Tandem synthesis method of 3, 4, 5-trimethoxybenzaldehyde
A tandem reaction method using dimethyl carbonate as a methylating agent to synthesize 3,4,5-trimethoxybenzaldehyde under normal pressure has solved the problems of high production cost, high toxicity, and long reaction time in the existing technology, and realized an efficient and safe synthesis method.
Patent Information
- Application Number
- CN202511051602.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-29
- Publication Date
- 2025-12-02
AI Technical Summary
The existing synthesis process of 3,4,5-trimethoxybenzaldehyde has problems such as high production cost, many by-products, complex operation, high reagent toxicity and long reaction time. In particular, the methylation reaction requires high pressure conditions and the separation of intermediate products increases costs.
Dimethyl carbonate was used as the methylating agent, and a tandem reaction was carried out under normal pressure. Cuprous chloride, cuprous bromide, and cuprous iodide were used as catalysts, and N,N-dimethylformamide was used as the solvent. The tandem reaction was used to synthesize 3,4,5-trimethoxybenzaldehyde, avoiding the separation of intermediate products and simplifying the operation steps.
It achieves simple and safe operation, low reagent toxicity, high yield, short reaction time, product purity of 92-95%, and yield of 70-75%, meeting the requirements of green process.
Smart Images
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Abstract
Description
[Technical Field]
[0001] This invention relates to the field of organic chemical synthesis technology, and more specifically to a method for synthesizing 3,4,5-trimethoxybenzaldehyde, an important fine chemical intermediate. [Background Technology]
[0002] 3,4,5-Trimethoxybenzaldehyde is an important pharmaceutical and fine chemical intermediate, mainly used in the synthesis of the sulfonamide potentiator trimethoprim (TMP) and the anticancer drug etoposide. Currently, the main synthetic processes for 3,4,5-trimethoxybenzaldehyde include the vanillin method, the p-hydroxybenzaldehyde method, and the p-cresol method. Among these, the vanillin method suffers from high production costs and numerous byproducts. Compared to the vanillin method, the p-hydroxybenzaldehyde and p-cresol methods offer advantages such as higher yields and lower production costs.
[0003] The process routes for synthesizing 3,4,5-trimethoxybenzaldehyde from p-hydroxybenzaldehyde and p-cresol all involve the methoxylation reaction of 3,5-dibromo-4-hydroxybenzaldehyde and subsequent methylation reaction (Applied Chemistry, 2001, 7, 581-583; Journal of Jilin Chemical Engineering Institute, 2006, 2, 3-6; Journal of Yancheng Institute of Technology (Natural Science Edition), 2007, 4, 1-3; Chinese Journal of Modern Applied Pharmacy, 2020, 37, 1584-1589). The first step of the methoxylation reaction mainly uses 3,5-dibromo-4-hydroxybenzaldehyde as a raw material, copper salt as a catalyst, sodium methoxide-methanol solution as the methoxylating agent, and N,N-dimethylformamide (DMF) as a solvent. After the reaction, the intermediate 3,5-dimethoxy-4-hydroxybenzaldehyde is obtained by separation. The second step of methylation mainly uses dimethyl sulfate or dimethyl carbonate as the methylating agent to synthesize 3,4,5-trimethoxybenzaldehyde under alkaline conditions. Dimethyl sulfate is commonly used as the reagent in methylation reactions, but it is highly toxic and produces a lot of wastewater, which does not meet the requirements of green processes. If dimethyl carbonate, which is less toxic, is used as the methylating agent, its reactivity is relatively low, often requiring high-pressure reaction conditions and a long reaction time. Therefore, it is necessary to develop methylation process conditions based on dimethyl carbonate under normal pressure with a faster reaction rate. Furthermore, the methoxylation and subsequent methylation reactions of 3,5-dibromo-4-hydroxybenzaldehyde require significantly different conditions, necessitating the separation of the intermediate 3,5-dimethoxy-4-hydroxybenzaldehyde during the process. This intermediate separation and purification increases costs, leads to raw material loss, and reduces production efficiency in actual production. Using a tandem reaction method can avoid the separation of the intermediate, shorten reaction time, and improve production efficiency. Therefore, a method for synthesizing 3,4,5-trimethoxybenzaldehyde via a tandem reaction is needed. [Summary of the Invention]
[0004] This invention provides a tandem synthesis method for 3,4,5-trimethoxybenzaldehyde, using dimethyl carbonate as the methylating agent. The reaction is carried out under normal pressure, without the need to separate reaction intermediates. It has the advantages of simple and safe operation, low reagent toxicity, high yield, and short reaction time.
