the directing rules, strong electron-donating groups (such as methoxy groups) are ortho- and para-directing groups. The para position, due to its highest electron cloud density and less steric hindrance, becomes the preferred attack site for electrophilic reagents. Therefore, in the formylation reaction, the amount of isovandrin intermediate is greater than that of vanillin intermediate.
[0026] Compared with the prior art, the present invention has the following beneficial effects:
[0027] 1. The yield of isovanthanin prepared by this invention can reach more than 70%, and the selectivity is greatly improved.
[0028] 2. This invention uses a 65wt%~70wt% sulfuric acid aqueous solution for acid debenzylation. The reagents are inexpensive and readily available, the reaction conditions are mild, and there are few side reactions. After the reaction is complete, simply pour the solution into boiling water to cool and crystallize to obtain high-purity crude isovandrin. Column chromatography separation is not required, significantly reducing the use of organic solvents and the discharge of metal-containing wastewater, which meets the requirements of green chemistry and clean production.
[0029] 3. This invention employs a three-step reaction process: benzylation, Vilsmeier-Haack formylation, and acid-debenzylation. All reagents used are bulk chemicals, and the equipment requirements are low. Attached Figure Description
[0030] Figure 1 The HPLC chromatogram of isovandrin prepared in Example 1;
[0031] Figure 2 The isovandin prepared in Example 1 1 H-NMR spectrum. Detailed Implementation
[0032] The present invention will be further described in detail below through specific embodiments:
[0033] To address the shortcomings of existing technologies, such as low yield and severe Lewis acid contamination of isovandin, this invention proposes a highly selective synthesis method for isovandin, comprising the following steps:
[0034] Step S1: In the presence of an alkaline catalyst and an organic solvent, guaiacol is reacted with a benzylating agent to generate o-benzyloxyanisole; wherein the benzylating agent is benzyl chloride, the alkaline catalyst is potassium carbonate, sodium hydroxide or potassium hydroxide, and the organic solvent is acetone, anhydrous ethanol, 1,2-dichloroethane or N,N-dimethylformamide.
[0035] Step S2: The o-benzyloxyanisole is reacted with Vilsmeier-Haack reagent to formylate, yielding 3-benzyloxy-4-methoxybenzaldehyde; wherein the molar ratio of the formylating reagent to o-benzyloxyanisole is 1-1.3:1, and the reaction is carried out at 25-70°C for 4-24 hours; the formylating reagent is N-methylformaniline or N,N-dimethylformamide; the Vilsmeier-Haack reagent is prepared by reacting the formylating reagent with phosphorus oxychloride; the molar ratio of phosphorus oxychloride to the formylating reagent is 1-1.3:1, and the reaction is carried out at 0-5°C for 0.5-1 hours.
[0036] Step S3: Mix 3-benzyloxy-4-methoxybenzaldehyde with a 65wt%-70wt% aqueous sulfuric acid solution to carry out an acid-de-benzyl reaction to obtain crude isovanillin; the molar ratio of sulfuric acid to 3-benzyloxy-4-methoxybenzaldehyde in the aqueous sulfuric acid solution is 1-2:0.5-1, and the reaction is carried out at a temperature of 70-90℃ for 0.5-2h.
[0037] Step S4: Dissolve crude isovanillin in hot water, cool and crystallize, and recrystallize to obtain pure isovanillin; wherein the solvent used for recrystallization is a mixed solvent of ethanol and water with a volume ratio of 1:1-3.
[0038] The specific implementation examples are as follows: Example 1
[0039] Step S1: Take 62g of guaiacol, 70g of benzyl chloride, and 93g of anhydrous ethanol into a flask. Dissolve 30g of sodium hydroxide in 30g of water and slowly add it dropwise to the flask. Reflux at 50℃ for 1h. Thin-layer chromatography (TLC) detects no raw material. After removing the ethanol by heating, add water to dissolve the sodium chloride. o-Benzyloxyanisole crystallizes out with a yield of 98.0% and a purity of 99.8%.
