A process for the preparation of 4-ethoxy-3-methoxybenzaldehyde

Abstract

This invention relates to the field of pharmaceutical and food flavoring synthesis technology, specifically disclosing a method for preparing 4-ethoxy-3-methoxybenzaldehyde. This method uses... N Using 4-ethoxy-3-methoxybenzyl)methanesulfonamide as a raw material, in an organic solvent, under light conditions, at 30°C, it reacts with... N Chlorosuccinimide (NCS) reacts with deionized water to produce 4-ethoxy-3-methoxybenzaldehyde. This method features mild reaction conditions, requires no expensive reagents or catalysts, does not require the use of hazardous oxidants such as peroxides or oxygen, and is safe and simple to operate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and food flavoring synthesis technology, specifically relating to a method for preparing 4-ethoxy-3-methoxybenzaldehyde. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] 4-Ethoxy-3-methoxybenzaldehyde is an organic compound with multiple applications. It has a strong curry aroma and is often used in the food industry as a natural flavor enhancer, significantly improving the flavor profile. This compound can also be used in the synthesis of flavorings such as vanillin. In the pharmaceutical field, it can be used in the synthesis of various natural products and drugs, including glucovannillin and tranilast. Furthermore, it exhibits significant pyrogenic activity, effectively accelerating local blood circulation and producing a mild warming sensation. Therefore, it can be used as a warming agent in cosmetics during winter and as a warming active ingredient in ointments to relieve joint pain and muscle soreness through its pyrogenic effect. Despite the significant application value of 4-ethoxy-3-methoxybenzaldehyde, current synthetic techniques still have many limitations.

[0004] The reported synthesis methods currently available suffer from the following main problems: First, some processes rely on peroxides as oxidants, which are unstable and prone to decomposition and explosion, posing serious safety hazards during production. Second, most methods require the use of metal catalysts such as iron and cobalt, which are not only expensive but also leave residual metal ions in the product, leading to decreased product purity, making them particularly unsuitable for the high standards required in the pharmaceutical and food industries. Third, a few biocatalytic methods use transaminases as the catalytic system; these enzyme-catalyzed methods are still immature, have high preparation costs, require stringent storage conditions, and the reaction system is sensitive to temperature and pH values. These unfavorable conditions limit the production of 4-ethoxy-3-methoxybenzaldehyde.

[0005] Therefore, developing a method for preparing 4-ethoxy-3-methoxybenzaldehyde that has mild reaction conditions, requires no expensive reagents or catalysts, and is safe and easy to operate has become an urgent technical problem to be solved in this field. Summary of the Invention

[0006] To address the significant safety hazards and high costs associated with existing methods for synthesizing 4-ethoxy-3-methoxybenzaldehyde, the core objective of this invention is to provide a method that... NA method for efficiently preparing 4-ethoxy-3-methoxybenzyl)methanesulfonamide under mild conditions using 4-ethoxy-3-methoxybenzaldehyde as a starting material is proposed. This method eliminates the need for hazardous oxidants such as peroxides and oxygen, as well as expensive catalysts, and combines safety and economy.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: A method for preparing 4-ethoxy-3-methoxybenzaldehyde includes the following steps:

[0008] by N Using 4-ethoxy-3-methoxybenzyl)methanesulfonamide as a raw material, in an organic solvent, under light conditions, at 30°C, it reacts with... N Chlorosuccinimide (NCS) reacts with deionized water to produce 4-ethoxy-3-methoxybenzaldehyde.

[0009] Preferably, the organic solvent is one of acetonitrile, tetrahydrofuran, or acetone.

[0010] Preferably, the N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide, N The molar ratio of chlorosuccinimide (NCS) to deionized water is 1:(1.0-1.8):(2.0-5.0).

[0011] In this invention, the inventors hypothesize that the mechanism by which water participates in the reaction is as follows: Under light irradiation, NCS undergoes a single-electron transfer with the raw materials to generate a free radical cation intermediate. Water molecules, acting as nucleophiles, attack this intermediate, and through subsequent transformations, ultimately generate the aldehyde product. Therefore, water serves as both a proton source and an oxygen source, and its amount directly affects the reaction efficiency.

[0012] Through extensive experimental research, the inventors discovered that when the molar ratio of N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide, NCS, and water is lower than 1:1.0:2.0, the reaction conversion rate decreases significantly; when the molar ratio is higher than 1:1.8:5.0, side reactions increase, and the yield decreases instead. More preferably, the molar ratio is 1:(1.2-1.5):(3.0-4.0).