[0005] This invention is achieved through the following technical solution:
[0006] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 3,5-dibromo-4-hydroxybenzaldehyde, catalyst 1, and solvent were added sequentially. The temperature was raised to 80–95°C, followed by the addition of sodium methoxide-methanol solution, and the reaction was allowed to proceed for 4–5 hours. The temperature was then lowered, and catalyst 2, phase transfer catalyst, and dimethyl carbonate were added. The temperature was raised to 85–95°C, and the reaction was allowed to proceed for 5–6 hours. The pH of the reaction solution was acidified to neutral with hydrochloric acid, impurities were removed by vacuum filtration, the solvent was removed by vacuum distillation, and recrystallization yielded the product 3,4,5-trimethoxybenzaldehyde. The reaction equation is as follows:
[0007]
[0008] The catalyst 1 is any one of cuprous chloride, cuprous bromide, and cuprous iodide;
[0009] The solvent is N,N-dimethylformamide;
[0010] The catalyst 2 is either lithium trifluoromethanesulfonate or zinc trifluoromethanesulfonate;
[0011] The phase transfer catalyst is any one of tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide;
[0012] The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to sodium methoxide-methanol solution is 1:3 to 1:4;
[0013] The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to catalyst 1 is 1:0.02 to 1:0.15;
[0014] The mass ratio of 3,5-dibromo-4-hydroxybenzaldehyde to the solvent is 1:4;
[0015] The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to dimethyl carbonate is 1:10 to 1:20;
[0016] The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to catalyst 2 is 1:0.02 to 1:0.15;
[0017] The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to the phase transfer catalyst is 1:1 to 1:2.
[0018] The synthesis method provided by this invention has the following characteristics compared with the prior art:
[0019] (1) The present invention adopts a series reaction method, which has a shorter reaction time, does not require separation of reaction intermediates, simplifies the operation steps, and improves the reaction efficiency.
[0020] (2) This invention uses non-toxic and inexpensive dimethyl carbonate instead of dimethyl sulfate commonly used in traditional processes, thus avoiding the use of toxic and harmful dimethyl sulfate. It has the advantages of safe operation and low reagent toxicity.
[0021] (3) The purity of 3,4,5-trimethoxybenzaldehyde prepared by the synthesis method described in this invention is 92-95%, and the yield is 70-75%. [Attached Image Description]
[0022] Figure 1 The high-performance liquid chromatogram of the reaction solution of 3,5-dimethoxy-4-hydroxybenzaldehyde;
[0023] Figure 2 The high-performance liquid chromatogram of the 3,4,5-trimethoxybenzaldehyde product is shown.
Detailed Implementation Methods
[0024] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to the following embodiments.
[0025]
Example 1
[0026] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 1.12 g of 3,5-dibromo-4-hydroxybenzaldehyde, 40 mg of cuprous bromide, and 5 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 80–85 °C, and 2.88 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95 °C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 60 mg of lithium trifluoromethanesulfonate, 1.93 g of tetrabutylammonium bromide, and 7 g of dimethyl carbonate were added. The temperature was raised to 95 °C, and the reaction was allowed to proceed for 5 hours. The total reaction time was 9 hours. The mixture was allowed to stand and cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. After dissolving the solid in water and cooling to crystallize, the mixture was filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 0.547 g of a creamy-white solid, with a yield of 70.5%.
[0027]
Example 2
[0028] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 1.12 g of 3,5-dibromo-4-hydroxybenzaldehyde, 40 mg of cuprous chloride, and 5 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 85°C, and 2.88 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95°C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 60 mg of lithium trifluoromethanesulfonate, 1.67 g of tetrabutylammonium chloride, and 7 g of dimethyl carbonate were added. The temperature was raised to 95°C, and the reaction was allowed to proceed for 5 hours. The total reaction time was 9 hours. The mixture was allowed to stand and cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. The solid was dissolved in water, cooled, and crystallized. The crystals were filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 0.580 g of a creamy-white solid, with a yield of 75.4%.
[0029]
Example 3
[0030] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 1.12 g of 3,5-dibromo-4-hydroxybenzaldehyde, 40 mg of cuprous iodide, and 5 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 85°C, and 2.88 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95°C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 60 mg of lithium trifluoromethanesulfonate, 2.20 g of tetrabutylammonium iodide, and 7 g of dimethyl carbonate were added. The temperature was raised to 95°C, and the reaction was allowed to proceed for 5 hours. The total reaction time was 9 hours. The mixture was allowed to stand and cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. After dissolving the solid in water and cooling to crystallize, the mixture was filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 0.556 g of a creamy-white solid, with a yield of 71.7%.