[0040] Step S2: 13.5 g of N-methylformaniline was placed in a flask, and 15.3 g of phosphorus oxychloride was added dropwise to the flask under ice bath conditions. The mixture was stirred for 1 h to form Vilsmeier's reagent. Then, 21.4 g of o-benzyloxyanisole was added, and the mixture was heated to 50 °C and reacted for 8 h. TLC showed that two products were formed (a large amount of 3-benzyloxy-4-methoxybenzaldehyde and a small amount of 3-methoxy-4-benzyloxybenzaldehyde). After the reaction was completed, the reaction solution was slowly poured into an ice-water mixture (0 °C) and rapidly stirred to quench and hydrolyze the solution. After hydrolysis, the solution was extracted with ethyl acetate, and the ethyl acetate was removed by rotary evaporation to obtain the product.
[0041] Step S3: Add 15.1 g of 65 wt% sulfuric acid solution to the product obtained above and react at 70 °C for 1 h. TLC showed no raw material and a large amount of isovanthanin and a small amount of vanillin were produced.
[0042] Step S4: Slowly pour the reaction solution prepared in step S3 into boiling water and stir rapidly to dissolve. Separate the organic layer, and allow the aqueous solution to stand and cool to obtain crude isovanillin. Recrystallize the crude isovanillin using an ethanol-water mixture with a volume ratio of 1:3 as a solvent to obtain pure isovanillin. Analyze the purified isovanillin using HPLC. 1 H-NMR analysis determined the structure and purity of the obtained product, such as Figure 1 , Figure 2 As shown.
[0043] According to the test and calculation, the overall yield of the isovandin was 63.3%, and the HPLC purity was 99.54%.
[0044] Example 2
[0045] Step S1: Take 62g of guaiacol, 69.5g of benzyl chloride, and 150g of acetone in a flask. Add 55.1g of potassium bicarbonate and heat under reflux for 2 hours. TLC detection showed no starting material. After the reaction was complete, filter to remove inorganic salts, distill the filtrate under reduced pressure to recover acetone, wash the residue with water, and dry to obtain o-benzyloxyanisole with a yield of 92.5% and a purity of 99.1%.
[0046] Step S2: 36.5 g of N,N-dimethylformamide was placed in a flask and cooled to 0-5°C in an ice bath. 76.5 g of phosphorus oxychloride was slowly added dropwise, and the mixture was stirred for 0.5 h to form Vilsmeier's reagent. 107 g of o-benzyloxyanisole was added, and the mixture was heated to 60°C and reacted for 6 h. TLC showed that the main product was 3-benzyloxy-4-methoxybenzaldehyde, with a small amount of isomers. The reaction mixture was quenched in ice water, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain the crude product.
[0047] Step S3: Add the crude product to a 70wt% sulfuric acid aqueous solution and react at 80℃ for 0.5h. TLC detection shows that the raw material disappears, and isovanthanin (main) and a small amount of vanillin are generated.
[0048] Step S4: The reaction solution was slowly poured into boiling water and stirred to dissolve. After cooling, it crystallized to obtain crude isovanillin. Recrystallization was performed using a 1:1 volume ratio of ethanol and water to obtain pure isovanillin. The overall yield of isovanillin was 61.2%, and the HPLC purity was 99.12%.
[0049] Example 3
[0050] Step S1: Take 62g of guaiacol, 63.3g of benzyl chloride, and 100g of 1,2-dichloroethane in a flask. Add a solution of 33.6g of potassium hydroxide dissolved in 30g of water, and react at 40℃ for 2h. TLC detection showed no starting material. Separate the reaction solution, wash the organic phase with water, dry it, and evaporate the solvent to obtain o-benzyloxyanisole, with a yield of 96.8% and a purity of 98.2%.