[0013] Preferably, the illumination wavelength is 365-405nm, the light source is an LED lamp or a mercury lamp, and the illuminance is 10-50mW / cm². 2 The distance between the light source and the reaction liquid is 5-15 cm. The reaction vessel is made of quartz or high-transmittance glass, and continuous stirring is performed during the reaction to ensure uniform irradiation.

[0014] Preferably, the reaction time is 8 to 15 hours.

[0015] The present invention also provides a method for preparing the raw material N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide, comprising the following steps: (1) Using 4-hydroxy-3-methoxybenzonitrile as a raw material, a nucleophilic substitution reaction was carried out with iodoethane to obtain 4-ethoxy-3-methoxybenzonitrile; (2) The product obtained in step (1) was reduced with lithium aluminum hydride to obtain (4-ethoxy-3-methoxyphenyl)methylamine; (3) The product obtained in step (2) is reacted with methanesulfonyl chloride under alkaline conditions to generate N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide.

[0016] The beneficial effects achieved by one or more technical solutions of the present invention are as follows: This method is based on N Using 4-ethoxy-3-methoxybenzyl)methanesulfonamide as a raw material, in an organic solvent, under light conditions, at 30°C, it reacts with... N 1-Chlorosuccinimide (NCS) reacts with deionized water to produce 4-ethoxy-3-methoxybenzaldehyde. This method features mild reaction conditions, requires no expensive reagents or catalysts, does not require the use of hazardous oxidants such as peroxides or oxygen, and is safe and simple to operate. Attached Figure Description

[0017] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0018] Figure 1 The 1H NMR spectrum of the substrate N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide.

[0019] Figure 2 The mass spectra of the substrate N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide are shown.

[0020] Figure 3 The 1H NMR spectrum of 4-ethoxy-3-methoxybenzaldehyde. Detailed Implementation

[0021] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0022] Synthesis of substrate N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide:

[0023] refer to Molecules 2008, 13(6), 1427-1440 and Angewandte Chemie, International Edition Two papers, 2025, 64(24), e202505033, use 4-hydroxy-3-methoxybenzonitrile as a raw material. It first undergoes a nucleophilic substitution reaction with iodoethane to obtain 4-ethoxy-3-methoxybenzonitrile, which is then reduced by lithium aluminum hydride to obtain (4-ethoxy-3-methoxyphenyl)methylamine.

[0024] (4-ethoxy-3-methoxyphenyl)methylamine (5 g, 27.6 mmol), triethylamine (5.7 mL, 41.4 mmol), and dichloromethane (50 mL) were added to a reaction flask. Methanesulfonyl chloride (2.3 mL, 30.3 mmol) was slowly added dropwise at 0 °C, and the resulting mixture was stirred overnight at room temperature. Then, 20 mL of deionized water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over Na₂SO₄ and subjected to vacuum distillation. The crude product was separated by column chromatography (ethyl acetate / petroleum ether, volume ratio 1:2, as eluent) to give 5.8 g of the target compound N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide, with a yield of 81%. The product was confirmed by 1H NMR and mass spectrometry. Figure 1 and Figure 2 .

[0025] 1 H NMR (500 MHz, Chloroform- d ) δ 7.10 – 6.65 (m, 3H), 4.93 (s, 1H), 4.23 (d, J = 5.6 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 2.83 (s,3H), 1.46 (t, J = 7.0 Hz, 3H). MS (ESI): calcd. for C 11 H 17 NNaO4S[M+Na] + 282.1, found 282.1. Example 1: Under nitrogen protection, 5 mL of acetonitrile, ... N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.14 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the reaction liquid surface, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.31 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 86%. 1 H NMR (500 MHz, CDCl3) δ 9.85 (s, 1H), 7.55 – 7.38 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.20(q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 1.52 (t, J = 7.0 Hz, 3H). For example... Figure 3 .

[0026] Example 2: Under nitrogen protection, 5 mL of acetonitrile, ... N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N 1,4-chlorosuccinimide (NCS, 0.48 g, 3.6 mmol) and deionized water (0.14 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the surface of the reaction liquid, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.30 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 83%.

[0027] Example 3: Under nitrogen protection, 5 mL of acetonitrile, ... N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.18 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 405 nm) was placed on one side of the reaction flask, 10 cm away from the surface of the reaction liquid, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.29 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 81%.