[0031]
Example 4
[0032] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 5.6 g of 3,5-dibromo-4-hydroxybenzaldehyde, 0.2 g of cuprous chloride, and 25 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 85°C, and 14.4 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95°C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 0.3 g of zinc trifluoromethanesulfonate, 8.6 g of tetrabutylammonium chloride, and 30 g of dimethyl carbonate were added. The temperature was raised to 95°C, and the reaction was allowed to proceed for 6 hours. The total reaction time was 10 hours. The mixture was allowed to stand and cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. After dissolving the solid in water and cooling to crystallize, the mixture was filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 2.84 g of a creamy-white solid, with a yield of 73.2%.
[0033]
Example 5
[0034] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 5.6 g of 3,5-dibromo-4-hydroxybenzaldehyde, 0.2 g of cuprous chloride, and 25 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 85°C, and 14.4 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95°C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 0.3 g of lithium trifluoromethanesulfonate, 10 g of tetrabutylammonium bromide, and 30 g of dimethyl carbonate were added. The temperature was raised to 95°C, and the reaction was allowed to proceed for 6 hours, for a total reaction time of 10 hours. The mixture was allowed to stand and cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. The solid was dissolved in water, cooled, and crystallized. The crystals were filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 2.71 g of a creamy-white solid, with a yield of 69.8%.
[0035]
Example 6
[0036] In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 5.6 g of 3,5-dibromo-4-hydroxybenzaldehyde, 0.2 g of cuprous chloride, and 25 g of N,N-dimethylformamide were added sequentially. The temperature was raised to 85°C, and 14.4 g of a 30% sodium methoxide-methanol solution was slowly added dropwise. The temperature was raised to 95°C, and the reaction was allowed to proceed for 4 hours. The mixture was then cooled, and 0.3 g of lithium trifluoromethanesulfonate, 11.4 g of tetrabutylammonium iodide, and 70 g of dimethyl carbonate were added. The temperature was raised to 95°C, and the reaction was allowed to proceed for 6 hours. The total reaction time was 10 hours. The mixture was allowed to cool to room temperature. The pH was acidified to 6–7 with hydrochloric acid, and the mixture was filtered. The filtrate was distilled under reduced pressure to obtain a yellowish-white solid. After dissolving the solid in water and cooling to crystallize, the mixture was filtered again, washed with purified water, and the filter cake was collected and dried to constant weight to obtain 2.84 g of a creamy-white solid, with a yield of 73.2%.
[0037] The above description is merely an embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalent alterations can be made within the scope defined by the claims of this invention, all of which will fall within the protection scope of this invention.
Claims
1. A method for the tandem synthesis of 3,4,5-trimethoxybenzaldehyde, characterized in that: In a dry three-necked flask equipped with a stirrer, thermometer, and condenser, 3,5-dibromo-4-hydroxybenzaldehyde, catalyst 1, and solvent were added sequentially. The temperature was raised to 80–95°C, and then sodium methoxide-methanol solution was added. The reaction was allowed to proceed for 4–5 hours. The temperature was lowered, and catalyst 2, phase transfer catalyst, and dimethyl carbonate were added. The temperature was raised to 85–95°C, and the reaction was allowed to proceed for 5–6 hours. The pH of the reaction solution was acidified to neutral with hydrochloric acid, impurities were removed by vacuum filtration, the solvent was removed by vacuum distillation, and the product 3,4,5-trimethoxybenzaldehyde was obtained by recrystallization.
2. The method according to claim 1, characterized in that: The catalyst 1 is any one of cuprous chloride, cuprous bromide, and cuprous iodide.
3. The method according to claim 1, characterized in that: The solvent is N,N-dimethylformamide.
4. The method according to claim 1, characterized in that: The catalyst 2 is either lithium trifluoromethanesulfonate or zinc trifluoromethanesulfonate.
5. The method according to claim 1, characterized in that: The phase transfer catalyst is any one of tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.
6. The method according to any one of claims 1 to 5, characterized in that: The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to catalyst 1 is 1:0.02 to 1:0.
15.
7. The method according to any one of claims 1 to 5, characterized in that: The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to catalyst 2 is 1:0.02 to 1:0.
15.
8. The method according to any one of claims 1 to 5, characterized in that: The molar ratio of 3,5-dibromo-4-hydroxybenzaldehyde to the phase transfer catalyst is 1:1 to 1:2.