[0051] Step S2: Take 81g of N-methylformaniline in a flask, add 107g of phosphorus oxychloride dropwise under ice bath, and react at 0℃ for 1h. Add 107g of o-benzyloxyanisole, and react at 25℃ for 24h. Monitor the reaction completion by TLC. Post-treatment is the same as in Example 1 to obtain crude 3-benzyloxy-4-methoxybenzaldehyde.
[0052] Step S3: Add the above crude product to a 68wt% sulfuric acid aqueous solution and react at 70°C for 2 hours. TLC showed that the reaction was complete.
[0053] Step S4: Cool and crystallize according to the method in Example 1, and recrystallize using an ethanol-water mixed solvent with a volume ratio of 1:2. The overall yield of isovandrin was 60.8%, and the HPLC purity was 99.08%.
[0054] Example 4
[0055] Step S1: Take 62g of guaiacol, 76g of benzyl chloride, and 93g of anhydrous ethanol into a flask. Dissolve 24g of sodium hydroxide in 24g of water, add dropwise, and reflux at 60°C for 1 hour. TLC detection showed no raw material. Post-processing was the same as in Example 1, yielding o-benzyloxyanisole with a yield of 92.8% and a purity of 99.2%.
[0056] Step S2: 47.5 g of N,N-dimethylformamide was placed in a flask, and 99.5 g of phosphorus oxychloride was added dropwise under ice bath conditions. The reaction was carried out at 5°C for 0.8 h. Then, 107 g of o-benzyloxyanisole was added, and the reaction was carried out at 70°C for 4 h. The reaction was monitored by TLC until completion. Post-treatment yielded crude 3-benzyloxy-4-methoxybenzaldehyde.
[0057] Step S3: Add the above crude product to a 65wt% sulfuric acid aqueous solution and react at 90℃ for 0.5h. TLC detection shows the raw material has disappeared.
[0058] Step S4: After cooling and crystallization, recrystallize using a 1:3 volume ratio ethanol-water mixed solvent (same as in Example 1). The overall yield of isovandrin was 60.3%, and the HPLC purity was 99.1%.
[0059] Example 5
[0060] Step S1: Take 62g of guaiacol, 69.5g of benzyl chloride, and 120g of DMF into a flask. Add 75.1g of potassium bicarbonate and react at 80℃ for 1.5h. TLC detection showed no starting material. Filter the reaction solution, add water to the filtrate to precipitate a solid, filter and dry to obtain o-benzyloxyanisole, yield 96.2%, purity 99.1%.
[0061] Step S2: 81 g of N-methylformaniline was placed in a flask, and 99.5 g of phosphorus oxychloride was added dropwise under ice bath conditions. The reaction was carried out at 2°C for 0.7 h. Then, 107 g of o-benzyloxyanisole was added, and the reaction was carried out at 50°C for 12 h. The reaction was monitored by TLC until completion. Post-treatment yielded crude 3-benzyloxy-4-methoxybenzaldehyde.
[0062] Step S3: Add the above crude product to a 70wt% sulfuric acid aqueous solution and react at 85°C for 1 hour. TLC showed that the reaction was complete.
[0063] Step S4: After cooling and crystallization, recrystallize using a 1:1.5 volume ratio ethanol-water mixed solvent. The overall yield of isovandrin was 59.3%, and the HPLC purity was 98.9%.
[0064] Example 6:
[0065] The only difference from Example 1 is that the anhydrous ethanol in step S1 is replaced with 1,2-dichloroethane.
[0066] The reaction results are as follows: the yield of o-benzyloxyanisole was 88.7%, and the overall yield of isovandrin was 57.3%.
[0067] Example 7:
[0068] The only difference from Example 1 is that in step S2, after adding 21.4 g of o-benzyloxyanisole, the reaction was carried out at 40°C for 12 h.
[0069] The reaction results are as follows: the overall yield of isovandrin was 75.2%.
[0070] Example 8:
[0071] The only difference from Example 1 is that in step S2, after adding 21.4 g of o-benzyloxyanisole, the reaction was carried out at 45°C for 10 h.
[0072] The reaction results are as follows: the overall yield of isovandrin was 77.8%.