[0028] Example 4: Under nitrogen protection, 5 mL of acetonitrile, ... N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N 1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.18 g, 10 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the reaction liquid surface, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.31 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 86%.

[0029] Example 5: Under nitrogen protection, 5 mL of tetrahydrofuran was added sequentially to the reaction flask. N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N 1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.14 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the reaction liquid surface, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.27 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 75%.

[0030] Example 6: Under nitrogen protection, 5 mL of acetone was added sequentially to the reaction flask. N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N 1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.14 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the reaction liquid surface, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 12 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.29 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 81%.

[0031] Example 7: Under nitrogen protection, 5 mL of acetonitrile, ... N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide (0.52 g, 2 mmol), N 1,4-chlorosuccinimide (NCS, 0.4 g, 3 mmol) and deionized water (0.14 g, 8 mmol) were used as the light source. A 30 W LED lamp (center wavelength 395 nm) was placed on one side of the reaction flask, 10 cm away from the reaction liquid surface, with a light intensity of approximately 25 mW / cm². 2 The mixture was stirred and irradiated at 30°C for 16 hours. After the reaction was complete, 30 mL of ethyl acetate was added for dilution, and 20 mL of deionized water was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain the crude product, which was then separated by column chromatography to obtain 0.26 g of 4-ethoxy-3-methoxybenzaldehyde, with a yield of 72%.

[0032] Example 8: Following the method of Example 1, keeping other conditions unchanged, the boundary conditions were verified by adjusting the reactant ratios: When the molar ratio of N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide, NCS, and deionized water was 1:1.0:2.0 (NCS 2.0 mmol, water 4 mmol), after reacting for 12 hours, the product was separated by column chromatography to obtain 0.25 g of product, with a yield of 70%. (2) When the molar ratio was 1:1.8:5.0 (NCS 3.6 mmol, water 10 mmol), after reacting for 12 hours, the product was separated by column chromatography to obtain 0.29 g, with a yield of 81%.

[0033] The results show that the reaction proceeds smoothly within the molar ratio range defined in this invention, and the yield can be consistently above 70%. When the amount of NCS or water is close to the lower limit of the proportion, the yield is 70%, which still has good industrial applicability; when it is close to the upper limit of the proportion, the yield can reach 81%.

[0034] Comparative Example 1: A method for preparing 4-ethoxy-3-methoxybenzaldehyde, which differs from Example 1 in that the reaction is carried out in the dark and a 30 W 395 nm lamp is not used for irradiation, while the remaining steps are the same as in Example 1.

[0035] The product 4-ethoxy-3-methoxybenzaldehyde could not be obtained.

[0036] Comparative Example 2: A method for preparing 4-ethoxy-3-methoxybenzaldehyde, which differs from Example 1 in that deionized water is not added, while the remaining steps are the same as in Example 1.

[0037] The product 4-ethoxy-3-methoxybenzaldehyde could not be obtained.

[0038] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing 4-ethoxy-3-methoxybenzaldehyde, characterized in that, The method includes the following steps: by N Using 4-ethoxy-3-methoxybenzyl)methanesulfonamide as a raw material, in an organic solvent, under light conditions, at 30°C, it reacts with... N Chlorosuccinimide (NCS) reacts with deionized water to produce 4-ethoxy-3-methoxybenzaldehyde.

2. The preparation method according to claim 1, characterized in that, The N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide is prepared by a method comprising the following steps: (1) Using 4-hydroxy-3-methoxybenzonitrile as a raw material, a nucleophilic substitution reaction was carried out with iodoethane to obtain 4-ethoxy-3-methoxybenzonitrile; (2) The product obtained in step (1) was reduced with lithium aluminum hydride to obtain (4-ethoxy-3-methoxyphenyl)methylamine; (3) The product obtained in step (2) is reacted with methanesulfonyl chloride under alkaline conditions to generate N-(4-ethoxy-3-methoxybenzyl)methanesulfonamide.

3. The preparation method according to claim 1, characterized in that, The organic solvent is one of acetonitrile, tetrahydrofuran, or acetone.

4. The preparation method according to claim 1, characterized in that, The N -(4-ethoxy-3-methoxybenzyl)methanesulfonamide, N The molar ratio of chlorosuccinimide (NCS) to deionized water is 1:(1.0-1.8):(2.0-5.0).

5. The preparation method according to claim 1, characterized in that, The illumination wavelength is 365-405nm.

6. The preparation method according to claim 1, characterized in that, The reaction time is 8-15 h.

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