[0073] Comparative Example 1
[0074] According to the method of Example 1 in CN102617313A: using guaiacol as raw material, it was first alkylated with bromoisopropane to obtain 1-methoxy-2-isopropoxybenzene, and then subjected to a Vilsmeier reaction with N,N-methylformylaniline / phosphorus oxychloride to obtain a mixture of 3-methoxy-4-isopropoxybenzaldehyde and 3-isopropoxy-4-methoxybenzaldehyde (yield 86.9%). Then, it was deisopropylated with aluminum trichloride and separated by silica gel column chromatography to obtain vanillin (yield 68.1%) and isovanil (yield 28.3%).
[0075] As can be seen from the above examples and comparative examples, the present invention employs a three-step reaction of benzylation, Vilsmeier-Haack formylation, and acid-de-benzylation, which significantly improves the yield of the isovandin precursor. Simultaneously, the use of acid hydrolysis to de-benzylation avoids the use of Lewis acids and column chromatography purification, making the entire process simpler, more efficient, and more environmentally friendly. Example 8 represents the optimal implementation scheme, achieving a total yield of 77.8% and a product purity ≥99.5%.
[0076] 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 highly selective method for synthesizing isovandin, characterized in that, Includes the following steps: Step S1: In the presence of an alkaline catalyst and an organic solvent, guaiacol is reacted with a benzylating agent to generate o-benzyloxyanisole. Step S2: The o-benzyloxyanisole is reacted with Vilsmeier-Haack reagent to formylate, yielding 3-benzyloxy-4-methoxybenzaldehyde; Step S3: Mix 3-benzyloxy-4-methoxybenzaldehyde with a 65wt%-70wt% aqueous sulfuric acid solution to carry out an acid-de-benzyl reaction, followed by hot dissolution and cooling crystallization to obtain crude isovanillin.
2. The highly selective synthesis method of isovandrin according to claim 1, characterized in that, Also includes: Step S4: The crude isovanillin is recrystallized to obtain pure isovanillin.
3. The highly selective synthesis method of isovandrin according to claim 1, characterized in that, In step S1, the benzylating agent is benzyl chloride, the alkaline catalyst is potassium bicarbonate, sodium hydroxide or potassium hydroxide, and the organic solvent is acetone, anhydrous ethanol, 1,2-dichloroethane or N,N-dimethylformamide.
4. A highly selective synthesis method for isovandrin according to claim 1 or 3, characterized in that, The molar ratio of the benzylating agent to guaiacol is 1-1.2:1, and the molar ratio of the alkaline catalyst to guaiacol is 1-1.5:
1.
5. The highly selective synthesis method of isovandrin according to claim 1, characterized in that, In step S2, the Vilsmeier-Haack reagent is prepared by reacting a formylated reagent with phosphorus oxychloride.
6. The highly selective synthesis method of isovandrin according to claim 5, characterized in that, The molar ratio of phosphorus oxychloride to the formylation reagent is 1-1.3:1, and the reaction is carried out at 0-5℃ for 0.5-1h. The molar ratio of the formylation reagent to o-benzyloxyanisole is 1-1.3:1, and the reaction is carried out at 25-70℃ for 4-24 hours.
7. The highly selective synthesis method of isovandrin according to claim 6, characterized in that, The formylation agent is N-methylformaniline or N,N-dimethylformamide.
8. The highly selective synthesis method of isovandrin according to claim 1, characterized in that, In step S3, the molar ratio of sulfuric acid to 3-benzyloxy-4-methoxybenzaldehyde in the sulfuric acid aqueous solution is 1-2:0.5-1, and the reaction is carried out at a temperature of 70-90°C for 0.5-2 hours.
9. The highly selective synthesis method of isovandrin according to claim 2, characterized in that, In step S4, the solvent used for recrystallization is a mixture of ethanol and water with a volume ratio of 1:1-3.
10. A vanillin, characterized in that, It is prepared by a highly selective synthesis method of isovandrin according to any one of claims 1-9.